Human type I IFN deficiency does not impair B cell response to SARS-CoV-2 mRNA vaccination.

Inborn and acquired deficits of type I interferon (IFN) immunity predispose to life-threatening COVID-19 pneumonia. We longitudinally profiled the B cell response to mRNA vaccination in SARS-CoV-2 naive patients with inherited TLR7, IRF7, or IFNAR1 deficiency, as well as young patients with autoantibodies neutralizing type I IFNs due to autoimmune polyendocrine syndrome type-1 (APS-1) and older individuals with age-associated autoantibodies to type I IFNs. The receptor-binding domain spike protein (RBD)-specific memory B cell response in all patients was quantitatively and qualitatively similar to healthy donors. Sustained germinal center responses led to accumulation of somatic hypermutations in immunoglobulin heavy chain genes. The amplitude and duration of, and viral neutralization by, RBD-specific IgG serological response were also largely unaffected by TLR7, IRF7, or IFNAR1 deficiencies up to 7 mo after vaccination in all patients. These results suggest that induction of type I IFN is not required for efficient generation of a humoral response against SARS-CoV-2 by mRNA vaccines.

Immune Responses after a Third Dose of mRNA Vaccine Differ in Virus-Naive versus SARS-CoV-2- Recovered Dialysis Patients.

BACKGROUND AND OBJECTIVES: After two doses of mRNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), patients on dialysis show a defective humoral response, but a third dose could increase anti-SARS-CoV-2 spike IgG titers. Responses could be different in virus-naive and SARS-CoV-2-recovered patients on dialysis. However, characterization of memory B cell response after three doses is lacking. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We evaluated the dynamics of antireceptor binding domain IgG titers and antireceptor binding domain memory B cells until 6 months after two and three doses (administered within 6 months after the second dose) of mRNA vaccine in SARS-CoV-2-recovered and virus-naive dialysis populations. Results were analyzed by ordinary one-way ANOVA, the Kruskal-Wallis test, or the Wilcoxon matched-pairs test as appropriate. RESULTS: In total, 108 individuals (59 patients on dialysis and 49 controls) were included. In virus-naive patients on dialysis, antireceptor binding domain IgG response was quantitatively lower after two doses compared with healthy controls, but IgG titers increased by three-fold after three doses (P=0.008). In SARS-CoV-2-recovered patients on dialysis, antireceptor binding domain IgG titers after two doses were significantly higher compared with virus-naive patients on dialysis but did not significantly increase after a third dose. Regarding memory B cell response, we detected receptor binding domain-specific memory B cells at similar proportions in virus-naive patients on dialysis and vaccinated controls after two doses. Moreover, a strong receptor binding domain-specific memory B cell expansion was observed after the third dose in virus-naive patients on dialysis (5.5-fold; P<0.001). However, in SARS-CoV-2-recovered patients on dialysis, antireceptor binding domain memory B cells remained unchanged after the third dose. CONCLUSIONS: The third dose of mRNA vaccine given within 6 months after the second dose boosts serologic and memory response in virus-naive patients but not in SARS-CoV-2-recovered patients on dialysis. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: COVID-19: SARS-CoV-2 Specific Memory B and T-CD4+ Cells (MEMO-COV2), NCT04402892.

Analysis of mRNA vaccination-elicited RBD-specific memory B cells reveals strong but incomplete immune escape of the SARS-CoV-2 Omicron variant.

The SARS-CoV-2 Omicron variant can escape neutralization by vaccine-elicited and convalescent antibodies. Memory B cells (MBCs) represent another layer of protection against SARS-CoV-2, as they persist after infection and vaccination and improve their affinity. Whether MBCs elicited by mRNA vaccines can recognize the Omicron variant remains unclear. We assessed the affinity and neutralization potency against the Omicron variant of several hundred naturally expressed MBC-derived monoclonal IgG antibodies from vaccinated COVID-19-recovered and -naive individuals. Compared with other variants of concern, Omicron evaded recognition by a larger proportion of MBC-derived antibodies, with only 30% retaining high affinity against the Omicron RBD, and the reduction in neutralization potency was even more pronounced. Nonetheless, neutralizing MBC clones could be found in all the analyzed individuals. Therefore, despite the strong immune escape potential of the Omicron variant, these results suggest that the MBC repertoire generated by mRNA vaccines still provides some protection against the Omicron variant in vaccinated individuals.

La diversité du répertoire des cellules B mémoires fait face aux variants du SRAS-CoV2 après la vaccination par ARNm chez les individus naïfs et guéris

L'émergence de variants portant des mutations dans des épitopes clés a fait craindre que l'évolution virale n'érode l'immunité acquise. Caractérisé la dynamique et la fonctionnalité de la réponse B mémoire naturelle et acquise après administration d'un vaccin à ARNm. Nous avons analysé, au cours du temps, 33 sujets avec un antécédent de la COVID-19 et 23 individus naïfs avant et après vaccination par ARNm. Nous avons combiné différentes approches, l'analyse transcriptomique en cellule unique, le séquençage du VH, le phénotypages cellulaire par cytométrie en flux multi-paramétriques ainsi que la mesure du pouvoir neutralisant des anticorps et leur affinité. La mémoire B anti-SARS-Cov-2 porte une empreinte d'un passage par le centre germinatif et parait stable chez la majorité des patients, et ce un an après l'infection initiale. Le rappel vaccinal mobilise les B mémoires sans entraîner de réduction de leur diversité. Chez les patients guéris, les B mémoires spécifiques du RBD montrent des preuves évidentes de sélection par affinité, un processus toujours en cours chez les individus naïfs, deux mois après leur deuxième dose. Seule une faible proportion de clones B mémoires spécifiques du domaine RBD n'a pas réussi à reconnaître le variant B.1.351. Néanmoins, de puissantes B mémoires neutralisant le B.1.351 pourraient toujours être détectés chez tous les individus naïfs et guéris de la Covid-19. En raison de sa diversité et de son affinité, le répertoire B mémoires anti la protéine RBDwt, sélectionné lors de l'infection ou la vaccination contient des clones capables de faire face à l'évolution virale. (French) [ABSTRACT FROM AUTHOR] Copyright of Transfusion Clinique et Biologique is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

mRNA vaccination of naive and COVID-19-recovered individuals elicits potent memory B cells that recognize SARS-CoV-2 variants.

In addition to serum immunoglobulins, memory B cell (MBC) generation against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is another layer of immune protection, but the quality of MBC responses in naive and coronavirus disease 2019 (COVID-19)-recovered individuals after vaccination remains ill defined. We studied longitudinal cohorts of naive and disease-recovered individuals for up to 2 months after SARS-CoV-2 mRNA vaccination. We assessed the quality of the memory response by analysis of antibody repertoires, affinity, and neutralization against variants of concern (VOCs) using unbiased cultures of 2,452 MBCs. Upon boosting, the MBC pool of recovered individuals expanded selectively, matured further, and harbored potent neutralizers against VOCs. Although naive individuals had weaker neutralizing serum responses, half of their RBD-specific MBCs displayed high affinity toward multiple VOCs, including delta (B.1.617.2), and one-third retained neutralizing potency against beta (B.1.351). Our data suggest that an additional challenge in naive vaccinees could recall such affinity-matured MBCs and allow them to respond efficiently to VOCs.

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

Memory B cells play a fundamental role in host defenses against viruses, but to date, their role has been relatively unsettled in the context of SARS-CoV-2. We report here a longitudinal single-cell and repertoire profiling of the B cell response up to 6 months in mild and severe COVID-19 patients. Distinct SARS-CoV-2 spike-specific activated B cell clones fueled an early antibody-secreting cell burst as well as a durable synchronous germinal center response. While highly mutated memory B cells, including pre-existing cross-reactive seasonal Betacoronavirus-specific clones, were recruited early in the response, neutralizing SARS-CoV-2 RBD-specific clones accumulated with time and largely contributed to the late, remarkably stable, memory B cell pool. Highlighting germinal center maturation, these cells displayed clear accumulation of somatic mutations in their variable region genes over time. Overall, these findings demonstrate that an antigen-driven activation persisted and matured up to 6 months after SARS-CoV-2 infection and may provide long-term protection.