Mucosal vaccines hold many advantages over parenteral vaccines in the prevention of respiratory infections, which remain a major global health burden. Unlike parenteral vaccines, which primarily induce systemic immunity, mucosal vaccines stimulate robust local immune responses, including secretory IgA, tissue-resident memory T and B cells, and mucosal IgG. These responses collectively block viral entry, limit replication, and reduce transmission. Critically, they provide protection at the site of infection, offering rapid and durable immunity. This review highlights recent advances in mucosal vaccine platforms and delivery strategies for respiratory viruses, including emerging vaccine platforms, adjuvants, and heterologous prime-boost approaches, with a focus on findings from both animal models and human studies that define the key immune components and mechanisms of action in mucosal immunity. We further discuss evidence across major respiratory viruses and the translational and clinical implications for next-generation vaccine design. These insights underscore the role of mucosal vaccines in strengthening future pandemic preparedness.
However, adverse side effects, low protection duration, poor cross-protection against emerging variants of concern, continued virus transmission in vaccinated individuals, and their storage and transportation requirements have emerged as significant limitations ( 18 , 19 ). Most importantly, while the majority of SARS-CoV-2 vaccines administered parenterally induce effective
, nose, sinuses, pharynx, larynx, and trachea), causing coryzal symptoms due to inflammation and swelling of the mucosa, and/or infect the LRT, involving bronchi, bronchioles, and alveoli, where involvement of the smaller airways and alveoli may compromise air exchange. Irrespective of the site, infection triggers a programmed set of similar sequential, intercalated responses between the innate and adaptive immune systems that serve to control and eradicate infection and generate robust local and systemic immunity against reinfection ( Table 1 ).
TABLE 1 Key differences between mucosal and systemic immunity on primary exposure Adaptive immunity Mucosal immunity Systemic immunity Immune function First line of defense to prevent respiratory virus entry—mucus reduces contact with epithelium Clearance of respiratory viral infection if respiratory mucosal barrier is breached Anatomical locations Mucosal surfaces and MALTs in respiratory tract Blood, internal organs, and lymphatic system, including spleen and lymph nodes Key antibodies Non-specific S-IgA (dimeric) Serum IgM, IgG, monomeric IgA Key memory lymphocytes T rm and B rm cells with emergence of adaptive response Circulating memory T and B cells Initial detection of, and responses to, inhaled pathogens usually occur in the URT and likely determine disease severity and outcome.
AMs help control viral load during influenza and HCoV infection by inducing IFN-independent resistance in epithelial cells and coordinating a controlled proinflammatory response that activates adaptive immunity ( 46 ). Depletion of AMs results in severe inflammation, alveolar damage, loss of respiratory function, and mortality ( 47 – 50 ). However, influenza viruses and HCoVs can also infect AMs and survive endosomal and lysosomal degradation, with persistent SARS-CoV-2 infection evading immune detection ( 51 , 52 ).
Memory B cells (B rm ), including IgG + and IgA + B rm subsets, are established in the respiratory mucosa and persist in the tissue to provide long-term immunity. Upon re-exposure to the same respiratory virus, these B rm cells rapidly differentiate into plasma cells that secrete virus-specific IgG and S-IgA antibodies. Figure created with BioRender.com. Cross-section of respiratory tract showing mucosal immune components during viral infection, including infected epithelial cells, tissue-resident T cells, plasma cells, and memory B cells producing IgG and IgA antibodies to neutralize respiratory viruses.
The rapid kinetics of this local recall response reduce early viral burden, limiting host cell infection and systemic spread, thereby decreasing disease severity and transmission. This temporal advantage underpins effective immunity following natural infection or vaccination. While systemic immunity induced by natural respiratory infection and parenteral vaccination is important against re-challenge, especially if the virus spreads systemically, the induced local response in natural infection remaining after pathogen clearance at both innate and adaptive levels clearly confers a substantial temporal advantage critical to the efficacy of the response to any future challenge.
In contrast, parenteral vaccination elicits primarily systemic immunity (e.g., serum IgG), which provides weaker mucosal protection, allowing increased viral infectivity and replication in the respiratory epithelium and consequently raising the risk of virus shedding, transmission, and variant emergence. Figure created with BioRender.com. Diagram comparing intranasal and parenteral vaccination immunity. Intranasal stimulates mucosal protection reducing virus transmission and variant emergence. Parenteral produces systemic immunity with weaker mucosal defense, increasing viral replication.
Live attenuated virus vaccines Live attenuated virus vaccines have historically been highly effective in preventing systemic infections, such as smallpox, influenza, measles, mumps, and rubella ( 282 ). Modern approaches use codon deoptimization, codon-pair deoptimization, or targeted mutations in viral genomes of SARS-CoV-2 and other pathogens ( 129 , 283 – 286 ), preserving native antigen conformations, and inducing broad immune responses while minimizing risk of reversion to pathogenic forms ( 287 – 289 ). For SARS-CoV-2, several groups have developed intranasal live-attenuated vaccines that elicit both systemic and mucosal immunity, comparable to mRNA vaccines, with Adler et al.
Next-generation vaccines are being developed to elicit durable and cross-protective immune responses against diverse pathogens, particularly those targeting the respiratory and enteric systems. By strategically engaging T cell-centric antigen design, mucosal immune engagement, and induction of trained innate immunity, these innovative platforms are expected to reshape the paradigm of immunoprophylaxis and to offer promising avenues for enhanced protection against complex infectious diseases. Conventional antibody-based vaccines, though effective against many infections, often lack the capacity to induce durable or cross-protective immunity at mucosal surfaces. Advances in antigen design, delivery platforms, and adjuvant technologies now facilitate precise activation of tissue-resident memory T cells and enhancement of mucosal secretory IgA responses, thereby achieving sterilizing immunity at barrier surfaces while reinforcing systemic immune protection. Advanced delivery platforms, including lipid nanoparticles, viral vectors, and nano or liposomal carriers, further refine antigen presentation, enhancing stability, targeting, and overall immunogenicity. Concurrently, progress in understanding trained innate immunity highlights opportunities to induce broad, non-antigen-specific protection through epigenetic and metabolic reprogramming of innate cells. The integration of these adaptive and innate mechanisms may enhance early pathogen control, limits transmission, and strengthens defense against variant and antimicrobial-resistant pathogens across diverse populations. However, translating these immunological insights into safe, scalable, and globally accessible vaccines remains a major challenge. This review explores the emerging conceptual framework of next-generation vaccines that demonstrate partial integration of these axes in preclinical models, though human translation and functional synergy require Phase II validation. It highlights progress toward next-generat
Conventional antibody-based vaccines, though effective against many infections, often lack the capacity to induce durable or cross-protective immunity at mucosal surfaces. Advances in antigen design, delivery platforms, and adjuvant technologies now facilitate precise activation of tissue-resident memory T cells and enhancement of mucosal secretory IgA responses, thereby achieving sterilizing immunity at barrier surfaces while reinforcing systemic immune protection. Advanced delivery platforms, including lipid nanoparticles, viral vectors, and nano or liposomal carriers, further refine antigen presentation, enhancing stability, targeting, and overall immunogenicity.
The schematic links mechanistic and platform design/delivery system (antigen/epitope selection, platform technologies such as mRNA, viral vectors, nanoparticles, and live-attenuated/inactivated vaccines, mucosal routes, and adjuvants/trained-immunity inducers), key immune correlates (systemic and tissue-resident T cells, mucosal IgA and local B/T cell responses, and trained innate reprogramming), and clinical/public-health outcomes (reduced severe disease and transmission, broader variant coverage, and improved equity through thermostable, needle-free, scalable vaccines). 4.
This is particularly relevant for respiratory and enteric viruses, where systemic antibody responses alone may not fully prevent reinfection or breakthrough disease. For example, live attenuated influenza vaccines (LAIV) (e.g., FluMist) can induce mucosal IgA and tissue-resident T cells, but their effectiveness against infection can vary across seasons because of antigenic mismatch and prior immunity [ 47 ]. Similarly, oral rotavirus vaccines (RV1, RotaTeq) provide partial infection protection (~50–70% in high-income settings) yet excel (>85–95%) against severe disease via heterotypic immunity, underscoring the distinction between sterilizing and disease-mitigating effects [ 48 ].
The COVID-19 experience showed that intramuscular vaccines were highly effective at preventing severe disease but were less effective at blocking upper airway infection. This highlights the need for local mucosal responses in addition to systemic immunity if true infection-blocking protection is the goal [ 11 , 49 , 50 , 51 , 52 ]. During Omicron waves, mRNA vaccines (BNT162b2, mRNA-1273)
Classic examples include Bacillus Calmette–Guérin (BCG) and other live or inactivated vaccines that confer nonspecific protection against heterologous infections, now attributed largely to trained immunity [ 61 ]. More recently, viral vectored and mRNA COVID-19 vaccines have been shown to produce long-term transcriptional and functional reprogramming of myeloid cells, suggesting that innate training contributes to their durability and breadth of protection [ 62 ]. These findings support the concept of TRIM-based vaccines (TIbVs), which aim to promote beneficial innate reprogramming alongside conventional adaptive immunity.
These technologies are increasingly being engineered to combine T cell-centric antigen design with mucosal delivery and trained innate immunity, especially for respiratory and enteric pathogens. This convergence shifts vaccine development beyond purely systemic, antibody-focused approaches toward adaptable platforms that can block infection at entry sites and promote durable, cross-strain cellular and innate protection [ 4 , 71 ].
These modular adjuvant systems allow innate activation to be tailored to different respiratory or enteric threats while preserving safety and scalability [ 75 , 76 ]. Viral vectors and recombinant nanoparticle systems can efficiently deliver antigens to dendritic cells, promoting cross-presentation to cytotoxic T cells together with strong antibody responses [ 77 ]. Similarly, protein and peptide vaccines displayed on nanoparticles or virus-like particles, when combined with mucosal adjuvants and delivered orally or intranasally, can induce balanced mucosal and systemic immunity.
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