Nanoparticle Adjuvant Design Enhances Germinal Center Responses Targeting Conserved Subdominant Epitopes for Pan‐Coronavirus Vaccine Development

Abstract Current SARS‐CoV‐2 vaccines primarily elicit antibodies targeting the variable receptor‐binding domain in the S1 subunit of the spike protein, resulting in limited cross‐reactivity and short‐lived immunity against emerging variants. The conserved S2 subunit presents a promising vaccine target for broad and durable protection, but the immunodominance in vaccine‐induced germinal center (GC) responses hinders effective antibody generation against S2. Here, a polymeric toll‐like receptor 7 agonist nanoparticle (TLR7‐NP) adjuvant is reported, well designed to enhance lymph node targeting and more efficiently activate S2‐specific B cells. When combined with Alum‐adsorbed SARS‐CoV‐2 HexaPro spike protein, TLR7‐NP promotes early GC recruitment of S2‐specific B cells and overcomes the immunodominance, leading to early and robust S2‐specific antibody responses. Compared to conventional TLR7‐Alum adjuvanted subunit vaccine and clinically used SARS‐CoV‐2 mRNA vaccine, TLR7‐NP adjuvant induces stronger humoral immune responses across sarbecoviruses and betacoronaviruses and promotes long‐lived plasma cell and memory B cell formation. These findings present a direct B cell‐activating adjuvant approach for effective pan‐coronavirus vaccine development.