Pre-existing immunity modulates responses to mRNA boosters

TLDR

mRNA vaccines are highly effective against severe COVID‑19, yet breakthrough infections, emerging variants, and waning antibody levels have led to widespread booster use, though the influence of pre‑existing immunity on booster efficacy remains unclear. In individuals primed with mRNA‑1273 or BNT162b2, lower pre‑boost antibody levels predict greater fold‑increases post‑boost, and mechanistic studies show that pre‑existing antibodies limit antigen expression and B‑cell priming, making the superiority of updated Omicron vaccines contingent on host serostatus and demonstrating that pre‑existing immunity governs mRNA vaccine responses.

Abstract

mRNA vaccines have shown high efficacy in preventing severe COVID-19, but breakthrough infections, emerging variants and waning antibody levels have warranted the use of boosters. Although mRNA boosters have been widely implemented, the extent to which pre-existing immunity influences the efficacy of boosters remains unclear. In a cohort of individuals primed with the mRNA-1273 or BNT162b2 vaccines, we observed that lower antibody levels before boost were associated with higher fold-increase in antibody levels after boost, suggesting that pre-existing antibody modulates the boosting capacity of mRNA vaccines. Mechanistic studies in mice show that pre-existing antibodies significantly limit antigen expression and priming of B cell responses after mRNA vaccination. Furthermore, we demonstrate that the relative superiority of an updated Omicron vaccine over the original vaccine is critically dependent on the serostatus of the host. These data demonstrate that pre-existing immunity dictates responses to mRNA vaccination, elucidating specific circumstances when updated SARS-CoV-2 vaccines confer superior protection to original vaccines.