Systemically administered vaccines played a central role in reducing severe disease, hospitalizations, and deaths during the SARS-CoV-2 pandemic. However, the evidence reviewed indicates these systemic approaches frequently failed to consistently generate robust immune responses at mucosal surfaces of the respiratory tract. Studies of both SARS-CoV-2 and influenza demonstrate that targeting the respiratory mucosa through vaccination can yield immune outcomes distinct from and potentially superior to systemic immunization for preventing infection and onward transmission.
Mucosal vaccination in the respiratory tract uniquely induces secretory IgA and establishes local populations of resident memory B and T cells within the upper and lower airways. These mucosal immune components can provide a first line of defense at the site of viral entry, offering broader and in some contexts more potent protection than systemic responses alone. The minireview emphasizes that induction of these local responses is a defining advantage of respiratory mucosal vaccines.
Empirical data from SARS-CoV-2 and influenza research underpin renewed interest in mucosal vaccine strategies. The pandemic highlighted both the successes of existing systemic vaccines in preventing severe outcomes and their limitations in blocking infection and transmission at mucosal portals of entry. These observations have catalyzed efforts to explore alternative regimens (for example, systemic prime–mucosal boost or mucosal-only vaccination) and to evaluate how mucosal immunity could alter epidemiologic dynamics by reducing spread and limiting opportunities for viral evolution.
Despite promising immunologic rationale and preclinical and early clinical evidence, significant knowledge gaps remain. Critical unresolved questions identified in the review include:
Determining optimal vaccination strategies: whether combining systemic priming with a mucosal boost or deploying mucosal-only regimens yields the best balance of systemic and mucosal protection.
Identifying mechanisms driving relatively rapid decay of mucosal immunity compared with systemic responses and how to prolong mucosal immune memory.
Establishing reproducible and standardized correlates of protection specifically at mucosal sites to guide development and regulatory assessment.
Defining mucosal immune responses and correlates of protection for many high-priority zoonotic pathogens and novel influenza strains, where data remain scarce.
The authors note these gaps limit rational design and assessment of mucosal vaccines for emerging threats.
The review highlights that high-priority zoonotic viruses—examples named include henipaviruses, hantaviruses, and arenaviruses—as well as emerging influenza strains, present particular challenges because mucosal immune responses and correlates of protection are poorly defined for these pathogens. For such threats, advancing mucosal vaccine strategies is especially important to improve frontline protection, reduce transmission risk, and limit early viral amplification in human populations.
A major theme is the need to develop and optimize delivery platforms and adjuvants that are both effective in the respiratory environment and safe for mucosal tissues. The review points to several technological directions that merit continued work, including improved viral vectors, nanoparticle-based delivery systems, and immunomodulatory adjuvants tailored for mucosal application. Achieving durable mucosal immunity will likely require innovations in these areas as well as formulation approaches and dosing regimens designed specifically for the respiratory tract.
The authors conclude that leveraging lessons learned during the SARS-CoV-2 pandemic could enable breakthroughs in mucosal vaccine design. If mucosal vaccines can reliably induce durable secretory IgA and resident memory lymphocytes at respiratory sites, they have the potential to reduce transmission, decrease the opportunity for viral evolution within human hosts, and therefore strengthen preparedness for future respiratory pandemics. The review frames mucosal vaccination as a strategic priority for improving control of emerging respiratory viruses, while emphasizing the substantial scientific and translational challenges that must be addressed.
Note: This content summarizes the findings and perspectives presented in the cited minireview (J Virol. 2026; DOI 10.1128/jvi.01748-25). The authors declared no conflicts of interest. Specific experimental data, quantitative outcomes, and detailed protocol recommendations were not reported in the abstract and are therefore not described here.