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Harnessing mucosal immunity for protective vaccines

Nature Reviews Immunology (2026)Cite this article

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Abstract

Mucosal surfaces are primary entry sites for many infectious pathogens, yet parenteral vaccination alone often fails to elicit effective mucosal immunity. Mucosally delivered vaccines offer a promising strategy for reinforcing frontline defences and inducing localized, pathogen-specific immune responses. Recent studies indicate that mucosal vaccines elicit tissue-resident memory T and B cells, along with robust local antibody secretion, to prevent infection and transmission. However, achieving sterilizing immunity at mucosal sites proves challenging owing to the complex immune environments consisting of epithelial barriers, varying mucus composition, pH differences and hormonal influences. In this Review, we outline how specialized immune-inductive and effector mechanisms across distinct mucosal compartments contribute to protective immunity and discuss emerging strategies to harness multilayered mucosal immunity to develop safe, effective vaccines that elicit durable protection.

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Fig. 1: The mucosal immunity cycle.
Fig. 2: Stepwise immune circuits linking systemic priming and mucosal boosting for recall responses in the lungs.
Fig. 3: Shared mucosal immunity.

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Acknowledgements

This work was supported by a grant from the Howard Hughes Medical Institute to A.I. D.K. was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (RS-2024-00406626). S.H.B. is supported by the National Cancer Institute (NCI) of the US National Institutes of Health (NIH) under award number K00CA264404. S.A.E. is supported by a training grant from the National Institute of Allergy and Infectious Disease of the NIH (T32-AI007019). The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of the NIAMS or NIH. The authors thank A. Ökten and M. Dresler for their careful reading and review of the manuscript.

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  1. These authors contributed equally: Dong-il Kwon, Sachin H. Bhagchandani, Stephen A. Ehrenzeller.

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  1. Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA

    Dong-il Kwon, Sachin H. Bhagchandani, Stephen A. Ehrenzeller & Akiko Iwasaki

  2. Center for Infection and Immunity, Yale School of Medicine, New Haven, CT, USA

    Dong-il Kwon, Sachin H. Bhagchandani, Stephen A. Ehrenzeller & Akiko Iwasaki

  3. Howard Hughes Medical Institute, Chevy Chase, MD, USA

    Dong-il Kwon & Akiko Iwasaki

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A.I. co-founded RIGImmune, Xanadu Bio, Rho Bio and PanV and is a member of the board of directors of Roche Holding Ltd and Genentech. The other authors declare no competing interests.

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Kwon, Di., Bhagchandani, S.H., Ehrenzeller, S.A. et al. Harnessing mucosal immunity for protective vaccines. Nat Rev Immunol (2026). https://doi.org/10.1038/s41577-026-01273-7

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