Vaccine Strategies to Elicit Mucosal Immunity

**Background:** Mucosal surfaces are the primary entry point for over 90% of human pathogens, making mucosal immunity critical for preventing infection and transmission. While most licensed vaccines are administered parenterally and induce systemic immunity, mucosal vaccines can elicit both local and systemic immune responses, potentially blocking pathogen entry at the site of infection. Despite the success of a few mucosal vaccines (e.g., oral polio, rotavirus, intranasal influenza), only 8 out of 96 licensed vaccines in the United States are mucosal. This review summarizes the current state of mucosal vaccine development, including immunological principles, formulation strategies, adjuvants, and remaining challenges.

**Methods:** This is a narrative review that synthesizes published literature on mucosal vaccine development. The authors describe the history of vaccination, the structure and function of mucosal barriers, the components of mucosal immunity (including innate and adaptive responses, IgA, IgG, tissue-resident memory cells, and trained innate immunity), and various vaccine platforms (live attenuated, killed whole-cell, subunit, viral vector, particle-based). They also discuss mucosal adjuvants (e.g., cholera toxin, CpG, MPL, flagellin) and delivery routes (oral, intranasal, sublingual, rectal). The review includes a table of FDA- and WHO-approved mucosal vaccines and a table of adjuvants in licensed or clinical-stage vaccines.

**Key Results:** The review highlights that mucosal vaccines can induce secretory IgA (SIgA), which serves as the first line of defense at mucosal surfaces. More than 90% of SIgA is produced in gut-associated lymphoid tissues (GALT), with an average of 3 g secreted into the gut lumen daily. Mucosal vaccination elicits tissue-resident memory T and B cells, which provide rapid local recall responses, whereas parenteral vaccines induce few such cells. Live attenuated mucosal vaccines (e.g., FluMist, oral polio, rotavirus) are the most common approved formulations, but killed whole-cell vaccines (e.g., Dukoral, ShanChol) are also used. Viral vector-based and particle-based vaccines are in development. Adjuvants such as cholera toxin (CT) and heat-labile enterotoxin (LT) enhance IgA and Th17 responses but have toxicity concerns. CpG ODN (TLR9 agonist) is used in the licensed hepatitis B vaccine HEPLISAV-B. The intranasal route can elicit immunity in the respiratory and reproductive tracts, while oral vaccines induce immunity in the GI tract. Challenges include identifying correlates of protection, improving animal models, overcoming pre-existing vector immunity (e.g., Ad5), and ensuring safety (e.g., risk of Bell's palsy with enterotoxin adjuvants, vaccine-associated poliomyelitis at 4.7 cases per million births).

**Clinical Implications:** Mucosal vaccines offer significant advantages over parenteral vaccines, including easier administration (no needles), lower cost, and the ability to block infection and transmission at mucosal surfaces. They are particularly important for pathogens that enter via mucosal routes, such as influenza, rotavirus, polio, and cholera. The development of effective mucosal vaccines could improve pandemic preparedness and reduce disease burden in lower-income countries. However, challenges remain in formulating stable, safe, and immunogenic vaccines, especially for oral delivery where tolerance and environmental enteropathy can reduce efficacy. Future research should focus on novel adjuvants, delivery systems, and better animal models to accelerate mucosal vaccine development.