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      Vaccine Breakthrough Infections with SARS-CoV-2 Variants

      research-article
      , Ph.D., , Ph.D., , Ph.D., , Ph.D., , B.S.N., , Ph.D., , Ph.D., , M.S., , Ph.D., , M.D., , M.D., Ph.D., , M.D., Ph.D., , Ph.D., , Ph.D., , M.D., Ph.D.
      The New England Journal of Medicine
      Massachusetts Medical Society
      Keyword part (code): 18Keyword part (keyword): Infectious DiseaseKeyword part (code): 18_2Keyword part (keyword): VaccinesKeyword part (code): 18_6Keyword part (keyword): Viral Infections , 18, Infectious Disease, Keyword part (code): 18_2Keyword part (keyword): VaccinesKeyword part (code): 18_6Keyword part (keyword): Viral Infections , 18_2, Vaccines, 18_6, Viral Infections

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          Summary

          Emerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are of clinical concern. In a cohort of 417 persons who had received the second dose of BNT162b2 (Pfizer–BioNTech) or mRNA-1273 (Moderna) vaccine at least 2 weeks previously, we identified 2 women with vaccine breakthrough infection. Despite evidence of vaccine efficacy in both women, symptoms of coronavirus disease 2019 developed, and they tested positive for SARS-CoV-2 by polymerase-chain-reaction testing. Viral sequencing revealed variants of likely clinical importance, including E484K in 1 woman and three mutations (T95I, del142–144, and D614G) in both. These observations indicate a potential risk of illness after successful vaccination and subsequent infection with variant virus, and they provide support for continued efforts to prevent and diagnose infection and to characterize variants in vaccinated persons. (Funded by the National Institutes of Health and others.)

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          Most cited references12

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          A dynamic nomenclature proposal for SARS-CoV-2 lineages to assist genomic epidemiology

          The ongoing pandemic spread of a novel human coronavirus, SARS-COV-2, associated with severe pneumonia disease (COVID-19), has resulted in the generation of tens of thousands of virus genome sequences. The rate of genome generation is unprecedented, yet there is currently no coherent nor accepted scheme for naming the expanding phylogenetic diversity of SARS-CoV-2. We present a rational and dynamic virus nomenclature that uses a phylogenetic framework to identify those lineages that contribute most to active spread. Our system is made tractable by constraining the number and depth of hierarchical lineage labels and by flagging and de-labelling virus lineages that become unobserved and hence are likely inactive. By focusing on active virus lineages and those spreading to new locations this nomenclature will assist in tracking and understanding the patterns and determinants of the global spread of SARS-CoV-2.
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            Convergent Antibody Responses to SARS-CoV-2 in Convalescent Individuals

            During the COVID-19 pandemic, SARS-CoV-2 infected millions of people and claimed hundreds of thousands of lives. Virus entry into cells depends on the receptor binding domain (RBD) of the SARS-CoV-2 spike protein (S). Although there is no vaccine, it is likely that antibodies will be essential for protection. However, little is known about the human antibody response to SARS-CoV-2 1–5 . Here we report on 149 COVID-19 convalescent individuals. Plasmas collected an average of 39 days after the onset of symptoms had variable half-maximal pseudovirus neutralizing titers: less than 1:50 in 33% and below 1:1000 in 79%, while only 1% showed titers >1:5000. Antibody sequencing revealed expanded clones of RBD-specific memory B cells expressing closely related antibodies in different individuals. Despite low plasma titers, antibodies to three distinct epitopes on RBD neutralized at half-maximal inhibitory concentrations (IC50s) as low as single digit ng/mL. Thus, most convalescent plasmas obtained from individuals who recover from COVID-19 do not contain high levels of neutralizing activity. Nevertheless, rare but recurring RBD-specific antibodies with potent antiviral activity were found in all individuals tested, suggesting that a vaccine designed to elicit such antibodies could be broadly effective.
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              Evolution of antibody immunity to SARS-CoV-2

              Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected 78 million individuals and is responsible for over 1.7 million deaths to date. Infection is associated with the development of variable levels of antibodies with neutralizing activity, which can protect against infection in animal models1,2. Antibody levels decrease with time, but, to our knowledge, the nature and quality of the memory B cells that would be required to produce antibodies upon reinfection has not been examined. Here we report on the humoral memory response in a cohort of 87 individuals assessed at 1.3 and 6.2 months after infection with SARS-CoV-2. We find that titres of IgM and IgG antibodies against the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 decrease significantly over this time period, with IgA being less affected. Concurrently, neutralizing activity in plasma decreases by fivefold in pseudotype virus assays. By contrast, the number of RBD-specific memory B cells remains unchanged at 6.2 months after infection. Memory B cells display clonal turnover after 6.2 months, and the antibodies that they express have greater somatic hypermutation, resistance to RBD mutations and increased potency, indicative of continued evolution of the humoral response. Immunofluorescence and PCR analyses of intestinal biopsies obtained from asymptomatic individuals at 4 months after the onset of coronavirus disease 2019 (COVID-19) revealed the persistence of SARS-CoV-2 nucleic acids and immunoreactivity in the small bowel of 7 out of 14 individuals. We conclude that the memory B cell response to SARS-CoV-2 evolves between 1.3 and 6.2 months after infection in a manner that is consistent with antigen persistence.
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                Author and article information

                Journal
                N Engl J Med
                N Engl J Med
                nejm
                The New England Journal of Medicine
                Massachusetts Medical Society
                0028-4793
                1533-4406
                21 April 2021
                : NEJMoa2105000
                Affiliations
                From the Laboratory of Molecular Neuro-oncology (E.H., C.H., Y.S., N.E.B., M.B., E.G.C., R.B.D.), the Laboratory of Molecular Immunology (D.J.S.-B., C.G., M.C.N.), the Laboratory of Human Genetics and Genomics (R.L.), the Laboratory of Retrovirology (J.D., F.M., T.H., P.D.B.), and the Howard Hughes Medical Institute (M.C.N., P.D.B., R.B.D.), Rockefeller University, New York.
                Author notes
                Address reprint requests to Dr. Darnell at the Laboratory of Molecular Neuro-oncology, Rockefeller University, 1230 York Ave., New York, NY 10065-6307, or at darnelr@ 123456rockefeller.edu .
                Author information
                http://orcid.org/0000-0002-5134-8088
                Article
                NJ202104213842306
                10.1056/NEJMoa2105000
                8117968
                33882219
                ab9dc5ba-cf73-47fd-b927-c42e2a86b52a
                Copyright © 2021 Massachusetts Medical Society. All rights reserved.

                This article is made available via the PMC Open Access Subset for unrestricted re-use, except commercial resale, and analyses in any form or by any means with acknowledgment of the original source. These permissions are granted for the duration of the Covid-19 pandemic or until revoked in writing. Upon expiration of these permissions, PMC is granted a license to make this article available via PMC and Europe PMC, subject to existing copyright protections.

                History
                Funding
                Funded by: Howard Hughes Medical Institute, FundRef http://dx.doi.org/10.13039/100000011;
                Categories
                Original Article
                Brief Report
                Custom metadata
                2021-04-21T17:00:00-04:00
                2021
                04
                21
                17
                00
                00
                -04:00

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