Induction of mucosal immune responses against SARS-CoV-2: a heterologous intramuscular mRNA-LNP prime/pulmonary recombinant subunit pull vaccination strategy.

Approved mRNA vaccines administered intramuscularly (i.m.) induce strong systemic immune responses, but provide limited protection at the respiratory mucosa, where many infections are initiated. Designing safe and efficacious mucosal vaccines is challenging because it requires vaccine administration at the mucosa that is equipped with protective barriers and characterized by tolerogenic predominance. Here we show that i.m. prime immunization of mice with lipid nanoparticles (LNPs) loaded with mRNA encoding the SARS-CoV-2 spike protein, followed by pulmonary pull immunization with either mRNA-LNPs or spike protein adjuvanted with cationic adjuvant formulation (CAF)01 induce high systemic immune responses and virus-neutralizing spike-specific antibody responses in the lungs. However, only pulmonary pull immunization with CAF01-adjuvanted spike protein induces spike-specific mucosal antibody and lung-resident T-cell responses in the respiratory tract. This suggests that i.m. priming of strong immune responses with mRNA-LNPs combined with mucosal pull immunization with a subunit vaccine can re-direct the immune response to the respiratory mucosa.