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Recent progress in mucosal vaccine development: potential and limitations

Nature Reviews Immunology volume 12, pages 592–605 (2012)Cite this article

Subjects

Key Points

  • This article presents the currently available mucosal vaccines and their principle mechanisms of action. The concepts of live attenuated and non-living subcomponent vaccines are explained.

  • Principles for mucosal vaccine design and development are discussed, with special reference to vaccine formulations based on soluble or particulate forms. The strengths and weaknesses of various routes of vaccine administration — including intranasal, oral, sublingual, aerosol and rectal — are also considered.

  • Mucosal adjuvants and their mechanisms of action, especially toxin-based adjuvants and derivatives of these, are explored.

  • Long-term B and T cell memory development following mucosal vaccination is discussed.

  • Concepts and regulatory mechanisms governing mucosal IgA responses and the synchronization of gut IgA immunity, in particular, are explained.

  • Finally, future directions, new technologies and new candidate mucosal vaccines that are in the pipeline are summarized.

Abstract

Most pathogens access the body through the mucosal membranes. Therefore, effective vaccines that protect at these sites are much needed. However, despite early success with the live attenuated oral polio vaccine over 50 years ago, only a few new mucosal vaccines have been subsequently launched. This is partly due to problems with developing safe and effective mucosal adjuvants. In the past decade, however, the successful development of live attenuated mucosal vaccines against influenza virus and rotavirus infections has boosted interest in this field, and great expectations for new mucosal vaccines lie ahead. Here, I discuss the expanding knowledge and strategies used in the development of mucosal vaccines.

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Figure 1: Mucosal immunization routes and compartmentalization of effector functions.
Figure 2: Intranasal vaccination stimulates immune responses in the nasopharynx-associated lymphoid tissue.
Figure 3: Induction of gut IgA responses by mucosal vaccines.

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Acknowledgements

I would like to thank all past and present members of my research group for their devotion and hard work. Special thanks to M. Bemark for collaborative work on gut IgA B cell immunity and to B. Löwenadler, co-inventor of the CTA1-DD adjuvant. Lastly, I would like to thank my mentor and friend W. Strober for always giving generous support and engaging in helpful discussions.

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  1. Department of Microbiology and Immunology, Center for Mucosal Immunobiology and Vaccines (MIVAC), Institute of Biomedicine, University of Gothenburg, Sweden

    Nils Lycke

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Correspondence to Nils Lycke.

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Glossary

Adjuvant

An agent that enhances the immunogenicity of an antigen. Etymologically, the term adjuvant comes from the latin verb adjuvare, which means 'to help'.

Mucosal tolerance

Specific unresponsiveness to systemic challenges after a prior mucosal exposure to the antigen.

Subcomponent vaccines

Non-living vaccines that consist of whole cell walls or complete protein structures.

Tropical barrier

An inability to fully respond to mucosal vaccination, especially oral vaccination, in developing countries.

Herd immunity

Protection against spread of infection in a population based on a critical mass of successfully vaccinated individuals.

Biodegradable microparticles and nanoparticles

Particles that are 1–1000 nm in size and made from materials that self-disintegrate, such as poly(lactide-co-glycolide). Biodegradable microparticles and nanoparticles have been extensively used in different mucosal vaccine formulations and are gaining increased attention for their ability to serve as viable carriers for site-specific delivery of vaccines. They offer enhanced biocompatibility, superior vaccine encapsulation and convenient release profiles for mucosal vaccines.

Follicle-associated epithelium

(FAE). The epithelium that overlies mucosal lymphoid tissues, such as the Peyer's patches and isolated lymphoid follicles in the intestine. Lymphoid tissues induce the differentiation of normal intestinal epithelium into FAE, which is specialized in antigen capture and transport.

Virus-like particles

Virus envelopes without nucleic acid that are used for the delivery of vaccine antigens.

Bacterial ghosts

Empty cell envelopes of Gram-negative bacteria devoid of cytoplasmic content and chromosomal and plasmid DNA that are used for the delivery of vaccine antigens.

Immunostimulating complexes

(ISCOMs). Spherical open cage-like structures (typically 40 nm in diameter) that spontaneously form from a mixture of cholesterol, phospholipids and Quillaja saponins. ISCOMs are used as vaccine adjuvants to induce an enhanced immune response and protection.

Epitope spreading

The process by which an antibody response to one epitope of an antigen leads to the production of antibodies specific for other epitopes of the same antigen, or for epitopes of entirely unrelated antigens. This results from the internalization of the whole antigen and the subsequent display of a range of peptides derived from that antigen, leading to the generation of T cells with different epitope specificities. Simultaneous processing of two unrelated antigens by an antigen-presenting cell can lead to the production of antibodies directed against both antigens.

Follicular dendritic cells

(FDCs). Stromal cells that are crucial for the development of germinal centres in B cell follicles. The interaction between FDCs and B cells is thought to be essential for isotype switching and somatic hypermutation.

Somatic hypermutation

The process by which point mutations occur in the heavy- or light-chain variable region gene segments, resulting in a change in the expressed protein, which may alter the affinity or specificity of the antibody for an antigen.

Germinal centres

The structures that are formed by the expansion of populations of antigen-activated B cell blasts that have migrated into the follicles of lymph nodes. The B cells in these structures proliferate and their immunoglobulin genes undergo somatic hypermutation, before the cells leave as plasma cells or memory B cells.

Affinity maturation

The mutation of antibody variable region genes followed by selection for higher affinity variants in the germinal centre leads to an increase in average antibody affinity as an immune response progresses.

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Lycke, N. Recent progress in mucosal vaccine development: potential and limitations. Nat Rev Immunol 12, 592–605 (2012). https://doi.org/10.1038/nri3251

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