Early human B cell signatures of the primary antibody response to mRNA vaccination

Messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective at inducing protective immunity. However, weak antibody responses are seen in some individuals, and cellular correlates of immunity remain poorly defined, especially for B cells. Here we used unbiased approaches to longitudinally dissect primary antibody, plasmablast, and memory B cell (MBC) responses to the two-dose mRNA-1273 vaccine in SARS-CoV-2–naive adults. Coordinated immunoglobulin A (IgA) and IgG antibody responses were preceded by bursts of spike-specific plasmablasts after both doses but earlier and more intensely after dose 2. While antibody and B cell cellular responses were generally robust, they also varied within the cohort and decreased over time after a dose-2 peak. Both antigen-nonspecific postvaccination plasmablast frequency after dose 1 and their spike-specific counterparts early after dose 2 correlated with subsequent antibody levels. This correlation between early plasmablasts and antibodies remained for titers measured at 6 months after vaccination. Several distinct antigen-specific MBC populations emerged postvaccination with varying kinetics, including two MBC populations that correlated with 2- and 6-month antibody titers. Both were IgG-expressing MBCs: one less mature, appearing as a correlate after the first dose, while the other MBC correlate showed a more mature and resting phenotype, emerging as a correlate later after dose 2. This latter MBC was also a major contributor to the sustained spike-specific MBC response observed at month 6. Thus, these plasmablasts and MBCs that emerged after both the first and second doses with distinct kinetics are potential determinants of the magnitude and durability of antibodies in response to mRNA-based vaccination.

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) instigated rapid worldwide COVID-19 vaccine prioritization strategies. Several vaccine candidates were developed, including two vaccines (Moderna mRNA-1273 and the Pfizer/BioNTech BNT162b2), based on novel messenger RNA (mRNA) platforms (1). Both mRNA vaccines encode a stabilized ectodomain of the spike protein trimer (S-2P) derived from the Wuhan Hu-1 isolate (2). Two doses of mRNA vaccines have been shown to be highly protective and elicit strong antibody responses (3, 4), although poorer responses have also been seen in some individuals, such as older adults (5, 6) and transplant recipients (7, 8), raising the question of what determines antibody response levels and whether cellular correlates can be defined. Several studies have shown that SARS-CoV-2 mRNA vaccines can elicit a durable cellular response, including among B cells (reviewed in (9)), with memory B cells (MBCs) shown to correlate with the antibody response (10).In the B cell compartment, one of the first detected responses in the blood after a primary immunization is a short transient burst around days 7–10 of plasmablasts (PBs) that are probably induced by the extrafollicular response and potentially responsible for the early serum antibodies to the immunogen, reviewed in (11). While it is unclear whether PBs are direct precursors of bone marrow–resident plasma cells that are the main source of circulating antibodies (12), several studies on inactivated and attenuated vaccines have shown that the PB response can predict the magnitude and longevity of protective antibodies (13–16). Among these predictors are PB responses that are independent of antigen specificity (17, 18), suggesting that the quantitative extent of antigen-specific responses is coupled to that of the total PB responses detectable in blood, including bystander and PBs with weak affinity for detection (13, 15). For mRNA-based SARS-CoV-2 vaccines, several studies have described a robust yet highly variable PB response in blood and draining lymph nodes (5, 19), and there is evidence of a clonal relationship between PBs in the blood and MBCs in the lymph nodes (20). Despite these advances, the role of PBs and other B cell populations in the induction and longevity of antibodies following mRNA-based vaccination and how they differ across individuals and potentially contribute to variability in antibody responses have not been fully assessed.Here we performed parallel antibody and cellular assays on frequent blood collections to capture the early events of the primary B cell response to the mRNA vaccine mRNA-1273. Using an unbiased approach, we identified PBs and other early B cell populations as correlates of the antibody response to SARS-CoV-2 mRNA-based vaccination.