Heterologous mucosal vaccine boosting enhances mucosal and systemic immunity by distinct mechanisms.

Seasonal booster vaccination is the primary intervention for protection from respiratory viral infections, such as influenza virus or SARS-CoV-2. However, efficacy is often limited because immune exposure to prior strains impairs development of new responses. In this study, we sought to determine how this issue could be overcome in a mouse model of heterologous immunization against WT and omicron strains of SARS-CoV-2. Intranasal booster immunization circumvented the shortcomings of intramuscular immunization, resulting in superior systemic and mucosal T and B cell immunity and better viral control following SARS-CoV-2 challenge in hamsters. Mechanistically, an intranasal omicron booster immunization bypassed deleterious immune imprinting following intramuscular ancestral strain prime, which allowed for induction of de novo lung B cell and antibody responses against the omicron strain. Cross-reactive memory T cells were also efficiently recruited into the lungs. These findings support further testing of mucosal booster vaccines against respiratory viruses, particularly as a means of simultaneously overcoming deleterious immunological imprinting and enhancing mucosal responses.