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

In a recent study published in Nature Reviews Immunologyresearchers examined available mucosal vaccines and discussed current challenges and ways to advance existing approaches.

Background

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

While vaccines are available for: Streptococcus pneumoniae, Mycobacterium tuberculosis, flu virus, and Bordetella pertussis, improved versions of vaccines against these pathogens are needed to increase suboptimal protection, with a particular emphasis on enhancing protective responses at the site of infection. As such, mucosal vaccination approaches may hold promise.

SARS-CoV-2, with more than 6.28 million deaths worldwide to date, has demonstrated the lethal nature of respiratory pathogens. While several vaccines have been approved for COVID-19, the apparent challenges associated with mass production and deployment justify the need for extensive global coverage. In recent decades there has been a transition from live attenuated vaccines to adjuvanted subunit vaccines and most recently viral vector, ribonucleic acid (RNA) and deoxy RNA (DNA) vaccines.

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

Single vaccination to elicit immune responses at distant mucosal sites

Despite the compartmentalized mucosal responses, the crosstalk between different mucosa could allow promoting immune responses at distant sites by vaccinating at one site. As such, understanding the nature of regulatory signals from such homing is critical to design vaccines that target a distant mucosal point from the vaccination site.

The surface area of ​​the mucous membranes is approximately 30 – 40 m^2, and consequently they represent important entry sites for various pathogens and are often sites of tumor development. The constant and high exposure to antigen requires immunoregulatory reactions in the mucosa to ensure homeostasis and prevent harmful inflammatory reactions.

One study noted that distal gut-draining lymph nodes supported the induction of effector T helper cells, while proximal gut-draining lymph nodes supported T-cell regulatory responses. This can help design vaccines; for example, delivery of oral vaccines may not be optimal if antigen uptake in the proximal gut promotes tolerogenic responses. Instead, targeting the distal gut with antigens might be effective. Furthermore, vaccines could circumvent this by inducing an inflammatory signature in the proximal gut 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 tissue dendritic cells and macrophages and thereby contribute to effector responses. Local inflammatory responses induced by mucosal vaccines could enhance adaptive immune responses by recruiting APCs.

Tissue-resident memory T cells (T_RM) present in various mucosal tissues is believed to determine rapid responses to infection or cancer. One study showed that the cluster of differentiation 4 (CD4^†) cell population in human duodenum was enriched in polyfunctional T helper 1 (T_huh1) cells with at least one year survival. This shows promise to induce a sustained cellular response if oral vaccines are optimized. In the lungs, CD8^† t_RM cells are crucial against respiratory viruses; but their short lives could compromise immunity to subsequent infections.

Interestingly, one study found that systemic vaccination T. could amplify_RM cells in the lungs of mice with previous flu by increasing the number of effector memory cells in circulation. This has significant implications for systemic boosters in previously infected to maintain memory CD8^† T lymphocytes in the lungs.

genital vaccination

Administration of vaccines in the genital tract could be beneficial in tackling STDs. In mice, vaginal administration of glycoprotein Herpes simplex virus-2 (HSV-2) D antigen and an adjuvant resulted in protective immunity against subsequent viral challenge. Others noted that vaginal administration of an attenuated strain of HSV-2 in mice increased a population of specific T. induced_RM 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. Therefore, vaginal or intestinal booster vaccination may be effective after systemic priming to elicit responses in the genital tract.

Mucosal adjuvants

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

Multiple mutated cholera toxin (mmCT) is a proposed alternative to dmLT. In preclinical studies, it improved T_huh1 and T_huh17 cell response to a whole cell antigen, in addition to enhancing serum and mucosal antibodies. Toxoid adjuvants, 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 vaccines (mRNA) against SARS-CoV-2 have been successfully tested and rolled out for parenteral administration. Mucosal vaccination with DNA or RNA can be challenging, as the nucleic acids must penetrate the mucus layer and enter the target cells, to avoid extra- and intracellular degradation.

Nevertheless, innovative approaches have been developed to safely deliver nucleic acids using biomaterials and nanocarriers. Remarkable, Nucleic Acidcomplexing materials such as polyethyleneimine (PEI) and chitosan and the encapsulation of 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 respiratory vaccination. One report revealed that intranasal delivery of nucleoprotein from adenovirus vectorized influenza virus induced lung CD8+ T._RM cells that survive for more than a year.

In general, mucosal vaccines can induce immune responses at major sites of infection. Advances in the current understanding of mucosal immunity could one day lead to the development of new mucosal vaccines for infectious diseases such as COVID-19 and cancers.