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MEDRXIV
Authors Elena Consolaro, Fredy Suter, Nadia Rubis, Stefania Pedroni, Chiara Moroni, Elena Pastò, Maria Vittoria Paganini, Grazia Pravettoni, Umberto Cantarelli, Norberto Perico, Annalisa Perna, Tobia Peracchi, Piero Ruggenenti, Giuseppe Remuzzi
Abstract Background and Aim While considerable success has been achieved in the management of patients hospitalized with severe coronavirus disease 2019 (COVID-19), far less progress has been made with early outpatient treatment. We assessed whether the implementation of a home treatment algorithm – designed based upon on a pathophysiologic and pharmacologic rationale - during the initial, mild phase of COVID-19, could effectively reduce hospital admissions. Methods This fully academic, matched-cohort study evaluated outcomes in 108 consecutive consenting patients with mild COVID-19 managed at home by their family doctors from January 2021 to May 2021, according to the proposed treatment algorithm and in 108 age-, sex-, and comorbidities-matched patients who were given other therapeutic schedules (ClinicalTrials.gov: NCT04854824). The primary outcome was COVID-19-related hospitalization. Analyses were by intention-to-treat. Results One (0.9%) patient in the ‘recommended’ cohort and 12 (11.1%) in the ‘control’ cohort were admitted to hospital (P=0.0136). The proposed algorithm reduced, by 85%, the cumulative length of hospital stays (from 141 to 19 days) and related costs (from € 60.316 to € 9.058). Only 9.8 patients needed to be treated with the recommended algorithm to prevent one hospitalization event. The rate of resolution of major symptoms was numerically, but not significantly, higher in the ‘recommended’ compared to the ‘control’ cohort (97.2% versus 93.5%, respectively; P=0.322). Other symptoms lingered in a lower proportion of patients in the ‘recommended’ than in the‘control’ cohort (20.4% versus 63.9%, respectively; P<0.001), and for a shorter period. Conclusion The adoption of the proposed outpatient treatment algorithm during the early, mild phase of COVID-19 reduced the incidence of subsequent hospitalization and related costs. 1. Introduction Over the past two years the novel coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), which causes coronavirus disease 2019 (COVID-19), has quickly spread globally, reaching pandemic proportions (1). Through genetic evolution resulting in multiple variants (2), SARS-CoV-2 has been responsible for several pandemic waves worldwide (1). The clinical manifestations of COVID-19 disease are broad, spanning asymptomatic infection, mild upper respiratory tract and/or mild extrapulmonary symptoms, and including severe pneumonia, acute respiratory distress syndrome and multiorgan system dysfunction, and even death (3,4). During the early phase of COVID-19 when patients are at home they are usually not seriously ill with acute respiratory distress, but present a variety of initially mild/moderate symptoms, including fever, cough, tiredness, shortness of breath and chills, a sore throat, headache, musculoskeletal pain, and a new loss of taste and smell (5). While drug/biological treatment options for severely ill COVID-19 patients requiring hospitalization are now available (6–11), interventions that can be administered by primary care physicians at home have been more difficult to determine and controversial (12). Nonetheless, the early initiation of treatment for COVID-19 might improve clinical outcomes, providing a potential window for immediate benefits by intervening before the development of severe disease, and possibly limiting or preventing the risk of patient hospitalization. Although guidelines or recommendations for managing patients with suspected or confirmed COVID-19 in the community have recently been made available by national health authorities (13,14), most family doctors initially treated their patients with various treatment regimens they believed appropriate based on their clinical expertise. Based on the increasing available knowledge on the pathophysiology underlying the mild/moderate symptoms encountered at the onset of the illness (15,16), we recently published a proposed regimen of simple drugs that should theoretically better fit these mechanisms (17). The proposed treatment recommendation (17) is based on three pillars: i) intervene at the very onset of mild/moderate symptoms at home; ii) start therapy as early as possible after the family doctor has been contacted by the patient, without awaiting the results of a nasopharyngeal swab; iii) rely on non-steroidal anti-inflammatory drugs, especially relatively selective cyclooxygenase-2 (COX-2) inhibitors (18,19), an approach intended to limit excessive host inflammatory responses to viral infection (16,17). In a recent academic matched-cohort study (20), we found that early treatment of COVID-19 patients at home by their family doctors, according to the proposed recommendation regimen, almost completely prevented the need for hospital admission due to progression toward more severe illness (2 out of 90 patients), compared to patients in the ‘control’ cohort, who were treated at home according to their family physician’s assessments (13 out of 90 patients). However, the rate of hospitalization was a secondary outcome of the study, and the possibility that this is a random finding cannot be excluded definitely. Thus, we considered the observed reduction in patient hospitalizations a hypothesis-generating finding that provides the background for the present, new matched-cohort study. The primary aim of this study was to test the effect of COVID-19 treatment at home on this outcome, according to the proposed recommendation algorithm.
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Authors Jamie Lopez Bernal, Nick Andrews, Charlotte Gower, Eileen Gallagher, Ruth Simmons, Simon Thelwall, Julia Stowe, Elise Tessier, Natalie Groves, Gavin Dabrera, Richard Myers, Colin Campbell, Gayatri Amirthalingam, Matt Edmunds, Maria Zambon, Kevin Brown, Susan Hopkins, Meera Chand, Mary Ramsay
Abstract Background The B.1.617.2 COVID-19 variant has contributed to the surge in cases in India and has now been detected across the globe, including a notable increase in cases in the UK. We estimate the effectiveness of the BNT162b2 and ChAdOx1 COVID-19 vaccines against this variant. Methods A test negative case control design was used to estimate the effectiveness of vaccination against symptomatic disease with both variants over the period that B.1.617.2 began circulating with cases identified based on sequencing and S-gene target status. Data on all symptomatic sequenced cases of COVID-19 in England was used to estimate the proportion of cases with B.1.617.2 compared to the predominant strain (B.1.1.7) by vaccination status. Results Effectiveness was notably lower after 1 dose of vaccine with B.1.617.2 cases 33.5% (95%CI: 20.6 to 44.3) compared to B.1.1.7 cases 51.1% (95%CI: 47.3 to 54.7) with similar results for both vaccines. With BNT162b2 2 dose effectiveness reduced from 93.4% (95%CI: 90.4 to 95.5) with B.1.1.7 to 87.9% (95%CI: 78.2 to 93.2) with B.1.617.2. With ChAdOx1 2 dose effectiveness reduced from 66.1% (95% CI: 54.0 to 75.0) with B.1.1.7 to 59.8% (95%CI: 28.9 to 77.3) with B.1.617.2. Sequenced cases detected after 1 or 2 doses of vaccination had a higher odds of infection with B.1.617.2 compared to unvaccinated cases (OR 1.40; 95%CI: 1.13-1.75). Conclusions After 2 doses of either vaccine there were only modest differences in vaccine effectiveness with the B.1.617.2 variant. Absolute differences in vaccine effectiveness were more marked with dose 1. This would support maximising vaccine uptake with two doses among vulnerable groups.
Authors Lishuang Shen, Jennifer Dien Bard, Timothy J. Triche, Alexander R. Judkins, Jaclyn A. Biegel, Xiaowu Gai
Abstract The SARS-CoV-2 B.1.1.7 lineage is highly infectious and as of April 2021 accounted for 92% of COVID-19 cases in Europe and 59% of COVID-19 cases in the U.S. It is defined by the N501Y mutation in the receptor binding domain (RBD) of the Spike (S) protein, and a few other mutations. These include two mutations in the N terminal domain (NTD) of the S protein, HV69-70del and Y144del (also known as Y145del due to the presence of tyrosine at both positions). We recently identified several emerging SARS-CoV-2 variants of concerns, characterized by Membrane (M) protein mutations, including I82T and V70L. We now identify a sub-lineage of B.1.1.7 that emerged through sequential acquisitions of M:V70L in November 2020 followed by a novel S:D178H mutation first observed in early February 2021. The percentage of B.1.1.7 isolates in the U.S. that belong to this sub-lineage increased from 0.15% in February 2021 to 1.8% in April 2021. To date this sub-lineage appears to be U.S.-specific with reported cases in 31 states, including Hawaii. As of April 2021 it constituted 36.8% of all B.1.1.7 isolates in Washington. Phylogenetic analysis and transmission inference with Nextstrain suggests this sub-lineage likely originated in either California or Washington. Structural analysis revealed that the S:D178H mutation is in the NTD of the S protein and close to two other signature mutations of B.1.1.7, HV69-70del and Y144del. It is surface exposed and may alter NTD tertiary configuration or accessibility, and thus has the potential to affect neutralization by NTD directed antibodies.
THE LANCET
Authors Isaac A. Ngere, Jeanette Dawa, Elizabeth Hunsperger, AA.VV.
Abstract Background: The lower-than-expected COVID-19 morbidity and mortality in Africa has been attributed to multiple factors, including weak surveillance. We set out to estimate the burden of SARS-CoV-2 infections eight months into the epidemic in Nairobi, Kenya. Methods: We conducted a population based cross-sectional survey using multi-stage random sampling to select households within Nairobi in November 2020. Sera from consenting household members were tested for IgM and IgG antibodies to SARS-CoV-2. Seroprevalence was estimated after adjusting for population structure and test performance. Risk factors were determined using logistic regression and Infection fatality ratios (IFRs) calculated by comparing our estimates to reported cases and deaths. Findings: Of 1,164 individuals from 527 households tested, the adjusted seroprevalence was 34·7% (95%CI 31·8-37·6), indicating that approximately 1·5 million Nairobi residents had been infected. Some 261 (49·5%) households had at least one positive participant, and positivity rates increased in more densely populated areas (spearman’s r=0·63; p=0·009). Individuals aged 20-59 years had up to 2-fold higher seropositivity when compared to those aged 0-9 years or ≥60 years. The IFR was 40 per 100,000 infections, with individuals ≥40 years old having higher IFRs. Interpretation: Over one third of Nairobi residents in half of the households were infected by November 2020, indicating extensive transmission in the city, comparable to countries reporting more severe forms of the pandemic. However, the IFR was >10-fold lower than that reported in Europe and the United States, supporting the perceived low morbidity and mortality in sub–Saharan Africa. Funding Statement: Funding was provided by the US National Institutes of Health (NIH), grant number U01AI151799, through the Centre for Research in Emerging Infectious Diseases – East and Central Africa (CREID-ECA).
BIORXIV
Authors Takuya Tada, Hao Zhou, Belinda M. Dcosta, Marie I. Samanovic, Mark J. Mulligan, Nathaniel R. Landau
Abstract Highly transmissible SARS-CoV-2 variants recently identified in India designated B.1.617 and B.1.618 have mutations within the spike protein that may contribute to their increased transmissibility and that could potentially result in re-infection or resistance to vaccine-elicited antibody. B.1.617 encodes a spike protein with mutations L452R, E484Q, D614G and P681R while the B.1.618 spike has mutations Δ145-146, E484K and D614G. We generated lentiviruses pseudotyped by the variant proteins and determined their resistance to neutralization by convalescent sera, vaccine-elicited antibodies and therapeutic monoclonal antibodies. Viruses with B.1.617 and B.1.618 spike were neutralized with a 2-5-fold decrease in titer by convalescent sera and vaccine-elicited antibodies. The E484Q and E484K versions were neutralized with a 2-4-fold decrease in titer. Virus with the B.1.617 spike protein was neutralized with a 4.7-fold decrease in titer by the Regeneron monoclonal antibody cocktail as a result of the L452R mutation. The modest neutralization resistance of the variant spike proteins to vaccine elicited antibody suggests that current vaccines will remain protective against the B.1.617 and B.1.618 variants.
Authors Eric J. Haas, John M. McLaughlin, Farid Khan AA.VV.
Abstract Background: Israel recently initiated a rapid nationwide COVID-19 vaccination campaign to immunize persons ≥16 years of age and used exclusively Pfizer–BioNTech BNT162b2 mRNA COVID-19 vaccine according to schedule (two doses, 21 days apart). We provide the first estimates of the number of COVID-19 cases, hospitalizations, and deaths averted by a nationwide vaccination campaign. Methods: We used national surveillance data from the first 112 days (Dec 20, 2020 ‒ Apr 10, 2021) of Israel’s vaccination campaign to estimate averted burden of four outcomes: SARS-CoV-2 infections and COVID-19-related hospitalizations, severe or critical hospitalizations, and deaths. The direct effects of the immunization program were estimated for all susceptible individuals (i.e., no previous evidence of laboratory-confirmed SARS-CoV-2 infection) who were at least partially vaccinated (defined as receipt of at least one dose with ≥14 days after the first dose). Cases averted were estimated based on cumulative daily, age-specific rate differences comparing rates among unvaccinated to those who were at least partially vaccinated for each of the four outcomes and the (age-specific) size of the susceptible population and proportion that was at least partially vaccinated. Findings: Through Apr 10, 2021, we estimated that Israel’s vaccination campaign averted 158,665 (95% uncertainty range: 115,899‒201,431) SARS-CoV-2 infections, 24,597 (6,622‒42,571) hospitalizations, 17,432 (3,065‒31,799) severe and critical hospitalizations, and 5,533 (-1,146‒12,213) deaths. Of these, 66% of hospitalizations and 91% of deaths averted were among those ≥65 years of age. Seventy-three percent of SARS-CoV-2 infections and 79% of COVID-19-related hospitalizations and deaths averted stemmed from the protective effects in fully vaccinated persons. Interpretations: Without vaccination, Israel would have likely experienced triple the number of hospitalizations and deaths compared to what actually occurred during their largest wave of SARS-CoV-2 to date, which would have likely overwhelmed the healthcare system. Indirect effects and long-term benefits of the program, which could be substantial, were not included in these estimates and warrant future research.
Authors Carlos A. Prete Jr, Lewis F. Buss, Claudia M. M. Abrahim, Tassila Salomon, Myuki A. E. Crispim, Marcio K. Oikawa, Renata Buccheri, Eduard Grebe, Allyson G. da Costa, Nelson A. Fraiji, Maria do P. S. S. Carvalho, Neal Alexander, Nuno R. Faria, Christopher Dye, Vítor H. Nascimento, Michael P. Busch, Ester C. Sabino
Abstract The city of Manaus, north Brazil, was stricken by a severe epidemic of SARS-Cov-2 in March 2020, reaching a seroprevalence of 76% by October 2020. Nevertheless, in late November an abrupt increase in hospitalizations and deaths hit Manaus, causing higher number of deaths compared to the first epidemic wave. It has been hypothesized that virus lineages circulating in the second wave, namely the P.1 variant of concern first detected in early December in Manaus, could be better at evading immunity generated in response to previous infection with other lineages. In order to estimate the reinfection rate during the resurgence of SARS-CoV-2 in Manaus, we tested serial samples from 238 unvaccinated repeat blood donors using a SARS-CoV-2 anti-N IgG chemiluminescence microparticle assay. Blood donors were divided into six groups that reflected the inferred sequence of infection and reinfection with non-P.1 and P.1 variants. We assumed that reinfections induce a recrudescence (or “boosting”) of plasma anti-N IgG antibody levels, yielding a V-shaped time series of antibody reactivity levels. We infer that 16.9% (95% CI [9.48%, 28.5%]) of all presumed P.1 infections that were observed in 2021 were reinfections. If we also include cases of probable or possible reinfections (defined by considering the time period when the antibody levels are expected to grow after recovery and the range of half-lives for antibody waning after seroconversion), these percentages increase respectively to 25.8% (95% CI [16.7%, 37.4%]), and 31.0% (95% CI [21.4%, 42.5%]). Our data suggest that reinfection due to P.1 is common and more frequent than what has been detected by traditional epidemiologic, molecular and genomic surveillance of clinical cases.
Authors Zijun Wang, Frauke Muecksch, Dennis Schaefer-Babajew, Shlomo Finkin, Charlotte Viant, Christian Gaebler, Christopher Barnes, Melissa Cipolla, Victor Ramos, Thiago Y. Oliveira, Alice Cho, Fabian Schmidt, Justin da Silva, Eva Bednarski, Mridushi Daga, Martina Turroja, Katrina G. Millard, Mila Jankovic, Anna Gazumyan, Paul D. Bieniasz, Marina Caskey, Theodora Hatziioannou, Michel C. Nussenzweig
Abstract Over one year after its inception, the coronavirus disease-2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) remains difficult to control despite the availability of several excellent vaccines. Progress in controlling the pandemic is slowed by the emergence of variants that appear to be more transmissible and more resistant to antibodies1,2. Here we report on a cohort of 63 COVID-19-convalescent individuals assessed at 1.3, 6.2 and 12 months after infection, 41% of whom also received mRNA vaccines3,4. In the absence of vaccination antibody reactivity to the receptor binding domain (RBD) of SARS-CoV-2, neutralizing activity and the number of RBD-specific memory B cells remain relatively stable from 6 to 12 months. Vaccination increases all components of the humoral response, and as expected, results in serum neutralizing activities against variants of concern that are comparable to or greater than neutralizing activity against the original Wuhan Hu-1 achieved by vaccination of naïve individuals2,5–8. The mechanism underlying these broad-based responses involves ongoing antibody somatic mutation, memory B cell clonal turnover, and development of monoclonal antibodies that are exceptionally resistant to SARS-CoV-2 RBD mutations, including those found in variants of concern4,9. In addition, B cell clones expressing broad and potent antibodies are selectively retained in the repertoire over time and expand dramatically after vaccination. The data suggest that immunity in convalescent individuals will be very long lasting and that convalescent individuals who receive available mRNA vaccines will produce antibodies and memory B cells that should be protective against circulating SARS-CoV-2 variants. Should memory responses evolve in a similar manner in vaccinated individuals, additional appropriately timed boosting with available vaccines could cover most circulating variants of concern. We initially characterized immune responses to SARS-CoV-2 in a cohort of convalescent individuals 1.3 and 6.2 months after infection3,4. Between February 8 and March 26, 2021, 63 participants returned for a 12-month follow-up visit among whom 26 (41%) had received at least one dose of either the Moderna (mRNA-1273) or Pfizer-BioNTech (BNT162b2) vaccines, on average 40 days before their study visit (Supplementary Table 1). Of the individuals that returned for a 12-month follow-up, 10% had been hospitalized and the remainder had experienced relatively mild initial infections. Only 14% of the individuals reported persistent long-term symptoms after 12 months, reduced from 44% at the 6-month time point4. Symptom persistence was not associated with the duration and severity of acute disease or with vaccination status (Extended Data Fig. 1 a-c). All participants tested negative for active infection at the 12-month time point as measured by a saliva-based PCR assay 4. The demographics and clinical characteristics of the participants are shown in Supplementary Tables 1 and 2.
Authors Gytis Dudas, Samuel L. Hong, Barney Potter, Sébastien Calvignac-Spencer, Frédéric S. Niatou-Singa, Thais B. Tombolomako, Terence Fuh-Neba, Ulrich Vickos, Markus Ulrich, Fabian H. Leendertz, Kamran Khan, Alexander Watts, Ingrida Olendraitė, Joost Snijder, Kim N. Wijnant, Alexandre M.J.J. Bonvin, Pascale Martres, Sylvie Behillil, Ahidjo Ayouba, Martin Foudi Maidadi, Dowbiss Meta Djomsi, Celestin Godwe, Christelle Butel, Aistis Šimaitis, Miglė Gabrielaitė, Monika Katėnaitė, Rimvydas Norvilas, Ligita Raugaitė, Rimvydas Jonikas, Inga Nasvytienė, Živilė Žemeckienė, Dovydas Gečys, Kamilė Tamušauskaitė, Milda Norkienė, Emilija Vasiliūnaitė, Danguolė Žiogienė, Albertas Timinskas, Marius Šukys, Mantas Šarauskas, Gediminas Alzbutas, Dovilė Juozapaitė, Daniel Naumovas, Arnoldas Pautienius, Astra Vitkauskienė, Rasa Ugenskienė, Alma Gedvilaitė, Darius Čereškevičius, Vaiva Lesauskaitė, Lukas Žemaitis, Laimonas Griškevičius, Guy Baele
ABSTRACT Many high-income countries have met the SARS-CoV-2 pandemic with overwhelming sequencing resources and have identified numerous distinct lineages, including some with notably altered biology. Over a year into the pandemic following unprecedented reductions in worldwide human mobility, distinct introduced lineages of SARS-CoV-2 without sequenced antecedents are increasingly discovered in high-income countries as a result of ongoing SARS-CoV-2 genomic surveillance initiatives. We here describe one such SARS-CoV-2 lineage, carrying many mutations and deletions in the spike protein shared with widespread variants of concern (VOCs), including E484K, S477N and deletions HV69Δ, Y144Δ, and LLA241/243Δ. This lineage – designated B.1.620 – is known to circulate in Lithuania and has now been found in several European states, but also in increasing numbers in central Africa owing to important recent increases in genome sequencing efforts on the continent. We provide evidence of likely ongoing local transmission of B.1.620 in Lithuania, France, Germany, Spain, Belgium and the Central African Republic. We describe the suite of mutations this lineage carries, its potential to be resistant to neutralising antibodies, travel histories for a subset of the European cases, and evidence of local B.1.620 transmission in Europe. We make a case for the likely Central African origin of this lineage by providing travel records as well as the outcomes of carefully crafted phylogenetic and phylogeographic inference methodologies, the latter of which is able to exploit individual travel histories recorded for infected travellers having entered different European countries.
Authors Frank Annie, Haytham Alkhaimy, Aravinda Nanjundappa, Ahmad Elashery
Abstract Background: This study investigates the relationship between SARS-CoV-2 infection and myocarditis. Myocarditis is assumed to be a negative prognostic factor without agreed-upon treatment. We present a large registry data assessing the association between myocarditis and mortality in patients with SARS-CoV-2 infection. Methods: The researchers identified adult patients aged 18-90 years with COVID-19 infections in the TriNetX (COVID-19 research network) database between January 20, 2020, and December 9, 2020. These patients were then divided into those who had a positive myocarditis diagnosis and those who did not. The researchers compared all-cause mortality between propensity-matched (PSM) pairs of patients in both groups. Results: Total of 259,352 patients with COVID-19 diagnosis were included in the study. Of those patients, 383 (0.01%) had myocarditis diagnosis, while 258,969 (99.9%) did not have myocarditis diagnosis during their hospital stay. Patients were more male in the myocarditis group (58.75% vs. 44.73%, P < 0.001). As to the PSM cohorts, 383/383 were matched, and the all-cause mortality was 13.4 % vs. 4.2% (P < 0.001) at 30 days. A Kaplan-Meier survival analysis was also statistically significant (P < 0.001) at 30 days. Conclusion: In a large multinational database of SARS-CoV-2 patients, we observed an association between myocarditis diagnosis and increased mortality. Further prospective studies are recommended to further assess myocarditis outcomes in COVID-19 patients and treatment options.
Authors Michael J Massare, Nita Patel, Bin Zhou, Sonia Maciejewski, Rhonda Flores, Mimi Guebre-Xabier, Jing-Hui Tian, Alyse D. Portnoff, Louis Fries, Vivek Shinde, Larry Ellingsworth, Gregory Glenn, Gale Smith
Abstract The 2019 outbreak of a severe respiratory disease caused by an emerging coronavirus, SARS-CoV-2, has spread globally with high morbidity and mortality. Co-circulating seasonal influenza has greatly diminished recently, but expected to return with novel strains emerging, thus requiring annual strain adjustments. We have developed a recombinant hemagglutinin (HA) quadrivalent nanoparticle influenza vaccine (qNIV) produced using an established recombinant insect cell expression system to produce nanoparticles. Influenza qNIV adjuvanted with Matrix-M was well-tolerated and induced robust antibody and cellular responses, notably against both homologous and drifted A/H3N2 viruses in Phase 1, 2, and 3 trials. We also developed a full-length SARS-CoV-2 spike protein vaccine which is stable in the prefusion conformation (NVX-CoV2373) using the same platform technology. In phase 3 clinical trials, NVX-CoV2373 is highly immunogenic and protective against the prototype strain and B.1.1.7 variant. Here we describe the immunogenicity and efficacy of a combination quadrivalent seasonal flu and COVID-19 vaccine (qNIV/CoV2373) in ferret and hamster models. The combination qNIV/CoV2373 vaccine produces high titer influenza hemagglutination inhibiting (HAI) and neutralizing antibodies against influenza A and B strains. The combination vaccine also elicited antibodies that block SARS-CoV-2 spike protein binding to the human angiotensin converting enzyme-2 (hACE2) receptor. Significantly, hamsters immunized with qNIV/CoV2373 vaccine and challenged with SARS-CoV-2 were protected against weight loss and were free of replicating SARS-CoV-2 in the upper and lower respiratory tract with no evidence of viral pneumonia. This study supports evaluation of qNIV/CoV2373 combination vaccine as a preventive measure for seasonal influenza and CoVID-19. Highlights Combination qNIV/CoV2373 vaccine induced protective hemagglutination inhibition (HAI) responses to seasonal influenza A and B unchanged when formulated with recombinant spike. Combination qNIV/CoV2373 vaccine maintained clinical and virologic protection against experimental challenge with SARS-CoV-2. Combination qNIV/CoV2373 vaccine showed no clinical or histological sign of enhanced disease following experimental challenge with SARS-CoV-2. Combination qNIV/CoV2373 vaccine induced antibodies against SARS-CoV-2 neutralizing epitopes common between US-WA and B.1.352 variant.
Authors Daniel J. Sheward, Marco Mandolesi, Changil Kim, Leo Hanke, Laura Perez Vidakovics, Gerald McInerney, Gunilla B. Karlsson Hedestam, Ben Murrell
Abstract The emergence of SARS-CoV-2 Variants of Concern (VOCs) with mutations in key neutralizing antibody epitopes threatens to undermine vaccines developed against the pandemic founder variant (Wu-Hu-1). Widespread vaccine rollout and continued transmission are creating a population that has antibody responses of varying potency to Wu-Hu-1. Against this background, it is critical to assess the outcomes of subsequent booster vaccination with variant antigens. It is not yet known whether such heterotypic vaccine boosts would be compromised by original antigenic sin, where pre-existing responses to a prior variant dampen responses to a new one, or whether the primed memory B cell repertoire would bridge the gap between Wu-Hu-1 and VOCs. Here, we show that a single adjuvanted dose of receptor binding domain (RBD) protein from VOC 501Y.V2 (B.1.351) drives an extremely potent neutralizing antibody response capable of cross-neutralizing both Wu-Hu-1 and 501Y.V2 in rhesus macaques previously immunized with Wu-Hu-1 spike protein. At least 20 candidate SARS-CoV-2 vaccines have already entered phase 3 clinical trials 1. A number of these demonstrated high efficacy 2–6, significantly reducing morbidity and mortality, and are being rolled-out globally. This first generation of vaccines all encode or deliver a spike glycoprotein derived from the pandemic founder strain, Wu-Hu-1 7. Driven by multiple evolutionary forces 8, SARS-CoV-2 is rapidly evading our response. Globally, a number of VOCs are rising in frequency (see Fig 1), each harbouring spike mutations that confer resistance to prior immunity. Of particular concern is the surge of variant 501Y.V2 9, with multiple mutations in dominant neutralizing antibody epitopes making it several fold more resistant to antibodies elicited by current vaccines 10–12. This underpins the substantially reduced vaccine efficacies in South Africa, where this variant is circulating at high frequency 13,14. Updated vaccines are likely required to protect against current and future mutated variants. Importantly, by the time these are rolled out, a significant proportion of the global population are likely to be seropositive as a result of either infection, or immunization with Wu-Hu-1 based vaccines.
Authors Florian A. Lempp, Leah Soriaga, Martin Montiel-Ruiz, Fabio Benigni, Julia Noack, Young-Jun Park, Siro Bianchi, Alexandra C. Walls, John E. Bowen, Jiayi Zhou, Hannah Kaiser, Maria Agostini, Marcel Meury, Exequiel Dellota Jr., Stefano Jaconi, Elisabetta Cameroni, Herbert W. Virgin, Antonio Lanzavecchia, David Veesler, Lisa Purcell, Amalio Telenti, Davide Corti
Abstract Investigating the mechanisms of SARS-CoV-2 cellular infection is key to better understand COVID-19 immunity and pathogenesis. Infection, which involves both cell attachment and membrane fusion, relies on the ACE2 receptor that is paradoxically found at low levels in the respiratory tract, suggesting that additional mechanisms facilitating infection may exist. Here we show that C-type lectin receptors, DC-SIGN, L-SIGN and the sialic acid-binding Ig-like lectin 1 (SIGLEC1) function as auxiliary receptors by enhancing ACE2-mediated infection and modulating the neutralizing activity of different classes of spike-specific antibodies. Antibodies to the N-terminal domain (NTD) or to the conserved proteoglycan site at the base of the Receptor Binding Domain (RBD), while poorly neutralizing infection of ACE2 over-expressing cells, effectively block lectin-facilitated infection. Conversely, antibodies to the Receptor Binding Motif (RBM), while potently neutralizing infection of ACE2 over-expressing cells, poorly neutralize infection of cells expressing DC-SIGN or L-SIGN and trigger fusogenic rearrangement of the spike promoting cell-to-cell fusion. Collectively, these findings identify a lectin-dependent pathway that enhances ACE2-dependent infection by SARS-CoV-2 and reveal distinct mechanisms of neutralization by different classes of spike-specific antibodies.
Authors Satoshi Ikegame, Mohammed N. A. Siddiquey, Chuan-Tien Hung, Griffin Haas, Luca Brambilla, Kasopefoluwa Y. Oguntuyo, Shreyas Kowdle, Ariel Esteban Vilardo, Alexis Edelstein, Claudia Perandones, Jeremy P. Kamil, Benhur Lee
ABSTRACT The novel pandemic betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected at least 120 million people since its identification as the cause of a December 2019 viral pneumonia outbreak in Wuhan, China. Despite the unprecedented pace of vaccine development, with six vaccines already in use worldwide, the emergence of SARS-CoV-2 ‘variants of concern’ (VOC) across diverse geographic locales suggests herd immunity may fail to eliminate the virus. All three officially designated VOC carry Spike (S) polymorphisms thought to enable escape from neutralizing antibodies elicited during initial waves of the pandemic. Here, we characterize the biological consequences of the ensemble of S mutations present in VOC lineages B.1.1.7 (501Y.V1) and B.1.351 (501Y.V2). Using a replication-competent EGFP-reporter vesicular stomatitis virus (VSV) system, rcVSV-CoV2-S, which encodes S from SARS coronavirus 2 in place of VSV-G, and coupled with a clonal HEK-293T ACE2 TMPRSS2 cell line optimized for highly efficient S-mediated infection, we determined that 8 out of 12 (67%) serum samples from a cohort of recipients of the Gamaleya Sputnik V Ad26 / Ad5 vaccine showed dose response curve slopes indicative of failure to neutralize rcVSV-CoV2-S: B.1.351. The same set of sera efficiently neutralized S from B.1.1.7 and showed only moderately reduced activity against S carrying the E484K substitution alone. Taken together, our data suggest that control of emergent SARS-CoV-2 variants may benefit from updated vaccines.
Authors Matthew McCallum, Jessica Bassi, Anna De Marco, Alex Chen, Alexandra C. Walls, Julia Di Iulio, M. Alejandra Tortorici, Mary-Jane Navarro, Chiara Silacci-Fregni, Christian Saliba, Maria Agostini, Dora Pinto, Katja Culap, Siro Bianchi, Stefano Jaconi, Elisabetta Cameroni, John E. Bowen, Sasha W Tilles, Matteo Samuele Pizzuto, Sonja Bernasconi Guastalla, Giovanni Bona, Alessandra Franzetti Pellanda, Christian Garzoni, Wesley C. Van Voorhis, Laura E. Rosen, Gyorgy Snell, Amalio Telenti, Herbert W. Virgin, Luca Piccoli, Davide Corti, David Veesler
Abstract SARS-CoV-2 entry is mediated by the spike (S) glycoprotein which contains the receptor-binding domain (RBD) and the N-terminal domain (NTD) as the two main targets of neutralizing antibodies (Abs). A novel variant of concern (VOC) named CAL.20C (B.1.427/B.1.429) was originally detected in California and is currently spreading throughout the US and 29 additional countries. It is unclear whether antibody responses to SARS-CoV-2 infection or to the prototypic Wuhan-1 isolate-based vaccines will be impacted by the three B.1.427/B.1.429 S mutations: S13I, W152C and L452R. Here, we assessed neutralizing Ab responses following natural infection or mRNA vaccination using pseudoviruses expressing the wildtype or the B.1.427/B.1.429 S protein. Plasma from vaccinated or convalescent individuals exhibited neutralizing titers, which were reduced 3-6 fold against the B.1.427/B.1.429 variant relative to wildtype pseudoviruses. The RBD L452R mutation reduced or abolished neutralizing activity of 14 out of 35 RBD-specific monoclonal antibodies (mAbs), including three clinical-stage mAbs. Furthermore, we observed a complete loss of B.1.427/B.1.429 neutralization for a panel of mAbs targeting the N-terminal domain due to a large structural rearrangement of the NTD antigenic supersite involving an S13I-mediated shift of the signal peptide cleavage site. These data warrant closer monitoring of signal peptide variants and their involvement in immune evasion and show that Abs directed to the NTD impose a selection pressure driving SARS-CoV-2 viral evolution through conventional and unconventional escape mechanisms.
Authors Fredy Suter, Elena Consolaro, Stefania Pedroni, Chiara Moroni, Elena Pastò, Maria Vittoria Paganini, Grazia Pravettoni, Umberto Cantarelli, Nadia Rubis, Norberto Perico, Annalisa Perna, Tobia Peracchi, Piero Ruggenenti, Giuseppe Remuzzi
Summary Background Effective home treatment algorithms implemented based on a pathophysiologic and pharmacologic rationale to accelerate recovery and prevent hospitalisation of patients with early coronavirus disease 2019 (COVID-19) would have major implications for patients and health system. Methods This academic, matched-cohort study compared outcomes of 90 consecutive consenting patients with mild COVID-19 treated at home by their family physicians between October 2020 and January 2021, according to the proposed recommendation algorithm, with outcomes for 90 age-, sex-, and comorbidities-matched patients who received other therapeutic regimens. Primary outcome was time to resolution of major symptoms. Secondary outcomes included prevention of hospitalisation. Analyses were by intention-to-treat. Findings All patients achieved complete remission. The median [IQR] time to resolution of major symptoms was 18 [14-23] days in the ‘recommended’ schedule cohort and 14 [7-30] days in the matched ‘control’ cohort (p=0·033). Other symptoms persisted in a lower percentage of patients in the ‘recommended’ than in the ‘control’ cohort (23·3% versus 73·3%, respectively, p<0·0001) and for a shorter period (p=0·0107). Two patients in the ‘recommended’ cohort were hospitalised compared to 13 (14·4%) controls (Log-rank test, p=0·0038). The prevention algorithm reduced the days and cumulative costs of hospitalisation by >90% (from 481 to 44 days and from €296.000 to €28.000, respectively. 1.2 patients had to be treated to prevent one hospitalisation event. Interpretation Implementation of an early home treatment algorithm failed to accelerate recovery from major symptoms of COVID 19, but almost eliminated the risk of hospitalisation and related treatment costs. Evidence before this study We searched PubMed and the Cochrane Library for peer-reviewed articles published in any language up to March 19, 2021, using the search terms “2019-nCoV” or “SARS-CoV-2” or “COVID-19” and “early” or “outpatient” or “treatment” or “home”. Our search did not identify any randomised clinical trials or observational studies that assessed the effectiveness of treatment regimens targeting early, mild symptoms of COVID-19 in the outpatient setting. Added value of this study In this fully academic, observational matched-cohort study, we found that early home treatment of 90 consecutive patients with mild COVID-19 by their family physicians according to the proposed recommendation algorithm, designed based on a pathophysiologic and pharmacologic rationale, required few more days to achieve resolution of major symptoms including fever, dyspnea, musculoskeletal pain, headache and cough compared to 90 age-, sex-, and comorbidities-matched patients who received other therapeutic regimens (primary outcome). Nonetheless, it is noteworthy that the home treatment of COVID-19 patients according to the proposed recommendation algorithm significantly reduced the risk of hospitalization compared to the other treatments in the ‘control’ cohort. Days of hospitalization and related treatment costs were reduced by over 90% in the ‘recommended’ cohort as compared to ‘control’ cohort. Just 1.2 patients needed to be treated according to the recommendation algorithm to prevent one hospitalization event. We also found that symptoms such as anosmia and ageusia/dysgeusia were less persistent and lasted a shorter time in the ‘recommendation’ than in the ‘control’ cohort. Implications of the available evidence The finding that the implementation of the proposed simple treatment algorithm during the initial, mild phase of COVID-19 has the potential to prevent disease progression, potentially limiting the need for hospital admission, may have major implications for patients and health care providers. Indeed, preventing hospitalisations due to the worsening of COVID-19 will not only save lives, but will also contribute to remarkably reduced treatment costs and to streamlining health care systems that are overburdened by the effects of the pandemic. However, time to hospitalization was a secondary outcome of the study and the possibility of a casual finding cannot be definitely excluded. Thus, the observed reduction in patients hospitalizations should be considered as an hypothesis generating finding that could provide a robust background for a prospective trial primarily aimed to test treatment effect on this outcome.
Authors Claudia Del Vecchio, Giuseppina Brancaccio, Alessandra Rosalba Brazzale, Enrico Lavezzo, Francesco Onelia, Elisa Franchin, Laura Manuto, Federico Bianca, Vito Cianci, Annamaria Cattelan, Stefano Toppo, Andrea Crisanti
ABSTRACT SARS-CoV-2 genetic variants are emerging as a major threat to vaccination efforts worldwide as they may increase virus transmission rate and/or confer the ability to escape vaccine induced immunity with knock on effects on the level of herd immunity and vaccine efficacy respectively. These variants concern the Spike protein, which is encoded by the S gene, involved in virus entry into host cells and the major target of vaccine development. We report here that genetic variants of the N gene can impair our ability to utilize antigenic tests for both diagnosis and mass testing efforts aimed at controlling virus transmission. While conducting a large validation study on the Abbott Panbio™ COVID-19 Ag test, we noticed that some swab samples failed to generate a positive result in spite of a high viral load in Rt-PCR assays. Sequencing analysis of viruses showing discordant results in the RT-PCR and antigen assays revealed the presence of multiple disruptive amino-acid substitutions in the N antigen (the viral protein detected in the antigen test) clustered from position 229 to 374 a region known to contain an immunodominant epitope. A relevant fraction of the variants, undetected by the antigen test, contained the mutations A376T coupled to M241I. Intriguingly we found that virus sequences with this mutation were over-represented in the antigen-test-negative and PCR-positive samples and progressively increased in frequency over time in Veneto, a region of Italy that has aggressively scaled up the utilization of antigen tests, which reached nearly 68% of all the SARS-CoV-2 swab assays performed there. We speculate that mass utilization of antigen assays could create a selection pressure on the target that may favor the spread of undetectable virus variants.
Authors DT Arnold, A Milne, E Samms, L Stadon, NA Maskell, FW Hamilton
Abstract Introduction Although the efficacy of SARS-CoV-2 vaccination to prevent symptomatic COVID-19 is well established, there are no published studies on the impact on symptoms in patients with Long Covid. Anecdotal reports have suggested both a potential benefit and worsening of symptoms post vaccination with the uncertainty leading to some vaccine hesitancy amongst affected individuals. Methods Patients initially hospitalised with COVID-19 were prospectively recruited to an observational study with clinical follow-up at 3 months (June-July 2020) and 8 months (Dec 2020-Jan 2021) post-admission. Participants who received the Pfizer-BioNTech (BNT162b2) or Oxford-AstraZeneca (ChAdOx1 nCoV-19) vaccine between January to February 2021 were identified and matched 2:1 (in terms of 8-month symptoms) with participants from the same cohort who were unvaccinated. All were re-assessed at 1 month post vaccination (or matched timepoint for unvaccinated cohort). Validated quality of life (SF-36), mental wellbeing (WEMWBS) and ongoing symptoms were assessed at all timepoints. Formal statistical analysis compared the effect of vaccination on recent quality of life using baseline symptoms, age, and gender in linear regression. Results Forty-four vaccinated participants were assessed at a median of 32 days (IQR 20-41) post vaccination with 22 matched unvaccinated participants. Most were highly symptomatic of Long Covid at 8 months (82% in both groups had at least 1 persistent symptom), with fatigue (61%), breathlessness (50%) and insomnia (38%) predominating. There was no significant worsening in quality-of-life or mental wellbeing metrics pre versus post vaccination. Nearly two-thirds (n=27) reported transient (<72hr duration) systemic effects (including fever, myalgia and headache). When compared to matched unvaccinated participants from the same cohort, those who had receive a vaccine had a small overall improvement in Long Covid symptoms, with a decrease in worsening symptoms (5.6% vaccinated vs 14.2% unvaccinated) and increase in symptom resolution (23.2% vaccinated vs 15.4% unvaccinated) (p=0.035). No difference in response was identified between Pfizer-BioNTech or Oxford-AstraZeneca vaccines. Conclusions Receipt of vaccination with either an mRNA or adenoviral vector vaccine was not associated with a worsening of Long Covid symptoms, quality of life, or mental wellbeing. Individuals with prolonged COVID-19 symptoms should receive vaccinations as suggested by national guidance.
Authors Jill K Baird, Shawn M Jensen, Walter J Urba, Bernard A Fox, Jason R Baird
Abstract Importance: The SARS-CoV-2 pandemic has infected over a hundred million people worldwide, with almost 2.5 million deaths at the date of this publication. In the United States, Pfizer-BioNTech and Moderna vaccines were first administered to the public starting in December 2020, and no lactating women were included in the initial trials of safety/efficacy. Research on SARS-CoV-2 vaccination in lactating women and the potential transmission of passive immunity to the infant through breast milk is needed to guide patients, clinicians and policy makers during the worldwide effort to curb the spread of this virus. Objective: To determine whether SARS-CoV-2 specific immunoglobins are found in breast milk post-vaccination, and to characterize the time course and types of immunoglobulins present. Design:.Prospective cohort study Setting: Providence Portland Medical Center, Oregon, USA Participants: Six lactating women who planned to receive both doses of the Pfizer-BioNTech or Moderna vaccine between December 2020 and January 2021. Breast milk samples were collected pre-vaccination and at 11 additional timepoints, with last sample at 14 days post 2nd dose of vaccine. Exposure: Two doses of Pfizer-BioNTech or Moderna SARS-CoV-2 vaccine. Main Outcome(s) and Measure(s): Levels of SARS-CoV-2 specific IgA and IgG immunoglobulins in breast milk. Results: In this cohort of 6 lactating women who received 2 doses of SARS-CoV-2 vaccine, we observed significantly elevated levels of SARS-CoV-2 specific IgG and IgA antibodies in breast milk beginning at Day 7 after the initial vaccine dose, with an IgG-dominant response. Conclusions and Relevance: We are the first to show that maternal vaccination results in SARS-CoV-2 specific immunoglobulins in breast milk that may be protective for infants.
Authors Fatima Amanat, Mahima Thapa, Tinting Lei, Shaza M. Sayed Ahmed, Daniel C. Adelsberg, Juan Manuel Carreno, Shirin Strohmeier, Aaron J. Schmitz, Sarah Zafar, Julian Q Zhou, Willemijn Rijnink, Hala Alshammary, Nicholas Borcherding, Ana Gonzalez Reiche, Komal Srivastava, Emilia Mia Sordillo, Harm van Bakel,, Jackson S. Turner, Goran Bajic, Viviana Simon, Ali H. Ellebedy, Florian Krammer
Authors Galit Perez, Tamar Banon, Sivan Gazit, Shay Ben Moshe, Joshua Wortsman, Daniel Grupel, Asaf Peretz, Amir Ben Tov, Gabriel Chodick, Miri Mizrahi-Reuveni, Tal Patalon
Abstract With more than 100 million confirmed COVID-19 cases as of March 2021, reinfection is still considered to be rare. In light of increasing reports of reinfected COVID-19 patients, the need to better understand the real risk for reinfection is critical, with potential effects on public health policies aimed at containing the spread of SARS-CoV-2. In this descriptive preliminary report, we conducted a large-scale assessment on the country level of the possible occurrence of COVID-19 reinfection within the members of a large healthcare provider in Israel. Out of 149,735 individuals with a documented positive PCR test between March 2020 and January 2021, 154 had two positive PCR tests at least 100 days apart, reflecting a reinfection proportion of 1 per 1000. Given our strict inclusion criteria, we believe these numbers represent true reinfection incidence in MHS and should be clinically regarded as such.
Authors Rishi R. Goel, Sokratis A. Apostolidis, Mark M. Painter, Divij Mathew, Ajinkya Pattekar, Oliva Kuthuru, Sigrid Gouma, Leticia Kuri-Cervantes, Wenzhao Meng, Sharon Adamski, Amy E. Baxter, Josephine R. Giles, Madison E. Weirick, Christopher M. McAllister, Amanda Hicks, Scott Korte, Jeanette Dougherty, Sherea Long, Kurt D’Andrea, Jacob T. Hamilton, Eline T Luning Prak, Michael R. Betts, Paul Bates, Scott E. Hensley, Allison R. Greenplate, E. John Wherry
ABSTRACT Novel mRNA vaccines for SARS-CoV2 have been authorized for emergency use and are currently being administered to millions of individuals worldwide. Despite their efficacy in clinical trials, there is limited data on vaccine-induced immune responses in individuals with a prior SARS-CoV2 infection compared to SARS-CoV2 naïve subjects. Moreover, how mRNA vaccines impact the development of antibodies as well as memory B cells in COVID-19 experienced versus COVID-19 naïve subjects remains poorly understood. In this study, we evaluated antibody responses and antigen-specific memory B cell responses over time in 33 SARS-CoV2 naïve and 11 SARS-CoV2 recovered subjects. mRNA vaccination induced significant antibody and memory B cell responses against full-length SARS-CoV2 spike protein and the spike receptor binding domain (RBD). SARS-CoV2 naïve individuals benefitted from both doses of mRNA vaccine with additional increases in antibodies and memory B cells following booster immunization. In contrast, SARS-CoV2 recovered individuals had a significant immune response after the first dose with no increase in circulating antibodies or antigen-specific memory B cells after the second dose. Moreover, the magnitude of the memory B cell response induced by vaccination was lower in older individuals, revealing an age-dependence to mRNA vaccine-induced B cell memory. Side effects also tended to associate with post-boost antibody levels, but not with post-boost memory B cells, suggesting that side effect severity may be a surrogate of short-term antibody responses. The frequency of pre-vaccine antigen-specific memory B cells in SARS-CoV2 recovered individuals strongly correlated with post-vaccine antibody levels, supporting a key role for memory B cells in humoral recall responses to SARS-CoV2. This observation may have relevance for future booster vaccines and for responses to viral variants that partially escape pre-existing antibodies and require new humoral responses to be generated from memory B cells. Finally, post-boost antibody levels were not correlated with post-boost memory responses in SARS-CoV2 naïve individuals, indicating that short-term antibody levels and memory B cells are complementary immunological endpoints that should be examined in tandem when evaluating vaccine response. Together, our data provide evidence of both serological response and immunological memory following mRNA vaccination that is distinct based on prior SARS-CoV2 exposure. These findings may inform vaccine distribution in a resource-limited setting.
Authors Merryn Voysey, Sue Ann Costa Clemens, Shabir A Madhi et al.
Authors Vivek Shinde, Sutika Bhikha, Zaheer Hoosain, Moherndran Archary, Qasim Bhorat, Lee Fairlie, Umesh Lalloo, Mduduzi S. L. Masilela, Dhayendre Moodley, Sherika Hanley, Leon Fouche, Cheryl Louw, Michele Tameris, Nishanta Singh, Ameena Goga, Keertan Dheda, Coert Grobbelaar, Gertruida Kruger, Nazira Carrim-Ganey, Vicky Baillie, Tulio de Oliveira, Anthonet Lombard Koen, Johan J. Lombaard, Rosie Mngqibisa, As’ad Ebrahim Bhorat, Gabriella Benadé, Natasha Lalloo, Annah Pitsi, Pieter-Louis Vollgraaff, Angelique Luabeya, Aliasgar Esmail, Friedrich G. Petrick, Aylin Oommen Jose, Sharne Foulkes, Khatija Ahmed, Asha Thombrayil, Lou Fries, Shane Cloney-Clark, Mingzhu Zhu, Chijioke Bennett, Gary Albert, Emmanuel Faust, Joyce S. Plested, Andreana Robertson, Susan Neal, Iksung Cho, Greg M. Glenn, Filip Dubovsky, Shabir A. Madhi
ABSTRACT Background The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens progress toward control of the Covid-19 pandemic. Evaluation of Covid-19 vaccine efficacy against SARS-CoV-2 variants is urgently needed to inform vaccine development and use. Methods In this phase 2a/b, multicenter, randomized, observer-blinded, placebo-controlled trial in South Africa, healthy human immunodeficiency virus (HIV)-negative adults (18 to 84 years) or medically stable people living with HIV (PLWH) (18 to 84 years) were randomized in a 1:1 ratio to receive two doses, administered 21 days apart, of either NVX-CoV2373 nanoparticle vaccine (5 µg recombinant spike protein with 50 µg Matrix-M1 adjuvant) or placebo. The primary endpoints were safety and vaccine efficacy ≥7 days following the second dose against laboratory-confirmed symptomatic Covid-19 in previously SARS-CoV-2 uninfected participants. Results A total of 4387 participants were randomized and dosed at least once, 2199 with NVX-CoV2373 and 2188 with placebo. Approximately 30% of participants were seropositive at baseline. Among 2684 baseline seronegative participants (94% HIV-negative; 6% PLWH), there were 15 and 29 predominantly mild to moderate Covid-19 cases in NVX-CoV2373 and placebo recipients, respectively; vaccine efficacy was 49.4% (95% confidence interval [CI]: 6.1 to 72.8). Efficacy in HIV-negative participants was 60.1% (95% CI: 19.9 to 80.1), and did not differ by baseline serostatus. Of the primary endpoint cases with available whole genome sequencing, 38 (92.7%) of 41 were the B.1.351 variant. Post-hoc vaccine efficacy against B.1.351 was 51.0% (95% CI: - 0.6 to 76.2) in HIV-negative participants. Among placebo recipients, the incidence of symptomatic Covid-19 was similar in baseline seronegative vs baseline seropositive participants during the first 2 months of follow-up (5.3% vs 5.2%). Preliminary local and systemic reactogenicity were primarily mild to moderate and transient, and higher with NVX-CoV2373; serious adverse events were rare in both groups. Conclusions The NVX-CoV2373 vaccine was efficacious in preventing Covid-19, which was predominantly mild to moderate and due to the B.1.351 variant, while evidence of prior infection with the presumptive original SARS-CoV-2 did not confer protection against probable B.1.351 disease. (Funded by Novavax, The Bill and Melinda Gates Foundation, and the Coalition for Epidemic Preparedness Innovations; ClinicalTrials.gov number, NCT04533399)
Authors Raul Pellini, Aldo Venuti, Fulvia Pimpinelli, Elva Abril, Giovanni Blandino, Flaminia Campo, Laura Conti, Armando De Virgilio, Federico De Marco, Enea Gino Di Domenico, Ornella Di Bella, Simona Di Martino, Fabrizio Ensoli, Diana Giannarelli, Chiara Mandoj, Valentina Manciocco, Paolo Marchesi, Francesco Mazzola, Silvia Moretto, Gerardo Petruzzi, Fabrizio Petrone, Barbara Pichi, Martina Pontone, Jacopo Zocchi, Antonello Vidiri, Branka Vujovic, Giulia Piaggio, Aldo Morrone, Gennaro Ciliberto
ABSTRACT Background The first goal of the study was to analyse the antibody titre 7 days after the second dose of BNT162b2 vaccine in a group of 248 healthcare workers (HCW). The second goal was to analyse how the antibody titre changes in correlation with age, gender and BMI. Methods Participants were assigned to receive the priming dose at baseline and booster dose at day 21. Blood and nasopharyngeal swabs were collected at baseline and 7 days after second dose of vaccine. Findings 248 HWCs were analysed, 158 women (63.7%) and 90 men (36.3%). After the second dose of BNT162b2 vaccine, 99.5% of participants developed a humoral immune response. The geometric mean concentration of antibodies among the vaccinated subjects after booster dose (285.9 AU/mL 95% CI: 249.5-327.7); was higher than that of human convalescent sera (39.4 AU/mL, 95% CI: 33.1-46.9), with p<0.0001. The antibody titre was found to be higher in young and female participants. A strong correlation of BMI classes with antibody titres was noticed: humoral response was more efficient in the group with under- and normal-weight vs the group with pre- and obesity participants (p<0.0001 at T1). Interpretation These findings imply that females, lean and young people have an increased capacity to mount humoral immune responses compared to males, overweight and the older population. Although further studies are needed, this data may have important implications for the development of vaccination strategies for COVID-19, particularly in obese people.
Authors Anthony P. West Jr., Christopher O. Barnes, Zhi Yang, Pamela J. Bjorkman
Abstract Wide-scale SARS-CoV-2 genome sequencing is critical to monitoring and understanding viral evolution during the ongoing pandemic. Variants first detected in the United Kingdom, South Africa, and Brazil have spread to multiple countries. We have developed a software tool, Variant Database (VDB), for quickly examining the changing landscape of spike mutations. Using this tool, we detected an emerging lineage of viral isolates in the New York region that shares mutations with previously reported variants. The most common sets of spike mutations in this lineage (now designated as B.1.526) are L5F, T95I, D253G, E484K or S477N, D614G, and A701V. This lineage appeared in late November 2020, and isolates from this lineage account for ~25% of coronavirus genomes sequenced and deposited from New York during February 2021. Competing Interest Statement P.J.B. is a co-inventor on a provisional application from the California Institute of Technology for the use of mosaic nanoparticles as coronavirus immunogens. P.J.B. and C.O.B. are co-inventors on a provisional application for several anti-SARS-CoV-2 monoclonal antibodies.
Authors 6 Hall V, Foulkes S, Saei A, Andrews N, Oguti B, Charlett A, Wellington E, Stowe J, Gillson N, Atti A, Islam J, Karagiannis I, Munro K, Khawam J, The SIREN Study Group, Chand MA , Brown CS, Ramsay M, Lopez-Bernal J , Hopkins S
Abstract Background: BNT162b2 mRNA and ChAdOx1 nCOV-19 adenoviral vector vaccines have been rapidly rolled out in the UK. We determined the factors associated with vaccine coverage for both vaccines and documented the vaccine effectiveness of the BNT162b2 mRNA vaccine in our healthcare worker (HCW) cohort study of staff undergoing regular asymptomatic testing. Methods: The SIREN study is a prospective cohort study among staff working in publicly funded hospitals. Baseline risk factors, vaccination status (from 8/12/2020-5/2/2021), and symptoms are recorded at 2 weekly intervals and all SARS-CoV-2 polymerase chain reaction (PCR) and antibody test results documented. A mixed effect proportional hazards frailty model using a Poisson distribution was used to calculate hazard ratios to compare time to infection in unvaccinated and vaccinated participants to estimate the impact of the BNT162b2 vaccine on all (asymptomatic and symptomatic) infection. Findings: Vaccine coverage was 89% on 5/2/2021. Significantly lower coverage was associated with prior infection (aOR 0.59 95% confidence interval [CI] 0.54-0.64), female (aOR 0.72, 95% CI 0.63-0.82), aged under 35 years, being from minority ethnic groups (especially Black, aOR 0.26, 95% CI 0.21-0.32), porters/security guards (aOR 0.61, 95% CI 0.42-0.90),or midwife (aOR 0.74, 95% CI 0.57-0.97), and living in more deprived neighbourhoods (IMD 1 (most) vs. 5 (least) (aOR 0.75, 95% CI 0.65-0.87). A single dose of BNT162b2 vaccine demonstrated vaccine effectiveness of 72% (95% CI 58-86) 21 days after first dose and 86% (95% CI 76-97) seven days after two doses in the antibody negative cohort. Conclusion: Our study demonstrates that the BNT162b2 vaccine effectively prevents both symptomatic and asymptomatic infection in working age adults; this cohort was vaccinated when the dominant variant in circulation was B1.1.7 and demonstrates effectiveness against this variant.
Authors Paul Z. Chen, Niklas Bobrovitz, Zahra Premji, Marion Koopmans, David N. Fisman, Frank X. Gu
Abstract Background SARS-CoV-2 shedding dynamics in the upper (URT) and lower respiratory tract (LRT) remain unclear. Objective To analyze SARS-CoV-2 shedding dynamics across COVID-19 severity, the respiratory tract, sex and age cohorts (aged 0 to 17 years, 18 to 59 years, and 60 years or older). Design Systematic review and pooled analyses. Setting MEDLINE, EMBASE, CENTRAL, Web of Science Core Collection, medRxiv and bioRxiv were searched up to 20 November 2020. Participants The systematic dataset included 1,266 adults and 136 children with COVID-19. Measurements Case characteristics (COVID-19 severity, age and sex) and quantitative respiratory viral loads (rVLs). Results In the URT, adults with severe COVID-19 had higher rVLs at 1 DFSO than adults (P = 0.005) or children (P = 0.017) with nonsevere illness. Between 1-10 DFSO, severe adults had comparable rates of SARS-CoV-2 clearance from the URT as nonsevere adults (P = 0.479) and nonsevere children (P = 0.863). In the LRT, severe adults showed higher post-symptom-onset rVLs than nonsevere adults (P = 0.006). In the analyzed period (4-10 DFSO), severely affected adults had no significant trend in SARS-CoV-2 clearance from LRT (P = 0.105), whereas nonsevere adults showed a clear trend (P < 0.001). After stratifying for disease severity, sex and age (including child vs. adult) were not predictive of the duration of respiratory shedding. Limitation Limited data on case comorbidities and few samples in some cohorts. Conclusion High, persistent LRT shedding of SARS-CoV-2 characterized severe COVID-19 in adults. After symptom onset, severe cases tended to have higher URT shedding than their nonsevere counterparts. Disease severity, rather than age or sex, predicted SARS-CoV-2 kinetics. LRT specimens should more accurately prognosticate COVID-19 severity than URT specimens. Primary Funding Source Natural Sciences and Engineering Research Council. Competing Interest Statement Dr. Fisman has received honoraria related to work with Pfizer, Astra Zeneca and Seqirus on vaccines for respiratory viruses. Funding Statement This study was supported by NSERC. Mr. Chen was supported by the NSERC Vanier Canada Graduate Scholarship (608544). Dr. Fisman was supported by the Canadian Institutes of Health Research (Canadian COVID-19 Rapid Research Fund, OV4-170360). Dr. Gu was supported by the NSERC Senior Industrial Research Chair.
Authors Eleftheria Vasileiou, Colin R. Simpson, Chris Robertson, Ting Shi, Steven Kerr, Utkarsh Agrawal, Ashley Akbari, Stuart Bedston, Jillian Beggs Declan Bradley, Antony Chuter, Simon de Lusignan, Annemarie Docherty, David Ford, Richard Hobbs, Mark Joy, Srinivasa Vittal Katikireddi, James Marple, Colin McCowan, Dylan McGagh Nuffield, Jim McMenamin, Emily Moore, Josephine-L.K Murray, Jiafeng Pan, Lewis Ritchie, Syed Ahmar Shah, Sarah Stock, Fatemeh Torabi, Ruby S. M. Tsang, Rachael Wood, Mark Woolhouse Aziz Sheikh
Abstract Background: The BNT162b2 mRNA (Pfizer-BioNTech) and ChAdOx1 (Oxford-AstraZeneca) COVID-19 vaccines have demonstrated high efficacy against infection in phase 3 clinical trials and are now being used in national vaccination programmes in the UK and several other countries. There is an urgent need to study the ‘real-world’ effects of these vaccines. The aim of our study was to estimate the effectiveness of the first dose of these COVID-19 vaccines in preventing hospital admissions. Methods: We conducted a prospective cohort study using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) database comprising of linked vaccination, primary care, Real-Time Polymerase Chain Reaction (RT-PCR) testing, hospitalisation and mortality records for 5.4 million people in Scotland (covering ~99% of population). A time-dependent Cox model and Poisson regression models were fitted to estimate effectiveness against COVID-19 related hospitalisation (defined as 1- Adjusted Hazard Ratio) following the first dose of vaccine. Findings: The first dose of the BNT162b2 vaccine was associated with a vaccine effect of 85% (95% confidence interval [CI] 76 to 91) for COVID-19 related hospitalisation at 28-34 days post-vaccination. Vaccine effect at the same time interval for the ChAdOx1 vaccine was 94% (95% CI 73 to 99). Results of combined vaccine effect for prevention of COVID-19 related hospitalisation were comparable when restricting the analysis to those aged ≥80 years (81%; 95% CI 65 to 90 at 28-34 days post-vaccination). Interpretation: A single dose of the BNT162b2 mRNA and ChAdOx1 vaccines resulted in substantial reductions in the risk of COVID-19 related hospitalisation in Scotland. Funding: UK Research and Innovation (Medical Research Council); Research and Innovation Industrial Strategy Challenge Fund; Health Data Research UK. Conflict of Interest: AS is a member of the Scottish Government Chief Medical Officer’s COVID-19Advisory Group and the New and Emerging Respiratory Virus Threats (NERVTAG) Risk Stratification Subgroup. CRS declares funding from the MRC, NIHR, CSO and New Zealand Ministry for Business, Innovation and Employment and Health Research Council during the conduct of this study. SVK is co-chair of the Scottish Government’s Expert Reference Group on COVID-19 and ethnicity, is a member of the Scientific Advisory Group on Emergencies (SAGE) subgroup on ethnicity and acknowledges funding from a NRS Senior Clinical Fellowship, MRC and CSO. All other authors report no conflicts of interest.
CELL
Authors Qianqian Li, Jianhui Nie, Jiajing Wu, Li Zhang, Ruxia Ding, Haixin Wang, Yue Zhang, Tao Li, Shuo Liu, Mengyi Zhang, Chenyan Zhao, Huan Liu, Lingling Nie, Haiyang Qin, Meng Wang, Qiong Lu, Xiaoyu Li, Junkai Liu, Haoyu Liang, Yi Shi, Yuelei Shen, Liangzhi Xie, Linqi Zhang, Xiaowang Qu, Wenbo Xu, Weijin Huang, Youchun Wang
Authors Emma B. Hodcroft, Daryl B. Domman, Daniel J. Snyder, Kasopefoluwa Oguntuyo, Maarten Van Diest, Kenneth H. Densmore, Kurt C. Schwalm, Jon Femling, Jennifer L. Carroll, Rona S. Scott, Martha M. Whyte, Michael D. Edwards, Noah C. Hull, Christopher G. Kevil, John A. Vanchiere, Benhur Lee, Darrell L. Dinwiddie, Vaughn S. Cooper, Jeremy P. Kamil
Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein (S) plays critical roles in host cell entry. Non-synonymous substitutions affecting S are not uncommon and have become fixed in a number of SARS-CoV-2 lineages. A subset of such mutations enable escape from neutralizing antibodies or are thought to enhance transmission through mechanisms such as increased affinity for the cell entry receptor, angiotensin-converting enzyme 2 (ACE2). Independent genomic surveillance programs based in New Mexico and Louisiana contemporaneously detected the rapid rise of numerous clade 20G (lineage B.1.2) infections carrying a Q677P substitution in S. The variant was first detected in the US on October 23, yet between 01 Dec 2020 and 19 Jan 2021 it rose to represent 27.8% and 11.3% of all SARS-CoV-2 genomes sequenced from Louisiana and New Mexico, respectively. Q677P cases have been detected predominantly in the south central and southwest United States; as of 03 Feb 2021, GISAID data show 499 viral sequences of this variant from the USA. Phylogenetic analyses revealed the independent evolution and spread of at least six distinct Q677H sub-lineages, with first collection dates ranging from mid-August to late November 2020. Four 677H clades from clade 20G (B.1.2), 20A (B.1.234), and 20B (B.1.1.220, and B.1.1.222) each contain roughly 100 or fewer sequenced cases, while a distinct pair of clade 20G clusters are represented by 754 and 298 cases, respectively. Although sampling bias and founder effects may have contributed to the rise of S:677 polymorphic variants, the proximity of this position to the polybasic cleavage site at the S1/S2 boundary are consistent with its potential functional relevance during cell entry, suggesting parallel evolution of a trait that may confer an advantage in spread or transmission. Taken together, our findings demonstrate simultaneous convergent evolution, thus providing an impetus to further evaluate S:677 polymorphisms for effects on proteolytic processing, cell tropism, and transmissibility.
Authors Shabir A. Madhi, Vicky Baillie, Clare L. Cutland, Merryn Voysey, Anthonet L. Koen, Lee Fairlie, Sherman D. Padayachee, Keertan Dheda, Shaun L. Barnabas, Qasim Ebrahim Bhorat, Carmen Briner, Gaurav Kwatra, NGS-SA, Wits-VIDA COVID team, Khatija Ahmed, Parvinder Aley, Sutika Bhikha, Jinal N. Bhiman, As’ad Ebrahim Bhorat, Jeanine du Plessis, Aliasgar Esmail, Marisa Groenewald, Elizea Horne, Shi-Hsia Hwa, Aylin Jose, Teresa Lambe, Matt Laubscher, Mookho Malahleha, Masebole Masenya, Mduduzi Masilela, Shakeel McKenzie, Kgaogelo Molapo, Andrew Moultrie, Suzette Oelofse, Faeezah Patel, Sureshnee Pillay, Sarah Rhead, Hylton Rodel, Lindie Rossouw, Carol Taoushanis, Houriiyah Tegally, Asha Thombrayil, Samuel van Eck, Constantinos Kurt Wibmer, Nicholas M. Durham, Elizabeth J Kelly, Tonya L Villafana, Sarah Gilbert, Andrew J Pollard, Tulio de Oliveira, Penny L. Moore, Alex Sigal, Alane Izu
Abstract Background Assessing safety and efficacy of Covid-19 vaccines in different populations is essential, as is investigation of efficacy against emerging SARS-CoV-2 variants of concern including the B.1.351 (501Y.V2) variant first identified in South Africa. Methods We conducted a randomized multicentre, double blinded controlled trial on safety and efficacy of ChAdOx1-nCoV19 in HIV-uninfected people in South Africa. Participants age 18 to <65 years randomized (1:1) to two doses of vaccine containing 5×1010 viral particles or placebo (0.9%NaCl) 21-35 days apart. Post 2nd-dose serum samples (n=25) were tested by pseudotyped (PSVNA) and live virus (LVNA) neutralization assays against the D614G and B.1.351 variants. Primary endpoints were safety and vaccine efficacy (VE) >14 days following second dose against laboratory confirmed symptomatic Covid-19. Results 2026 HIV-uninfected adults were enrolled between June 24th and Nov 9th, 2020; 1010 and 1011 received at least one dose of placebo or vaccine, respectively. Median age was 31 years. The B.1.351 variant showed increased resistance to vaccinee sera using the PSVNA and LVNA. In the primary endpoint analysis, 23/717 (3.2%) placebo and 19/750 (2.5%) vaccine recipients developed mild-moderate Covid-19; VE 21.9% (95%Confidence Interval: −49.9; 59.8). Of the primary endpoint cases, 39/42 (92.9%) were the B.1.351 variant; against which VE was 10.4% (95%CI: −76.8; 54.8) analyzed as a secondary objective. The incidence of serious adverse events was balanced between the vaccine and placebo groups. Conclusions A two-dose regimen of ChAdOx1-nCoV19 did not show protection against mild-moderate Covid-19 due to B.1.351 variant, however, VE against severe Covid-19 is undetermined.
Authors Peter W Horby, Guilherme Pessoa-Amorim, Leon Peto, Christopher E Brightling, Rahuldeb Sarkar, Koshy Thomas, Vandana Jeebun, Abdul Ashish, Redmond Tully, David Chadwick, Muhammad Sharafat, Richard Stewart, Banu Rudran, J Kenneth Baillie, Maya H Buch, Lucy C Chappell, Jeremy N Day, Saul N Furst, Thomas Jaki, Katie Jeffery, Edmund Juszczak, Wei Shen Lim, Alan Montgomery, Andrew Mumford, Kathryn Rowan, Guy Thwaites, Marion Mafham, Richard Haynes, Martin J Landray
Authors Marie I. Samanovic, Amber R. Cornelius, Jimmy P. Wilson, Trishala Karmacharya, Sophie L. Gray-Gaillard, Joseph Richard Allen, Sara Wesley Hyman, Gali Moritz, Mahnoor Ali, Sergei B. Koralov, Mark J. Mulligan, Ramin Sedaghat Herati
Abstract The advent of COVID-19 vaccines will play a major role in helping to end the pandemic that has killed millions worldwide. Vaccine candidates have demonstrated robust humoral responses and have protected against infection. However, efficacy trials were focused on individuals with no prior exposure to SARS-CoV-2, and, as a result, little is known about immune responses induced by these mRNA vaccines in individuals who recovered from COVID-19. Here, we evaluated immune responses in 32 subjects who received two-dose BNT162b2 mRNA vaccination. In individuals naive to SARS-CoV-2, we observed robust increases in humoral and antigen-specific antibody-secreting cell (ASC) responses following each dose of vaccine, whereas individuals with prior exposure to SARS-CoV-2 demonstrated strong humoral and antigen-specific ASC responses to the first dose but muted responses to the second dose of the vaccine for the time points studied. These data highlight an important gap in our knowledge and may have major implications for how these vaccines should be used to prevent COVID-19. One sentence summary Immune responses to the booster dose of mRNA vaccine BNT162b2 are poor in subjects with a prior history of SARS-CoV-2 infection. Competing Interest Statement MJM reported potential competing interests: laboratory research and clinical trials contracts with Lilly, Pfizer (exclusive of the current work), and Sanofi for vaccines or MAB vs SARS-CoV-2; contract funding from USG/HHS/BARDA for research specimen characterization and repository; research grant funding from USG/HHS/NIH for SARS-CoV-2 vaccine and MAB clinical trials; personal fees from Meissa Vaccines, Inc. for Scientific Advisory Board service
Authors Marie I. Samanovic, Amber R. Cornelius, Jimmy P. Wilson, Trishala Karmacharya, Sophie L. Gray-Gaillard, Joseph Richard Allen, Sara Wesley Hyman, Gali Moritz, Mahnoor Ali, Sergei B. Koralov, Mark J. Mulligan, Sedaghat Herati
Abstract The advent of COVID-19 vaccines will play a major role in helping to end the pandemic that has killed millions worldwide. Vaccine candidates have demonstrated robust humoral responses and have protected against infection. However, efficacy trials were focused on individuals with no prior exposure to SARS-CoV-2, and, as a result, little is known about immune responses induced by these mRNA vaccines in individuals who recovered from COVID-19. Here, we evaluated immune responses in 32 subjects who received two-dose BNT162b2 mRNA vaccination. In individuals naive to SARS-CoV-2, we observed robust increases in humoral and antigen-specific antibody-secreting cell (ASC) responses following each dose of vaccine, whereas individuals with prior exposure to SARS-CoV-2 demonstrated strong humoral and antigen-specific ASC responses to the first dose but muted responses to the second dose of the vaccine for the time points studied. These data highlight an important gap in our knowledge and may have major implications for how these vaccines should be used to prevent COVID-19. One sentence summary Immune responses to the booster dose of mRNA vaccine BNT162b2 are poor in subjects with a prior history of SARS-CoV-2 infection.
Authors Leonidas Stamatatos, Julie Czartoski, Yu-Hsin Wan, Leah J. Homad, Vanessa Rubin, Hayley Glantz, Moni Neradilek, Emilie Seydoux, Maedeline F. Jennewein, Anna J. MacCamy, Junli Feng, Gregory Mize, Stephen C. De Rosa, Andrés Finzi, Maria Lemos, Kristen W. Cohen, Zoe Moodie, M. Juliana McElrath, Andrew T. McGuire
Abstract The emergence of SARS-CoV-2 variants raises concerns about their resistance to neutralizing antibodies elicited from previous infection, or from vaccination. Here we examined whether sera and monoclonal antibodies from convalescent donors, prior to and following a single immunization with the Pfizer or Moderna mRNA vaccines, neutralize the Wuhan-Hu-1 strain and a variant, B.1.351 from South Africa. Pre-vaccination sera weakly neutralized Wuhan-Hu-1 and sporadically neutralized B.1.351. Immunization with either vaccine generated anamnestic B and CD4+ T cell responses and a 1000-fold increase in neutralizing antibody titers against both strains and SARS-CoV-1. Neutralization was likely due to anti-RBD and anti-S2 antibodies. Our study highlights the importance of vaccination of both uninfected and of previously infected subjects, as the elicited immune response will neutralize distinct viral strains.
Authors Nicole L. Washington, Karthik Gangavarapu, Mark Zeller, Alexandre Bolze, Elizabeth T. Cirulli, Kelly M. Schiabor Barrett, Brendan B. Larsen, Catelyn Anderson, Simon White, Tyler Cassens, Sharoni Jacobs, Geraint Levan, Jason Nguyen, Jimmy M. Ramirez III, Charlotte Rivera-Garcia, Efren Sandoval, Xueqing Wang, David Wong, Emily Spencer, Refugio Robles-Sikisaka, Ezra Kurzban, Laura D. Hughes, Xianding Deng, Candace Wang, Venice Servellita, Holly Valentine, Peter De Hoff, Phoebe Seaver, Shashank Sathe, Kimberly Gietzen, Brad Sickler, Jay Antico, Kelly Hoon, Jingtao Liu, Aaron Harding, Omid Bakhtar, Tracy Basler, Brett Austin, Magnus Isaksson, Phillip G. Febbo, David Becker, Marc Laurent, Eric McDonald, Gene W. Yeo, Rob Knight, Louise C. Laurent, Eileen de Feo, Michael Worobey, Charles Chiu, Marc A. Suchard, James T. Lu, William Lee, Kristian G. Andersen
Summary As of January of 2021, the highly transmissible B.1.1.7 variant of SARS-CoV-2, which was first identified in the United Kingdom (U.K.), has gained a strong foothold across the world. Because of the sudden and rapid rise of B.1.1.7, we investigated the prevalence and growth dynamics of this variant in the United States (U.S.), tracking it back to its early emergence and onward local transmission. We found that the RT-qPCR testing anomaly of S gene target failure (SGTF), first observed in the U.K., was a reliable proxy for B.1.1.7 detection. We sequenced 212 B.1.1.7 SARS-CoV-2 genomes collected from testing facilities in the U.S. from December 2020 to January 2021. We found that while the fraction of B.1.1.7 among SGTF samples varied by state, detection of the variant increased at a logistic rate similar to those observed elsewhere, with a doubling rate of a little over a week and an increased transmission rate of 35-45%. By performing time-aware Bayesian phylodynamic analyses, we revealed several independent introductions of B.1.1.7 into the U.S. as early as late November 2020, with onward community transmission enabling the variant to spread to at least 30 states as of January 2021. Our study shows that the U.S. is on a similar trajectory as other countries where B.1.1.7 rapidly became the dominant SARS-CoV-2 variant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality.
Authors Emary, Katherine R. W. and Golubchik, Tanya and Aley, Parvinder K. and Ariani, Cristina V. and Angus, Brian John and Bibi, Sagida and Blane, Beth and Bonsall, David and Cicconi, Paola and Charlton, Sue and Clutterbuck, Elizabeth and Collins, Andrea M. and Cox, Tony and Darton, Thomas and Dold, Christina and Douglas, Alexander D. and Duncan, Christopher J. A. and Ewer, Katie and Flaxman, Amy and Faust, Saul N. and Ferreira, Daniela M. and Feng, Shuo and Finn, Adam and Folegatti, Pedro M. and Fuskova, Michelle and Galiza, Eva and Goodman, Anna L. and Green, Catherine M. and Green, Christopher A. and Greenland, Melanie and Hallis, Bassam and Heath, Paul T. and Hay, Jodie and Hill, Helen C. and Jenkin, Daniel and Kerridge, Simon and Lazarus, Rajeka and Libri, Vincenzo and Lillie, Patrick J. and Ludden, Catherine and Marchevsky, Natalie G. and Minassian, Angela M. and McGregor, Alastair C. and Farooq Mujadidi, Yama and Phillips, Daniel J. and Plested, Emma and Pollock, Katrina M. and Robinson, Hannah and Smith, Andrew and Song, Rinn and Snape, Matthew D. and Sutherland, Rebecca K. and Thomson, Emma C. and Toshner, Mark and Turner, David P. J. and Vekemans, Johan and Villafana, Tonya L. and Williams, Christopher J. and Hill, Adrian V. S. and Lambe, Teresa and Gilbert, Sarah C. and Voysey, Merryn and Ramasamy, Maheshi N. and Pollard, Andrew
Abstract Background: A new variant of SARS-CoV-2, B.1.1.7, emerged as the dominant cause of COVID-19infection in the United Kingdom from November 2020 with a transmission advantage over the previous variants of the virus. Here we report efficacy of the adenoviral vector vaccine, ChAdOx1 nCoV-19, against this variant in comparison with non-B.1.1.7 lineages. Methods: Volunteers enrolled in phase II/III vaccine efficacy studies in the United Kingdom and randomised 1:1 to receive ChAdOx1 nCoV-19 or a MenACWY control vaccine, providedupper airway swabs every week during the trial and also if they developed possible symptomatic COVID-19 infection. Swabs were tested by nucleic acid amplification test (NAAT) for SARS-CoV-2, and positive samples were sequenced through the COVID-19Genomics UK consortium (COG UK). NAAT data were used to assess the duration ofdetectable viral RNA in diagnostic specimens and the viral load. Anti-spike IgG wasmeasured by ELISA at baseline, 14 and 28 days after prime and 28 days after boostervaccination. Neutralising antibody responses were measured using a live virus neutralisation assay against the B.1.1.7 and Victoria lineages of the virus. The efficacy analysis included symptomatic COVID-19 in seronegative participants with a NAAT positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cut-off on Jan 14, 2021. Vaccine efficacy was calculated as 1 − relative risk derived from a robust Poisson regression model. This study is ongoing and is registered with ClinicalTrials.gov NCT04400838 and ISRCTN 15281137.5 Findings: Between 1st October 2020 and 14th January 2021, 499 participants developed Covid-19infection. 1524 NAAT positive nose/throat swabs were collected from these participants during the trial. Of these, 323 swabs from 256 participants were successfully sequenced.ChAdOx1 nCoV-19 recipients had a significantly lower viral load as represented byminimum PCR Ct value (p<0.0001) and were NAAT positive for a shorter time (p<0.0001) than participants who received the control vaccine. Virus neutralisation activity by vaccineinduced antibodies was 9-fold lower against the B.1.1.7 variant than against a canonical non B.1.1.7 lineage. Vaccine efficacy against symptomatic NAAT positive infection was similar for B.1.1.7 and non-B1.1.7 lineages (74.6% [95%CI 41.6-88.9] and 84% [95% CI 70.7-91.4] respectively). There was no difference in anti-spike antibody titres between individuals who had received a prior ChAdOx1 vectored vaccine and those who were naïve to ChAdOx1. Interpretation: Efficacy of ChAdOx1 nCoV-19 against the B.1.1.7 variant of SARS-CoV-2 is similar to the efficacy of the vaccine against other lineages. Furthermore, vaccination with ChAdOx1 nCoV-19 results in a reduction in the duration of shedding and viral load, which may translate into a material impact on transmission of disease.
Authors Gabriel Chodick, Lilac Tene, Tal Patalon, Sivan Gazit, Amir Ben Tov, Dani Cohen, Khitam Muhsen
Abstract Background BNT162b2 vaccines showed high efficacy against COVID-19 in a randomised controlled phase-III trial. A vaccine effectiveness evaluation in real life settings is urgently needed, especially given the global disease surge. Hence, we assessed the short-term effectiveness of the first dose of BNT162b2-vaccine against SARS-CoV-2 infection. Given the BNT162b2 Phase-III results, we hypothesized that the cumulative incidence of SARS-CoV-2 infection among vaccinees will decline after 12 days following immunization compared to the incidence during the preceding days. Methods We conducted a retrospective cohort study using data from 2·6 million-member state-mandated health provider in Israel. Study population consisted of all members aged 16 or above years who were vaccinated with BNT162b2-vaccine between December/19/2020 and January/15/2021. We collected information regarding medical history and positive SARS-CoV-2 polymerase chain reaction test from days after first dose to January/17/2021. Daily and cumulative infection rates in days 13-24 were compared to days 1-12 after first dose using Kaplan-Meier survival analysis and generalized linear models. Findings Data of 503,875 individuals (mean age 59·7 years SD=14·7, 47·8% males) were analysed, of whom 351,897 had 13-24 days of follow-up. The cumulative incidence of SARS-CoV-2 infection was 0·57% (n=2484) during days 1-12 and 0·27% (n=614) in days 13-24. A 51·4% relative risk reduction (RRR) was calculated in weighted-average daily incidence of SARS-CoV-2 infection from 43·41-per-100,000(SE=12·07) in days 1-12 to 21·08-per-100,000(SE=6·16) in days 13-24 following immunization. The decrement in incidence was evident from day 18 after first dose. Similar RRRs were calculated in individuals aged 60 or above (44.5%), younger individuals (50.2%), females (50.0%) and males (52.1%). Findings were similar in sub-populations and patients with various comorbidities. Conclusions We demonstrated an effectiveness of 51% of BNT162b2 vaccine against SARS-CoV-2 infection 13-24 days after immunization with the first dose. Immunization with the second dose should be continued to attain the anticipated protection.
Authors Xuping Xie, Yang Liu, Jianying Liu, Xianwen Zhang, Jing Zou, Camila R. Fontes-Garfias, Hongjie Xia, Kena A. Swanson, Mark Cutler, David Cooper, Vineet D. Menachery, Scott Weaver, Philip R. Dormitzer, Pei-Yong Shi
Abstract We engineered three SARS-CoV-2 viruses containing key spike mutations from the newly emerged United Kingdom (UK) and South African (SA) variants: N501Y from UK and SA; 69/70-deletion+N501Y+D614G from UK; and E484K+N501Y+D614G from SA. Neutralization geometric mean titers (GMTs) of twenty BTN162b2 vaccine-elicited human sera against the three mutant viruses were 0.81- to 1.46-fold of the GMTs against parental virus, indicating small effects of these mutations on neutralization by sera elicited by two BNT162b2 doses.
Authors Danilo Buonsenso, Daniel Munblit, Cristina De Rose, Dario Sinatti, Antonia Ricchiuto, Angelo Carfi, Piero Valentini
Abstract There is increasing evidence that adult patients diagnosed with acute COVID-19 suffer from Long COVID initially described in Italy. To date, data on Long COVID in children are lacking. We assessed persistent symptoms in pediatric patients previously diagnosed with COVID-19. More than a half reported at least one persisting symptom even after 120 days since COVID-19, with 42.6% being impaired by these symptoms during daily activities. Symptoms like fatigue, muscle and joint pain, headache, insomnia, respiratory problems and palpitations were particularly frequent, as also described in adults. The evidence that COVID-19 can have long-term impact children as well, including those with asymptomatic/paucisymptomatic COVID-19, highlight the need for pediatricians, mental health experts and policy makers of implementing measures to reduce impact of the pandemic on child’s health.
Authors Pengfei Wang, Lihong Liu, Sho Iketani, Yang Luo, Yicheng Guo, Maple Wang, Jian Yu, Baoshan Zhang, Peter D. Kwong, Barney S. Graham, John R. Mascola, Jennifer Y. Chang, Michael T. Yin, Magdalena Sobieszczyk, Christos A. Kyratsous, Lawrence Shapiro, Zizhang Sheng, Manoj S. Nair, Yaoxing Huang, David D. Ho
Abstract The Covid-19 pandemic has ravaged the globe, and its causative agent, SARS-CoV-2, continues to rage. Prospects of ending this pandemic rest on the development of effective interventions. Single and combination monoclonal antibody (mAb) therapeutics have received emergency use authorization1,2, with more in the pipeline3–6. Furthermore, multiple vaccine constructs have shown promise7, including two with ~95% protective efficacy against Covid-198,9. However, these interventions were directed toward the initial SARS-CoV-2 that emerged in 2019. Considerable viral evolution has occurred since, including variants with a D614G mutation10 that have become dominant. Viruses with this mutation alone do not appear to be antigenically distinct, however11. Recent emergence of new SARS-CoV-2 variants B.1.1.7 in the UK12 and B.1.351 in South Africa13 is of concern because of their purported ease of transmission and extensive mutations in the spike protein. We now report that B.1.1.7 is refractory to neutralization by most mAbs to the N-terminal domain (NTD) of spike and relatively resistant to a number of mAbs to the receptor-binding domain (RBD). It is modestly more resistant to convalescent plasma (~3 fold) and vaccinee sera (~2 fold). Findings on B.1.351 are more worrisome in that this variant is not only refractory to neutralization by most NTD mAbs but also by multiple individual mAbs to the receptor-binding motif on RBD, largely due to an E484K mutation, although some mAb combinations retain activity. Moreover, B.1.351 is markedly more resistant to neutralization by convalescent plasma (~11-33 fold) and vaccinee sera (~6.5-8.6 fold). B.1.351 and emergent variants14,15 with similar spike mutations present new challenges for mAb therapy and threaten the protective efficacy of current vaccines.
Authors Constantinos Kurt Wibmer, Frances Ayres, Tandile Hermanus, Mashudu Madzivhandila, Prudence Kgagudi, Bronwen E. Lambson, Marion Vermeulen, Karin van den Berg, Theresa Rossouw, Michael Boswell, Veronica Ueckermann, Susan Meiring, Anne von Gottberg, Cheryl Cohen, Lynn Morris, Jinal N. Bhiman, Penny L. Moore
Abstract SARS-CoV-2 501Y.V2, a novel lineage of the coronavirus causing COVID-19, contains multiple mutations within two immunodominant domains of the spike protein. Here we show that this lineage exhibits complete escape from three classes of therapeutically relevant monoclonal antibodies. Furthermore 501Y.V2 shows substantial or complete escape from neutralizing antibodies in COVID-19 convalescent plasma. These data highlight the prospect of reinfection with antigenically distinct variants and may foreshadow reduced efficacy of current spike-based vaccines.
Authors Adrian A Pater, Michael S Bosmeny, Christopher L Barkau, Katy N Ovington, Ramdevi Chilamkurthy, Mansi Parasrampuria, Seth B Eddington, Abadat O Yinusa, Adam A White, Paige E Metz, Rourke J Sylvain, Madison M Hebert, Scott W Benzinger, Koushik T Sinha, Keith T Gagnon
Abstract Genomic surveillance can lead to early identification of novel viral variants and inform pandemic response. Using this approach, we identified a new variant of the SARS-CoV-2 virus that emerged in the United States (U.S.). The earliest sequenced genomes of this variant, referred to as 20C-US, can be traced to Texas in late May of 2020. This variant circulated in the U.S. uncharacterized for months and rose to recent prevalence during the third pandemic wave. It initially acquired five novel, relatively unique non-synonymous mutations. 20C-US is continuing to acquire multiple new mutations, including three independently occurring spike protein mutations. Monitoring the ongoing evolution of 20C-US, as well as other novel emerging variants, will be essential for understanding SARS-CoV-2 host adaptation and predicting pandemic outcomes.
Authors Laith J. Abu-Raddad, Hiam Chemaitelly, Peter Coyle, Joel A. Malek, Ayeda A. Ahmed, Yasmin A. Mohamoud, Shameem Younuskunju, Houssein H. Ayoub, Zaina Al Kanaani, Einas Al Kuwari, Adeel A. Butt, Andrew Jeremijenko, Anvar Hassan Kaleeckal, Ali Nizar Latif, Riyazuddin Mohammad Shaik, Hanan F. Abdul Rahim, Gheyath K. Nasrallah, Hadi M. Yassine, Mohamed G. Al Kuwari, Hamad Eid Al Romaihi, Mohamed H. Al-Thani, Abdullatif Al Khal, Roberto Bertollini
ABSTRACT Background Reinfection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been documented, raising public health concerns. Risk and incidence rate of SARS-CoV-2 reinfection were assessed in a large cohort of antibody-positive persons in Qatar. Methods All SARS-CoV-2 antibody-positive persons with a PCR-positive swab ≥14 days after the first-positive antibody test were individually investigated for evidence of reinfection. Viral genome sequencing was conducted for paired viral specimens to confirm reinfection. Results Among 43,044 anti-SARS-CoV-2 positive persons who were followed for a median of 16.3 weeks (range: 0-34.6), 314 individuals (0.7%) had at least one PCR positive swab ≥14 days after the first-positive antibody test. Of these individuals, 129 (41.1%) had supporting epidemiological evidence for reinfection. Reinfection was next investigated using viral genome sequencing. Applying the viral-genome-sequencing confirmation rate, the risk of reinfection was estimated at 0.10% (95% CI: 0.08-0.11%). The incidence rate of reinfection was estimated at 0.66 per 10,000 person-weeks (95% CI: 0.56-0.78). Incidence rate of reinfection versus month of follow-up did not show any evidence of waning of immunity for over seven months of follow-up. Efficacy of natural infection against reinfection was estimated at >90%. Reinfections were less severe than primary infections. Only one reinfection was severe, two were moderate, and none were critical or fatal. Most reinfections (66.7%) were diagnosed incidentally through random or routine testing, or through contact tracing. Conclusions Reinfection is rare. Natural infection appears to elicit strong protection against reinfection with an efficacy >90% for at least seven months.
Authors Daniel Ayoubkhani, Kamlesh Khunti, Vahé Nafilyan, Thomas Maddox, Ben Humberstone, Sir Ian Diamond, Amitava Banerjee
Abstract Objectives The epidemiology of post-COVID syndrome (PCS) is currently undefined. We quantified rates of organ-specific impairment following recovery from COVID-19 hospitalisation compared with those in a matched control group, and how the rate ratio (RR) varies by age, sex, and ethnicity. Design Observational, retrospective, matched cohort study. Setting NHS hospitals in England. Participants 47,780 individuals (mean age 65 years, 55% male) in hospital with COVID-19 and discharged alive by 31 August 2020, matched to controls on demographic and clinical characteristics. Outcome measures Rates of hospital readmission, all-cause mortality, and diagnoses of respiratory, cardiovascular, metabolic, kidney and liver diseases until 30 September 2020. Results Mean follow-up time was 140 days for COVID-19 cases and 153 days for controls. 766 (95% confidence interval: 753 to 779) readmissions and 320 (312 to 328) deaths per 1,000 person-years were observed in COVID-19 cases, 3.5 (3.4 to 3.6) and 7.7 (7.2 to 8.3) times greater, respectively, than in controls. Rates of respiratory, diabetes and cardiovascular events were also significantly elevated in COVID-19 cases, at 770 (758 to 783), 127 (122 to 132) and 126 (121 to 131) events per 1,000 person-years, respectively. RRs were greater for individuals aged <70 than ≥ 70 years, and in ethnic minority groups than the White population, with the biggest differences observed for respiratory disease: 10.5 [9.7 to 11.4] for <70 years versus 4.6 [4.3 to 4.8] for ≥ 70 years, and 11.4 (9.8 to 13.3) for Non-White versus 5.2 (5.0 to 5.5) for White. Conclusions Individuals discharged from hospital following COVID-19 face elevated rates of multi-organ dysfunction compared with background levels, and the increase in risk is neither confined to the elderly nor uniform across ethnicities. The diagnosis, treatment and prevention of PCS require integrated rather than organ- or disease-specific approaches. Urgent research is required to establish risk factors for PCS.
Authors Mary Hongying Cheng, James M Krieger, Burak Kaynak, Moshe Arditi, Ivet Bahar
Abstract Motivation The SARS-CoV-2 variants emerging from South Africa (501.V2) and the UK (B.1.1.7) necessitate rapid assessment of the effects of the corresponding amino acid substitutions in the spike (S) receptor-binding domain (RBD) of the variants on the interactions with the human ACE2 receptor and monoclonal antibodies (mAbs) reported earlier to neutralize the spike. Results Molecular modeling and simulations reveal that N501Y, shared by both variants, increases ACE2 binding affinity, and may impact the collective dynamics of the ACE2-RBD complex, occupying a central hinge site that modulates the overall dynamics of the complex. In contrast, the substitutions K417N and E484K in the South African variant 501.V2 would reduce the ACE2-binding affinity by abolishing two interfacial salt bridges that facilitate RBD binding to ACE2, K417(S)-D30(ACE2) and E484 (S)-K31(ACE2). These two mutations may thus be more than compensating the attractive effect induced by N501Y, overall resulting in an ACE2-binding affinity comparable to that of the wildtype RBD. Further analysis of the impact of these mutations on the interactions with mAbs targeting the spike indicate that the substitutions K417N and E484K may also abolish the salt bridges between the spike and selected mAbs, such as REGN10933, BD23, H11_H4, and C105, thus reducing the binding affinity and effectiveness of these mAbs.
Authors Anthony C. Gordon, Paul R. Mouncey, Farah Al-Beidh, Kathryn M. Rowan, Alistair D. Nichol, Yaseen M. Arabi, Djillali Annane, Abi Beane, Wilma van Bentum-Puijk, Lindsay R. Berry, Zahra Bhimani, Marc J.M. Bonten, Charlotte A. Bradbury, Frank M. Brunkhorst, Adrian Buzgau, Allen C. Cheng, Michelle A. Detry, Eamon J. Duffy, Lise J. Estcourt, Mark Fitzgerald, Herman Goossens, Rashan Haniffa, Alisa M. Higgins, Thomas E. Hills, Christopher M. Horvat, Francois Lamontagne, Patrick R. Lawler, Helen L. Leavis, Kelsey M. Linstrum, Edward Litton, Elizabeth Lorenzi, John C. Marshall, Florian B. Mayr, Danny McAuley, Anna McGlothlin, Shay P McGuinness, Bryan J. McVerry, Stephanie K. Montgomery, Susan C. Morpeth, Srinivas Murthy, Katrina Orr, Rachael L. Parke, Jane C. Parker, Asad E. Patanwala, Ville Pettilä, Emma Rademaker, Marlene S. Santos, Christina T. Saunders, Christopher W. Seymour, Manu Shankar-Hari, Wendy I. Sligl, Alexis F. Turgeon, Anne M. Turner, Frank L. van de Veerdonk, Ryan Zarychanski, Cameron Green, Roger J. Lewis, Derek C. Angus, Colin J. McArthur, Scott Berry, Steve A. Webb, Lennie P.G. Derde
Abstract Background The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. Methods We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours of commencing organ support in an intensive care unit, were randomized to receive either tocilizumab (8mg/kg) or sarilumab (400mg) or standard care (control). The primary outcome was an ordinal scale combining in-hospital mortality (assigned −1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with pre-defined triggers to declare superiority, efficacy, equivalence or futility. Results Tocilizumab and sarilumab both met the pre-defined triggers for efficacy. At the time of full analysis 353 patients had been assigned to tocilizumab, 48 to sarilumab and 402 to control. Median organ support-free days were 10 (interquartile range [IQR] −1, 16), 11 (IQR 0, 16) and 0 (IQR −1, 15) for tocilizumab, sarilumab and control, respectively. Relative to control, median adjusted odds ratios were 1.64 (95% credible intervals [CrI] 1.25, 2.14) for tocilizumab and 1.76 (95%CrI 1.17, 2.91) for sarilumab, yielding >99.9% and 99.5% posterior probabilities of superiority compared with control. Hospital mortality was 28.0% (98/350) for tocilizumab, 22.2% (10/45) for sarilumab and 35.8% (142/397) for control. All secondary outcomes and analyses supported efficacy of these IL-6 receptor antagonists. Conclusions In critically ill patients with Covid-19 receiving organ support in intensive care, treatment with the IL-6 receptor antagonists, tocilizumab and sarilumab, improved outcome, including survival. (ClinicalTrials.gov number: NCT02735707)
Authors Xuping Xie, Jing Zou, Camila R. Fontes-Garfias, Hongjie Xia, Kena A. Swanson, Mark Cutler, David Cooper, Vineet D. Menachery, Scott Weaver, Philip R. Dormitzer, Pei-Yong Shi
Abstract Rapidly spreading variants of SARS-CoV-2 that have arisen in the United Kingdom and South Africa share the spike N501Y substitution, which is of particular concern because it is located in the viral receptor binding site for cell entry and increases binding to the receptor (angiotensin converting enzyme 2). We generated isogenic N501 and Y501 SARS-CoV-2. Sera of 20 participants in a previously reported trial of the mRNA-based COVID-19 vaccine BNT162b2 had equivalent neutralizing titers to the N501 and Y501 viruses.
PREPRINTS
Authors Carolina Kymie Vasques Nonaka , Marília Miranda Franco , Tiago Gräf , Ana Verena Almeida Mendes , Renato Santana de Aguiar, Marta Giovanetti, Bruno Solano de Freitas Souza
Abstract To date, uncertainty remains about how long the protective immune responses against SARS-CoV-2 persists and the first reports of suspected reinfection began to be described in recovered patients months after the first episode. Viral evolution may favor reinfections, and the recently described spike mutations, particularly in the receptor binding domain (RBD) in SARS-CoV-2 lineages circulating in the UK, South Africa, and most recently in Brazil, have raised concern on their potential impact in infectivity and immune escape. We report the first case of reinfection from genetically distinct SARS-CoV-2 lineage presenting the E484K spike mutation in Brazil, a variant associated with escape from neutralizing antibodies.
Authors Allison J. Greaney, Andrea N. Loes, Katharine H.D. Crawford, Tyler N. Starr, Keara D. Malone, Helen Y. Chu, Jesse D. Bloom
Abstract The evolution of SARS-CoV-2 could impair recognition of the virus by human antibody-mediated immunity. To facilitate prospective surveillance for such evolution, we map how convalescent serum antibodies are impacted by all mutations to the spike’s receptor-binding domain (RBD), the main target of serum neutralizing activity. Binding by polyclonal serum antibodies is affected by mutations in three main epitopes in the RBD, but there is substantial variation in the impact of mutations both among individuals and within the same individual over time. Despite this inter- and intra-person heterogeneity, the mutations that most reduce antibody binding usually occur at just a few sites in the RBD’s receptor binding motif. The most important site is E484, where neutralization by some sera is reduced >10-fold by several mutations, including one in emerging viral lineages in South Africa and Brazil. Going forward, these serum escape maps can inform surveillance of SARS-CoV-2 evolution.
Authors SA Kemp, DA Collier, R Datir, IATM Ferreira, S Gayed, A Jahun, M Hosmillo, C Rees-Spear, P Mlcochova, Ines Ushiro Lumb, David J Roberts, Anita Chandra, N Temperton, The CITIID-NIHR BioResource COVID-19 Collaboration, The COVID-19 Genomics UK (COG-UK) Consortium, K Sharrocks, E Blane, JAG Briggs, MJ van Gils, KGC Smith, JR Bradley, C Smith, R Doffinger, L Ceron-Gutierrez, G Barcenas-Morales, DD Pollock, RA Goldstein, A Smielewska, JP Skittrall, T Gouliouris, IG Goodfellow, E Gkrania-Klotsas, CJR Illingworth, LE McCoy, RK Gupta
Abstract SARS-CoV-2 Spike protein is critical for virus infection via engagement of ACE2, and amino acid variation in Spike is increasingly appreciated. Given both vaccines and therapeutics are designed around Wuhan-1 Spike, this raises the theoretical possibility of virus escape, particularly in immunocompromised individuals where prolonged viral replication occurs. Here we report chronic SARS-CoV-2 with reduced sensitivity to neutralising antibodies in an immune suppressed individual treated with convalescent plasma, generating whole genome ultradeep sequences by both short and long read technologies over 23 time points spanning 101 days. Although little change was observed in the overall viral population structure following two courses of remdesivir over the first 57 days, N501Y in Spike was transiently detected at day 55 and V157L in RdRp emerged. However, following convalescent plasma we observed large, dynamic virus population shifts, with the emergence of a dominant viral strain bearing D796H in S2 and ΔH69/ΔV70 in the S1 N-terminal domain NTD of the Spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype diminished in frequency, before returning during a final, unsuccessful course of convalescent plasma. In vitro, the Spike escape double mutant bearing ΔH69/ΔV70 and D796H conferred decreased sensitivity to convalescent plasma, whilst maintaining infectivity similar to wild type. D796H appeared to be the main contributor to decreased susceptibility, but incurred an infectivity defect. The ΔH69/ΔV70 single mutant had two-fold higher infectivity compared to wild type and appeared to compensate for the reduced infectivity of D796H. Consistent with the observed mutations being outside the RBD, monoclonal antibodies targeting the RBD were not impacted by either or both mutations, but a non RBD binding monoclonal antibody was less potent against ΔH69/ΔV70 and the double mutant. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy associated with emergence of viral variants with reduced susceptibility to neutralising antibodies.
Authors Emanuele Andreano, Giulia Piccini, Danilo Licastro, Lorenzo Casalino, Nicole V. Johnson, Ida Paciello, Simeone Dal Monego, Elisa Pantano, Noemi Manganaro, Alessandro Manenti, Rachele Manna, Elisa Casa, Inesa Hyseni, Linda Benincasa, Emanuele Montomoli, Rommie E. Amaro, Jason S. McLellan, Rino Rappuoli
ABSTRACT To investigate the evolution of SARS-CoV-2 in the immune population, we co-incubated authentic virus with a highly neutralizing plasma from a COVID-19 convalescent patient. The plasma fully neutralized the virus for 7 passages, but after 45 days, the deletion of F140 in the spike N-terminal domain (NTD) N3 loop led to partial breakthrough. At day 73, an E484K substitution in the receptor-binding domain (RBD) occurred, followed at day 80 by an insertion in the NTD N5 loop containing a new glycan sequon, which generated a variant completely resistant to plasma neutralization. Computational modeling predicts that the deletion and insertion in loops N3 and N5 prevent binding of neutralizing antibodies. The recent emergence in the United Kingdom and South Africa of natural variants with similar changes suggests that SARS-CoV-2 has the potential to escape an effective immune response and that vaccines and antibodies able to control emerging variants should be developed. One Sentence Summary Three mutations allowed SARS-CoV-2 to evade the polyclonal antibody response of a highly neutralizing COVID-19 convalescent plasma.
Authors Liguo Zhang, Alexsia Richards, Andrew Khalil, Emile Wogram, Haiting Ma, Richard A. Young, Rudolf Jaenisch
Prolonged SARS-CoV-2 RNA shedding and recurrence of PCR-positive tests have been widely reported in patients after recovery, yet these patients most commonly are non-infectious1–14. Here we investigated the possibility that SARS-CoV-2 RNAs can be reverse-transcribed and integrated into the human genome and that transcription of the integrated sequences might account for PCR-positive tests. In support of this hypothesis, we found chimeric transcripts consisting of viral fused to cellular sequences in published data sets of SARS-CoV-2 infected cultured cells and primary cells of patients, consistent with the transcription of viral sequences integrated into the genome. To experimentally corroborate the possibility of viral retro-integration, we describe evidence that SARS-CoV-2 RNAs can be reverse transcribed in human cells by reverse transcriptase (RT) from LINE-1 elements or by HIV-1 RT, and that these DNA sequences can be integrated into the cell genome and subsequently be transcribed. Human endogenous LINE-1 expression was induced upon SARS-CoV-2 infection or by cytokine exposure in cultured cells, suggesting a molecular mechanism for SARS-CoV-2 retro-integration in patients. This novel feature of SARS-CoV-2 infection may explain why patients can continue to produce viral RNA after recovery and suggests a new aspect of RNA virus replication.
Authors Kevin R. McCarthy, Linda J. Rennick, Sham Nambulli, Lindsey R. Robinson-McCarthy, William G. Bain, Ghady Haidar, Paul Duprex
Zoonotic pandemics follow the spillover of animal viruses into highly susceptible human populations. Often, pandemics wane, becoming endemic pathogens. Sustained circulation requires evasion of protective immunity elicited by previous infections. The emergence of SARS-CoV-2 has initiated a global pandemic. Since coronaviruses have a lower substitution rate than other RNA viruses this gave hope that spike glycoprotein is an antigenically stable vaccine target. However, we describe an evolutionary pattern of recurrent deletions at four antigenic sites in the spike glycoprotein. Deletions abolish binding of a reported neutralizing antibody. Circulating SARS-CoV-2 variants are continually exploring genetic and antigenic space via deletion in individual patients and at global scales. In viruses where substitutions are relatively infrequent, deletions represent a mechanism to drive rapid evolution, potentially promoting antigenic drift.
Authors Emma C. Thomson, Laura E. Rosen, James G. Shepherd, Roberto Spreafico, Ana da Silva Filipe, Jason A. Wojcechowskyj, Chris Davis, Luca Piccoli, David J. Pascall, Josh Dillen, Spyros Lytras, Nadine Czudnochowski, Rajiv Shah, Marcel Meury, Natasha Jesudason, Anna De Marco, Kathy Li, Jessica Bassi, Aine O’Toole, Dora Pinto, Rachel M. Colquhoun, Katja Culap, Ben Jackson, Fabrizia Zatta, Andrew Rambaut, Stefano Jaconi, Vattipally B. Sreenu, Jay Nix, Ruth F. Jarrett, Martina Beltramello, Kyriaki Nomikou, Matteo Pizzuto, Lily Tong, Elisabetta Cameroni, Natasha Johnson, Arthur Wickenhagen, Alessandro Ceschi, Daniel Mair, Paolo Ferrari, Katherine Smollett, Federica Sallusto, Stephen Carmichael, Christian Garzoni, Jenna Nichols, Massimo Galli, Joseph Hughes, Agostino Riva, Antonia Ho, Malcolm G. Semple, Peter J.M. Openshaw, J. Kenneth Baillie
Abstract SARS-CoV-2 can mutate to evade immunity, with consequences for the efficacy of emerging vaccines and antibody therapeutics. Herein we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is the most divergent region of S, and provide epidemiological, clinical, and molecular characterization of a prevalent RBM variant, N439K. We demonstrate that N439K S protein has enhanced binding affinity to the hACE2 receptor, and that N439K virus has similar clinical outcomes and in vitro replication fitness as compared to wild- type. We observed that the N439K mutation resulted in immune escape from a panel of neutralizing monoclonal antibodies, including one in clinical trials, as well as from polyclonal sera from a sizeable fraction of persons recovered from infection. Immune evasion mutations that maintain virulence and fitness such as N439K can emerge within SARS-CoV-2 S, highlighting the need for ongoing molecular surveillance to guide development and usage of vaccines and therapeutics.
Authors Trevor Bedford, Jennifer K. Logue, Peter D. Han, Caitlin R. Wolf, Chris D. Frazar, Benjamin Pelle, Erica Ryke, Jover Lee, Mark J. Rieder, Deborah A. Nickerson, Christina M. Lockwood, Lea M. Starita, Helen Y. Chu, Jay Shendure
Abstract In October 2020, an outbreak of at least 50 COVID-19 cases was reported surrounding individuals employed at or visiting the White House. Here, we applied genomic epidemiology to investigate the origins of this outbreak. We enrolled two individuals with exposures linked to the White House COVID-19 outbreak into an IRB-approved research study and sequenced their SARS-CoV-2 infections. We find these viral sequences are highly genetically similar to each other, but are distinct from over 160,000 publicly available SARS-CoV-2 genomes, possessing 5 nucleotide mutations that differentiate this lineage from all other circulating lineages sequenced to date. We estimate this lineage has a common ancestor in the USA in April or May 2020, but its whereabouts for the past 5 to 6 months are not clear. Looking forwards, sequencing of additional community SARS-CoV-2 infections collected in the USA prior to October 2020 may reveal linked infections and shed light on its geographic ancestry. In sequencing of SARS-CoV-2 infections collected after October 2020, the relative rarity of this constellation of mutations may make it possible to identify infections that likely descend from the White House COVID-19 outbreak.
Authors Shane Miersch, Zhijie Li, Reza Saberianfar, Mart Ustav, Levi Blazer, Chao Chen, Wei Ye, Alia Pavlenco, Suryasree Subramania, Serena Singh, Lynda Ploder, Safder Ganaie, Daisy Leung, Rita E. Chen, James Brett Case, Giuseppe Novelli, Giulia Matusali, Francesca Colavita, Maria R. Copabianchi, Suresh Jain, J.B. Gupta, Gaya Amarasinghe, Michael Diamond, James Rini, Sachdev S. Sidhu
ABSTRACT Recombinant neutralizing antibodies (nAbs) derived from recovered patients have proven to be effective therapeutics for COVID-19. Here, we describe the use of advanced protein engineering and modular design principles to develop tetravalent synthetic nAbs that mimic the multi-valency exhibited by IgA molecules, which are especially effective natural inhibitors of viral disease. At the same time, these nAbs display high affinity and modularity typical of IgG molecules, which are the preferred format for drugs. We show that highly specific tetravalent nAbs can be produced at large scale and possess stability and specificity comparable to approved antibody drugs. Moreover, structural studies reveal that the best nAb targets the host receptor binding site of the virus spike protein, and thus, its tetravalent version can block virus infection with a potency that exceeds that of the bivalent IgG by an order of magnitude. Design principles defined here can be readily applied to any antibody drug, including IgGs that are showing efficacy in clinical trials. Thus, our results present a general framework to develop potent antiviral therapies against COVID-19, and the strategy can be readily deployed in response to future pathogenic threats.
Authors Emma B. Hodcroft, Moira Zuber, Sarah Nadeau, Inaki Comas, Fernando Gonzalez Candelas, Tanja Stadler, Richard A. Neher
Abstract A variant of SARS-CoV-2 emerged in early summer 2020, presumably in Spain, and has since spread to multiple European countries. The variant was first observed in Spain in June and has been at frequencies above 40% since July. Outside of Spain, the frequency of this variant has increased from very low values prior to 15th July to 40-70% in Switzerland, Ireland, and the United Kingdom in September. It is also prevalent in Norway, Latvia, the Netherlands, and France. Little can be said about other European countries because few recent sequences are available. Sequences in this cluster (20A.EU1) differ from ancestral sequences at 6 or more positions, including the mutation A222V in the spike protein and A220V in the nucleoprotein. We show that this variant was exported from Spain to other European countries multiple times and that much of the diversity of this cluster in Spain is observed across Europe. It is currently unclear whether this variant is spreading because of a transmission advantage of the virus or whether high incidence in Spain followed by dissemination through tourists is sufficient to explain the rapid rise in multiple countries.
Authors Stefania Capone, Angelo Raggioli, Michela Gentile, Simone Battella, Armin Lahm, Andrea Sommella, Alessandra Maria Contino, Richard A. Urbanowicz, Romina Scala, Federica Barra, Adriano Leuzzi, Eleonora Lilli, Giuseppina Miselli, Alessia Noto, Maria Ferraiuolo, Francesco Talotta, Theocharis Tsoleridis, Concetta Castilletti, Giulia Matusali, Francesca Colavita, Daniele Lapa, Silvia Meschi, Maria Capobianchi, Marco Soriani, Antonella Folgori, Jonathan K. Ball, Stefano Colloca, Alessandra Vitelli
ABSTRACT The COVID-19 pandemic caused by the emergent SARS-CoV-2 coronavirus threatens global public health and there is an urgent need to develop safe and effective vaccines. Here we report the generation and the preclinical evaluation of a novel replication-defective gorilla adenovirus-vectored vaccine encoding the pre-fusion stabilized Spike (S) protein of SARS-CoV2. We show that our vaccine candidate, GRAd- COV2, is highly immunogenic both in mice and macaques, eliciting both functional antibodies which neutralize SARS-CoV-2 infection and block Spike protein binding to the ACE2 receptor, and a robust, Th1- dominated cellular response in the periphery and in the lung. We show here that the pre-fusion stabilized Spike antigen is superior to the wild type in inducing ACE2-interfering, SARS-CoV2 neutralizing antibodies. To face the unprecedented need for vaccine manufacturing at massive scale, different GRAd genome deletions were compared to select the vector backbone showing the highest productivity in stirred tank bioreactors. This preliminary dataset identified GRAd-COV2 as a potential COVID-19 vaccine candidate, supporting the translation of GRAd-COV2 vaccine in a currently ongoing Phase I clinical trial (NCT04528641).
Authors Adam Hampshire, William Trender, Samuel R Chamberlain, Amy Jolly, Jon E. Grant, Fiona Patrick, Ndaba Mazibuko, Steve Williams, Joseph M Barnby, Peter Hellyer, Mitul A Mehta
Abstract Case studies have revealed neurological problems in severely affected COVID-19 patients. However, there is little information regarding the nature and broader prevalence of cognitive problems post-infection or across the full spread of severity. We analysed cognitive test data from 84,285 Great British Intelligence Test participants who completed a questionnaire regarding suspected and biologically confirmed COVID-19 infection. People who had recovered, including those no longer reporting symptoms, exhibited significant cognitive deficits when controlling for age, gender, education level, income, racial-ethnic group and pre-existing medical disorders. They were of substantial effect size for people who had been hospitalised, but also for mild but biologically confirmed cases who reported no breathing difficulty. Finer grained analyses of performance support the hypothesis that COVID-19 has a multi-system impact on human cognition. Significance statement There is evidence that COVID-19 may cause long term health changes past acute symptoms, termed ‘long COVID’. Our analyses of detailed cognitive assessment and questionnaire data from tens thousands of datasets, collected in collaboration with BBC2 Horizon, align with the view that there are chronic cognitive consequences of having COVID-19. Individuals who recovered from suspected or confirmed COVID-19 perform worse on cognitive tests in multiple domains than would be expected given their detailed age and demographic profiles. This deficit scales with symptom severity and is evident amongst those without hospital treatment. These results should act as a clarion call for more detailed research investigating the basis of cognitive deficits in people who have survived SARS-COV-2 infection.
Authors Eszter Somogyi, Zsolt Csiszovszki, Levente Molnár, Orsolya Lőrincz, József Tóth, Sofie Pattijn, Jana Schockaert, Aurélie Mazy, István Miklós, Katalin Pántya, Péter Páles, Enikő R. Tőke
Abstract We developed a global peptide vaccine against SARS-CoV-2 that addresses the dual challenges of heterogeneity in the immune responses of different individuals and potential heterogeneity of the infecting virus. PolyPEPI-SCoV-2 is a polypeptide vaccine containing nine 30-mer peptides derived from all four major structural proteins of the SARS-CoV-2. Vaccine peptides were selected based on their frequency as HLA class I and class II personal epitopes (PEPIs) restricted to multiple autologous HLA alleles of individuals in an in silico cohort of 433 subjects of different ethnicities. PolyPEPI-SCoV-2 vaccine administered with Montanide ISA 51VG adjuvant generated robust, Th1-biased CD8+ and CD4+ T cell responses against all four structural proteins of the virus, as well as binding antibodies upon subcutaneous injection into BALB/c and CD34+ transgenic mice. In addition, PolyPEPI-SCoV-2-specific, polyfunctional CD8+ and CD4+ T cells were detected ex vivo in each of the 17 asymptomatic/mild COVID-19 convalescents' blood investigated, 1-5 months after symptom onset. The PolyPEPI-SCoV-2-specific T cell repertoire used for recovery from COVID-19 was extremely diverse: donors had an average of seven different peptide-specific T cells, against the SARS-CoV-2 proteins, 87% of donors had multiple targets against at least three SARS-CoV-2 proteins and 53% against all four. In addition, PEPIs determined based on the complete HLA class I genotype of the convalescent donors were validated, with 84% accuracy, to predict PEPI-specific CD8+ T cell responses measured for the individuals. Extrapolation of the above findings to a US bone marrow donor cohort of 16,000 HLA-genotyped individuals with 16 different ethnicities (n=1,000 each ethnic group) suggest that PolyPEPI-SCoV-2 vaccination in a general population will likely elicit broad, multi-antigenic CD8+ and CD4+ T cell responses in 98% of individuals, independent of ethnicity, including Black, Asian, and Minority Ethnic (BAME) cohorts.
Authors Rita Carsetti, Salvatore Zaffina, Eva Piano Mortari, Sara Terreri, Francesco Corrente, Claudia Capponi, Patrizia Palomba, Mattia Mirabella, Simona Cascioli, Paolo Palange, Ilaria Cuccaro, Cinzia Milito, Alimuddin Zumla, Markus Maeurer, Vincenzo Camisa, Maria Rosaria Vinci, Annapaola Santoro, Eleonora Cimini, Luisa Marchioni, Emanuele Nicastri, Fabrizio Palmieri, Chiara Agrati, Giuseppe Ippolito, Ottavia Porzio, Carlo Concato, Andrea Onetti Muda, Massimiliano Raponi, Concetta Quintarelli, Isabella Quinti, Franco Locatelli
ABSTRACT: SARS-CoV-2 is a novel coronavirus, not encountered before by humans. The wide spectrum of clinical expression of SARS-CoV-2 illness suggests that individual immune responses to SARS- CoV-2 play a crucial role in determining the clinical course after first infection. Immunological studies have focussed on patients with moderate to severe disease, demonstrating excessive inflammation in tissues and organ damage. In order to understand the basis of the protective immune response in COVID-19, we performed a longitudinal follow-up, flow-cytometric and serological analysis of innate and adaptive immunity in 64 adults with a spectrum of clinical presentations: 28 healthy SARS-CoV-2-negative contacts of COVID-19 cases; 20 asymptomatic SARS-CoV-2-infected cases; 8 patients with Mild COVID-19 disease and 8 cases of Severe COVID- 19 disease. Our data show that high frequency of NK cells and early and transient increase of specific IgA, IgM and, to a lower extent, IgG are associated to asymptomatic SARS-CoV-2 infection. By contrast, monocyte expansion and high and persistent levels of IgA and IgG, produced relatively late in the course of the infection, characterize severe disease. Modest increase of monocytes and different kinetics of antibodies are detected in mild COVID-19. The importance of innate NK cells and the short-lived antibody response of asymptomatic individuals and patients with mild disease suggest that only severe COVID-19 may result in protective memory established by the adaptive immune response.
Authors Bálint Kiss, Zoltán Kis, Bernadett Pályi, Miklós S.Z. Kellermayer
SARS-CoV-2, the virus responsible for the current COVID-19 pandemic, displays a corona-shaped layer of spikes which play fundamental role in the infection process. Recent structural data suggest that the spikes possess orientational freedom and the ribonucleoproteins segregate into basketlike structures. How these structural features regulate the dynamic and mechanical behavior of the native virion, however, remain unknown. By imaging and mechanically manipulating individual, native SARS-CoV-2 virions with atomic force microscopy, here we show that their surface displays a dynamic brush owing to the flexibility and rapid motion of the spikes. The virions are highly compliant and able to recover from drastic mechanical perturbations. Their global structure is remarkably temperature resistant, but the virion surface becomes progressively denuded of spikes upon thermal exposure. Thus, both the infectivity and thermal sensitivity of SARS-CoV-2 rely on the dynamics and the mechanics of the virus. One sentence summary The native coronavirus 2 displays a dynamic surface layer of spikes, a large mechanical compliance and unique self-healing capacity.
NATURE
Authors Sean T. H. Liu, Hung-Mo Lin, Ian Baine, Ania Wajnberg, Jeffrey P. Gumprecht, Farah Rahman, Denise Rodriguez, Pranai Tandon, Adel Bassily-Marcus, Jeffrey Bander, Charles Sanky, Amy Dupper, Allen Zheng, Deena R. Altman, Benjamin K. Chen, Florian Krammer, Damodara Rao Mendu, Adolfo Firpo-Betancourt, Matthew A. Levin, Emilia Bagiella, Arturo Casadevall, Carlos Cordon-Cardo, Jeffrey S. Jhang, Suzanne A. Arinsburg, David L. Reich, Judith A. Aberg, Nicole M. Bouvier
Abstract Background Since December 2019, Coronavirus Disease 2019 (COVID-19) has become a global pandemic, causing mass morbidity and mortality. Prior studies in other respiratory infections suggest that convalescent plasma transfusion may offer benefit to some patients. Here, the outcomes of thirty-nine hospitalized patients with severe to life-threatening COVID-19 who received convalescent plasma transfusion were compared against a cohort of retrospectively matched controls. Methods Plasma recipients were selected based on supplemental oxygen needs at the time of enrollment and the time elapsed since the onset of symptoms. Recipients were transfused with convalescent plasma from donors with a SARS-CoV-2 (severe acute respiratory disease coronavirus 2) anti-spike antibody titer of ³1:320 dilution. Matched control patients were retrospectively identified within the electronic health record database. Supplemental oxygen requirements and survival were compared between plasma recipients and controls. Results Convalescent plasma recipients were more likely than control patients to remain the same or have improvements in their supplemental oxygen requirements by post-transfusion day 14, with an odds ratio of 0.86 (95% CI: 0.75∼0.98; p = 0.028). Plasma recipients also demonstrated improved survival, compared to control patients (log-rank test: p = 0.039). In a covariates-adjusted Cox model, convalescent plasma transfusion improved survival for non-intubated patients (hazard ratio 0.19 (95% CI: 0.05 ∼0.72); p = 0.015), but not for intubated patients (1.24 (0.33∼4.67); p = 0.752). Conclusions Convalescent plasma transfusion is a potentially efficacious treatment option for patients hospitalized with COVID-19; however, these data suggest that non-intubated patients may benefit more than those requiring mechanical ventilation. Competing Interest Statement Dr. Krammer reports that patent applications have been filed for the assay used to select plasma donors, and Mount Sinai has licensed its use to several companies. Dr. Aberg reports grants and personal fees from Gilead, grants and personal fees from Merck, grants and personal fees from Janssen, personal fees from Theratech, personal fees from Medicure, grants from Regeneron, grants and personal fees from Viiv, outside the submitted work. All other authors have nothing to disclose.
Authors Matthieu Domenech de Cellès, Jean-Sébastien Casalegno, Bruno Lina, Lulla Opatowski
Abstract As in past pandemics, co-circulating pathogens may play a role in the epidemiology of coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we hypothesized that influenza interacted with SARS-CoV-2 during the early 2020 epidemic of COVID-19 in Europe. We developed a population-based model of SARS-CoV-2 transmission, combined with mortality incidence data in four European countries, to test a range of assumptions about the impact of influenza. We found consistent evidence for a 2-2.5-fold population-level increase in SARS-CoV-2 transmission associated with influenza during the period of co-circulation. These results suggest the need to increase vaccination against influenza, not only to reduce the burden due to influenza viruses, but also to counteract their facilitatory impact on SARS-CoV-2. Competing Interest Statement MDdC received postdoctoral funding (2017-2019) from Pfizer and consulting fees from GSK. JSC declares no competing interests. BL is chair of the ISC for the Global Influenza Surveillance Network, and co-chair of the Global Influenza and RSV initiative; he is also a member of the French COVID-19 Scientific Committee (no personal income for all these activities). LO has received consulting fees from WHO for work on antimicrobial resistance.
Authors Eric Song, Ce Zhang, Benjamin Israelow, Alice Lu-Culligan, Alba Vieites Prado, Sophie Skriabine, Peiwen Lu, Orr-El Weizman, Feimei Liu, Yile Dai, Klara Szigeti-Buck, Yuki Yasumoto, Guilin Wang, Christopher Castaldi, Jaime Heltke, Evelyn Ng, John Wheeler, Mia Madel Alfajaro, Etienne Levavasseur, Benjamin Fontes, Neal G. Ravindra, David Van Dijk, Shrikant Mane, Murat Gunel, Aaron Ring, Syed A. Jaffar Kazmi, Kai Zhang, Craig B Wilen, Tamas L. Horvath, Isabelle Plu, Stephane Haik, Jean-Leon Thomas, Angeliki Louvi, Shelli F. Farhadian, Anita Huttner, Danielle Seilhean, Nicolas Renier, Kaya Bilguvar, Akiko Iwasaki
Abstract Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus whether the virus can infect the brain, or what the consequences of CNS infection are. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in the infected and neighboring neurons. However, no evidence for the type I interferon responses was detected. We demonstrate that neuronal infection can be prevented either by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate in vivo that SARS-CoV-2 neuroinvasion, but not respiratory infection, is associated with mortality. Finally, in brain autopsy from patients who died of COVID-19, we detect SARS-CoV-2 in the cortical neurons, and note pathologic features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV2, and an unexpected consequence of direct infection of neurons by SARS-CoV-2.
Authors Richard Beesley
ABSTRACT Many countries chose to close schools as part of their response to the SARS-CoV2 coronavirus (COVID-19) pandemic. Whilst nations are gradually reopening schools, and many politicians advise that schools remain safe and the risks of increases in the spread of COVID-19 are low, little evidence has been presented to confirm those statements. A review of the numbers of new confirmed COVID-19 cases by country suggests that the reopening of schools is likely to be a driver in the increase of the number of new cases. This is likely exacerbated by accompanying changes and easing of restrictions. However, with the exception of China, notable for its robust test, track, trace, and isolate processes, no other countries that had significant numbers of COVID-19 cases have successfully reopened schools without an increase in cases as a consequence. Whilst reopening of schools following an initial peak and decrease in COVID-19 infections is desirable for a range of reasons, doing so without adequate controls and protections may lead to an exacerbation of spread within the school environment, which could then lead to increased community spread of disease.
Authors Joshua S. Bloom, Eric M. Jones, Molly Gasperini, Nathan B. Lubock, Laila Sathe,Chetan Munugala, A. Sina Booeshaghi, Oliver F. Brandenberg, Longhua Guo, James Boocock, Scott W. Simpkins, Isabella Lin, Nathan LaPierre, Duke Hong, Yi Zhang,Gabriel Oland, Bianca Judy Choe, Sukantha Chandrasekaran, Evann E. Hilt, Manish J.Butte, Robert Damoiseaux, Aaron R. Cooper, Yi Yin, Lior Pachter, Omai B. Garner, Jonathan Flint, Eleazar Eskin, Chongyuan Luo, Sriram Kosuri, Leonid Kruglyak Valerie A. Arboleda
ABSTRACT The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is due to the high rates of transmission by individuals who are asymptomatic at the time of transmission. Frequent, widespread testing of the asymptomatic population for SARS-CoV-2 is essential to suppress viral transmission and is a key element in safely reopening society. Despite increases in testing capacity, multiple challenges remain in deploying traditional reverse transcription and quantitative PCR (RT-qPCR) tests at the scale required for population screening of asymptomatic individuals. We have developed SwabSeq, a high-throughput testing platform for SARS-CoV-2 that uses next-generation sequencing as a readout. SwabSeq employs sample-specific molecular barcodes to enable thousands of samples to be combined and simultaneously analyzed for the presence or absence of SARS-CoV-2 in a single run. Importantly, SwabSeq incorporates an in vitro RNA standard that mimics the viral amplicon, but can be distinguished by sequencing. This standard allows for end-point rather than quantitative PCR, improves quantitation, reduces requirements for automation and sample-to-sample normalization, enables purification-free detection, and gives better ability to call true negatives. We show that SwabSeq can test nasal and oral specimens for SARS-CoV-2 with or without RNA extraction while maintaining analytical sensitivity better than or comparable to that of fluorescence-based RT-qPCR tests. SwabSeq is simple, sensitive, flexible, rapidly scalable, inexpensive enough to test widely and frequently, and can provide a turn around time of 12 to 24 hours.
Authors Jessica A. Plante, Yang Liu, Jianying Liu, Hongjie Xia, Bryan A. Johnson, Kumari G. Lokugamage, Xianwen Zhang, Antonio E. Muruato, Jing Zou, Camila R. Fontes-Garfias, Divya Mirchandani, Dionna Scharton, John P. Bilello, Zhiqiang Ku, Zhiqiang An, Birte Kalveram, Alexander N. Freiberg, Vineet D. Menachery, Xuping Xie, Kenneth S. Plante, Scott C. Weaver, Pei-Yong Shi
ABSTRACT A spike protein mutation D614G became dominant in SARS-CoV-2 during the COVID-19 pandemic. However, the mutational impact on viral spread and vaccine efficacy remains to be defined. Here we engineer the D614G mutation in the SARS-CoV-2 USA-WA1/2020 strain and characterize its effect on viral replication, pathogenesis, and antibody neutralization. The D614G mutation significantly enhances SARS-CoV-2 replication on human lung epithelial cells and primary human airway tissues, through an improved infectivity of virions with the spike receptor38 binding domain in an “up” conformation for binding to ACE2 receptor. Hamsters infected with D614 or G614 variants developed similar levels of weight loss. However, the G614 virus produced higher infectious titers in the nasal washes and trachea, but not lungs, than the D614 virus. The hamster results confirm clinical evidence that the D614G mutation enhances viral loads in the upper respiratory tract of COVID-19 patients and may increases transmission. For antibody neutralization, sera from D614 virus-infected hamsters consistently exhibit higher neutralization titers against G614 virus than those against D614 virus, indicating that (i) the mutation may not reduce the ability of vaccines in clinical trials to protect against COVID-19 and (ii) therapeutic antibodies should be tested against the circulating G614 virus before clinical development. Importance Understanding the evolution of SARS-CoV-2 during the COVID-19 pandemic is essential for disease control and prevention. A spike protein mutation D614G emerged and became dominant soon after the pandemic started. By engineering the D614G mutation into an authentic wild-type SARS-CoV-2 strain, we demonstrate the importance of this mutation to (i) enhanced viral replication on human lung epithelial cells and primary human airway tissues, (ii) improved viral fitness in the upper airway of infected hamsters, and (iii) increased susceptibility to (which was not certified by peer review) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license. bioRxiv preprint doi: https://doi.org/10.1101/2020.09.01.278689. this version posted September 2, 202The copyright holder for this preprint neutralization. Together with clinical findings, our work underscores the importance of this mutation in viral spread, vaccine efficacy, and antibody therapy
Authors Carolyn Bramante, Christopher J. Tignanelli, Nirjhar Dutta, Emma Jones, Leonardo Tamariz, Jeanne M Clark, Michael Usher, Genevieve Metlon-Meaux, Sayeed Ikramuddin
ABSTRACT Background: Covid-19 disease causes significant morbidity and mortality through increase inflammation and thrombosis. Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis are states of chronic inflammation and indicate advanced metabolic disease. We sought to understand the risk of hospitalization for Covid-19 associated with NAFLD/NASH. Methods: Retrospective analysis of electronic medical record data of 6,700 adults with a positive SARS-CoV-2 PCR from March 1, 2020 to Aug 25, 2020. Logistic regression and competing risk were used to assess odds of being hospitalized. Additional adjustment was added to assess risk of hospitalization among patients with a prescription for metformin use within the 3 months prior to the SARS-CoV-2 PCR result, history of home glucagon-like-peptide 1 receptor agonist (GLP-1 RA) use, and history of metabolic and bariatric surgery (MBS). Interactions were assessed by gender and race. Results: A history of NAFLD/NASH was associated with increased odds of admission for Covid-19: logistic regression OR 2.04 (1.55, 2.96, p<0.01), competing risks OR 1.43 (1.09-1.88, p<0.01); and each additional year of having NAFLD/NASH was associated with a significant increased risk of being hospitalized for Covid-19, OR 1.86 (1.43-2.42, p<0.01). After controlling for NAFLD/NASH, persons with obesity had decreased odds of hospitalization for Covid-19, OR 0.41 (0.34-0.49, p<0.01). NAFLD/NASH increased risk of hospitalization in men and women, and in all racial/ethnic subgroups. Mediation treatments for metabolic syndrome were associated with non-significant reduced risk of admission: OR 0.42 (0.18-1.01, p=0.05) for home metformin use and OR 0.40 (0.14-1.17, p=0.10) for home GLP-1RA use. MBS was associated with a significant decreased risk of admission: OR 0.22 (0.05-0.98, p<0.05). Conclusions: NAFLD/NASH is a significant risk factor for hospitalization for Covid-19, and appears to account for risk attributed to obesity. Treatments for metabolic disease mitigated risks from NAFLD/NASH. More research is needed to confirm risk associated with visceral adiposity, and patients should be screened for and informed of treatments for metabolic syndrome.
Authors Hananeh Aliee, Florian Massip, Cancan Qi, Maria Stella de Biase, Johannes L van Nijnatten, Elin T.G. Kersten, Nazanin Z. Kermani, Basil Khuder, Judith M Vonk, Roel C H Vermeulen, U-BIOPRED study group, Cambridge Lung Cancer Early Detection Programme, INER-Ciencias Mexican Lung Program, NHLBI LungMAP Consortium, Margaret Neighbors, Gaik W. Tew, Michele Grimbaldeston, Nick H.T. ten Hacken, Sile Hu, Yike Guo, Xiaoyu Zhang, Kai Sun, Pieter S. Hiemstra, Bruce A. Ponder, Mika J Makela, Kristiina Malmstrom, Robert C. Rintoul, Paul A. Reyfman, Fabian J. Theis, Corry-A Brandsma, Ian Adcock, Wim Timens, Cheng J. Xu, Maarten van den Berge, Roland F. Schwarz, Gerard H. Koppelman, Martijn C. Nawijn, Alen Faiz
ABSTRACT Background The recent outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has led to a worldwide pandemic. A subset of COVID-19 patients progresses to severe disease, with high mortality and limited treatment options. Detailed knowledge of the expression regulation of genes required for viral entry into respiratory epithelial cells is urgently needed. Methods Here we assess the expression patterns of genes required for SARS-CoV-2 entry into cells, and their regulation by genetic, epigenetic and environmental factors, throughout the respiratory tract using samples collected from the upper (nasal) and lower airways (bronchi). Findings Genes encoding viral receptors and activating protease are increased in the nose compared to the bronchi in matched samples and associated with the proportion of secretory epithelial cells in cellular deconvolution analyses. Current or ex-smoking was found to increase expression of these genes only in lower airways, which was associated with a significant increase in the predicted proportion of goblet cells. Both acute and second hand smoke exposure were found to increase ACE2 expression while inhaled corticosteroids decrease ACE2 expression in the lower airways. A strong association of DNA- methylation with ACE2 and TMPRSS2- mRNA expression was identified. Interpretation It is made available under a CC-BY-NC 4.0 International license . (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. medRxiv preprint doi: https://doi.org/10.1101/2020.08.31.20169946.this version posted September 2, 2020. The copyright holder for this preprint Genes associated with SARS-CoV-2 viral entry into cells are high in upper airways, but strongly increased in lower airways by smoke exposure. In contrast, ICS decreases ACE2 expression, indicating that inhaled corticosteroids are unlikely to increase the risk for more severe COVID-19 disease. Funding This work was supported by a Seed Network grant from the Chan Zuckerberg Initiative to M.C.N. and by the European Union’s H2020 Research and Innovation Program under grant agreement no. 874656 (discovAIR) to M.C.N. UBIOPRED was supported by an Innovative Medicines Initiative Joint Undertaking (No.115010), resources from the European Union's Seventh Framework Programme (FP7/20072013) and EFPIA companies' inkind contribution (www.imi.europa.eu). Longfonds Junior Fellowship. We acknowledge the contribution of the whole UBIOPRED team as listed in the Appendix S1.’ SDB, FM and RFS would like to thank the Helmholtz Association, Germany, for support." NIH K08HL146943; Parker B. Francis Fellowship; ATS Foundation/Boehringer Ingelheim Pharmaceuticals Inc. Research Fellowship in IPF. RCR is part funded by Cancer Research UK Cambridge Centre and the Cambridge NIHR Biomedical Research Centre. BAP was funded by programme support from Cancer Research UK. The CRUKPAP Study was supported by the CRUK Cambridge Cancer Centre, by the NIHR Cambridge Biomedical Research Centre and by the Cambridge Bioresource. PIAMA was supported by The Netherlands Organization for Health Research and Development; The Netherlands Organization for Scientific Research; The Netherlands Lung Foundation (with methylation studies supported by AF 4.1.14.001); The Netherlands Ministry of Spatial Planning, Housing, and the Environment; and The Netherlands Ministry of Health, Welfare, and Sport. Dr. Qi is supported by a grant from the China Scholarship Counc
Authors Catherine A. Gao, Joseph I. Bailey, James M. Walter, John M. Coleman, Elizabeth S. Malsin, A. Christine Argento, Michelle H. Prickett, NU COVID Investigators, Richard G. Wunderink, Sean B. Smith
ABSTRACT Background: The coronavirus disease 2019 (COVID-19) pandemic raised concern for exposure to healthcare providers through aerosol generating procedures, such as bronchoalveolar lavage (BAL). Current society guidelines recommended limiting use of BAL to reduce operators' risk for infection, yet data on the infection rate for providers after BAL is sparse. Since March 2020, our institution used a modified protocol to perform over 450 BALs on intubated COVID-19 patients. We therefore sought to describe the subsequent infectious risks to providers associated with BAL. Methods: Fifty-two pulmonary and critical care providers (faculty and fellows) at our tertiary-care, urban medical center were surveyed. Survey participants were asked to provide the number of BALs on COVID-19 patients they performed, the number of weeks they cared for intensive care unit (ICU) patients with COVID-19, and the results of any SARS-CoV-2 testing that they received. Participants were asked to assess the difficulty of BAL on intubated COVID-19 patients as compared to routine ICU BAL using a numeric perceived difficulty score ranging from 1 (easier) to 10 (harder). Results: We received forty-seven responses from fifty-two surveyed (90% response rate), with 2 declining to participate. Many respondents (19/45, 42%) spent >5 weeks on an ICU service with COVID-19 patients. The number of BALs performed by providers ranged from 0 to >60. Sixteen of the 35 providers (46%) who performed BALs underwent at least one nasopharyngeal (NP) swab to test for SARS-CoV-2, but none were positive. Twenty-seven of the 35 providers (77%) who performed BALs underwent SARS-CoV-2 serology testing, and only one (3.7%) was positive. Respondents indicated occasionally not being able to follow aerosol-minimizing steps but overall felt BALs in COVID-19 patients was only slightly more difficult than routine ICU BAL. Discussion: At a high-volume center having performed >450 BALs on intubated COVID-19 patients with aerosol-limiting precautions, our survey of bronchoscopists found no positive NP SARS-CoV-2 tests and only one positive antibody test result. While the optimal role for COVID-19 BAL remains to be determined, these data suggest that BAL can be safely performed in intubated COVID-19 patients if experienced providers take precautions to limit aerosol generation and wear personal protective equipment.
Authors L. Sigfrid, M. Cevik, E. Jesudason, W.S Lim, J. Rello, J. H. Amuasi, F. Bozza, C.Palmieri, D. Munblit, J.C.Holter, A.B. Kildal, C.D. Russell, A.Ho, L.Turtle, T.M. Drake, A. Beltrame, K. Hann, I.R. Bangura, R. Fowler, S. Lakoh, C. Berry, D.J. Lowe, J. McPeake, M. Hashmi, A.M. Dyrhol-Riise, C.Donohue, D.R. Plotkin, H. Hardwick, N. Elkheir, N. Lone, A.B. Docherty, E.M. Harrison, K.J. Baille, G. Carson, M.G. Semple, J.T. Scott
ABSTRACT Introduction Very little is known about possible clinical sequelae that may persist after resolution of the acute Coronavirus Disease 2019 (COVID-19). A recent longitudinal cohort from Italy including 143 patients recovered after hospitalisation with COVID-19 reported that 87% had at least one ongoing symptom at 60 day follow-up. Early indications suggest that patients with COVID-19 may need even more psychological support than typical ICU patients. The assessment of risk factors for longer term consequences requires a longitudinal study linked to data on pre-existing conditions and care received during the acute phase of illness. Methods and analysis This is an international open-access prospective, observational multi-site study. It will enrol patients following a diagnosis of COVID-19. Tier 1 is developed for following up patients day 28 post-discharge, additionally at 3 to 6 months intervals. This module can be used to identify sub-sets of patients experiencing specific symptomatology or syndromes for further follow up. A Tier 2 module will be developed for in-clinic, in-depth follow up. The primary aim is to characterise physical consequences in patients post-COVID-19. Secondary aim includes estimating the frequency of and risk factors for post-COVID- 19 medical sequalae, psychosocial consequences and post-COVID-19 mortality. A subset of patients will have sampling to characterize longer term antibody, innate and cell-mediated immune responses to SARS-CoV-2. Ethics and dissemination This collaborative, open-access study aims to characterize the frequency of and risk factors for long-term consequences and characterise the immune response over time in patients following a diagnosis of COVID-19 and facilitate standardized and longitudinal data collection globally. The outcomes of this study will inform strategies to prevent long term consequences; inform clinical management, direct rehabilitation, and inform public health management to reduce overall morbidity and improve outcomes of COVID-19.
Authors Bas B. Oude Munnink, Reina S. Sikkema, David F. Nieuwenhuijse, Robert Jan Molenaar, Emmanuelle Munger, Richard Molenkamp, Arco van der Spek, Paulin Tolsma, Ariene Rietveld, Miranda Brouwer, Noortje Bouwmeester-Vincken, Frank Harders, Renate Hakze-van der Honing, Marjolein C.A. Wegdam-Blans, Ruth J. Bouwstra, Corine GeurtsvanKessel, Annemiek A. van der Eijk, Francisca C. Velkers, Lidwien A.M. Smit, Arjan Stegeman, Wim H.M. van der Poel, Marion P.G. Koopmans
Abstract The zoonotic origin of the SARS-CoV-2 pandemic is still unknown. Animal experiments have shown that non-human primates, cats, ferrets, hamsters, rabbits and bats can be infected by SARS-CoV-2. In addition, SARS-CoV-2 RNA has been detected in felids, mink and dogs in the field. Here, we describe an in-depth investigation of outbreaks on 16 mink farms and humans living or working on these farms, using whole genome sequencing. We conclude that the virus was initially introduced from humans and has evolved, most likely reflecting widespread circulation among mink in the beginning of the infection period several weeks prior to detection. At the moment, despite enhanced biosecurity, early warning surveillance and immediate culling of infected farms, there is ongoing transmission between mink farms with three big transmission clusters with unknown modes of transmission. We also describe the first animal to human transmissions of SARS-CoV-2 in mink farms.
Authors Edward E. Walsh, Robert Frenck, Ann R. Falsey, Nicholas Kitchin, Judith Absalon, Alejandra Gurtman, Stephen Lockhart, Kathleen Neuzil, Mark J Mulligan, Ruth Bailey, Kena A Swanson, Ping Li, Kenneth Koury, Warren Kalina, David Cooper, Camila Fontes-Garfias, Pei-Yong Shi, Özlem Türeci, Kristin R Thompkins, Kirsten E. Lyke, Vanessa Raabe, Philip R Dormitzer, Kathrin U Jansen, Uğur Sahin, William C. Gruber
ABSTRACT Background: Severe acute respiratory syndrome coronavirus 2 (SARS−CoV−2) infections and the resulting disease, coronavirus disease 2019 (COVID−19), have spread to millions of people globally. Multiple vaccine candidates are under development, but no vaccine is currently available. Methods: Healthy adults 18−55 and 65−85 years of age were randomized in an ongoing, placebo−controlled, observer−blinded dose−escalation study to receive 2 doses at 21−day intervals of placebo or either of 2 lipid nanoparticle−formulated, nucleoside−modified RNA vaccine candidates: BNT162b1, which encodes a secreted trimerized SARS−CoV−2 receptor-binding domain, or BNT162b2, which encodes a prefusion stabilized membrane-anchored SARS−CoV−2 full-length spike. In each of 13 groups of 15 participants, 12 received vaccine and 3 received placebo. Groups were distinguished by vaccine candidate, age of participant, and vaccine dose level. Interim safety and immunogenicity data of BNT162b1 in younger adults have been reported previously from US and German trials. We now present additional safety and immunogenicity data from the US Phase 1 trial that supported selection of the vaccine candidate advanced to a pivotal Phase 2/3 safety and efficacy evaluation. Results: In both younger and older adults, the 2 vaccine candidates elicited similar dose-dependent SARS−CoV−2−neutralizing geometric mean titers (GMTs), comparable to or higher than the GMT of a panel of SARS−CoV−2 convalescent sera. BNT162b2 was associated with less systemic reactogenicity, particularly in older adults. Conclusion: These results support selection of the BNT162b2 vaccine candidate for Phase 2/3 large−scale safety and efficacy evaluation, currently underway.
PNAS
Authors Max S. Y. Lau, Bryan Grenfell, Michael Thomas, View ORCID ProfileMichael Bryan, Kristin Nelson, Ben Lopman
ABSTRACT It is imperative to advance our understanding of heterogeneities in the transmission of SARS-CoV-2 such as age-specific infectiousness and superspreading. To this end, it is important to exploit multiple data streams that are becoming abundantly available during the pandemic. In this paper, we formulate an individual-level spatiotemporal mechanistic framework to integrate individual surveillance data with geolocation data and aggregate mobility data, enabling a more granular understanding of the transmission dynamics of SARS-CoV-2. We analyze reported cases, between March and early May 2020, in five (urban and rural) counties in the state of Georgia. First, our results show that the reproductive number reduced to below one in about 2 wk after the shelter-in-place order. Superspreading appears to be widespread across space and time, and it may have a particularly important role in driving the outbreak in rural areas and an increasing importance toward later stages of outbreaks in both urban and rural settings. Overall, about 2% of cases were directly responsible for 20% of all infections. We estimate that the infected nonelderly cases (<60 y) may be 2.78 [2.10, 4.22] times more infectious than the elderly, and the former tend to be the main driver of superspreading. Our results improve our understanding of the natural history and transmission dynamics of SARS-CoV-2. More importantly, we reveal the roles of age-specific infectiousness and characterize systematic variations and associated risk factors of superspreading. These have important implications for the planning of relaxing social distancing and, more generally, designing optimal control measures.
CORNELL UNIVERSITY
Authors S. Balachandar, S. Zaleski, A. Soldati, G. Ahmadi, L. Bourouiba
ABSTRACT COVID-19 pandemic has strikingly demonstrated how important it is to develop fundamen- tal knowledge related to generation, transport and inhalation of pathogen-laden droplets and their subsequent possible fate as airborne particles, or aerosols, in the context of human to human transmission. It is also increasingly clear that airborne transmission is an important contributor to rapid spreading of the disease. In this paper, we discuss the processes of droplet generation by exhalation, their potential transformation into airborne particles by evaporation, transport over long distances by the exhaled puff and by ambient air turbulence, and final in- halation by the receiving host as interconnected multiphase flow processes. A simple model for the time evolution of droplet/aerosol concentration is presented based on a theoretical analysis of the relevant physical processes. The modeling framework along with detailed experiments and simulations can be used to study a wide variety of scenarios involving breathing, talking, cough- ing and sneezing and in a number of environmental conditions, as humid or dry atmosphere, confined or open environment. Although a number of questions remain open on the physics of evaporation and coupling with persistence of the virus, it is clear that with a more reliable understanding of the underlying flow physics of virus transmission one can set the foundation for an improved methodology in designing case-specific social distancing and infection control guidelines.
Authors Sophie Uyoga, Ifedayo M.O. Adetifa, Henry K. Karanja, James Nyagwange, James Tuju, Perpetual Wanjiku, Rashid Aman, Mercy Mwangangi, Patrick Amoth, Kadondi Kasera, Wangari Ng'ang'a, Charles Rombo, Christine K. Yegon, Khamisi Kithi, Elizabeth Odhiambo, Thomas Rotich, Irene Orgut, Sammy Kihara, Mark Otiende, Christian Bottomley, Zonia N. Mupe, Eunice W. Kagucia, Katherine Gallagher, Anthony Etyang, Shirine Voller, John Gitonga, Daisy Mugo, Charles N. Agoti, Edward Otieno, Leonard Ndwiga, Teresa Lambe, Daniel Wright, Edwine Barasa, Benjamin Tsofa, Philip Bejon, Lynette I. Ochola-Oyier, Ambrose Agweyu, J. Anthony G. Scott, George M Warimwe
ABSTRACT Background There are no data on SARS-CoV-2 seroprevalence in Africa though the COVID-19 epidemic curve and reported mortality differ from patterns seen elsewhere. We estimated the anti-SARS-CoV-2 antibody prevalence among blood donors in Kenya. Methods We measured anti-SARS-CoV-2 spike IgG prevalence by ELISA on residual blood donor samples obtained between April 30 and June 16, 2020. Assay sensitivity and specificity were 83% (95% CI 59, 96%) and 99.0% (95% CI 98.1, 99.5%), respectively. National seroprevalence was estimated using Bayesian multilevel regression and post-stratification to account for non-random sampling with respect to age, sex and region, adjusted for assay performance. Results Complete data were available for 3098 of 3174 donors, aged 15-64 years. By comparison with the Kenyan population, the sample over-represented males (82% versus 49%), adults aged 25-34 years (40% versus 27%) and residents of coastal Counties (49% versus 9%). Crude overall seroprevalence was 5.6% (174/3098). Population-weighted, test-adjusted national seroprevalence was 5.2% (95% CI 3.7, 7.1%). Seroprevalence was highest in the 3 largest urban Counties; Mombasa (9.3% [95% CI 6.4, 13.2%)], Nairobi (8.5% [95% CI 4.9, 13.5%]) and Kisumu (6.5% [95% CI 3.3, 11.2%]). Conclusions We estimate that 1 in 20 adults in Kenya had SARS-CoV-2 antibodies during the study period. By the median date of our survey, only 2093 COVID-19 cases and 71 deaths had been reported through the national screening system. This contrasts, by several orders of magnitude, with the numbers of cases and deaths reported in parts of Europe and America when seroprevalence was similar.
Authors Muge Cevik, Matthew Tate, Oliver Lloyd, Alberto Enrico Maraolo, Jenna Schafers, Antonia Ho
ABSTRACT Background Viral load kinetics and the duration of viral shedding are important determinants for disease transmission. We aim i) to characterise viral load dynamics, duration of viral RNA, and viable virus shedding of SARS-CoV-2 in various body fluids and ii) to compare SARS-CoV-2 viral dynamics with SARS-CoV-1 and MERS-CoV. Methods: Medline, EMBASE, Europe PMC, preprint servers and grey literature were searched to retrieve all articles reporting viral dynamics and duration of SARS-CoV-2, SARS-CoV-1 and MERS-CoV shedding. We excluded case reports and case series with < 5 patients, or studies that did not report shedding duration from symptom onset. PROSPERO registration: CRD42020181914. Findings: Seventy-nine studies on SARS-CoV-2, 8 on SARS-CoV-1, and 11 on MERS-CoV were included. Mean SARS-CoV-2 RNA shedding duration in upper respiratory tract, lower respiratory tract, stool and serum were 17.0, 14.6, 17.2 and 16.6 days, respectively. Maximum duration of SARS-CoV-2 RNA shedding reported in URT, LRT, stool and serum was 83, 59, 35 and 60 days, respectively. Pooled mean duration of SARS-CoV-2 RNA shedding was positively associated with age (p=0.002), but not gender (p = 0.277). No study to date has detected live virus beyond day nine of illness despite persistently high viral loads. SARS-CoV-2 viral load in the upper respiratory tract appears to peak in the first week of illness, while SARS-CoV-1 and MERS-CoV peak later. Conclusion: Although SARS-CoV-2 RNA shedding in respiratory and stool can be prolonged, duration of viable virus is relatively short-lived. Thus, detection of viral RNA cannot be used to infer infectiousness. High SARS-CoV-2 titres are detectable in the first week of illness with an early peak observed at symptom onset to day 5 of illness. This review underscores the importance of early case finding and isolation, as well as public education on the spectrum of illness. However, given potential delays in the isolation of patients, effective containment of SARS-CoV-2 may be challenging even with an early detection and isolation strategy. Funding: No funding was received.
Authors Niall J Lennon, Roby P Bhattacharyya, Michael J Mina, Heidi L Rehm, Deborah T Hung, Sandra Smole, Ann Woolley, Eric S Lander, Stacey B Gabriel
ABSTRACT Background Transmission of COVID-19 from people without symptoms poses considerable challenges to public health containment measures. The distribution of viral loads in individuals with and without symptoms remains uncertain. Comprehensive cross-sectional screening of all individuals in a given setting provides an unbiased way to assess viral loads independent of symptoms, which informs transmission risks. COVID-19 cases initially peaked in Massachusetts in mid-April 2020 before declining through June, and congregate living facilities were particularly affected during this early surge. We performed a retrospective analysis of data from a large public health-directed outbreak response initiative that involved comprehensive screening within nursing homes and assisted living facilities in Massachusetts to compare nasopharyngeal (NP) viral loads (as measured by RT-PCR cycle threshold (Ct) levels) in residents and staff to inform our ability to detect SARS-CoV-2 in individuals with or without symptoms in the population. Methods Between April 9 and June 9, 2020, we tested NP swabs from 32,480 unique individuals comprising staff and residents of the majority of nursing homes and assisted living facilities in Massachusetts. Under the direction of the MA Department of Public Health (MDPH), symptomatology at the time of sampling and demographic information was provided by each facility for each individual to facilitate reporting to health officials. NP swabs were collected, RNA extracted, and SARS-CoV-2 testing performed using quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). Results The nursing home and assisted living facilities resident cohort (N =16,966) was 65% female with a mean age of 82 years (SD 13 yrs). The staff cohort (N = 15,514) was 76% female with a median age of 45 (SD 15 yrs). A total 2654 residents (15.5%) and 624 staff (4.1%) tested positive for SARS-CoV-2. 12.7% of residents and 3.7% of staff without symptoms tested positive for SARS-CoV-2, compared to 53.1% of residents and 18.2% of staff with symptoms. Of the individuals who tested positive, 70.8% of residents and 92.4% of staff lacked symptoms at the time of testing. In aggregate, the distributions of Cts for viral probes used in the qRT-PCR assay were very similar, with a statistically but not meaningfully different mean (∆Ct 0.71 cycles, p = 0.006) and a similar range (12-38 cycles), between populations with and without symptoms over the entire time period, across all sub-categories examined (age, race, ethnicity, sex, resident/staff). Importantly, the Ct mean values and range were indistinguishable between the populations by symptom class during the peak of the outbreak in Massachusetts, with a Ct gap appearing only later in the survey period, reaching >3 cycles (p ≤ 0.001) for facilities sampled during the last two weeks of the study. Conclusions In a large cohort of individuals screened for SARS-CoV-2 by qRT-PCR, we found strikingly similar distributions of viral load in patients with or without symptoms at the time of testing during the local peak of the epidemic; as the epidemic waned, individuals without symptoms at the time of testing had lower viral loads. The size of the study population, including both staff and residents spanning a wide range of ages, provides a comprehensive cross-sectional point prevalence measurement of viral burden in a study spanning 2 months. Because the distributions of viral loads in infected individuals irrespective of symptomatology are very similar, existing testing modalities that have been validated for detection of SARS-CoV-2 RNA in symptomatic patients should perform similarly in individuals without symptoms at the time of testing.
Authors Joshua L Santarpia, Vicki L Herrera, Danielle N Rivera, Shanna Ratnesar-Shumate, St. Patrick Reid, Paul W Denton, Jacob W.S. Martens, Ying Fang, Nicholas Conoan, Michael V Callahan, James V Lawler, David M Brett-Major, John J Lowe
ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission causing coronavirus disease 2019 (COVID-19) may occur through multiple routes. We collected aerosol samples around six patients admitted into mixed acuity wards in April of 2020 to identify the risk of airborne SARS-CoV-2. Measurements were made to characterize the size distribution of aerosol particles, and size-fractionated, aerosol samples were collected to assess the presence of infectious virus in particles sizes of >4.1 μm, 1-4 μm, and <1 μm in the patient environment. Samples were analyzed by real-time reverse-transcriptase polymerase chain reaction (rRT-PCR), cell culture, western blot, and transmission electron microscopy (TEM). SARS-CoV-2 RNA was detected in all six rooms in all particle size fractions (>4.1 μm, 1-4 μm, and <1 μm). Increases in viral RNA during cell culture of the virus from recovered aerosol samples demonstrated the presence of infectious, replicating virions in three <1 μm aerosol samples (P<0.05). Viral replication of aerosol was also observed in the 1-4 μm stage but did not reach statistical significance (0.05
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Authors Parham Azimi, Zahra Keshavarz, Jose Guillermo Cedeno Laurent, Brent R. Stephens, Joseph G. Allen
ABSTRACT Background The current prevailing position is that coronavirus disease 2019 (COVID-19) is transmitted primarily through large respiratory droplets within close proximity (i.e., 1-2 m) of infected individuals. However, quantitative information on the relative importance of specific transmission pathways of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (i.e., droplets, aerosols, and fomites across short- and long-range distances) remains limited. Methods To evaluate the relative importance of multiple transmission routes for SARS-CoV-2, we leveraged detailed information available from the Diamond Princess Cruise Ship outbreak that occurred in early 2020. We developed a framework that combines stochastic Markov chain and negative exponential dose-response modeling with available empirical data on mechanisms of SARS-CoV-2 dynamics and human behaviors, which informs a modified version of the Reed-Frost epidemic model to predict daily and cumulative daily case counts on the ship. We modeled 21,600 scenarios to generate a matrix of solutions across a full range of assumptions for eight unknown or uncertain epidemic and mechanistic transmission factors, including the magnitude of droplet and aerosol emissions from infected individuals, the infectious dose for deposition of droplets and aerosols to the upper and lower respiratory tracts, and others. Findings A total of 132 model iterations met acceptability criteria (R2 > 0.95 for modeled vs. reported cumulative daily cases and R2 > 0 for daily cases). Analyzing only these successful model iterations yields insights into the likely values for uncertain parameters and quantifies the likely contributions of each defined mode of transmission. Mean estimates of the contributions of short-range, long-range, and fomite transmission modes to infected cases aboard the ship across the entire simulation time period were 35%, 35%, and 30%, respectively. Mean estimates of the contributions of large respiratory droplets and small respiratory aerosols were 41% and 59%. Short-range transmission was the dominant mode after passenger quarantine began, albeit due primarily to aerosol transmission, not droplets. Interpretation Our results demonstrate that aerosol inhalation was likely the dominant contributor to COVID-19 transmission among passengers aboard the Diamond Princess Cruise Ship. Moreover, close-range and long-range transmission likely contributed similarly to disease progression aboard the ship, with fomite transmission playing a smaller role. The passenger quarantine also affected the importance of each mode, demonstrating the impacts of the interventions. Although cruise ships represent unique built environments with high ventilation rates and no air recirculation, these findings underscore the importance of implementing public health measures that target the control of inhalation of aerosols in addition to ongoing measures targeting control of large droplet and fomite transmission, not only aboard cruise ships but in other indoor environments as well.
Authors Jeffrey Seow, Carl Graham, Blair Merrick, Sam Acors, Kathryn J.A. Steel, Oliver Hemmings, Aoife O'Bryne, Neophytos Kouphou, Suzanne Pickering, Rui Galao, Gilberto Betancor, Harry D Wilson, Adrian W Signell, Helena Winstone, Claire Kerridge, Nigel Temperton, Luke Snell, Karen Bisnauthsing, Amelia Moore, Adrian Green, Lauren Martinez, Brielle Stokes, Johanna Honey, Alba Izquierdo-Barras, Gill Arbane, Amita Patel, Lorcan OConnell, Geraldine O Hara, Eithne MacMahon, Sam Douthwaite, Gaia Nebbia, Rahul Batra, Rocio Martinez-Nunez, Jonathan D. Edgeworth, Stuart J.D. Neil, Michael H. Malim, Katie Doores
ABSTRACT Antibody (Ab) responses to SARS-CoV-2 can be detected in most infected individuals 10-15 days following the onset of COVID-19 symptoms. However, due to the recent emergence of this virus in the human population it is not yet known how long these Ab responses will be maintained or whether they will provide protection from re-infection. Using sequential serum samples collected up to 94 days post onset of symptoms (POS) from 65 RT-qPCR confirmed SARS-CoV-2-infected individuals, we show seroconversion in >95% of cases and neutralizing antibody (nAb) responses when sampled beyond 8 days POS. We demonstrate that the magnitude of the nAb response is dependent upon the disease severity, but this does not affect the kinetics of the nAb response. Declining nAb titres were observed during the follow up period. Whilst some individuals with high peak ID50 (>10,000) maintained titres >1,000 at >60 days POS, some with lower peak ID50 had titres approaching baseline within the follow up period. A similar decline in nAb titres was also observed in a cohort of seropositive healthcare workers from Guy′s and St Thomas′ Hospitals. We suggest that this transient nAb response is a feature shared by both a SARS-CoV-2 infection that causes low disease severity and the circulating seasonal coronaviruses that are associated with common colds. This study has important implications when considering widespread serological testing, Ab protection against re-infection with SARS-CoV-2 and the durability of vaccine protection.
AMERICAN JOURNAL OF GASTROENTEROLOGY
Authors CV ALMARIO, W.D. CHEY, B.M.R. SPIEGEL
Authors Hugo Zeberg, Svante Pääbo
ABSTRACT A recent genetic association study (Ellinghaus et al. 2020) identified a gene cluster on chromosome 3 as a risk locus for respiratory failure in SARS-CoV-2. Recent data comprising 3,199 hospitalized COVID-19 patients and controls reproduce this and find that it is the major genetic risk factor for severe SARS-CoV-2 infection and hospitalization (COVID-19 Host Genetics Initiative). Here, we show that the risk is conferred by a genomic segment of ~50 kb that is inherited from Neandertals and occurs at a frequency of ~30% in south Asia and ~8% in Europe.
Authors Takuya Sekine, View ORCID ProfileAndre Perez-Potti, Olga Rivera-Ballesteros, Kristoffer Straling, Jean-Baptiste Gorin, Annika Olsson, Sian Llewellyn-Lacey, Habiba Kamal, Gordana Bogdanovic, Sandra Muschiol, David J Wulliman, View ORCID ProfileTobias Kammann, Johanna Emgard, Tiphaine Parrot, Elin Folkesson, Olav Rooyackers, Lars I Eriksson, Anders Sonnerborg, Tobias Allander, Jan Albert, View ORCID ProfileMorten Nielsen, Jonas Klingstrom, Sara Gredmark-Russ, Niklas K Bjorkstrom, View ORCID ProfileJohan K Sandberg, David A Price, Hans-Gustaf Ljunggren, Soo Aleman, View ORCID ProfileMarcus Buggert
ABSTRACT SARS-CoV-2-specific memory T cells will likely prove critical for long-term immune protection against COVID-19. We systematically mapped the functional and phenotypic landscape of SARS-CoV-2-specific T cell responses in a large cohort of unexposed individuals as well as exposed family members and individuals with acute or convalescent COVID-19. Acute phase SARS-CoV-2-specific T cells displayed a highly activated cytotoxic phenotype that correlated with various clinical markers of disease severity, whereas convalescent phase SARS-CoV-2-specific T cells were polyfunctional and displayed a stem-like memory phenotype. Importantly, SARS-CoV-2-specific T cells were detectable in antibody-seronegative family members and individuals with a history of asymptomatic or mild COVID-19. Our collective dataset shows that SARS-CoV-2 elicits robust memory T cell responses akin to those observed in the context of successful vaccines, suggesting that natural exposure or infection may prevent recurrent episodes of severe COVID-19 also in seronegative individuals.
ABSTRACT Background: SARS-CoV-2 is a novel coronavirus, not encountered before by humans. The wide spectrum of clinical expression of SARS-CoV-2 illness suggests that individual immune responses to SARS-CoV-2 play a crucial role in determining the clinical course after first infection. Immunological studies have focussed on patients with moderate to severe disease, demonstrating excessive inflammation in tissues and organ damage. We have studied the individual response to SARS-CoV-2 of asympromatic, mild and severe COVID-19 patients in order to investigate the role of innnate and adaptive immunity in determining the clinical course after first infection. Methods: To understand the basis of the protective immune response in COVID-19, we performed a longitudinal follow-up analysis of innate and adaptive immunity in 64 adults with a spectrum of clinical presentations: (28 healthy SARS-CoV-2-negative contacts of COVID-19 cases; 20 asymptomatic SARS-CoV-2-infected cases; 8 patients with mild COVID-19 disease and 8 cases of severe COVID-19 disease). Results: Our data show that high frequency of NK cells and early and transient increase of specific IgA and, to a lower extent, IgG are associated to asymptomatic SARS-CoV-2 infection. By contrast, monocyte expansion and high and persistent levels of IgA and IgG, produced relatively late in the course of the infection, characterize severe disease. Modest increase of monocytes and rapidly declining antibodies are detected in mild COVID-19. Conclusions: The importance of innate NK cells and the short-lived antibody response of asymptomatic individuals and patients with mild disease suggest that only severe COVID-19 may result in protective memory established by the adaptive immune response.
Authors Peter Horby, Wei Shen Lim, Jonathan Emberson, Marion Mafham, Jennifer Bell, Louise Linsell, Natalie Staplin, Christopher Brightling, Andrew Ustianowski, Einas Elmahi, Benjamin Prudon, Christopher Green, Timothy Felton, David Chadwick, Kanchan Rege, Christopher Fegan, Lucy C Chappell, Saul N Faust, Thomas Jaki, Katie Jeffery, Alan Montgomery, Kathryn Rowan, Edmund Juszczak, J Kenneth Baillie, Richard Haynes, Martin J Landray
ABSTRACT Background: Coronavirus disease 2019 (COVID-19) is associated with diffuse lung damage. Corticosteroids may modulate immune-mediated lung injury and reducing progression to respiratory failure and death. Methods: The Randomised Evaluation of COVID-19 therapy (RECOVERY) trial is a randomized, controlled, open-label, adaptive, platform trial comparing a range of possible treatments with usual care in patients hospitalized with COVID-19. We report the preliminary results for the comparison of dexamethasone 6 mg given once daily for up to ten days vs. usual care alone. The primary outcome was 28-day mortality. Results: 2104 patients randomly allocated to receive dexamethasone were compared with 4321 patients concurrently allocated to usual care. Overall, 454 (21.6%) patients allocated dexamethasone and 1065 (24.6%) patients allocated usual care died within 28 days (age-adjusted rate ratio [RR] 0.83; 95% confidence interval [CI] 0.74 to 0.92; P<0.001). The proportional and absolute mortality rate reductions varied significantly depending on level of respiratory support at randomization (test for trend p<0.001): Dexamethasone reduced deaths by one-third in patients receiving invasive mechanical ventilation (29.0% vs. 40.7%, RR 0.65 [95% CI 0.51 to 0.82]; p<0.001), by one-fifth in patients receiving oxygen without invasive mechanical ventilation (21.5% vs. 25.0%, RR 0.80 [95% CI 0.70 to 0.92]; p=0.002), but did not reduce mortality in patients not receiving respiratory support at randomization (17.0% vs. 13.2%, RR 1.22 [95% CI 0.93 to 1.61]; p=0.14). Conclusions: In patients hospitalized with COVID-19, dexamethasone reduced 28-day mortality among those receiving invasive mechanical ventilation or oxygen at randomization, but not among patients not receiving respiratory support.
ELSEVIER
Authors Teruhiko Imamura
Authors Ludovico Cantuti-Castelvetri, Ravi Ojha, Liliana D. Pedro, Minou Djannatian, Jonas Franz, Suvi Kuivanen, Katri Kallio, Tuğberk Kaya, Maria Anastasina, Teemu Smura, Lev Levanov, Leonora Szirovicza, Allan Tobi, Hannimari Kallio-Kokko, Pamela Österlund, Merja Joensuu, Frédéric A. Meunier, Sarah Butcher, Martin Sebastian Winkler, Brit Mollenhauer, Ari Helenius, Ozgun Gokce, Tambet Teesalu, Jussi Hepojoki, Olli Vapalahti, Christine Stadelmann, Giuseppe Balistreri, Mikael Simons
ABSTRACT The causative agent of the current pandemic and coronavirus disease 2019 (COVID-19) is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1. Understanding how SARS-CoV-2 enters and spreads within human organs is crucial for developing strategies to prevent viral dissemination. For many viruses, tissue tropism is determined by the availability of virus receptors on the surface of host cells2. Both SARS-CoV and SARS-CoV-2 use angiotensin-converting enzyme 2 (ACE2) as a host receptor, yet, their tropisms differ3-5. Here, we found that the cellular receptor neuropilin-1 (NRP1), known to bind furin-cleaved substrates, significantly potentiates SARS-CoV-2 infectivity, which was inhibited by a monoclonal blocking antibody against the extracellular b1b2 domain of NRP1. NRP1 is abundantly expressed in the respiratory and olfactory epithelium, with highest expression in endothelial cells and in the epithelial cells facing the nasal cavity. Neuropathological analysis of human COVID-19 autopsies revealed SARS-CoV-2 infected NRP1-positive cells in the olfactory epithelium and bulb. In the olfactory bulb infection was detected particularly within NRP1-positive endothelial cells of small capillaries and medium-sized vessels. Studies in mice demonstrated, after intranasal application, NRP1-mediated transport of virus-sized particles into the central nervous system. Thus, NRP1 could explain the enhanced tropism and spreading of SARS-CoV-2.
Authors Henry M Staines, Daniela E Kirwan, David J Clark, Emily R Adams, Yolanda Augustin, Rachel L Byrne, Michael Cocozza, Ana I Cubas-Atienza, Luis E Cuevas, Martina Cusinato, Benedict M O Davies, Mark Davis, Paul Davis, Annelyse Duvoix, Nicholas M Eckersley, Daniel Forton, Alice Fraser, Gala Garrod, Linda Hadcocks, Qinxue Hu, Michael Johnson, Grant A Kay, Kesja Klekotko, Zawditu Lewis, Josephine Mensah-Kane, Stefanie Menzies, Irene Monahan, Catherine Moore, Gerhard Nebe-von-Caron, Sophie I Owen, Chris Sainter, Amadou A Sall, James Schouten, Chris Williams, John Wilkins, Kevin Woolston, Joseph R A Fitchett, Sanjeev Krishna, Tim Planche
ABSTRACT We report dynamics of seroconversion to SARS-CoV-2 infections detected by IgG ELISA in 177 individuals diagnosed by RT-PCR. Longitudinal analysis identifies 2-8.5% of individuals who do not seroconvert even weeks after infection. They are younger than seroconverters who have increased co-morbidity and higher inflammatory markers such as C-Reactive Protein. Higher antibody responses are associated with non-white ethnicity. Antibody responses do not decline during follow up almost to 2 months. Serological assays increase understanding of disease severity. Their application in regular surveillance will clarify the duration and protective nature of humoral responses to SARS-CoV-2.
Authors James L. Daly, Boris Simonetti, Carlos Antón-Plágaro, Maia Kavanagh Williamson, Deborah K. Shoemark, Lorena Simón-Gracia, Katja Klein, Michael Bauer, Reka Hollandi, Urs F. Greber, Peter Horvath, Richard B. Sessions, Ari Helenius, Julian A. Hiscox, Tambet Teesalu, View ORCID ProfileDavid A. Matthews, Andrew D. Davidson, Peter J. Cullen, Yohei Yamauchi
ABSTRACT SARS-CoV-2 is the causative agent of COVID-19, a coronavirus disease that has infected more than 6.6 million people and caused over 390,000 deaths worldwide1,2. The Spike (S) protein of the virus forms projections on the virion surface responsible for host cell attachment and penetration. This viral glycoprotein is synthesized as a precursor in infected cells and, to be active, must be cleaved to two associated polypeptides: S1 and S2(3,4). For SARS-CoV-2 the cleavage is catalysed by furin, a host cell protease, which cleaves the S protein precursor at a specific sequence motif that generates a polybasic Arg-Arg-Ala-Arg (RRAR) C-terminal sequence on S1. This sequence motif conforms to the C-end rule (CendR), which means that the C-terminal sequence may allow the protein to associate with cell surface neuropilin-1 (NRP1) and neuropilin-2 (NRP2) receptors5. Here we demonstrate using immunoprecipitation, site-specific mutagenesis, structural modelling, and antibody blockade that, in addition to engaging the known receptor ACE2, S1 can bind to NRP1 through the canonical CendR mechanism. This interaction enhances infection by SARS-CoV-2 in cell culture. NRP1 thus serves as a host factor for SARS-CoV-2 infection, and provides a therapeutic target for COVID-19. A striking difference in the S protein of SARS-CoV-2 and SARS-CoV is the presence, in the former, of a polybasic sequence motif, RRAR, at the S1/S2 boundary. It provides a cleavage site for a proprotein convertase, furin, a membrane-bound host cell protease3–5 (Figure 1A). The resulting two proteins, S1 and S2, remain non-covalently associated, with the serine protease TMPRSS2 further priming the S2 protein by proteolytic cleavage6. Several observations indicate that the furin-mediated processing of the S protein increases the infection and affects the tropism of SARS-CoV-2(3–5). Proprotein convertase inhibitors that target furin robustly diminish SARS-CoV-2 entry into Calu-3 and HeLa cells exogenously expressing ACE2(7). Moreover, furin knockdown impairs S processing, and abrogation of the polybasic site in the S reduces syncytia formation in infected cells
RESEARCH SQUARE
Authors Maria Pachetti, Bruna Marini, Fabiola Giudici, Francesca Benedetti, Silvia Angeletti, Massimo Ciccozzi, Claudio Masciovecchio, Rudy Ipprodrino, Davide Zella
Background Severe acute respiratory syndrome CoV-2 (SARS-CoV-2) caused the first coronavirus disease 2019 (COVID-19) outbreak in China and has become a public health emergency of international concern. SARS-CoV-2 outbreak has been declared a pandemic by WHO on March 11th, 2020 and the same month several countries put in place different lockdown restrictions and testing strategies in order to contain the spread of the virus. Methods The calculation of the Case Fatality Rate of SARS-CoV-2 in the countries selected was made by using the data available at https://github.com/owid/covi-19-data/tree/master/public/data. Case fatality rate was calculated as the ratio between the death cases due to COVID-19, over the total number of SARS-CoV-2 reported cases 14 days before. Standard Case Fatality Rate values were normalized by the country-specific ρ factor, i.e. the number of PCR tests/1 million inhabitants over the number of reported cases/1 million inhabitants. Case-fatality rates between countries were compared using proportion test. Post-hoc analysis in the case of more than two groups was performed using pairwise comparison of proportions and p-value was adjusted using Holm method. We also analyzed 487 genomic sequences from the GISAID database derived from patients infected by SARS-CoV-2 from January 2020 to April 2020 in Italy, Spain, Germany, France, Sweden, UK and USA. SARS-CoV-2 reference genome was obtained from the GenBank database (NC_045512.2). Genomes alignment was performed using Muscle and Jalview software. We, then, calculated the Case Fatality Rate of SARS-CoV-2 in the countries selected Results In this study we analyse how different lockdown strategies and PCR testing capability adopted by Italy, France, Germany, Spain, Sweden, UK and USA have influenced the Case Fatality Rate and the viral mutations spread. We calculated case fatality rates by dividing the death number of a specific day by the number of patients with confirmed COVID-19 infection observed 14 days before and normalized by a ρ factor which takes into account the diagnostic PCR testing capability of each country and the number of positive cases detected. We notice the stabilization of a clear pattern of mutations at sites nt241, nt3037, nt14408 and nt23403. A novel nonsynonymous SARS-CoV-2 mutation in the spike protein (nt24368) has been found in genomes sequenced in Sweden, which enacted a soft lockdown strategy. Conclusions Strict lockdown strategies together with a wide diagnostic PCR testing of the population were correlated with a relevant decline of the case fatality rate in different countries. The emergence of specific patterns of mutations concomitant with the decline in case fatality rate needs further confirmation and their biological significance remains unclear.
Authors Shubham Misra, Manabesh Nath, Vijay Hadda, Deepti Vibha
Authors Mathias Peirlinck, Kevin Linka, Francisco Sahli Costabal, Eran Bendavid, Jayanta Bhattacharya, John Ioannidis, Ellen Kuhl
ABSTRACT Understanding the outbreak dynamics of the COVID-19 pandemic has important implications for successful containment and mitigation strategies. Recent studies suggest that the population prevalence of SARS-CoV-2 antibodies, a proxy for the number of asymptomatic cases, could be an order of magnitude larger than expected from the number of reported symptomatic cases. Knowing the precise prevalence and contagiousness of asymptomatic transmission is critical to estimate the overall dimension and pandemic potential of COVID-19. However, at this stage, the effect of the asymptomatic population, its size, and its outbreak dynamics remain largely unknown. Here we use reported symptomatic case data in conjunction with antibody seroprevalence studies, a mathematical epidemiology model, and a Bayesian framework to infer the epidemiological characteristics of COVID-19. Our model learns, in real time, the time-varying contact rate of the outbreak, and projects the temporal evolution and credible intervals of the effective reproduction number and the symptomatic, asymptomatic, and recovered populations. Our study reveals that the outbreak dynamics of COVID-19 are sensitive to three parameters: the effective reproduction number, the ratio between the symptomatic and asymptomatic populations, and the infectious periods of both groups. For three distinct locations, Santa Clara County (CA, USA), New York City (NY, USA), and Heinsberg (NRW, Germany), our model estimates the fraction of the population that has been infected and recovered by May 13, 2020 to 6.2% (95% CI: 3.3%-9.0%), 22.7% (95% CI: 15.7%-29.8%), and 20.5% (95% CI: 17.0%-24.3%). Our method traces the initial outbreak date in Santa Clara County back to January 20, 2020 (95% CI: January 16, 2020 - January 24, 2020). Our results could significantly change our understanding and management of the COVID-19 pandemic: A large asymptomatic population will make isolation, containment, and tracing of individual cases challenging. Instead, if needed, managing community transmission through increasing population awareness, promoting physical distancing, and encouraging behavioral changes could become more relevant.
Authors Tao Li, Li Wang, Huihui Wang, Xuemei Li, Shubing Zhang, Yuanhong Xu, Wei Wei
ABSTRACT Objective: This study aimed to explore the diagnostic value of serum severe acute respiratory syndrome coronavirus 2 (SARSCoV2) nucleocapsid(N) protein assay in the early stage of SARSCOV2 infection. Method: Serum N protein in SARSCOV2 infected patients and non SARSCOV2 infected population was measured by enzyme-linked immunosorbent assay (ELISA) double antibody sandwich assay. Colloidal gold immunochromatography assay is used to detect serum N protein antibodies in the above population. Results: 50 cases of SARSCoV2 nucleic acid positive and SARSCoV2 antibody negative patients had a serum N protein positive rate of 76%, including 2% with a concentration of 10.00~49.99 pg / mL, 8% with a concentration of 50.00~99.99 pg / mL, 22% with a concentration of 100.00 ~299.99 pg/mL, and 44% with a concentration ≥300.00 pg / mL. 37 samples of patients with serum SARSCoV2 antibody positive after infection had a serum SARSCoV2 N protein positive rate of 2.7%, of which 2.7% had the concentration of 10.00~49.99 pg / mL and 0% had the concentration of 50.00~99.99 pg / mL, 100.00 ~299.99 pg / mL, and ≥300.00 pg / mL. Serum N protein test results of 633 non SARSCOV2 infected patients including pregnant women, other respiratory infections, and increased rheumatoid factor were all negative, having a serum N protein concentration less than 10.00 pg/mL, with a specificity of 100%. Using SPSS 19.0 to calculate the receiver operating characteristic curve, the area under the curve was 0.9756 (95% confidence interval 0.9485~1.000, p <0.0001), sensitivity and specificity were 92% (95% confidence interval 81.16% to 96.85%) and 96.84% (95% confidence interval 95.17% to 97.15%). The best CUTOFF value is 1.850 pg / mL. Conclusion: The measurement of SARSCOV2 serum N protein has a high diagnostic value for the infected patients before the antibody appears, and shortens the window period of serological diagnosis. The laboratory needs to establish an individual CUTOFF value according to purpose of the application.
Authors Josh Reifer, Nosson Hayum, Benzion Heszkel, Ikey Klagsbald, Vincent A Streva
ABSTRACT Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a strain of coronavirus that causes coronavirus disease 2019 (Covid-19) and has been declared a global pandemic by the World Health Organization. Total cases of SARS-CoV-2 worldwide exceed 4.8 million, with over 320,000 deaths recorded. Little is known about the body's immune response to SARS-CoV-2 infection. In this paper, we describe SARS-CoV-2 IgG antibody responses in 11,092 patients from the New York City metropolitan area and report a SARS-CoV-2 IgG positivity rate of nearly 50%, indicating the widespread nature of the pandemic in the city and state of New York. Additionally, we report on the correlation between SARS-CoV-2 patient symptom severity and level of SARS-CoV-2 IgG antibody found in the patient sample.
Authors Shi Tai, Jianjun Tang, Bilian Yu, Liang Tang, Yang Wang, Huilin Zhang, Weihong Zhu, Kui Xiao, Chuan Wen, Chongqing Tan, Zhongbiao Jiang, Chuanhao Jiang, Li Zhu, Li Jiang, Qiming Liu, Xinqun Hu, Zhenfei Fang, Xuping Li, Jiaxing Sun, Zhaowei Zhu, Hui Yang, Tao Tu, Yichao Xiao, Mingxian Chen, Yuhu He, Xiangping Chai, Junmei Xu, Shenghua Zhou
ABSTRACT Background: Information regarding the impact of cardiovascular disease (CVD) on disease progression among patients with mild coronavirus disease 2019 (COVID-19) is limited. Methods: This study evaluated the association of underlying CVD with disease progression in patients with mild COVID-19. The primary outcome was the need to be transferred to intensive care due to disease progression. The patients were divided with and without CVD as well as stable and intensive care groups. Results: Of 332 patients with mild COVID-19, median age was 51 years (IQR, 40-59 years), and 200 (61.2%) were female. Of 48 (14.5%) patients with CVD, 23 (47.9%) progressed to severe disease status and required intensive care. Compared with patients without CVD, patients with CVD were older, and more likely to have fatigue, chest tightness, and myalgia. The rate of requiring intensive care was significantly higher among patients with CVD than in patients without CVD (47.92% vs. 12.4%; P<0.001). In subgroup analysis, rate of requiring intensive care was also higher among patients with either hypertension or coronary heart disease than in patients without hypertension or coronary heart disease. The multivariable regression model showed CVD served as an independent risk factor for intensive care (Odd ratio [OR], 2.652 [95% CI, 1.019-6.899]) after adjustment for various cofounders. Conclusions: Patients with mild COVID-19 complicating CVD in are susceptible to develop severe disease status and requirement for intensive care.
Authors Mor Saban, Tal Shachar, Oren Miron, Rachel Wilf Meron
ABSTRACT Background. During infectious disease outbreaks the weakest communities are more vulnerable to the infection and its deleterious effects. In Israel, the Arab and Ultra-Orthodox Jewish communities have unique demographic and cultural characteristics that place them at risk for infection. Objective. To examine the socioeconomic and ethnic differences in relation to COVID-19 testing, cases and deaths, and to analyze infection spread patterns in ethnically diverse communities. Methods. Consecutive data on COVID-19 diagnostic testing, confirmed cases and deaths collected from March 31st through May 1st, 2020 in 174 localities across Israel (84% of the population) were analyzed by socioeconomic ranking and ethnicity. Findings. Tests were performed on 331,594 individuals (4.29% of the total population). Of those, 14,865 individuals (4.48%) were positive and 203 died (1.37% of confirmed cases). The percentage of the population tested was 26% and the risk of testing positive was 2.16 times higher in the lowest, compared with the highest socioeconomic category. The proportion of confirmed cases was 4.96 times higher in the Jewish compared with the Arab population. The rate of confirmed cases in 2 Ultra-Orthodox localities increased relatively early and quickly. Other Jewish and Arab localities showed consistently low rates of confirmed COVID-19 cases, regardless of socioeconomic ranking. Interpretation Culturally different communities reacted differently to the COVID-19 outbreak and to government measures, resulting in different outcomes. Therefore, socioeconomic and ethnic variables cannot fully explain communities reaction to the pandemic. Our findings stress the need for designing a culturally adapted approach for dealing with health crises.
Authors Fabio Ciceri, Luigi Beretta, Anna Mara Scandroglio, Sergio Colombo, Giovanni Landoni, Annalisa Ruggeri, Jacopo Peccatori, Armando D’Angelo, Francesco De Cobelli, Patrizia Rovere-Querini, Moreno Tresoldi, Lorenzo Dagna and Alberto Zangrillo
ABSTRACT Objective To provide population-level knowledge on individuals at high risk of severe and fatal coronavirus disease 2019 (COVID-19) in order to inform targeted protection strategies in the general population and appropriate triage of hospital contacts. Design, Setting, and Participants Nationwide population-based cohort of all 228.677 consecutive Danish individuals tested (positive or negative) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA from the identification of the first COVID-19 case on February 27th, 2020 until April 30th, 2020. Main Outcomes and Measures We examined characteristics and predictors of inpatient hospitalization versus community-management, and death versus survival, adjusted for age-, sex- and number of comorbidities. Results We identified 9,519 SARS-CoV-2 PCR-positive cases of whom 78% were community-managed, 22% were hospitalized (3.2% at an intensive care unit) and 5.5% had died within 30 days. Median age varied from 45 years (interquartile range (IQR) 31-57) among community-managed cases to 82 years (IQR 75-89) among those who died. Age was a strong predictor of fatal disease (odds ratio (OR) 14 for 70-79-year old, OR 26 for 80-89-year old, and OR 82 for cases older than 90 years, when compared to 50-59-year old and adjusted for sex and number of comorbidities). Similarly, the number of comorbidities was strongly associated with fatal disease (OR 5.2, for cases with ≥4 comorbidities versus no comorbidities), and 82% of fatal cases had at least 2 comorbidities. A wide range of major chronic diseases were associated with hospitalization with ORs ranging from 1.3-1.4 (e.g. stroke, ischemic heart disease) to 2.2-2.7 (e.g. heart failure, hospital-diagnosed kidney disease, chronic liver disease). Similarly, chronic diseases were associated with mortality with ORs ranging from 1.2-1.3 (e.g. ischemic heart disease, hypertension) to 2.4-2.7 (e.g. major psychiatric disorder, organ transplantation). In the absence of comorbidities, mortality was relatively low (5% or less) in persons aged up to 80 years. Conclusions and Relevance In this first nationwide population-based study, increasing age and number of comorbidities were strongly associated with hospitalization requirement and death in COVID-19. In the absence of comorbidities, the mortality was, however, lowest until the age of 80 years. These results may help in accurate identification, triage and protection of high-risk groups in general populations, i.e. when reopening societies. Competing Interest Statement KBK, NBJ, MAV, SC, NCB, CFC, JH, MTE, KM, TGK, SG and MKT declare no conflicts of interest. RWT, and HTS declare no personal conflicts of interest. The Department of Clinical Epidemiology is involved in studies with funding from various companies as research grants to and administered by Aarhus University. None of these studies are related to the current study. HS reports personal fees from Bristol-Myers Squibb, personal fees from Novartis, personal fees from Roche, outside the submitted work. AP report participation in research funded by Alcon, Almirall, Astellas, AstraZeneca, Boehringer-Ingelheim, Novo Nordisk, Servier and LEO Pharma, all with funds paid to the institution where they were employed (no personal fees) and with no relation to the work reported in this paper. LCL reports participation in research projects funded by Menarini Pharmaceutical and LEO Pharma, with funds paid to the institution where he was employed (no personal fees) and with no relation to the work reported in this paper. MR reports participation in research projects funded by LEO Pharma, with funds paid to the institution where she was employed (no personal fees) and with no relation to the work reported in this paper.
Authors Mihaela Curmei, Andrew Ilyas, Owain Evans, Jacob Steinhardt
ABSTRACT Introduction and Goals: SARS-CoV-2 is transmitted both in the community and within households. Social distancing and lockdowns reduce community transmission but do not directly address household transmission. We provide quantitative measures of household transmission based on empirical data, and estimate the contribution of households to overall spread. We highlight policy implications from our analysis of household transmission, and more generally, of changes in contact patterns under social distancing. Methods: We investigate the household secondary attack rate (SAR) for SARS-CoV-2, as well as R_h, which is the average number of within-household infections caused by a single index case. We estimate the SAR through a meta-analysis of previous studies. Taking a Bayesian approach, we correct estimates for the false-negative rate (FNR) of testing and compute posterior credible intervals for SAR. We estimate R_h using results from population testing in Vo', Italy and contact tracing data that we curate from Singapore. The code and data behind our analysis are publicly available at: https://github.com/andrewilyas/covid-household-transmission. Results: Our analysis of eight recent attack rate studies yields an SAR estimate of 0.28 (0.10, 0.61). From contact tracing data, we infer an R_h value of 0.32 (0.22, 0.42). Blanket testing data from Vo' yields an R_h estimate of 0.37 (0.34, 040) and a CRI estimate of 0.5 after correcting for FNR and asymptomatic cases. Interpretation: Our estimates of R_h suggest that household transmission was a small fraction (5%-35%) of R before social distancing but a large fraction after (30%-55%). This suggests that household transmission may be an effective target for interventions. A remaining uncertainty is whether household infections actually contribute to further community transmission or are contained within households. This can be estimated given high-quality contact tracing data. More broadly, our study points to emerging contact patterns (i.e., increased time at home relative to the community) playing a role in transmission of SARS-CoV-2. We briefly highlight another instance of this phenomenon (differences in contact between essential workers and the rest of the population), provide coarse estimates of its effect on transmission, and discuss how future data could enable a more reliable estimate.
Authors Ehtisham Mahmud, Harold L. Dauerman, Frederick GP. Welt, John C. Messenger, Sunil V. Rao, Cindy Grines, Amal Mattu, Ajay J. Kirtane, Rajiv Jauhar, Perwaiz Meraj, Ivan C. Rokos, John S. Rumsfeld, Timothy D. Henry
ABSTRACT The worldwide pandemic caused by the novel acute respiratory syndrome coronavirus 2 (SARS-CoV2) has resulted in a new and lethal disease termed coronavirus disease 2019 (COVID-19). Although there is an association between cardiovascular disease and COVID-19, the majority of patients who need cardiovascular care for the management of ischemic heart disease may not be infected with COVID-19. The objective of this document is to provide recommendations for a systematic approach for the care of patients with an acute myocardial infarction (AMI) during the COVID-19 pandemic. There is a recognition of two major challenges in providing recommendations for AMI care in the COVID-19 era. Cardiovascular manifestations of COVID-19 are complex with patients presenting with AMI, myocarditis simulating a ST-elevation MI presentation, stress cardiomyopathy, non-ischemic cardiomyopathy, coronary spasm, or nonspecific myocardial injury and the prevalence of COVID-19 disease in the US population remains unknown with risk of asymptomatic spread. This document addresses the care of these patients focusing on 1) the varied clinical presentations; 2) appropriate personal protection equipment (PPE) for health care workers; 3) role of the Emergency Department, Emergency Medical System and the Cardiac Catheterization Laboratory; and 4) Regional STEMI systems of care. During the COVID-19 pandemic, primary PCI remains the standard of care for STEMI patients at PCI capable hospitals when it can be provided in a timely fashion, with an expert team outfitted with PPE in a dedicated CCL room. A fibrinolysis-based strategy may be entertained at non-PCI capable referral hospitals or in specific situations where primary PCI cannot be executed or is not deemed the best option.
Authors Mayte Suárez-Fariñas, Minami Tokuyama, Gabrielle Wei, Ruiqi Huang, Alexandra Livanos, Divya Jha, Anais Levescot, Roman Kosoy, Haritz Irizar, Sascha Cording, Wenhui Wang, Ryan Ungaro, Antonio Di’Narzo, Gustavo Martinez, Maria Suprun, Michael J. Corley, Aleksandar Stojmirovic, View ORCID ProfileSander M. Houten, Mark Curran, Carrie Brodmerkel, Jacqueline Perrigoue, Joshua R. Friedman, Ke Hao, Eric E. Schadt, Jun Zhu, Huaibin M. Ko, Judy Cho, Marla C. Dubinsky, Bruce E. Sands, Lishomwa Ndhlovu, Nadine Cerf-Benssusan, Andrew Kasarskis, Jean Frederic Colombel, Noam Harpaz, Carmen Argmann, View ORCID ProfileSaurabh Mehandru
ABSTRACT Immune dysregulation and cytokine release syndrome have emerged as pathological hallmarks of severe Coronavirus Disease 2019 (COVID-19), leading to the evaluation of cytokine antagonists as therapeutic agents. A number of immune-directed therapies being considered for COVID-19 patients are already in clinical use in chronic inflammatory conditions like inflammatory bowel disease (IBD). These considerations led us to systematically examine the intersections between COVID-19 and the GI tract during health and intestinal inflammation. We have observed that IBD medications, both biologic and non-biologic, do not significantly impact ACE2 and TMPRSS2 expression in the uninflamed intestines. Additionally, by comparing SARS CoV2-induced epithelial gene signatures with IBD-associated genes, we have identified a shared molecular subnetwork between COVID-19 and IBD. These data generate a novel appreciation of the confluence of COVID-19- and IBD-associated inflammation and provide mechanistic insights supporting further investigation of specific IBD drugs in the treatment of COVID-19. Competing Interest Statement SM and JFC have an unrestricted, investigator-initiated grant from Takeda Pharmaceuticals to examine novel homing mechanisms to the GI tract. RCU has served as an advisory board member or consultant for Eli Lilly, Janssen, Pfizer and Takeda. Mount Sinai co-authors (from Genetics and Genomics, Icahn Institute for Data Science and Genomic Technology, Human Immune Monitoring Center, Population Health Science and Policy, Division of Gastroenterology, Pediatric GI and Hepatology, Susan and Leonard Feinstein IBD Clinical Center at Icahn School of Medicine at Mount Sinai) were partially funded as part of research alliance between Janssen Biotech and The Icahn School of Medicine at Mount Sinai. MC, AS, JP and CB are employees at Research and Development. and JRF is a former employee at Janssen Research and Development and is currently employed at Alnylam Pharmaceuticals. MD is a consultant for Janssen. BES discloses consulting fees from 4D Pharma, Abbvie, Allergan, Amgen, Arena Pharmaceuticals, AstraZeneca, BoehringerIngelheim, Boston Pharmaceuticals, Capella Biosciences, Celgene, Celltrion Healthcare, EnGene, Ferring, Genentech, Gilead, Hoffmann-La Roche, Immunic, Ironwood Pharmaceuticals, Janssen, Lilly, Lyndra, MedImmune, Morphic Therapeutic, Oppilan Pharma, OSE Immunotherapeutics, Otsuka, Palatin Technologies, Pfizer, Progenity, Prometheus Laboratories, Redhill Biopharma, Rheos Medicines, Seres Therapeutics, Shire, Synergy Pharmaceuticals, Takeda, Target PharmaSolutions, Theravance Biopharma R&D, TiGenix, Vivelix Pharmaceuticals; honoraria for speaking in CME programs from Takeda, Janssen, Lilly, Gilead, Pfizer, Genetech; research funding from Celgene, Pfizer, Takeda, Theravance Biopharma R&D, Janssen. MCD discloses consulting fees from Abbvie, Allergan, Amgen, Arena Pharmaceuticals, AstraZeneca, BoehringerIngelheim, Celgene, Ferring, Genentech, Gilead, Hoffmann-La Roche, Janssen, Pfizer, Prometheus Biosciences, Takeda, Target PharmaSolutions and research funding from Abbvie, Janssen, Pfizer, Prometheus Biosciences Takeda. Dr. Colombel reports receiving research grants from AbbVie, Janssen Pharmaceuticals and Takeda; receiving payment for lectures from AbbVie, Amgen, Allergan, Inc. Ferring Pharmaceuticals, Shire, and Takeda; receiving consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene Corporation, Celltrion, Eli Lilly, Enterome, Ferring Pharmaceuticals, Geneva, Genentech, Janssen Pharmaceuticals, Landos, Ipsen, Imedex, Medimmune, Merck, Novartis, O Mass, Otsuka, Pfizer, Shire, Takeda, Tigenix, Viela bio; and holds stock options in Intestinal Biotech Development and Genfit.
IMMUNITY
Authors Kanta Subbarao, Siddhartha Mahanty
RESEARCHE SQUARE
Authors Scott Pallett, Sarah Denny, Aatish Patel, Esmita Charani, Nabeela Mughal, Justin Stebbing, Gary Davies, Luke Moore
ABSTRACT Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Case identification is currently made by real-time polymerase chain reaction (PCR) during the acute phase and largely restricted to healthcare laboratories. Serological assays are emerging but independent validation is urgently required to assess their utility. We evaluated five different point-of-care (POC) SARS-CoV-2 antibody test kits against PCR, finding concordance across the assays (n=15). We subsequently tested 200 patients using the OrientGene COVID-19 IgG/IgM Rapid Test Cassette and find a sensitivity of 74% in the early infection period (day 5-9 post symptom onset), with 100% sensitivity not seen until day 13. Specificity was 96%, but in validating the serological tests uncovered potential false-negatives from PCR testing late-presenting cases. A positive predictive value (PPV) of 37% in the general population precludes any use for general screening. Where a case definition is applied however, the PPV is substantially improved (95·4%), supporting use of serology testing in carefully targeted populations. Larger studies in specific patient cohorts, including those with mild infection are urgently required to inform on the applicability of POC serological assays to help control the spread of SARS-CoV-2 and improve case finding of patients that may experience late complications.
CMAJ
Authors Peter Jüni, Martina Rothenbühler, Pavlos Bobos, Kevin E. Thorpe, Bruno R. da Costa, David N. Fisman, Arthur S. Slutsky, Dionne Gesink
ABSTRACT Background: It is unclear whether seasonal changes, school closures or other public health interventions will result in a slowdown of the current coronavirus disease 2019 (COVID-19) pandemic. We aimed to determine whether epidemic growth is globally associated with climate or public health interventions intended to reduce transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods: We performed a prospective cohort study of all 144 geopolitical areas worldwide (375 609 cases) with at least 10 COVID-19 cases and local transmission by Mar. 20, 2020, excluding China, South Korea, Iran and Italy. Using weighted random-effects regression, we determined the association between epidemic growth (expressed as ratios of rate ratios [RRR] comparing cumulative counts of COVID-19 cases on Mar. 27, 2020, with cumulative counts on Mar. 20, 2020) and latitude, temperature, humidity, school closures, restrictions of mass gatherings, and measures of social distancing during an exposure period 14 days previously (Mar. 7 to 13, 2020). Results: In univariate analyses, there were few or no associations of epidemic growth with latitude and temperature, but weak negative associations with relative humidity (RRR per 10% 0.91, 95% confidence interval [CI] 0.85–0.96) and absolute humidity (RRR per 5 g/m3 0.92, 95% CI 0.85–0.99). Strong associations were found for restrictions of mass gatherings (RRR 0.65, 95% CI 0.53–0.79), school closures (RRR 0.63, 95% CI 0.52–0.78) and measures of social distancing (RRR 0.62, 95% CI 0.45–0.85). In a multivariable model, there was a strong association with the number of implemented public health interventions (p for trend = 0.001), whereas the association with absolute humidity was no longer significant. Interpretation: Epidemic growth of COVID-19 was not associated with latitude and temperature, but may be associated weakly with relative or absolute humidity. Conversely, public health interventions were strongly associated with reduced epidemic growth.
The Journal of Hospital Infection
Authors Marco Schiavone, Giovanni B. Forleo, Gianfranco Mitacchione, Alessio Gasperetti, Maurizio Viecca, Claudio Tondo
Authors Ishan Paranjpe, Valentin Fuster, Anuradha Lala, Adam Russak, Benjamin S. Glicksberg, Matthew A. Levin, Alexander W. Charney, Jagat Narula, Zahi A. Fayad, Emilia Bagiella, Shan Zhao, Girish N. Nadkarni
Authors Lucy van Dorp, Mislav Acman, Damien Richard, Liam P. Shaw, Charlotte E. Ford, Louise Ormond, Christopher J. Owen, Juanita Pang, Cedric C.S. Tan, Florencia A.T. Boshier, Arturo Torres Ortiz, François Balloux
Authors Emanuele Andreano, Emanuele Nicastri, Ida Paciello, Piero Pileri, Noemi Manganaro, Giulia Piccini, Alessandro Manenti, Elisa Pantano, Anna Kabanova, Marco Troisi, Fabiola Vacca, Dario Cardamone, Concetta De Santi, Chiara Agrati, Maria Rosaria Capobianchi, Concetta Castilletti, Arianna Emiliozzi, Massimiliano Fabbiani, Francesca Montagnani, Emanuele Montomoli, Claudia Sala, Giuseppe Ippolito, Rino Rappuoli
ABSTRACT In the absence of approved drugs or vaccines, there is a pressing need to develop tools for therapy and prevention of Covid-19. Human monoclonal antibodies have very good probability of being safe and effective tools for therapy and prevention of SARS-CoV-2 infection and disease. Here we describe the screening of PBMCs from seven people who survived Covid-19 infection to isolate human monoclonal antibodies against SARS-CoV-2. Over 1,100 memory B cells were single-cell sorted using the stabilized prefusion form of the spike protein and incubated for two weeks to allow natural production of antibodies. Supernatants from each cell were tested by ELISA for spike protein binding, and positive antibodies were further tested for neutralization of spike binding to receptor(s) on Vero E6 cells and for virus neutralization in vitro. From the 1,167 memory B specific for SARS-CoV-2, we recovered 318 B lymphocytes expressing human monoclonals recognizing the spike protein and 74 of these were able to inhibit the binding of the spike protein to the receptor. Finally, 17 mAbs were able to neutralize the virus when assessed for neutralization in vitro. Lead candidates to progress into the drug development pipeline will be selected from the panel of neutralizing antibodies identified with the procedure described in this study.
Authors Saverio Caini, Federica Bellerba, Federica Corso, Angelica Diaz-Basabe, Gioacchino Natoli, John Paget, Federica Facciotti, Sara Raimondi, Domenico Palli, Luca Mazzarella, Pier Giuseppe Pelicci, Paolo Vineis, Sara Gandini
ABSTRACT Serology-based tests have become a key public health element in the COVID-19 pandemic to assess the degree of herd immunity that has been achieved in the population. These tests differ between one another in several ways. Here, we conducted a systematic review and meta-analysis of the diagnostic accuracy of currently available SARS-CoV-2 serological tests, and assessed their real-world performance under scenarios of varying proportion of infected individuals. We included independent studies that specified the antigen used for antibody detection and used quantitative methods. We identified nine independent studies, of which six were based on commercial ELISA or CMIA/CLIA assays, and three on in-house tests. Test sensitivity ranged from 68% to 93% for IgM, from 65% to 100% for IgG, and from 83% to 98% for total antibodies. Random-effects models yielded a summary sensitivity of 82% (95%CI 75-88%) for IgM, and 85% for both IgG (95%CI 73-93%) and total antibodies (95%CI 74-94%). Specificity was very high for most tests, and its pooled estimate was 98% (95%CI 92-100%) for IgM and 99% (95%CI 98-100%) for both IgG and total antibodies. The heterogeneity of sensitivity and specificity across tests was generally high (I2≤50%). In populations with a low prevalence (≤5%) of seroconverted individuals, the positive predictive value would be ≤88% for most assays, except those reporting perfect specificity. Our data suggest that the use of serological tests for large-scale prevalence surveys (or to grant "immunity passports") are currently only justified in hard-hit regions, while they should be used with caution elsewhere
Authors Mehul S Suthar, Matthew Zimmerman, Robert Kauffman, Grace Mantus, Susanne Linderman, Abigail Vanderheiden, Lindsay Nyhoff, Carl Davis, Seyi Adekunle, Maurizio Affer, Melanie Sherman, Stacian Reynolds, Hans Verkerke, David N Alter, Jeannette Guarner, Janetta Bryksin, Michael Horwath, Connie Arthur, Natia Saakadze, Geoffrey Hughes Smith, Srilatha Edupuganti, Erin M Scherer, Kieffer Hellmeister, Andrew Cheng, Juliet A Morales, Andrew S Neish, Sean R Stowell, Filipp Frank, Eric Ortlund, Evan Anderson, Vineet Menachery, Nadine Rouphael, Aneesh Metha, David S Stephens, Rafi Ahmed, John Roback, View ORCID ProfileJens Wrammert
ABSTRACT SARS-CoV-2 is currently causing a devastating pandemic and there is a pressing need to understand the dynamics, specificity, and neutralizing potency of the humoral immune response during acute infection. Herein, we report the dynamics of antibody responses to the receptor-binding domain (RBD) of the spike protein and virus neutralization activity in 44 COVID-19 patients. RBD-specific IgG responses were detectable in all patients 6 days after PCR confirmation. Using a clinical isolate of SARS-CoV-2, neutralizing antibody titers were also detectable in all patients 6 days after PCR confirmation. The magnitude of RBD-specific IgG binding titers correlated strongly with viral neutralization. In a clinical setting, the initial analysis of the dynamics of RBD-specific IgG titers was corroborated in a larger cohort of PCR-confirmed patients (n=231). These findings have important implications for our understanding of protective immunity against SARS-CoV-2, the use of immune plasma as a therapy, and the development of much-needed vaccines.
Authors Maria Vastarella, Angela Patrì, Maria Carmela Annunziata, Mariateresa Cantelli, Paola Nappa, Marco Tasso, Luisa Costa, Francesco Caso, Gabriella Fabbrocini
ABSTRACT Background SARS-CoV-2 is the causative agent of coronavirus disease 2019 (COVID-19), which has rapidly become epidemic in Italy and other European countries. The disease spectrum ranges from asymptomatic/mildly symptomatic presentations to acute respiratory failure. At the present time the absolute number of severe cases requiring ventilator support is reaching or even surpassing the intensive care unit bed capacity in the most affected regions and countries. Objectives To narratively summarize the available literature on the management of COVID-19, in the attempt to combine current evidence and frontline opinions and provide balanced answers to pressing clinical questions. Sources Inductive PubMed search for publications relevant to the topic. Content The available literature and the authors’ frontline-based opinion are summarized in brief narrative answers to selected clinical questions, plus a conclusive statement for each answer. Implications Many off-label antiviral and anti-inflammatory drugs are currently being administered to patients with COVID-19. Physicians must be aware that, being not supported by high-level evidence, these treatments may often be ethically justifiable only in those worsening patients unlikely to improve only with supportive care, and who cannot be enrolled in randomized clinical trials (RCT). Access to well-designed RCT should be expanded as much as possible, being the most secure way to change for the better our approach to COVID-19 patients.
Authors Weihong Zeng, Hongliang He, Dan Zhao, Yunru Yang, Dehua Jiang, Peigen Zhou, Yingjie Qi, Weihuang He, Changcheng Zhao, Ruting Yi, Xiaofang Wang, Bo Wang, Yuanhong Xu, Yun Yang, Arnaud John Kombe Kombe, Chengchao Ding, Jiajia Xie, Yong Gao, Linzhao Cheng, Yajuan Li, Xiaoling Ma, Tengchuan Jin
ABSTRACT Background. The pandemic of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is causing great loss. Detecting viral RNAs is standard approach for SARS-CoV-2 diagnosis with variable success. Currently, studies describing the serological diagnostic methods are emerging, while most of them just involve the detection of SARS-CoV-2-specific IgM and IgG by ELISA or flow immunoassay with limited accuracy. Methods. Diagnostic approach depends on chemiluminescence immunoanalysis (CLIA) for detecting IgA, IgM and IgG specific to SARS-CoV-2 nucleocapsid protein (NP) and receptor-binding domain (RBD) was developed. The approach was tested with 216 sera from 87 COVID-19 patients and 483 sera from SARS-CoV-2 negative individuals. The diagnostic accuracy was evaluated by receiver operating characteristic (ROC) analysis. Concentration kinetics of RBD-specific serum antibodies were characterized. The relationship of serum RBD-specific antibodies and disease severity was analyzed. Results. The diagnostic accuracy based on RBD outperformed those based on NP. Adding IgA to a conventional serological test containing IgM and IgG improves sensitivity of SARS-CoV-2 diagnosis at early stage. CLIA for detecting RBD-specific IgA, IgM and IgG showed diagnostic sensitivities of 98.6%, 96.8% and 96.8%, and specificities of 98.1%, 92.3% and 99.8%, respectively. Median concentration of IgA and IgM peaked during 16-20 days after illness onset at 8.84 μg/mL and 7.25 μg/mL, respectively, while IgG peaked during 21-25 days after illness onset at 16.47 μg/mL. Furthermore, the serum IgA level positively correlates with COVID-19 severity. Conclusion. CLIA for detecting SARS-CoV-2 RBD-specific IgA, IgM and IgG in blood provides additional values for diagnosing and monitoring of COVID-19.
Authors Matteo Bassetti, Daniele Roberto Giacobbe, Stefano Aliberti, Emanuela Barisione, Stefano Centanni, Francesco GiuseppeDe Rosa, Fabiano Di Marco, Andrea Gori, Guido Granata, Malgorzata Mikulska, Nicola Petrosillo, Luca Richeldi, Pierachille Santus, Carlo Tascini, Antonio Vena,Pierluigi Viale, Francesco Blasi
Authors Germano Melissano, Daniele Mascia, Domenico Baccellieri, Andrea Kahlberg, Luca Bertoglio, Enrico Rinaldi, Roberto Chiesa
Authors Bin Lou, Tigndong Li, Shufa Zheng, Yingying Su, Zhiyong Li, Wei Liu, Fei Yu, Shengxiang Ge, Qianda Zou, Quan Yuan, Sha Lin, Congming Hong, Xiangyang Yao, Xuejie Zhang, Dinghui Wu, Guoliang Zhou, Wangheng Hou, Tingting Li, Yali Zhang, Shiyin Zhang, Jian Fan, Jun Zhang, Ningshao Xia, Yu Chen
Background Timely diagnosis of SARS-CoV-2 infection is the prerequisite for treatment and preventive quarantine. The serology characteristics and complement diagnosis value of antibody test to RNA test needs to be demonstrated. Method A patient cohort study was conducted at the first affiliated hospital of Zhejiang University, China. Serial sera of COVID-19 patients were collected and total antibody (Ab), IgM and IgG antibody against SARS-CoV-2 were detected. The antibody dynamics during the infection were described. Results The seroconversion rate for Ab, IgM and IgG in COVID-19 patients was 98.8% (79/80), 93.8% (75/80) and 93.8% (75/80), respectively. The first detectible serology marker is total antibody and followed by IgM and IgG, with a median seroconversion time of 15, 18 and 20 day post exposure (d.p.e) or 9, 10 and 12 days post onset, separately. The antibody levels increased rapidly since 6 d.p.o and accompanied with the decline of viral load. For patients in the early stage of illness (0-7d.p.o),Ab showed the highest sensitivity (64.1%) compared to the IgM and IgG (33.3% for both, p<0.001). The sensitivities of Ab, IgM and IgG detection increased to 100%, 96.7% and 93.3% two weeks later, respectively. Conclusions Typical acute antibody response is induced during the SARS-CoV-2 infection. The serology testing provides important complementation to RNA test for pathogenic specific diagnosis and helpful information to evaluate the adapted immunity status of patient. It should be strongly recommended to apply well-validated antibody tests in the clinical management and public health practice to improve the control of COVID-19 infection.
OXFORD ACADEMY
Authors Aifen Lin, Ze-Bao He, Sheng Zhang, Jian-Gang Zhang, Xia Zhang, Wei-Hua Yan
Authors Joseph Magagnoli, Siddharth Narendran, Felipe Pereira, Tammy Cummings, James W Hardin, S Scott Sutton, Jayakrishna Ambati
Background Despite limited and conflicting data on the use of hydroxychloroquine in patients with Covid-19, the U.S. Food and Drug Administration has authorized the emergency use of this drug when clinical trials are unavailable or infeasible. Hydroxychloroquine, alone or in combination with azithromycin, is being widely used in Covid-19 therapy based on anecdotal and limited observational evidence. METHODS: We performed a retrospective analysis of data from patients hospitalized with confirmed SARS-CoV-2 infection in all United States Veterans Health Administration medical centers until April 11, 2020. Patients were categorized based on their exposure to hydroxychloroquine alone (HC) or with azithromycin (HC+AZ) as treatments in addition to standard supportive management for Covid-19. The two primary outcomes were death and the need for mechanical ventilation. We determined the association between treatment and the primary outcomes using competing risk hazard regression adjusting for clinical characteristics via propensity scores. Discharge and death were taken into account as competing risks and subdistribution hazard ratios are presented. RESULTS: A total of 368 patients were evaluated (HC, n=97; HC+AZ, n=113; no HC, n=158). Rates of death in the HC, HC+AZ, and no HC groups were 27.8%, 22.1%, 11.4%, respectively. Rates of ventilation in the HC, HC+AZ, and no HC groups were 13.3%, 6.9%, 14.1%, respectively. Compared to the no HC group, the risk of death from any cause was higher in the HC group (adjusted hazard ratio, 2.61; 95% CI, 1.10 to 6.17; P=0.03) but not in the HC+AZ group (adjusted hazard ratio, 1.14; 95% CI, 0.56 to 2.32; P=0.72). The risk of ventilation was similar in the HC group (adjusted hazard ratio, 1.43; 95% CI, 0.53 to 3.79; P=0.48) and in the HC+AZ group (adjusted hazard ratio, 0.43; 95% CI, 0.16 to 1.12; P=0.09), compared to the no HC group. CONCLUSIONS: In this study, we found no evidence that use of hydroxychloroquine, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with Covid-19. An association of increased overall mortality was identified in patients treated with hydroxychloroquine alone. These findings highlight the importance of awaiting the results of ongoing prospective, randomized, controlled studies before widespread adoption of these drugs
Authors Luca Carsana, Aurelio Sonzogni, Ahmed Nasr, Roberta Rossi, Alessandro Pellegrinelli, Pietro Zerbi, Roberto Rech, Riccardo Colombo, Spinello Antinori, Mario Corbellino, Massimo Galli, Emanuele Catena, Antonella Tosoni, Andrea Gianatti, Manuela Nebuloni
ABSTRACT Importance. The analysis of lung tissues of patients with COVID-19 may help understand pathogenesis and clinical outcomes in this life-threatening respiratory illness. Objective. To determine the histological patterns in lung tissue of patients with severe COVID-19. Design and participants. Lungs tissues of 38 cases who died for COVID-19 in two hospital of Northern Italy were systematically analysed. Hematoxylin-eosin staining, immunohistochemistry for the inflammatory infiltrate and cellular components, electron microscopy were performed. Results. The features of the exudative and proliferative phases of Diffuse Alveolar Disease (DAD) were found: capillary congestion, necrosis of pneumocytes, hyaline membrane, interstitial oedema, pneumocyte hyperplasia and reactive atypia, platelet-fibrin thrombi. The inflammatory infiltrate was composed by macrophages in alveolar lumens and lymphocytes mainly in the interstitium. Electron microscopy revealed viral particles within cytoplasmic vacuoles of pneumocytes. Conclusions and relevance. The predominant pattern of lung lesions in COVID-19 patients is DAD, as described for the other two coronavirus that infect humans, SARS-CoV and MERS-CoV. Hyaline membrane formation and pneumocyte atypical hyperplasia are frequently found. The main relevant finding is the presence of platelet-fibrin thrombi in small arterial vessels; this important observation fits into the clinical context of coagulopathy which dominates in these patients and which is one of the main targets of therapy.
Authors Edward Burn, Seng Chan You, Anthony Sena, Kristin Kostka, Hamed Abedtash, Maria Tereza F. Abrahao, Amanda Alberga, Heba Alghoul, Osaid Alser, Thamir M Alshammari, Carlos Areia, Juan M Banda, Jaehyeong Cho, Aedin C Culhane, Alexander Davydov, Frank J DeFalco, Talita Duarte-Salles, Scott L DuVall, Thomas Falconer, Weihua Gao, Asieh Golozar, Jill Hardin, George Hripcsak, Vojtech Huser, Hokyun Jeon, Yonghua Jing, Chi Young Jung, Benjamin Skov Kaas-Hansen, Denys Kaduk, Seamus Kent, Yeesuk Kim, Spyros Kolovos, Jennifer Lane, Hyejin Lee, Kristine E. Lynch, Rupa Makadia, Michael E. Matheny, Paras Mehta, Daniel R. Morales, Karthik Natarajan, Fredrik Nyberg, Anna Ostropolets, Rae Woong Park, Jimyung Park, Jose D. Posada, Albert Prats-Uribe, Gowtham A. Rao, Christian Reich, Yeunsook Rho, Peter Rijnbeek, Selva Muthu Kumaran Sathappan, Lisa M. Schilling, Martijn Schuemie, Nigam H. Shah, Azza Shoaibi, Seokyoung Song, Matthew Spotnitz, Marc A. Suchard, Joel Swerdel, David Vizcaya, Salvatore Volpe, Haini Wen, Andrew E Williams, Belay B Yimer, Lin Zhang, Oleg Zhuk, Daniel Prieto-Alhambra, Patrick Ryan
Background To better understand the profile of individuals with severe coronavirus disease 2019 (COVID-19), we characterised individuals hospitalised with COVID-19 and compared them to individuals previously hospitalised with influenza. Methods We report the characteristics (demographics, prior conditions and medication use) of patients hospitalised with COVID-19 between December 2019 and April 2020 in the US (Columbia University Irving Medical Center [CUIMC], STAnford Medicine Research data Repository [STARR-OMOP], and the Department of Veterans Affairs [VA OMOP]) and Health Insurance Review & Assessment [HIRA] of South Korea. Patients hospitalised with COVID-19 were compared with patients previously hospitalised with influenza in 2014-19. Results 6,806 (US: 1,634, South Korea: 5,172) individuals hospitalised with COVID-19 were included. Patients in the US were majority male (VA OMOP: 94%, STARR-OMOP: 57%, CUIMC: 52%), but were majority female in HIRA (56%). Age profiles varied across data sources. Prevalence of asthma ranged from 7% to 14%, diabetes from 18% to 43%, and hypertensive disorder from 22% to 70% across data sources, while between 9% and 39% were taking drugs acting on the renin-angiotensin system in the 30 days prior to their hospitalisation. Compared to 52,422 individuals hospitalised with influenza, patients admitted with COVID-19 were more likely male, younger, and, in the US, had fewer comorbidities and lower medication use. Conclusions Rates of comorbidities and medication use are high among individuals hospitalised with COVID-19. However, COVID-19 patients are more likely to be male and appear to be younger and, in the US, generally healthier than those typically admitted with influenza.
Authors Frances MK Williams, Maxim Freydin, Massimo Mangino, Simon Couvreur,, Alessia Visconti, Ruth CE Bowyer, Caroline I Le Roy, Mario Falchi, Carole Sudre, Richard Davies, Christopher Hammond, Cristina Menni, Claire Steves, Tim Spector
ABSTRACT Susceptibility to infection such as SARS-CoV-2 may be influenced by host genotype. TwinsUK volunteers (n=2633) completing the C-19 Covid symptom tracker app allowed classical twin studies of covid-19 symptoms including predicted covid-19, a symptom-based algorithm predicting true infection derived in app users tested for SARS-CoV-2. We found heritability for fever = 41 (95% confidence intervals 12-70)%; anosmia 47 (27-67)%; delirium 49 (24-75)%; and predicted covid-19 gave heritability = 50 (29-70)%. Competing Interest Statement TDS is consultant to Zoe Global Ltd ("Zoe"). RD is an employee of Zoe Global Limited. Other authors have no conflict of interest to declare. Funding Statement TwinsUK is funded by the Wellcome Trust, Medical Research Council, European Union, Chronic Disease Research Foundation (CDRF), Zoe Global Ltd and the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guys and St Thomas NHS Foundation Trust in partnership with Kings College London. We are grateful to all the users of C-19 Covid Symptom Tracker app for their contribution to this study.
Authors Enrico Lavezzo, Elisa Franchin, Constanze Ciavarella, Gina Cuomo-Dannenburg, Luisa Barzon, Claudia Del Vecchio, Lucia Rossi, Riccardo Manganelli, Arianna Loregian, Nicolò Navarin, Davide Abate, Manuela Sciro, Stefano Merigliano, Ettore Decanale, Maria Cristina Vanuzzo, Francesca Saluzzo, Francesco Onelia, Monia Pacenti, Saverio Parisi, Giovanni Carretta, Daniele Donato, Luciano Flor, Silvia Cocchio, Giulia Masi, Alessandro Sperduti, Lorenzo Cattarino, Renato Salvador, Katy A.M. Gaythorpe, Imperial College London COVID-19 Response Team, Alessandra R Brazzale, Stefano Toppo, Marta Trevisan, Vincenzo Baldo, Christl A. Donnelly, Neil M. Ferguson, Ilaria Dorigatti, Andrea Crisanti
On the 21st of February 2020 a resident of the municipality of Vo, a small town near Padua, died of pneumonia due to SARS-CoV-2 infection. This was the first COVID-19 death detected in Italy since the emergence of SARS-CoV-2 in the Chinese city of Wuhan, Hubei province. In response, the regional authorities imposed the lockdown of the whole municipality for 14 days. We collected information on the demography, clinical presentation, hospitalization, contact network and presence of SARS-CoV-2 infection in nasopharyngeal swabs for 85.9% and 71.5% of the population of Vo at two consecutive time points. On the first survey, which was conducted around the time the town lockdown started, we found a prevalence of infection of 2.6% (95% confidence interval (CI) 2.1-3.3%). On the second survey, which was conducted at the end of the lockdown, we found a prevalence of 1.2% (95% CI 0.8-1.8%). Notably, 43.2% (95% CI 32.2-54.7%) of the confirmed SARS-CoV-2 infections detected across the two surveys were asymptomatic. The mean serial interval was 6.9 days (95% CI 2.6-13.4). We found no statistically significant difference in the viral load (as measured by genome equivalents inferred from cycle threshold data) of symptomatic versus asymptomatic infections (p-values 0.6 and 0.2 for E and RdRp genes, respectively, Exact Wilcoxon-Mann-Whitney test). Contact tracing of the newly infected cases and transmission chain reconstruction revealed that most new infections in the second survey were infected in the community before the lockdown or from asymptomatic infections living in the same household. This study sheds new light on the frequency of asymptomatic SARS-CoV-2 infection and their infectivity (as measured by the viral load) and provides new insights into its transmission dynamics, the duration of viral load detectability and the efficacy of the implemented control measures.
JOURNAL OF INFECTION
Authors Zhaohai Zheng, Fang Peng, Buyun Xu, Jingjing Zhao, Huahua Liu, Jiahao Peng, Qingsong Li, Chongfu Jiang, Yan Zhou, Shuqing Liu, Chunji Ye, Peng Zhang , Yangbo Xing , Hangyuan Guo, Weiliang Tang
ABSTRACT Background An epidemic of Coronavirus Disease 2019 (COVID-19) began in December 2019 and triggered a Public Health Emergency of International Concern (PHEIC). We aimed to find risk factors for the progression of COVID-19 to help reducing the risk of critical illness and death for clinical help. Methods The data of COVID-19 patients until March 20, 2020 were retrieved from four databases. We statistically analyzed the risk factors of critical/mortal and non-critical COVID-19 patients with meta-analysis. Results Thirteen studies were included in Meta-analysis, including a total number of 3027 patients with SARS-CoV-2 infection. Male, older than 65, and smoking were risk factors for disease progression in patients with COVID-19 (male: OR = 1.76, 95% CI (1.41, 2.18), P < 0.00001; age over 65 years old: OR =6.06, 95% CI(3.98, 9.22), P < 0.00001; current smoking: OR =2.51, 95% CI(1.39, 3.32), P = 0.0006). The proportion of underlying diseases such as hypertension, diabetes, cardiovascular disease, and respiratory disease were statistically significant higher in critical/mortal patients compared to the non-critical patients (diabetes: OR=3.68, 95% CI (2.68, 5.03), P < 0.00001; hypertension: OR = 2.72, 95% CI (1.60,4.64), P = 0.0002; cardiovascular disease: OR = 5.19, 95% CI(3.25, 8.29), P < 0.00001; respiratory disease: OR = 5.15, 95% CI(2.51, 10.57), P < 0.00001). Clinical manifestations such as fever, shortness of breath or dyspnea were associated with the progression of disease [fever: 0R = 0.56, 95% CI (0.38, 0.82), P = 0.003;shortness of breath or dyspnea: 0R=4.16, 95% CI (3.13, 5.53), P < 0.00001]. Laboratory examination such as aspartate amino transferase(AST) > 40U/L, creatinine(Cr) ≥ 133mol/L, hypersensitive cardiac troponin I(hs-cTnI) > 28pg/mL, procalcitonin(PCT) > 0.5ng/mL, lactatede hydrogenase(LDH) > 245U/L, and D-dimer > 0.5mg/L predicted the deterioration of disease while white blood cells(WBC)<4 × 109/L meant a better clinical status[AST > 40U/L:OR=4.00, 95% CI (2.46, 6.52), P < 0.00001; Cr ≥ 133μmol/L: OR = 5.30, 95% CI (2.19, 12.83), P = 0.0002; hs-cTnI > 28 pg/mL: OR = 43.24, 95% CI (9.92, 188.49), P < 0.00001; PCT > 0.5 ng/mL: OR = 43.24, 95% CI (9.92, 188.49), P < 0.00001;LDH > 245U/L: OR = 43.24, 95% CI (9.92, 188.49), P < 0.00001; D-dimer > 0.5mg/L: OR = 43.24, 95% CI (9.92, 188.49), P < 0.00001; WBC < 4 × 109/L: OR = 0.30, 95% CI (0.17, 0.51), P < 0.00001]. Conclusion Male, aged over 65, smoking patients might face a greater risk of developing into the critical or mortal condition and the comorbidities such as hypertension, diabetes, cardiovascular disease, and respiratory diseases could also greatly affect the prognosis of the COVID-19. Clinical manifestation such as fever, shortness of breath or dyspnea and laboratory examination such as WBC, AST, Cr, PCT, LDH, hs-cTnI and D-dimer could imply the progression of COVID-19. Keywords COVID-19Risk factorComorbidityClinical manifestationLaboratory examination
Authors Aditi Shastri, Justin Wheat, Sachee Agrawal, Nirjhar Chaterjee, Kith Pradhan, Mendel Goldfinger, Noah Kornblum, Ulrich Steidl, Amit Verma, Jayanthi Shastri
The novel coronavirus SARS-CoV2 has been observed to cause a higher incidence and greater severity of disease in males, as seen in multiple cohorts across the globe. The reasons for gender disparity in disease severity is unclear and can be due to host factors. To determine whether males have delayed viral clearance after infection, we evaluated the time to clearance in symptomatic patients tested by serial oropharyngeal/nasopharyngeal swabs followed by RT-PCR at a reference lab in Mumbai, India. A total of 68 subjects with median age of 37 years (3-75 range) were examined and included 48 (71%) males and 20 (29%) females. We observed that females were able to achieve viral clearance significantly earlier than males, with a median difference of 2 days in achieving a negative PCR result (P value = 0.038). Furthermore, examination of 3 families with both male and female patients followed serially, demonstrated that female members of the same household cleared the SARS-CoV2 infection earlier in each family. To determine reasons for delayed clearance in males, we examined the expression patterns of the SARS-CoV2 receptor, Angiotensin-converting enzyme 2 (ACE2), in tissue specific repositories. We observed that the testes was one of the highest sites of ACE2 expression in 3 independent RNA expression databases (Human Protein Atlas, FAMTOM5 and GETx). ACE2 was also determined to be highly expressed in testicular cells at the protein levels. Interestingly, very little expression of ACE2 was seen in ovarian tissue. Taken together, these observations demonstrate for the first time that male subjects have delayed viral clearance of SARS-CoV2. High expression of ACE2 in testes raises the possibility that testicular viral reservoirs may play a role in viral persistence in males and should be further investigated.
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Authors Brian D. Quinlan, Huihui Mou, Lizhou Zhang, Yan Guo, Wenhui He, Amrita Ojha, Mark S. Parcells, Guangxiang Luo, Wenhui Li, Guocai Zhong
Abstract The SARS-coronavirus 2 (SARS-CoV-2) spike (S) protein mediates entry of SARS-CoV-2 into cells expressing the angiotensin-converting enzyme 2 (ACE2). The S protein engages ACE2 through its receptor-binding domain (RBD), an independently folded 197-amino acid fragment of the 1273-amino acid S-protein protomer. Antibodies to the RBD domain of SARS-CoV (SARS-CoV-1), a closely related coronavirus which emerged in 2002-2003, have been shown to potently neutralize SARS-CoV-1 S-protein-mediated entry, and the presence of anti-RBD antibodies correlates with neutralization in SARS-CoV-2 convalescent sera. Here we show that immunization with the SARS-CoV-2 RBD elicits a robust neutralizing antibody response in rodents, comparable to 100 µg/ml of ACE2-Ig, a potent SARS-CoV-2 entry inhibitor. Importantly, anti-sera from immunized animals did not mediate antibody-dependent enhancement (ADE) of S-protein-mediated entry under conditions in which Zika virus ADE was readily observed. These data suggest that an RBD-based vaccine for SARS-CoV-2 could be safe and effective.
EBIO MEDICINE
Authors Yu-Jun Dai, Wei-Na Zhang, Wei-Da Wang, Si-Yuan He, Cheng-Cai Liang, Da-Wei Wang
Background: SARS-COV-2-induced corona virus disease 2019 (COVID-19) broke out in China at the end of 2019. ACE2 was considered as the receptor of SARS-COV-2 and wildly expressed in human tissues. Whereas, the extremely low expression of ACE2 in lung could hardly interpret the severe symptom of pneumonia in patients. Methods: The tissue and blood atlas were used to analyze the RNA and protein expression in human tissues. Mutation spectrum and protein structure were analyzed by cBioPortal. ENCORI was utilized to analyze the gene expression and prognosis in pan-cancers. Findings: We performed profiling analysis of two novel SARS-CoV-2 entries, TMPRSS2 and IFITM3, in human tissues and organs. Consistent with ACE2, TMPRSS2 was high expressed in digestive, urinary and reproductive systems, but low expressed in lung. Notably, the anti-virus protein IFITM3 expressed much lower in lung than other tissues, which might be related to the severe lung symptoms of COVID-19. In addition, the low expression of IFITM3 in immune cells suggested that SARS-CoV-2 might attack lymphocytes and induce the cytokine release syndrome. Furthermore, our data detailly analyzed different susceptibility of tumors to SARS-CoV-2 according to ACE2, TMPRSS2 or IFITM3 expression. We finally found the prognosis of six cancers (BRCA, LUAD, UCEC, KIRC, PRAD and LIHC) were closely related to these gene expressions. Interpretation: Our study explored the profiling of two potential novel entries of SARS-CoV-2 and provided a supplementary clue for preventing infection of SARS-CoV-2. Funding Statement: This work was supported by Innovative Research Team of High-level Local Universities in Shanghai, and Guangci Distinguished Young Scholars Training Program (GCQN-2019-B17).
SSRN
Authors hejing bao, Yinhua Fang, Qin Lai, Hehong Bao, Xianxiang Zhang, Yu Zheng, Yanjun Hu, Gang Li
Background: Coronavirus disease 2019 (COVID-19) has spread throughout the world since the outbreak in Wuhan, China. This paper summarized 101 patients diagnosed as COVID-19 aimed to describe the changes across different timepoints throughout the disease course. Methods: The patients diagnosed as COVID-19 pneumonia who underwent serial peripheral blood collection and chest CT scans were enrolled. Patients were grouped on the basis of the severity of illness. Clinical datas were compared were analyzed and compared across each group. Findings: 101 patients admitted to hospital were enrolled. The study included 43 (42.6%) women and 58 (57.4%) men, and the median age was 45 years (interquartile range [IQR], 16-71). We first used Monaca system to show the 3D outline of spleen, liver and kidney of the typical patients, and found spleen shrink in 27.7% patients, severe patients had suffered more than mild patients. Lymphopenia was observed in 66 (65.3%) of the 101 patients. In our study, 27.3% still have low levels of lymphocytes after discharge. Tachycardia occurred mainly in the first two days of hospitalization, with an increase in myocardial-band creatine kinase (CK-MB) in 10 patients, in troponin I in 1 patient, in brain natriuretic peptide (BNP) in 3 patients and in arrhythmia in 16 (15.8%) patients. Interpretation: In addition to the common belief that SARS-CoV-2 can cause pneumonia, our studies show that other organ systems could also be affected during COVID-19 infection. The injuries could lead to immunosuppression and cardiovascular dysfunction, which might contribute to increased mortality in critically ill patients.
NCBI
Authors Niuniu Sun , Suling Shi , Dandan Jiao , Runluo Song , Lili Ma , Hongwei Wang , Chao Wang , Zhaoguo Wang , Yanli You , Shuhua Liu , Hongyun Wang
The coronavirus disease 2019 (COVID-19) is spreading rapidly, bringing pressure and challenges to nursing staff. Objective To explore the psychology of nurses caring for COVID-19 patients. Method Using a phenomenological approach, we enrolled 20 nurses who provided care for COVID-19 patients in the First Affiliated Hospital of Henan University of Science and Technology from 20 January to 10 February 2020. The interviews were conducted face-to-face or by telephone and were analysed by Colaizzi's 7-step method. Results The psychological experience of nurses caring for COVID-19 patients can be summarized into four themes. Firstly, negative emotions present in early stage consisting of fatigue, discomfort, and helplessness was caused by high-intensity work, fear and anxiety, and concern for patients and family members. Secondly, self-coping styles included psychological and life adjustment, altruistic acts, team support, and rational cognition. Thirdly, we found growth under pressure, which included increased affection and gratefulness, development of professional responsibility, and self-reflection. Finally, we showed that positive emotions occurred simultaneously with negative emotions. Conclusions During an epidemic outbreak, positive and negative emotions of the front-line nurses interweaved and coexisted. In the early stage, negative emotions were dominant and positive emotions appeared gradually. Self-coping styles and psychological growth played an important role in maintaining mental health of nurses.
Authors Angelo Virgilio Paradiso, Simona De Summa, Daniela Loconsole, Vito Procacci, Anna Sallustio, Francesca Centrone, Nicola Silvestris, Vito Cafagna, Giuseppe De Palma, Antonio Tufaro, Vito Garrisi, Maria Chironna
INREVIEW
Authors Sara De Biasi, Marianna Meschiari, Lara Gibellini, Caterina Bellinazzi, Rebecca Borella, Lucia Fidanza, Domenico Lo Tartaro, Marco Mattioli, Annamaria Paolini, Marianna Menozzi, Jovana Milić, Giacomo Franceschi, Riccardo Fantini, Roberto Tonelli, Marco Sita, Mario Sarti, Enrico Clini, Massimo Girardis, Giovanni Guaraldi, Cristina Mussini, Andrea Cossarizza
ABSTRACT We have deeply investigated T cell compartment, plasma cytokines and cells producing cytokines in patients affected by Covid-19. At admission, patients were lymphopenic; in all of them SARS-CoV-2 was detected in a nasopharyngeal swab specimen by real-time RT-PCR, and pneumonia was subsequently confirmed by X-rays. Detailed 18-parameter flow cytometry was performed in 21 patients and 13 controls. Coupling polychromatic cytometry with unsupervised data analysis, we found that patients show an increased amount of CD4+ T lymphocytes that were activated, exhausted, stem memory or Treg. Similar results concerning activation and exhaustion were found in the CD8+ T cell compartment, within which the differences were even greater. Measuring plasma level of 31 cytokines linked to inflammation revealed that Covid-19 showed a dramatic increase of several molecules, such as TH1 and TH2 cytokines, chemokines, galectins, pro- and anti-inflammatory mediators, confirming the importance of a massive immune activation causing the cytokine storm. Then, intracellular staining detecting the simultaneous production of different cytokines after a para-physiologic stimulus given by anti-CD3/CD28 mAbs revealed not only a high capacity to produce a variety of molecules, including TNF-a, IFN-g and IL-2, but also a significant skewing of CD4+ T cells towards the TH17 phenotype. A therapeutic approach now exists based on the administration of drugs that block IL-6 pathway, and is now consistently improving the course of the disease. IL-17 is crucial in recruiting and activating neutrophils, cells that can migrate to the lung and are heavily involved in the pathogenesis of Covid-19. We show here that a significant skewing of activated T cells towards TH17 functional phenotype exists in Covid-19 patients. Thus, we suggest that blocking IL-17 pathway by already available biological drugs that are used to treat different pathologies could be a novel, additional strategy to improve the health of patients infected by SARS-CoV-2.
JOURNAL OF TRANSLATION MEDICINE
Authors Maria Pachetti, Bruna Marini, Francesca Benedetti, Fabiola Giudici, Elisabetta Mauro, Paola Storici, Claudio Masciovecchio, Silvia Angeletti, Massimo Ciccozzi, Robert Charles Gallo, Davide Zella, Rudy Ippodrino
Background. SARS-CoV-2 is a RNA coronavirus responsible for the pandemic of the Severe Acute Respiratory Syndrome (COVID-19). RNA viruses are characterized by a high mutation rate, up to a million times higher than that of their hosts. Virus mutagenic capability depends upon several factors, including the fidelity of viral enzymes that replicate nucleic acids, as SARS-CoV-2 RNA dependent RNA Polymerase (RdRp). Mutation rate drives viral evolution and genome variability, thereby enabling viruses to escape host immunity and to develop drug resistance. Methods. We analyzed 220 genomic sequences from the GISAID database derived from patients infected by SARS-CoV-2 worldwide from December 2019 to mid-March 2020. SARS-CoV-2 reference genome was obtained from the GenBank database. Genomes alignment was performed using Clustal Omega. Mann-Whitney and Fisher-Exact tests were used to assess statistical significance. Results. We characterized 8 novel recurrent mutations of SARS-CoV-2, located at positions 1397, 2891, 14408, 17746, 17857, 18060, 23403 and 28881. Mutations in 2891, 3036, 14408, 23403 and 28881 positions are predominantly observed in Europe, whereas those located at positions 17746, 17857 and 18060 are exclusively present in North America. We noticed that the 14408 mutation, emerged for the first time in Europe in mid-February 2020, is present in the SARS-CoV-2 RdRp gene sequence. Viruses with RdRp mutation have a median of 3 point mutations [range: 2-5], otherwise they have a median of 1 mutation [range: 0-3] (p value < 0.001). Conclusions. These findings suggest that the virus is evolving and European, North American and Asian strains might coexist, each of them characterized by a different mutation pattern. The contribution of the mutated RdRp to this phenomenon needs to be investigated. To date, several drugs targeting RdRp enzymes are being employed for SARS-CoV-2 infection treatment. Some of them have a predicted binding moiety in a SARS-CoV-2 RdRp hydrophobic cleft, which is adjacent to the 14408 mutation we identified. Consequently, it is important to study and characterize SARS-CoV-2 RdRp mutation in order to assess possible drug-resistance viral phenotypes. It is also important to recognize whether the presence of some mutations might correlate with different SARS-CoV-2 mortality rates.
Authors Fan Wu, Aojie Wang, Mei Liu, Qimin Wang, Jun Chen, Shuai Xia, Yun Ling, Yuling Zhang, Jingna Xun, Lu Lu, Shibo Jiang, Hongzhou Lu, Yumei Wen, Jinghe Huang
Background The COVID-19 pandemic caused by SARS-CoV-2 coronavirus threatens global public health. Currently, neutralizing antibodies (NAbs) versus this virus are expected to correlate with recovery and protection of this disease. However, the characteristics of these antibodies have not been well studied in association with the clinical manifestations in patients. Methods Plasma collected from 175 COVID-19 recovered patients with mild symptoms were screened using a safe and sensitive pseudotyped-lentiviral-vector-based neutralization assay. Spike-binding antibody in plasma were determined by ELISA using RBD, S1, and S2 proteins of SARS-CoV-2. The levels and the time course of SARS-CoV-2-specific NAbs and the spike-binding antibodies were monitored at the same time. Findings SARS-CoV-2 NAbs were unable to cross-reactive with SARS-CoV virus. SARS-CoV-2-specific NAbs were detected in patients from day 10-15 after the onset of the disease and remained thereafter. The titers of NAb among these patients correlated with the spike-binding antibodies targeting S1, RBD, and S2 regions. The titers of NAbs were variable in different patients. Elderly and middle-age patients had significantly higher plasma NAb titers (P<0.0001) and spike-binding antibodies (P=0.0003) than young patients. Notably, among these patients, there were ten patients whose NAb titers were under the detectable level of our assay (ID50: < 40); while in contrast, two patients, showed very high titers of NAb, with ID50 :15989 and 21567 respectively. The NAb titers were positive correlated with plasma CRP levels but negative correlated with the lymphocyte counts of patients at the time of admission, indicating an association between humoral response and cellular immune response. Interpretation The variations of SARS-CoV-2 specific NAbs in recovered COVID-19 patients may raise the concern about the role of NAbs on disease progression. The correlation of NAb titers with age, lymphocyte counts, and blood CRP levels suggested that the interplay between virus and host immune response in coronavirus infections should be further explored for the development of effective vaccine against SARS-CoV-2 virus. Furthermore, titration of NAb is helpful prior to the use of convalescent plasma for prevention or treatment. Funding Ministry of Science and Technology of China, National Natural Science Foundation of China, Shanghai Municipal Health Commission, and Chinese Academy of Medical Sciences
Authors David E. Gordon, View ORCID ProfileGwendolyn M. Jang, View ORCID ProfileMehdi Bouhaddou, View ORCID ProfileJiewei Xu, View ORCID ProfileKirsten Obernier, View ORCID ProfileMatthew J. O’Meara, Jeffrey Z. Guo, View ORCID ProfileDanielle L. Swaney, View ORCID ProfileTia A. Tummino, View ORCID ProfileRuth Huettenhain, View ORCID ProfileRobyn M. Kaake, View ORCID ProfileAlicia L. Richards, View ORCID ProfileBeril Tutuncuoglu, Helene Foussard, View ORCID ProfileJyoti Batra, View ORCID ProfileKelsey Haas, View ORCID ProfileMaya Modak, View ORCID ProfileMinkyu Kim, View ORCID ProfilePaige Haas, View ORCID ProfileBenjamin J. Polacco, View ORCID ProfileHannes Braberg, Jacqueline M. Fabius, View ORCID ProfileManon Eckhardt, View ORCID ProfileMargaret Soucheray, Melanie J. Bennett, View ORCID ProfileMerve Cakir, View ORCID ProfileMichael J. McGregor, View ORCID ProfileQiongyu Li, View ORCID ProfileZun Zar Chi Naing, View ORCID ProfileYuan Zhou, Shiming Peng, View ORCID ProfileIlsa T. Kirby, View ORCID ProfileJames E. Melnyk, View ORCID ProfileJohn S. Chorba, View ORCID ProfileKevin Lou, View ORCID ProfileShizhong A. Dai, View ORCID ProfileWenqi Shen, View ORCID ProfileYing Shi, View ORCID ProfileZiyang Zhang, View ORCID ProfileInigo Barrio-Hernandez, View ORCID ProfileDanish Memon, View ORCID ProfileClaudia Hernandez-Armenta, View ORCID ProfileChristopher J.P. Mathy, View ORCID ProfileTina Perica, View ORCID ProfileKala B. Pilla, View ORCID ProfileSai J. Ganesan, View ORCID ProfileDaniel J. Saltzberg, View ORCID ProfileRakesh Ramachandran, Xi Liu, View ORCID ProfileSara B. Rosenthal, View ORCID ProfileLorenzo Calviello, View ORCID ProfileSrivats Venkataramanan, Jose Liboy-Lugo, View ORCID ProfileYizhu Lin, View ORCID ProfileStephanie A. Wankowicz, View ORCID ProfileMarkus Bohn, Phillip P. Sharp, View ORCID ProfileRaphael Trenker, View ORCID ProfileJanet M. Young, View ORCID ProfileDevin A. Cavero, View ORCID ProfileJoseph Hiatt, View ORCID ProfileTheodore L. Roth, View ORCID ProfileUjjwal Rathore, View ORCID ProfileAdvait Subramanian, Julia Noack, Mathieu Hubert, Ferdinand Roesch, Thomas Vallet, Björn Meyer, View ORCID ProfileKris M. White, View ORCID ProfileLisa Miorin, Oren S. Rosenberg, Kliment A Verba, View ORCID ProfileDavid Agard, Melanie Ott, View ORCID ProfileMichael Emerman, View ORCID ProfileDavide Ruggero, View ORCID ProfileAdolfo García-Sastre, View ORCID ProfileNatalia Jura, View ORCID ProfileMark von Zastrow, View ORCID ProfileJack Taunton, Alan Ashworth, View ORCID ProfileOlivier Schwartz, View ORCID ProfileMarco Vignuzzi, View ORCID ProfileChristophe d’Enfert, View ORCID ProfileShaeri Mukherjee, Matt Jacobson, View ORCID ProfileHarmit S. Malik, View ORCID ProfileDanica G. Fujimori, View ORCID ProfileTrey Ideker, View ORCID ProfileCharles S. Craik, View ORCID ProfileStephen Floor, View ORCID ProfileJames S. Fraser, View ORCID ProfileJohn Gross, View ORCID ProfileAndrej Sali, View ORCID ProfileTanja Kortemme, View ORCID ProfilePedro Beltrao, View ORCID ProfileKevan Shokat, View ORCID ProfileBrian K. Shoichet, View ORCID ProfileNevan J. Krogan
An outbreak of the novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 290,000 people since the end of 2019, killed over 12,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven efficacy nor are there vaccines for its prevention. Unfortunately, the scientific community has little knowledge of the molecular details of SARS-CoV-2 infection. To illuminate this, we cloned, tagged and expressed 26 of the 29 viral proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), which identified 332 high confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 67 druggable human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials and/or preclinical compounds, that we are currently evaluating for efficacy in live SARS-CoV-2 infection assays. The identification of host dependency factors mediating virus infection may provide key insights into effective molecular targets for developing broadly acting antiviral therapeutics against SARS-CoV-2 and other deadly coronavirus strains.
WINLEY
Authors SEBASTIANO RECALCATI
In December 2019 unexplained pneumonia cases were initially reported in Wuhan, China. The pathogen, a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), was isolated from lower respiratory tract samples of infected patients and the resultant disease was termed as COVID‐19 (Coronavirus Disease 2019)1. By Feb 15, COVID‐19 has rapidly spread throughout China and across the world, until a pandemic condition was announced by March 11
Authors The COVID-19 Investigation Team
Introduction: More than 93,000 cases of coronavirus disease (COVID-19) have been reported worldwide. We describe the epidemiology, clinical course, and virologic characteristics of the first 12 U.S. patients with COVID-19. Methods: We collected demographic, exposure, and clinical information from 12 patients confirmed by CDC during January 20-February 5, 2020 to have COVID-19. Respiratory, stool, serum, and urine specimens were submitted for SARS-CoV-2 rRT-PCR testing, virus culture, and whole genome sequencing. Results: Among the 12 patients, median age was 53 years (range: 21-68); 8 were male, 10 had traveled to China, and two were contacts of patients in this series. Commonly reported signs and symptoms at illness onset were fever (n=7) and cough (n=8). Seven patients were hospitalized with radiographic evidence of pneumonia and demonstrated clinical or laboratory signs of worsening during the second week of illness. Three were treated with the investigational antiviral remdesivir. All patients had SARS-CoV-2 RNA detected in respiratory specimens, typically for 2-3 weeks after illness onset, with lowest rRT-PCR Ct values often detected in the first week. SARS-CoV-2 RNA was detected after reported symptom resolution in seven patients. SARS-CoV-2 was cultured from respiratory specimens, and SARS-CoV-2 RNA was detected in stool from 7/10 patients. Conclusions: In 12 patients with mild to moderately severe illness, SARS-CoV-2 RNA and viable virus were detected early, and prolonged RNA detection suggests the window for diagnosis is long. Hospitalized patients showed signs of worsening in the second week after illness onset.
Journal of Thoracic Oncology
Authors Michele Carbone, Joshua B. Green, Enrico M. Bucci, John A. Lednicky,
In this issue of Journal of Thoracic Oncology (JTO), Tian et al.1 provided the first description of early pathology of coronavirus disease—2019 (COVID-19). As of today, February 26, 2020, there have been over 78,000 confirmed cases and over 2500 deaths in the People’s Republic of China, based on the official figure by the National Health Commission of the People’s Republic of China. The infection is rapidly spreading in the United States, Europe, South Korea, Iran, and other countries. COVID-19 has already caused havoc to travel and global markets and has the potential to become a devastating disease in the People’s Republic of China and globally
RESEARCH GATE
Authors Zhengtu Li, Yongxiang Yi, Xiaomei Luo, Nian Xiong
The outbreak of the novel coronavirus disease (COVID‐19) quickly spread all over China and to more than 20 other countries. Although the virus (SARS‐Cov‐2) nucleic acid RT‐PCR test has become the standard method for diagnosis of SARS‐CoV‐2 infection, these real‐time PCR test kits have many limitations. In addition, high false negative rates were reported. There is an urgent need for an accurate and rapid test method to quickly identify large number of infected patients and asymptomatic carriers to prevent virus transmission and assure timely treatment of patients. We have developed a rapid and simple point‐of‐care lateral flow immunoassay which can detect IgM and IgG antibodies simultaneously against SARS‐CoV‐2 virus in human blood within 15 minutes which can detect patients at different infection stages. With this test kit, we carried out clinical studies to validate its clinical efficacy uses. The clinical detection sensitivity and specificity of this test were measured using blood samples collected from 397 PCR confirmed COVID‐19 patients and 128 negative patients at 8 different clinical sites. The overall testing sensitivity was 88.66% and specificity was 90.63%. In addition, we evaluated clinical diagnosis results obtained from different types of venous and fingerstick blood samples. The results indicated great detection consistency among samples from fingerstick blood, serum and plasma of venous blood. The IgM‐IgG combined assay has better utility and sensitivity compared with a single IgM or IgG test. It can be used for the rapid screening of SARS‐CoV‐2 carriers, symptomatic or asymptomatic, in hospitals, clinics, and test laboratories.
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