Abstract
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.