Mengyun Hu

Vaccine adjuvants increase the breadth of serum antibody responses, but whether this is due to the generation of antigen-specific B cell clones with distinct specificities or the maturation of memory B cell clones that produce broadly cross-reactive antibodies is unknown. Here, we longitudinally analyzed immune responses in healthy adults after two-dose vaccination with either a virus-like particle COVID-19 vaccine (CoVLP), CoVLP adjuvanted with AS03 (CoVLP+AS03), or a messenger RNA vaccination (mRNA-1273). CoVLP+AS03 enhanced the magnitude and durability of circulating antibodies and antigen-specific CD4 + T cell and memory B cell responses. Antigen-specific CD4 + T cells in the CoVLP+AS03 group at day 42 correlated with antigen-specific memory B cells at 6 months. CoVLP+AS03 induced memory B cell responses, which accumulated somatic hypermutations over 6 months, resulting in enhanced neutralization breadth of monoclonal antibodies. Furthermore, the fraction of broadly neutralizing antibodies encoded by memory B cells increased between day 42 and 6 months. These results indicate that AS03 enhances the antigenic breadth of B cell memory at the clonal level and induces progressive maturation of the B cell response.

T follicular helper (T FH ) cells play an essential role in promoting B cell responses and antibody affinity maturation in germinal centers (GC). A subset of memory CD4 + T cells expressing the chemokine receptor CXCR5 has been described in human blood as phenotypically and clonally related to GC T FH cells. However, the antigen specificity and relationship of these circulating T FH (cT FH ) cells with other memory CD4 + T cells remain poorly defined. Combining antigenic stimulation and T cell receptor (TCR) Vβ sequencing, we found T cells specific to tetanus toxoid (TT), influenza vaccine (Flu), or Candida albicans ( C.alb ) in both cT FH and non‐cT FH subsets, although with different frequencies and effector functions. Interestingly, cT FH and non‐cT FH cells specific for C.alb or TT had a largely overlapping TCR Vβ repertoire while the repertoire of Flu‐specific cT FH and non‐cT FH cells was distinct. Furthermore, Flu‐specific but not C.alb ‐specific PD‐1 + cT FH cells had a “GC T FH ‐like” phenotype, with overexpression of IL21, CXCL13 , and BCL6 . Longitudinal analysis of serial blood donations showed that Flu‐specific cT FH and non‐cT FH cells persisted as stable repertoires for years. Collectively, our study provides insights on the relationship of cT FH with non‐cT FH cells and on the heterogeneity and persistence of antigen‐specific human cT FH cells.