Abstract
Several effective SARS-CoV-2 vaccines are currently in use, but effective boosters are needed to maintain or increase immunity due to waning responses and the emergence of novel variants. Here we report that intranasal vaccinations with adenovirus 5 and 19a vectored vaccines following a systemic plasmid DNA or mRNA priming result in systemic and mucosal immunity in mice. In contrast to two intramuscular applications of an mRNA vaccine, intranasal boosts with adenoviral vectors induce high levels of mucosal IgA and lung-resident memory T cells (TRM); mucosal neutralization of virus variants of concern is also enhanced. The mRNA prime provokes a comprehensive T cell response consisting of circulating and lung TRM after the boost, while the plasmid DNA prime induces mostly mucosal T cells. Concomitantly, the intranasal boost strategies lead to complete protection against a SARS-CoV-2 infection in mice. Our data thus suggest that mucosal booster immunizations after mRNA priming is a promising approach to establish mucosal immunity in addition to systemic responses.
Highlights
Several effective SARS-CoV-2 vaccines are currently in use, but effective boosters are needed to maintain or increase immunity due to waning responses and the emergence of novel variants
We demonstrate that a systemic plasmid DNA or messenger RNA (mRNA) prime followed by an intranasal boost with an adenoviral serotype 5 vector (Ad5) enables a comprehensive systemic and local T cell immunity as well as substantial mucosal neutralization of SARS-CoV-2 VOCs
Codon-optimized sequences encoding the full-length S and nucleocapsid (N) proteins of SARS-CoV-2 were inserted into pVax-1 expression plasmids and into replication-deficient adenoviral vector vaccines based on serotype 5 (Ad5) or serotype 19a (Ad19a)
Summary
Several effective SARS-CoV-2 vaccines are currently in use, but effective boosters are needed to maintain or increase immunity due to waning responses and the emergence of novel variants. While IgA can be effectively induced by intranasal delivery of protein-based vaccines, an efficient induction of respiratory CD8+ TRM usually requires local antigen production in the mucosa followed by major histocompatibility complex-I-mediated peptidepresentation by stromal and, most importantly, by migratory CD103+ dendritic cells[33]. A second remarkable characteristic is the ability to exert innate and adaptive functions within a few hours after secondary infection[36,37], in part due to the storage of ready-made mRNAs encoding cytokines like IFNγ at steady state[38,39] These unique features of mucosal immune responses enable an immediate and effective countermeasure against pulmonary infections as described for flu[40,41], respiratory syncytial virus (RSV)[42], and Mycobacterium tuberculosis[43,44]. Small experimental human challenge studies started to look precisely at the role of mucosal immunity against respiratory viruses[45,46]
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