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      Antibody response to first BNT162b2 dose in previously SARS-CoV-2-infected individuals

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          Abstract

          Rapid vaccine-induced population immunity is a key global strategy to control COVID-19. Vaccination programmes must maximise early impact, particularly with accelerated spread of new variants. 1 Most vaccine platforms use a two-dose prime-boost approach to generate an immune response against the virus S1 spike protein, the titres of which correlate with functional virus neutralisation and increase with boosting.2, 3 To enable larger numbers of people to receive the first dose, delayed administration of the second dose has been advocated and implemented by some. 1 The impact of previous SARS-CoV-2 infection on the need for boosting is not known. We reasoned that previous infection could be analogous to immune priming. As such, a first prime vaccine dose would effectively act as boost, so a second dose might not be needed. To test this, we undertook a nested case-control analysis of 51 participants of COVIDsortium,4, 5 an ongoing longitudinal observational study of health-care workers (HCWs) in London who underwent weekly PCR and quantitative serology testing from the day of the first UK lockdown on March 23, 2020, and for 16 weeks onwards. 24 of 51 HCWs had a previous laboratory-confirmed mild or asymptomatic SARS-CoV-2 infection, as confirmed by positive detection of antibodies against the SARS-CoV-2 nucleocapsid (Elecsys Anti-SARS-CoV-2 N ECLIA, Roche Diagnostics, Burgess Hill, UK) or the receptor binding domain of the SARS-CoV-2 S1 subunit of the spike protein (anti-S; Elecsys anti-SARS-CoV-2 spike ECLIA, Roche Diagnostics), whereas 27 HCWs remained seronegative. A median of 12·5 sampling timepoints per participant permitted the identification of peak antibody titres in seropositive individuals while avoiding false negatives. All participants received their first dose of the BNT162b2 mRNA COVID-19 vaccine (Pfizer-BioNTech, Mainz, Germany)2, 3 and were tested 19–29 days later (median 22 days, IQR 2). Among previously uninfected, seronegative individuals, anti-S titres after one vaccine dose were comparable to peak anti-S titres in individuals with a previous natural infection who had not yet been vaccinated. Among those with a previous SARS-CoV-2 infection, vaccination increased anti-S titres more than 140-fold from peak pre-vaccine levels (figure ). This increase appears to be at least one order of magnitude greater than reported after a conventional prime-boost vaccine strategy in previously uninfected individuals. 3 Figure Serological response to one dose of the BNT162b2 mRNA COVID-19 vaccine in individuals with and without laboratory-confirmed previous SARS-CoV-2 infection SARS-CoV-2 anti-S antibody titres in individuals with no previous infection are similar to titres in individuals who have had a mild SARS-CoV-2 infection. Anti-S titres in those with previous SARS-CoV-2 infection are more than 140-fold greater than at time of peak infection. Statistical analysis was by unpaired two-tailed t test. U=unit. NS=non-significant. These serological data suggest that for individuals receiving the BNT162b2 mRNA vaccine, a potential approach is to include serology testing at or before the time of first vaccination to prioritise use of booster doses for individuals with no previous infection. This could potentially accelerate vaccine rollout. With increasing variants (UK, South Africa, Brazil), wider coverage without compromising vaccine-induced immunity could help reduce variant emergence. Furthermore, reactogenicity after unnecessary boost risks an avoidable and unwelcome increase in vaccine hesitancy. Whether enhanced vaccine-induced antibody responses among previously seropositive individuals will show differential longevity compared to boosted vaccines remains to be seen. In the meantime, our findings provide a rationale for serology-based vaccine dosing to maximise coverage and impact.

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          Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

          Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently. Methods In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 μg per dose). BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against laboratory-confirmed Covid-19 and safety. Results A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups. Conclusions A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.)
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            Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates

            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 persons worldwide. Multiple vaccine candidates are under development, but no vaccine is currently available. Interim safety and immunogenicity data about the vaccine candidate BNT162b1 in younger adults have been reported previously from trials in Germany and the United States. Methods In an ongoing, placebo-controlled, observer-blinded, dose-escalation, phase 1 trial conducted in the United States, we randomly assigned healthy adults 18 to 55 years of age and those 65 to 85 years of age to receive either placebo or one of two 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 membrane-anchored SARS-CoV-2 full-length spike, stabilized in the prefusion conformation. The primary outcome was safety (e.g., local and systemic reactions and adverse events); immunogenicity was a secondary outcome. Trial groups were defined according to vaccine candidate, age of the participants, and vaccine dose level (10 μg, 20 μg, 30 μg, and 100 μg). In all groups but one, participants received two doses, with a 21-day interval between doses; in one group (100 μg of BNT162b1), participants received one dose. Results A total of 195 participants underwent randomization. In each of 13 groups of 15 participants, 12 participants received vaccine and 3 received placebo. BNT162b2 was associated with a lower incidence and severity of systemic reactions than BNT162b1, particularly in older adults. In both younger and older adults, the two vaccine candidates elicited similar dose-dependent SARS-CoV-2–neutralizing geometric mean titers, which were similar to or higher than the geometric mean titer of a panel of SARS-CoV-2 convalescent serum samples. Conclusions The safety and immunogenicity data from this U.S. phase 1 trial of two vaccine candidates in younger and older adults, added to earlier interim safety and immunogenicity data regarding BNT162b1 in younger adults from trials in Germany and the United States, support the selection of BNT162b2 for advancement to a pivotal phase 2–3 safety and efficacy evaluation. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.)
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              COVID-19: PCR screening of asymptomatic health-care workers at London hospital

              The exponential growth in coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) across the UK has been successfully reversed by social distancing and lockdown. 1 RNA testing for prevalent infection is a key part of the exit strategy, but the role of testing for asymptomatic infection remains unclear. 2 Understanding the determinants of asymptomatic or pauci-symptomatic infection will provide new opportunities for personalised risk stratification and reveal much-needed correlates of protective immunity, whether induced by vaccination or natural exposure. To address this, we set up COVIDsortium (NCT04318314), a bioresource focusing on asymptomatic health-care workers (HCWs—doctors, nurses, allied health professionals, administrators, and others) at Barts Health NHS Trust, London, UK, to collect data through 16 weekly assessments (unless ill, self-isolating, on holiday, or redeployed) with a health questionnaire, nasal swab, and blood samples and two concluding assessments at 6 month and 12 months. HCWs were self-declared as healthy and fit to work for study visits. Participants were not given swab results, and those with symptoms or in self-isolation resumed study visits on return to work. Across London, case-doubling time in March, 2020, was approximately 3–4 days. The number of nasal swabs testing positive for SARS-CoV-2 peaked on March 30, 2020, suggesting infections peaked on March 23, 2020, the day of UK lockdown. COVIDsortium was established with all national and local permissions in 7 days. Recruitment started on March 23, 2020, and was completed 8 days later. Here we present the SARS-CoV-2 PCR results from nasal swabs collected at the first five time-points from the first 400 participants (figure ). We show the number and percentage of asymptomatic HCWs who tested positive for SARS-CoV-2 on consecutive weeks from March 23, 2020: 28 (7·1%; 95% CI 4·9–10·0) of 396 HCWs in week 1, 14 (4·9%; 3·0–8·1) of 284 HCWs in week 2, four (1·5%; 0·6–3·8) of 263 HCWs in week 3, four (1·5%; 0·6–3·8) of 267 HCWs in week 4, and three (1·1%, 0·4–3·2) of 269 HCWs in week 5 (figure). Seven HCWs tested positive on two consecutive timepoints, and one HCW tested positive on three consecutive timepoints. During this time, 50 HCWs (not necessarily those who were SARS-CoV-2 positive) self-isolated for symptoms. Of the 44 HCWs who tested positive for SARS-CoV-2, 12 (27%) had no symptoms in the week before or after positivity. Figure Number of patients testing positive for SARS-CoV-2 in Greater London and Barts Health NHS Trust and proportion of the HCW study cohort with SARS-CoV-2-positive nasal swab The left y-axis shows number of daily new SARS-CoV-2 positive patients in the Greater London area, derived from Public Health England data (red curve) and the total number of SARS-CoV-2 positive inpatients at Barts Health NHS Trust (blue curve). Both curves show 7-day averages. The right y-axis shows the percentage (95% CI) of asymptomatic HCWs in this study with SARS-CoV-2 positive swabs in the first 5 weeks of testing. COVID-19=coronavirus disease 2019. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. HCWs=health-care workers. HCWs have been particularly hard hit by the COVID-19 pandemic, with high reported rates of infection from Italian data, 3 raising concerns about the effectiveness of personal protective equipment and of nosocomial transmission. 4 Public fear of hospitals is also currently high, and many serious and treatable diseases are presenting late with adverse outcomes. 5 Testing of HCWs has so far been restricted to symptomatic individuals, and no studies have reported serial testing in high-exposure asymptomatic volunteers. If our results are generalisable to the wider HCW population, then asymptomatic infection rates among HCWs tracked the London general population infection curve, peaking at 7·1% and falling six-fold over 4 weeks, despite the persistence of a high burden of COVID-19 patients through this time (representing most inpatients). Taken together, these data suggest that the rate of asymptomatic infection among HCWs more likely reflects general community transmission than in-hospital exposure. Prospective patients should be reassured that as the overall epidemic wave recedes, asymptomatic infection among HCWs is low and unlikely to be a major source of transmission. These data reinforce the importance of epidemic multi-timepoint surveillance of HCWs. The data also suggest that a testing strategy should link population-representative epidemiological surveillance to predict prevalence, with adaptive testing for symptomatic individuals at times of low prevalence, and rapidly expanding to include the asymptomatic HCWs during possible new infection waves.
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                Author and article information

                Journal
                Lancet
                Lancet
                Lancet (London, England)
                Elsevier Ltd.
                0140-6736
                1474-547X
                25 February 2021
                20-26 March 2021
                25 February 2021
                : 397
                : 10279
                : 1057-1058
                Affiliations
                [a ]Institute of Cardiovascular Science, University College London, London, UK
                [b ]Division of Infection and Immunity, University College London, London, UK
                [c ]Department of Cardiology, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK
                [d ]National Infection Service, Public Health England, Porton Down, UK
                [e ]The Blizard Institute, Queen Mary University of London School of Medicine and Dentistry, London, UK
                [f ]Department of Immunology and Inflammation, Imperial College London, London W12 0NN, UK
                [g ]Department of Infectious Disease, Imperial College London, London W12 0NN, UK
                [h ]Lung Division, Royal Brompton and Harefield Hospitals, London, UK
                Article
                S0140-6736(21)00501-8
                10.1016/S0140-6736(21)00501-8
                7972310
                33640038
                © 2021 Elsevier Ltd. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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