Respiratory mucosal vaccines for emerging viruses: promise and challenges

Systemically administered vaccines were instrumental in reducing severe disease, hospitalizations, and deaths during the SARS-CoV-2 pandemic. However, they often failed to consistently elicit robust immunity at mucosal sites. This minireview examines a central role for respiratory mucosal immunity in protection against emerging viral pathogens and highlights key takeaways from the SARS-CoV-2 pandemic. Evidence from SARS-CoV-2 and influenza studies demonstrates that mucosal vaccination uniquely induces secretory IgA, as well as resident memory B and T cells within the upper and lower airways, thereby promoting broader and more potent protection. Accordingly, interest in mucosal vaccination strategies has been recently renewed. However, significant knowledge gaps remain, which include determining optimal vaccination strategies (systemic prime-mucosal boost versus mucosal-only), identifying the underlying mechanisms that cause the relatively rapid decay of mucosal immunity, establishing reproducible and standardized correlates of protection, and developing safe, effective delivery platforms and adjuvants that are compatible with the respiratory environment. These challenges are particularly relevant for high-priority zoonotic threats, such as henipaviruses, hantaviruses, arenaviruses, and emerging influenza strains, for which mucosal immune responses and correlates of protection remain poorly defined. Moreover, advancing mucosal vaccine design through improved viral vectors, nanoparticle systems, and immunomodulatory adjuvants will be critical for achieving durable immunity. Ultimately, leveraging insights gained from the SARS-CoV-2 pandemic may enable breakthroughs in mucosal vaccination strategies that reduce transmission, limit viral evolution, and strengthen preparedness for future respiratory pandemics.