Conversion of vaccines from low to high immunogenicity by antibodies with epitope complementarity

• DOI: 10.1016/j.immuni.2024.08.017
• Publication Date: 2024-09-20T15:02:11Z
• Authors: Alexandra R. Dvor...; Craig I. McKenzie; Vera C. Stäheli; Zhoujie Ding; Jacqueline White; Stewart A. Fabb; Leonard Lim; Kristy O’Donnell; Catherine Pitt; Daniel Christ; Danika L. Hill; Colin W. Pouton; Deborah L. Burnett; Robert Brink; Marcus J. Robinson; David M. Tarlinton; Isaak Quast

Existing antibodies (Abs) have varied effects on humoral immunity during subsequent infections. Here, we leveraged in vivo systems that allow precise control of antigen-specific Abs and B cells to examine the impact of Ab dose, affinity, and specificity in directing B cell activation and differentiation. Abs competing with the B cell receptor (BCR) epitope showed affinity-dependent suppression. By contrast, Abs targeting a complementary epitope, not overlapping with the BCR, shifted B cell differentiation toward Ab-secreting cells. Such Abs allowed for potent germinal center (GC) responses to otherwise poorly immunogenic sites by promoting antigen capture and presentation by low-affinity B cells. These mechanisms jointly diversified the B cell repertoire by facilitating the recruitment of high- and low-affinity B cells into Ab-secreting cell, GC, and memory B cell fates. Incorporation of small amounts of monoclonal Abs into protein- or mRNA-based vaccines enhanced immunogenicity and facilitated sustained immune responses, with implications for vaccine design and our understanding of protective immunity.