Highly Specific Memory B Cells Generation after the 2nd Dose of BNT162b2 Vaccine Compensate for the Decline of Serum Antibodies and Absence of Mucosal IgA

Specific memory B cells and antibodies are a reliable read-out of vaccine efficacy. We analysed these biomarkers after one and two doses of BNT162b2 vaccine. The second dose significantly increases the level of highly specific memory B cells and antibodies. Two months after the second dose, specific antibody levels decline, but highly specific memory B cells continue to increase, thus predicting a sustained protection from COVID-19. We show that although mucosal IgA is not induced by the vaccination, memory B cells migrate in response to inflammation and secrete IgA at mucosal sites. We show that the first vaccine dose may lead to an insufficient number of highly specific memory B cells and low concentration of serum antibodies, thus leaving vaccinees without the immune robustness needed to ensure viral elimination and herd immunity. We also clarify that the reduction of serum antibodies does not diminish the force and duration of the immune protection induced by vaccination. The vaccine does not induce sterilizing immunity. Infection after vaccination may be caused by the lack of local preventive immunity because of the absence of mucosal IgA.

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Highly-specific memory B cells generation after the 2nd dose of BNT162b2 vaccine compensate for the decline of serum antibodies and absence of mucosal IgA

10.1101/2021.06.08.21258284 ◽

2021 ◽

Author(s):

Eva Piano Mortari ◽

Cristina Russo ◽

Maria Rosaria Vinci ◽

Sara Terreri ◽

Ane Fernandez Salinas ◽

...

Keyword(s):

B Cells ◽

Specific Antibody ◽

Herd Immunity ◽

Vaccine Dose ◽

Memory B Cells ◽

Immune Protection ◽

Serum Antibodies ◽

Specific Memory ◽

Antibody Levels ◽

Insufficient Number

Specific memory B cells and antibodies are reliable read-out of vaccine efficacy. We analyzed these biomarkers after one and two doses of BNT162b2 vaccine. The second dose significantly increases the level of highly-specific memory B cells and antibodies. Two months after the second dose, specific antibody levels decline, but highly specific memory B cells continue to increase thus predicting a sustained protection from COVID-19. We show that although mucosal IgA is not induced by the vaccination, memory B cells migrate in response to inflammation and secrete IgA at mucosal sites. We show that first vaccine dose may lead to an insufficient number of highly specific memory B cells and low concentration of serum antibodies thus leaving vaccinees without the immune robustness needed to ensure viral elimination and herd immunity. We also clarify that the reduction of serum antibodies does not diminish the force and duration of the immune protection induced by vaccination. The vaccine does not induce sterile immunity. Infection after vaccination may be caused by the lack of local preventive immunity because of the absence of mucosal IgA.

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Induction of long-lived germinal centers associated with persisting antigen after viral infection.

Journal of Experimental Medicine ◽

10.1084/jem.183.5.2259 ◽

1996 ◽

Vol 183 (5) ◽

pp. 2259-2269 ◽

Cited By ~ 132

Author(s):

M F Bachmann ◽

B Odermatt ◽

H Hengartner ◽

R M Zinkernagel

Keyword(s):

T Cell ◽

B Cells ◽

Viral Infection ◽

Neutralizing Antibody ◽

Germinal Centers ◽

Memory B Cells ◽

Specific Memory ◽

Specific Amplification ◽

Antibody Levels ◽

Red Pulp

Vesicular stomatitis virus (VSV) induces an early T cell-independent neutralizing lgM response that is followed by a long-lived, T cell-dependent lgG response. We used the specific amplification factor of several 100x of VSV-virions for immunohistology to analyze the localization of VSV-specific B cells at different time points after immunization. At the peak of the IgM response (day 4), VSV-specific B cells were predominantly present in the red pulp and marginal zone but not in the T area. These B cells were mostly stained in the cytoplasm, characterizing them as antibody secreting cells. By day 6 after immunization, germinal centers (GC) containing surface-stained VSV-specific B cells became detectable and were fully established by day 12. At the same time, large VSV-specific B cell aggregates were present in the red pulp. High numbers of VSV-specific GC associated with persisting antigen were present 1 mo after immunization and later, i.e., considerably longer than has been observed for haptens. Some GC, exhibiting follicular dendritic cells and containing VSV-specific, proliferating B cells were still detectable up to 100 d after immunization. Long-lived GC were also observed after immunization with recombinant VSV-glycoprotein in absence of adjuvants. Thus some anti-virally protective (memory) B cells are cycling and locally proliferate in long-lived GC in association with persisting antigen and therefore seem responsible for long-term maintenance of elevated antibody levels. These observations extend earlier studies with carrier hapten antigens in adjuvant depots or complexed with specific IgG; they are the first to show colocalization of antigen and specific memory B cells and to analyze a protective neutralizing antibody response against an acute viral infection.

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Switched memory B cells maintain specific memory independently of serum antibodies: The hepatitis B example

European Journal of Immunology ◽

10.1002/eji.201041187 ◽

2011 ◽

Vol 41 (6) ◽

pp. 1800-1808 ◽

Cited By ~ 34

Author(s):

M. Manuela Rosado ◽

Marco Scarsella ◽

Elisabetta Pandolfi ◽

Simona Cascioli ◽

Ezio Giorda ◽

...

Keyword(s):

B Cells ◽

Hepatitis B ◽

Memory B Cells ◽

Serum Antibodies ◽

Specific Memory

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SARS-CoV-2 Vaccine Induced Atypical Immune Responses in Antibody Defects: Everybody Does their Best

Journal of Clinical Immunology ◽

10.1007/s10875-021-01133-0 ◽

2021 ◽

Author(s):

Ane Fernandez Salinas ◽

Eva Piano Mortari ◽

Sara Terreri ◽

Concetta Quintarelli ◽

Federica Pulvirenti ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

Immune Responses ◽

Vaccine Dose ◽

Memory B Cells ◽

Cell Responses ◽

Specific Memory ◽

Immune Deficiencies ◽

Iga Antibody ◽

Specific Igg

Abstract Background Data on immune responses to SARS-CoV-2 in patients with Primary Antibody Deficiencies (PAD) are limited to infected patients and to heterogeneous cohorts after immunization. Methods Forty-one patients with Common Variable Immune Deficiencies (CVID), six patients with X-linked Agammaglobulinemia (XLA), and 28 healthy age-matched controls (HD) were analyzed for anti-Spike and anti-receptor binding domain (RBD) antibody production, generation of Spike-specific memory B-cells, and Spike-specific T-cells before vaccination and one week after the second dose of BNT162b2 vaccine. Results The vaccine induced Spike-specific IgG and IgA antibody responses in all HD and in 20% of SARS-CoV-2 naive CVID patients. Anti-Spike IgG were detectable before vaccination in 4 out 7 CVID previously infected with SARS-CoV-2 and were boosted in six out of seven patients by the subsequent immunization raising higher levels than patients naïve to infection. While HD generated Spike-specific memory B-cells, and RBD-specific B-cells, CVID generated Spike-specific atypical B-cells, while RBD-specific B-cells were undetectable in all patients, indicating the incapability to generate this new specificity. Specific T-cell responses were evident in all HD and defective in 30% of CVID. All but one patient with XLA responded by specific T-cell only. Conclusion In PAD patients, early atypical immune responses after BNT162b2 immunization occurred, possibly by extra-follicular or incomplete germinal center reactions. If these responses to vaccination might result in a partial protection from infection or reinfection is now unknown. Our data suggests that SARS-CoV-2 infection more effectively primes the immune response than the immunization alone, possibly suggesting the need for a third vaccine dose for patients not previously infected.

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Distinct antibody and memory B cell responses in SARS-CoV-2 naïve and recovered individuals following mRNA vaccination

Science Immunology ◽

10.1126/sciimmunol.abi6950 ◽

2021 ◽

Vol 6 (58) ◽

pp. eabi6950 ◽

Cited By ~ 1

Author(s):

Rishi R. Goel ◽

Sokratis A. Apostolidis ◽

Mark M. Painter ◽

Divij Mathew ◽

Ajinkya Pattekar ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Vaccine Dose ◽

Memory B Cells ◽

Memory B Cell ◽

Cell Responses ◽

Specific Memory ◽

Resource Limited ◽

B Cell Responses ◽

Vaccine Distribution

Novel mRNA vaccines for SARS-CoV-2 have been authorized for emergency use. Despite their efficacy in clinical trials, data on mRNA vaccine-induced immune responses are mostly limited to serological analyses. Here, we interrogated antibody and antigen-specific memory B cells over time in 33 SARS-CoV-2 naïve and 11 SARS-CoV-2 recovered subjects. SARS-CoV-2 naïve individuals required both vaccine doses for optimal increases in antibodies, particularly for neutralizing titers against the B.1.351 variant. Memory B cells specific for full-length spike protein and the spike receptor binding domain (RBD) were also efficiently primed by mRNA vaccination and detectable in all SARS-CoV-2 naive subjects after the second vaccine dose, though the memory B cell response declined slightly with age. In SARS-CoV-2 recovered individuals, antibody and memory B cell responses were significantly boosted after the first vaccine dose; however, there was no increase in circulating antibodies, neutralizing titers, or antigen-specific memory B cells after the second dose. This robust boosting after the first vaccine dose strongly correlated with levels of pre-existing memory B cells in recovered individuals, identifying a key role for memory B cells in mounting recall responses to SARS-CoV-2 antigens. Together, our data demonstrated robust serological and cellular priming by mRNA vaccines and revealed distinct responses based on prior SARS-CoV-2 exposure, whereby COVID-19 recovered subjects may only require a single vaccine dose to achieve peak antibody and memory B cell responses. These findings also highlight the utility of defining cellular responses in addition to serologies and may inform SARS-CoV-2 vaccine distribution in a resource-limited setting.

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Immune escape of SARS-CoV-2 Omicron variant from mRNA vaccination-elicited RBD-specific memory B cells.

10.1101/2021.12.21.473528 ◽

2021 ◽

Author(s):

Aurelien Sokal ◽

Matteo Broketa ◽

Annalisa Meola ◽

Giovanna Barba-Spaeth ◽

Ignacio Fernandez ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Receptor Binding ◽

Immune Escape ◽

Memory B Cells ◽

Receptor Binding Domain ◽

Immune Protection ◽

Neutralizing Activity ◽

High Affinity ◽

Specific Memory

Memory B cells (MBCs) represent a second layer of immune protection against SARS-CoV-2. Whether MBCs elicited by mRNA vaccines can recognize the Omicron variant is of major concern. We used bio-layer interferometry to assess the affinity against the receptor-binding-domain (RBD) of Omicron spike of 313 naturally expressed monoclonal IgG that were previously tested for affinity and neutralization against VOC prior to Omicron. We report here that Omicron evades recognition from a larger fraction of these antibodies than any of the previous VOCs. Additionally, whereas 30% of these antibodies retained high affinity against Omicron-RBD, our analysis suggest that Omicron specifically evades antibodies displaying potent neutralizing activity against the D614G and Beta variant viruses. Further studies are warranted to understand the consequences of a lower memory B cell potency on the overall protection associated with current vaccines.

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Longitudinal Analysis Reveals Distinct Antibody and Memory B Cell Responses in SARS-CoV2 Naïve and Recovered Individuals Following mRNA Vaccination

10.1101/2021.03.03.21252872 ◽

2021 ◽

Author(s):

Rishi R. Goel ◽

Sokratis A. Apostolidis ◽

Mark M. Painter ◽

Divij Mathew ◽

Ajinkya Pattekar ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Memory B Cells ◽

Antibody Responses ◽

Short Term ◽

Memory B Cell ◽

Cell Responses ◽

Specific Memory ◽

B Cell Responses ◽

Antibody Levels

ABSTRACTNovel 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.Abstract Figure

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