Review addresses the need for innovative adjuvant approaches and delivery strategies for the advancement of new mucosal vaccines

In a recent study published in Nature Reviews Immunology, researchers reviewed available mucosal vaccines discussing the current challenges and ways to advance the existing approaches.

Study: Mucosal vaccines — fortifying the frontiers. Image Credit: PhotobyTawat/Shutterstock
Study: Mucosal vaccines — fortifying the frontiers. Image Credit: PhotobyTawat/Shutterstock


The burden of morbidity and mortality associated with infectious diseases caused by mucosal pathogens is alarmingly high worldwide. The current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a grim reminder of the continuous threat of novel mucosal infections. There is a clear focus on vaccine requirements now more than ever; at the same time, new or improved vaccines are required for several enteric pathogens, oncogenic viruses, and those causing sexually transmitted diseases (STDs).

Although vaccines are available for Streptococcus pneumoniae, Mycobacterium tuberculosis, influenza virus, and Bordetella pertussis, improved versions of vaccines against these pathogens are needed to augment the sub-optimal protection with a particular emphasis on enhancing protective responses at the site of infection. As such, mucosal vaccination approaches might be promising.

SARS-CoV-2, with over 6.28 million global deaths to date, has shown the deadly nature of respiratory pathogens. Although several vaccines have been approved for COVID-19, the apparent challenges associated with mass production and deployment warrant the need for comprehensive worldwide coverage. Over the past decades, there has been a transition from live-attenuated vaccines to adjuvanted subunit vaccines and lately, viral vectored, ribonucleic acid (RNA), and deoxy RNA (DNA) vaccines.

So far, only nine mucosal vaccines have been approved for human use, which are whole-cell inactivated or live attenuated vaccine formulations; eight of these are orally administered and one intranasally. This dichotomy in approaches could be partly attributed to the higher tolerability of oral whole-cell inactivated antigens, susceptibility of subunit antigens to be degraded and cleared, and lack of mucosal adjuvants.

Single vaccination to induce immune responses at distant mucosal sites

Despite the compartmentalized mucosal responses, the crosstalk between different mucosae might make it possible to promote immune responses at distant sites by vaccinating at one site. As such, it is critical to understand the nature of regulatory signals of such homing to design vaccines targeting a distant mucosal point from the vaccination site.

The surface area of mucosal sites is approximately 30 – 40 m2, and consequently, they constitute major entry sites for different pathogens and often are sites of tumor development. The constant and high antigen exposure requires immunoregulatory responses in the mucosa to ensure homeostasis and prevent harmful inflammatory responses.

One study observed that distal intestinal gut-draining lymph nodes supported the induction of effector T helper cells, whereas proximal gut-draining lymph nodes supported T cell regulatory responses. This might help vaccine design; for instance, delivering oral vaccines might not be optimal if antigen uptake in the proximal intestine promotes tolerogenic responses. Instead, targeting the distal intestine with antigens might prove effective. Further, vaccines could circumvent this by inducing an inflammatory signature in the proximal intestine to elicit effector T cell responses.

Antigen-presenting cells and T cells and their role in mucosal immunity

Antigen-presenting cells (APCs) in mucosal tissues are dynamic. In response to inflammation or infection, more APCs are recruited to the site in addition to the tissue-resident dendritic cells and macrophages and thereby contributing to effector responses. Local inflammatory reactions induced by mucosal vaccines could enhance adaptive immune responses by recruiting APCs.

Tissue-resident memory T cells (T­­­RM­) present in different mucosal tissues are thought to be decisive in rapid responses to infection or cancers. One study found that the cluster of differentiation 4 (CD4+) cell population in the human duodenum was enriched with polyfunctional T helper 1 (TH1) cells with a minimum of a year of survival. This is promising to induce a sustained cellular response if oral vaccines are optimized. In the lungs, CD8+ TRM cells are critical against respiratory viruses; but their short life could compromise immunity to subsequent infections.

Interestingly, a study observed that systemic vaccination could amplify TRM cells in the lungs of mice with prior influenza by enhancing the numbers of effector memory cells in circulation. This has significant implications for systemic boosters in previously infected to sustain memory CD8+ T lymphocytes in the lungs.

Genital vaccination

Vaccine administration in the genital tract could be beneficial in targeting STDs. In mice, vaginal administration of glycoprotein D antigen of herpes simplex virus-2 (HSV-2) and an adjuvant resulted in protective immunity against subsequent viral challenge. Others observed that vaginal administration of an attenuated strain of HSV-2 in mice induced a population of specific TRM cells that resulted in enhanced recruitment of memory B cells after secondary challenge.

In contrast, primary vaccination did not induce tissue-resident plasma cells in the genital tract. Hence, vaginal or intestinal booster vaccination might be effective after systemic priming to elicit responses in the genital tract.

Mucosal adjuvants

Toxoid adjuvants, safer and more potent derivatives of the heat-labile toxin of Escherichia coli and cholera toxin, led to their incorporation in vaccine formulations. For example, incorporating double-mutant heat-labile toxin (dmLT) of E. coli improved the clinical responses to different whole-cell antigens.

Multiple mutated cholera toxin (mmCT) is a proposed alternative to dmLT. In preclinical trials, it enhanced TH1 and TH17 cell response to a whole-cell antigen, besides enhancing serum and mucosal antibodies. Toxoid adjuvants which are the best-studied class of mucosal adjuvants are the most advanced and have shown exceptional efficacy in clinical trials for orally administered whole-cell vaccines.

Advanced vaccine types: nucleic acids and virus vectors

Until the COVID-19 pandemic, there were no approved DNA or RNA vaccines, but messenger RNA (mRNA) vaccines against SARS-CoV-2 have been successfully tested and rolled out for parenteral administration. Mucosal vaccination using DNA or RNA could be challenging, given that the nucleic acids must penetrate the mucus layer and enter target cells, evading extra- and intracellular degradation.

Nonetheless, innovative approaches to delivering nucleic acids safely have been developed using biomaterials and nanocarriers. Notably, nucleic acid-complexing materials like polyethyleneimine (PEI) and chitosan and encapsulating nucleic acids in liposomes and polymersomes have shown potential.

Viral vectors are among the most promising candidates for mucosal vaccination due to their intrinsic immunogenicity, versatility, and capacity for intracellular delivery. These are also potent for vaccination in the respiratory tract. One report revealed that intranasal delivery of adenovirus-vectored influenza virus nucleoprotein induced lung CD8+ TRM cells that survived for longer than one year.

Overall, mucosal vaccines could induce immune responses at the principal sites of infection. Advances in the current understanding of mucosal immunity might someday lead to the development of novel mucosal vaccines for infectious diseases such as COVID-19 and cancers.

Journal reference:
Tarun Sai Lomte

Written by

Tarun Sai Lomte

Tarun is a writer based in Hyderabad, India. He has a Master’s degree in Biotechnology from the University of Hyderabad and is enthusiastic about scientific research. He enjoys reading research papers and literature reviews and is passionate about writing.


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