ABSTRACT
Characterizing the antibody epitope profiles of messenger RNA (mRNA)-based vaccines against SARS-CoV-2 can aid in elucidating the mechanisms underlying the antibody-mediated immune responses elicited by these vaccines. This study investigated the distinct antibody epitopes toward the SARS-CoV-2 spike (S) protein targeted after a 2-dose primary series of mRNA-1273 followed by a booster dose of mRNA-1273 or a variant-updated vaccine among serum samples from clinical trial adult participants. Multiple S-specific epitopes were targeted after primary vaccination; while signal decreased over time, a booster dose after >6 months largely revived waning antibody signals. Epitope identity also changed after booster vaccination in some subjects, with 4 new S-specific epitopes detected with stronger signals after boosting than with primary vaccination. Notably, the strength of antibody responses after booster vaccination differed by the exact vaccine formulation, with variant-updated mRNA-1273.211 and mRNA-1273.617.2 booster formulations inducing significantly stronger S-specific signals than a mRNA-1273 booster.
ABSTRACT
BackgroundThis interim analysis of an ongoing phase I randomized clinical trial evaluated the safety, reactogenicity, and immunogenicity of mRNA-1283, a next-generation SARS-CoV-2 messenger RNA (mRNA)-based vaccine encoding 2 segments of the spike protein (ie, receptor binding and N-terminal domains). MethodsHealthy aged adults 18-55 years (n = 104) were randomized (1:1:1:1:1) to receive 2 doses of mRNA-1283 (10, 30, or 100 g) or mRNA-1273 (100 g) administered 28 days apart, or a single dose of mRNA-1283 (100 g). Safety was assessed and immunogenicity was measured by serum neutralizing antibody (nAb) or binding antibody (bAb) responses. ResultsAt the interim analysis, no safety concerns were identified and no serious adverse events, adverse events of special interest, or deaths were reported. Solicited systemic adverse reactions were more frequent with higher dose levels of mRNA-1283 than with mRNA-1273. At day 57, all dose levels of the 2-dose mRNA-1283 regimen (including the lowest dose level [10 g]) induced robust nAb and bAb responses that were comparable to those of mRNA-1273 (100 g). ConclusionsmRNA-1283 was generally safe in adults, with all dose levels of the 2-dose regimen (10, 30, and 100 g) eliciting similar immunogenicity as the 2-dose mRNA-1273 regimen (100 g). Clinical Trials RegistrationClinicaltrials.gov, NCT04813796
Subject(s)
DeathABSTRACT
The primary two-dose SARS-CoV-2 mRNA vaccine series are strongly immunogenic in humans, but the emergence of highly infectious variants necessitated additional doses of these vaccines and the development of new variant-derived ones. SARS-CoV-2 booster immunizations in humans primarily recruit pre-existing memory B cells (MBCs). It remains unclear, however, whether the additional doses induce germinal centre (GC) reactions where reengaged B cells can further mature and whether variant-derived vaccines can elicit responses to novel epitopes specific to such variants. Here, we show that boosting with the original SARS-CoV-2 spike vaccine (mRNA-1273) or a B.1.351/B.1.617.2 (Beta/Delta) bivalent vaccine (mRNA-1273.213) induces robust spike-specific GC B cell responses in humans. The GC response persisted for at least eight weeks, leading to significantly more mutated antigen-specific MBC and bone marrow plasma cell compartments. Interrogation of MBC-derived spike-binding monoclonal antibodies (mAbs) isolated from individuals boosted with either mRNA-1273, mRNA-1273.213, or a monovalent Omicron BA.1-based vaccine (mRNA-1273.529) revealed a striking imprinting effect by the primary vaccination series, with all mAbs (n=769) recognizing the original SARS-CoV-2 spike protein. Nonetheless, using a more targeted approach, we isolated mAbs that recognized the spike protein of the SARS-CoV-2 Omicron (BA.1) but not the original SARS-CoV-2 spike from the mRNA-1273.529 boosted individuals. The latter mAbs were less mutated and recognized novel epitopes within the spike protein, suggesting a naive B cell origin. Thus, SARS-CoV-2 boosting in humans induce robust GC B cell responses, and immunization with an antigenically distant spike can overcome the antigenic imprinting by the primary vaccination series.