Licensed SARS-CoV-2 vaccines induce robust systemic immune responses, but mucosal immunity in the respiratory tract in form of secretory immunoglobulin A (IgA) or tissue-resident memory T cells (TRM) is not established. Inducing such front-line immunity by mucosal boosting might reduce the individual risk of breakthrough infections and thereby likely mitigate infection dynamics on population level as well. The following project evaluates preclinical and licensed adenoviral vector (Ad) platforms as mucosal SARS-CoV-2 boosters.

We show that nasal instillation of Ad5- and Ad19a-Spike following a systemic DNA or mRNA priming results in strong systemic and mucosal immunity in mice. In contrast to two intramuscular injections with a licensed mRNA vaccine, the mucosal boost with Ad vectors induced CD103 +CD69 +tissue-resident memory CD8 +T cells and high levels of Spike-specific IgA in the respiratory tract as well as an enhanced mucosal neutralization of variants of concern. Moreover, the protective efficacy of the mRNA prime/intranasal Ad5 boost strategy was not inferior to two intramuscular mRNA immunizations.

In a more translational approach, we employed Janssen’s Ad26.COV2.S as a mucosal booster delivered by a medical mucosal atomization device after a systemic mRNA prime of mice. Concerning systemic responses, the mucosal boost was similarly immunogenic compared to an intramuscular boost with the same vaccine. However, only a mucosal delivery provoked TRM and IgA in the respiratory tract as well as a robust mucosal neutralization of Omicron variants.

In conclusion, a mucosal booster immunization is a promising approach to establish mucosal immunity in addition to systemic responses in an mRNA vaccine-primed population.