CD25 modulation enhances broadly neutralizing antibody response of SARS-CoV-2 subunit vaccine.

The primary aim of COVID-19 vaccine development is to induce highly efficient broadly neutralizing antibodies (bNAbs) against circulating and emergent SARS-CoV-2 variants. Rapid and sustained germinal center (GC) responses at an early stage are crucial to produce bNAbs. However, the mechanisms underlying the formation of early GC responses and strategies to effectively promote these responses remain to be further investigated. In this study, we found that the combination of anti-CD25 monoclonal antibodies (mAb) with the COVID-19 subunit vaccine significantly enhances cross-reactive neutralizing antibody responses in mice. Modulation of CD25 at different time points before and after vaccination resulted in varying effects on the GC response, with day 0 being the most effective in assisting the vaccine to induce a stronger GC response. This enhancement is achieved by rapidly inhibiting regulatory T (Treg) cells in draining lymph nodes, an effect observed not only in antigen-specific subsets but also across the bulk lymphocyte population-thereby creating a pro-immune microenvironment that facilitates the induction of an effective early GC response. This leads to the generation of more antigen-recognizing B cells and significantly increases both the potency and breadth of neutralizing antibody responses. Our findings propose a strategy to enhance vaccine efficacy against SARS-CoV-2 and other hypervariable pathogens by effectively promoting the development of early and robust GC responses.