Maturation and persistence of the anti-SARS-CoV-2 memory B cell response

Sokal, Aurélien; Chappert, Pascal; Roeser, Anaïs; Barba-Spaeth, Giovanna; Fourati, Slim; Azzaoui, Imane; Vandenberghe, Alexis; Fernández, Ignacio; Bouvier‐Alias, Magali; Crickx, Étienne; Ferchiou, Asma Beldi; Hüe, Sophie; Languille, Laetitia; Baloul, Samia; Luka, Marine; Mégret, Jérôme; Ménager, Mickaël; Pawlotsky, Jean‐Michel; Fillatreau, Simon; Rey, F.A.; Weill, Jean‐Claude; Reynaud, Claude‐Agnès; Mahévas, Matthieu

doi:10.1101/2020.11.17.385252

Cited by 106 publications

(178 citation statements)

References 71 publications

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“…Memory responses are responsible for protection from reinfection and are essential for effective vaccination. The observation that memory B cell responses do not decay after 6.2 months 34,35,42 , but instead continue to evolve, is strongly suggestive that individuals who are infected with SARS-CoV-2 could mount a rapid and effective response to the virus upon re-exposure.…”

Section: Articlementioning

confidence: 99%

Evolution of antibody immunity to SARS-CoV-2

Gaebler

Wang

Lorenzi

et al. 2021

Nature

1,585

164

1,662

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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 models 1,2. 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. Antibody responses to SARS-CoV-2 were initially characterized in a cohort of individuals convalescing from COVID-19 at approximately 40 days (1.3 months) after infection 1. Between 31 August and 16 October 2020, 100 participants returned for a 6-month follow-up study visit. Although the initial criteria allowed enrolment of the close contacts of individuals with SARS-CoV-2 infection confirmed by reverse-transcription PCR (RT-PCR) 1 , 13 of the contacts did not seroconvert and were excluded from further analyses. The remaining 87 participants with RT-PCR-confirmed SARS-CoV-2 infection and/ or seroconversion returned for analysis at approximately 191 days (6.2 months; range of 165 to 223 days) after the onset of symptoms. In this cohort, symptoms lasted for a median of 12 days (range of 0 to 44 days) during the acute phase, and 10 (11%) of the participants were hospitalized. Consistent with other reports 3,4 , 38 (44%) of the participants reported persistent long-term symptoms attributable to COVID-19 (Methods, Supplementary Tables 1, 2). The duration and severity of symptoms during acute disease was significantly greater among participants with persistent post-acute symptoms at the second study visit (Extended Data Fig. 1m-q). Importantly, all 87 participants tested negative for SARS-CoV-2 at the 6-month follow...

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Section: Articlementioning

confidence: 99%

Evolution of antibody immunity to SARS-CoV-2

Gaebler

Wang

Lorenzi

et al. 2021

Nature

1,585

164

1,662

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“…In humans, the presence of neutralizing antibodies can predict disease severity and survival after primary SARS-CoV-2 infection ( 9 ) and correlates with protection from secondary infection ( 10, 11 ). Further, memory B cells induced by natural infection in humans may persist and, in some cases, continue to affinity mature for greater than 6 months after primary infection ( 12–15 ) providing potentially durable long-term protection. Comparable levels of neutralizing antibody titers were present in convalescent COVID-19 subjects and vaccine recipients ( 16–18 ) further supporting the role of adaptive immune responses in helping to control and prevent disease severity.…”

Section: Main Textmentioning

confidence: 99%

Naive human B cells engage the receptor binding domain of SARS-CoV-2, variants of concern, and related sarbecoviruses

Feldman

Bals

Altomare

et al. 2021

Preprint

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Exposure to a pathogen elicits an adaptive immune response aimed to control and eradicate. This initial exposure is imprinted on the immune system, so that a subsequent encounter to the same pathogen or a variant will result in a memory recall response that is often protective. Interrogating the naive B cell repertoire in terms of both abundance and specificity to said pathogen may contribute to an understanding of how to potentially elicit protective responses. Here, we isolated naive B cells across 8 human donors, targeting the SARS-CoV-2 receptor-binding domain (RBD). Single B cell sorting, and subsequent sequence analysis, showed diverse gene usage and pairing with no apparent restriction on complementarity determining region length in either the heavy or light chains. We show that recombinantly expressed IgGs and Fabs of these germline precursors bind SARS-CoV-2 RBD. Importantly, a subset of these naive antibodies also bind SARS-CoV, an emergent variant (501Y.V2) and a potential pandemic (WIV-1) coronavirus. Furthermore, naive antibodies can also neutralize SARS-CoV-2 pseudoviruses in the absence of any somatic hypermutation, suggesting that protective immunity to coronaviruses, more broadly, may be genetically encoded. Future studies aimed at understanding the naive repertoire to other coronaviruses may ultimately reveal shared specificities that could be leveraged to develop pan-coronavirus vaccines aimed at priming encoded germline responses.

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“…Memory responses are responsible for protection from re-infection and are essential for effective vaccination. The observation that memory B cell responses do not decay after 6.2 months 34,35,42 , but instead continue to evolve, is strongly suggestive that individuals who are infected with SARS-CoV-2 could mount a rapid and effective response to the virus upon re-exposure.…”

mentioning

confidence: 99%

Evolution of Antibody Immunity to SARS-CoV-2

Gaebler

Wang

Lorenzi

et al. 2020

Preprint

178

221

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SARS-CoV-2 has infected 47 million individuals and is responsible for over 1.2 million deaths to date. Infection is associated with development of variable levels of antibodies with neutralizing activity that can protect against infection in animal models. Antibody levels decrease with time, but the nature and quality of the memory B cells that would be called upon to produce antibodies upon re-infection 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. We find that IgM, and IgG anti-SARS-CoV-2 spike protein receptor binding domain (RBD) antibody titers decrease significantly with IgA being less affected. Concurrently, neutralizing activity in plasma decreases by five-fold in pseudotype virus assays. In contrast, the number of RBD-specific memory B cells is unchanged. Memory B cells display clonal turnover after 6.2 months, and the antibodies they express have greater somatic hypermutation, increased potency and resistance to RBD mutations, indicative of continued evolution of the humoral response. Analysis of intestinal biopsies obtained from asymptomatic individuals 3 months after COVID-19 onset, using immunofluorescence, electron tomography or polymerase chain reaction, revealed persistence of SARS-CoV-2 in the small bowel of 7 out of 14 volunteers. 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.

show abstract

Maturation and persistence of the anti-SARS-CoV-2 memory B cell response

Cited by 106 publications

References 71 publications

Evolution of antibody immunity to SARS-CoV-2

Evolution of antibody immunity to SARS-CoV-2

Naive human B cells engage the receptor binding domain of SARS-CoV-2, variants of concern, and related sarbecoviruses

Evolution of Antibody Immunity to SARS-CoV-2

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