Mucosal vaccines - fortifying the frontiers

Abstract

Mucosal vaccines offer the potential to trigger robust protective immune responses at the predominant sites of pathogen infection. In principle, the induction of adaptive immunity at mucosal sites, involving secretory antibody responses and tissue-resident T cells, has the capacity to prevent an infection from becoming established in the first place, rather than only curtailing infection and protecting against the development of disease symptoms. Although numerous effective mucosal vaccines are in use, the major advances seen with injectable vaccines (including adjuvanted subunit antigens, RNA and DNA vaccines) have not yet been translated into licensed mucosal vaccines, which currently comprise solely live attenuated and inactivated whole-cell preparations. The identification of safe and effective mucosal adjuvants allied to innovative antigen discovery and delivery strategies is key to advancing mucosal vaccines. Significant progress has been made in resolving the mechanisms that regulate innate and adaptive mucosal immunity and in understanding the crosstalk between mucosal sites, and this provides valuable pointers to inform mucosal adjuvant design. In particular, increased knowledge on mucosal antigen-presenting cells, innate lymphoid cell populations and resident memory cells at mucosal sites highlights attractive targets for vaccine design. Exploiting these insights will allow new vaccine technologies to be leveraged to facilitate rational mucosal vaccine design for pathogens including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and for cancer.

Fig. 1. Burden of mucosal diseases with unmet vaccine needs.

Respiratory, enteric and sexually transmitted infections constitute prominent causes of death worldwide, and this is exacerbated in low-income regions. Aetiological agents shown are vaccine targetable, but there remains an unmet need for new or improved vaccination approaches to address global vaccine coverage. Mucosal vaccination strategies hold promise to address this unmet need, providing more robust mucosal immunity and an alternative to parenteral vaccination. In addition to their centrality in the pathogenesis of infectious disease, mucosal tissues are frequent sites of tumour development and mucosal vaccination strategies may play a role in the prophylactic and therapeutic targeting of these malignancies. CRC, colorectal cancer; ETEC, enterotoxigenic Escherichia coli; p.a., per annum; RSV, respiratory syncytial disease; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Fig. 2. Licensed mucosal vaccines.

Eight oral vaccines are currently licensed for use against cholera, salmonella, poliovirus and rotavirus. Live attenuated influenza vaccines remain the sole licenced intranasal vaccines. To date, live attenuated and inactivated vaccines have proved the most successful platforms for mucosal vaccine design. CTB, cholera toxin B subunit; LPS, lipopolysaccharide.

Fig. 3. Vaccine uptake at mucosal sites.

Nature of antigen uptake in the intestine is dependent on the type of vaccine components used, whether soluble or particulate, inert or live. Innovative encapsulation and targeting strategies have the potential to protect antigens while enhancing uptake and delivery to optimal intestinal regions. Inclusion of an effective mucosal vaccine adjuvant can confer multiple benefits from preventing tolerogenic responses to antigens, recruiting and activating antigen-presenting cells (APCs) and engaging other innate immune cells that contribute to protective immunity. Although there are currently few safe and effective adjuvants, cell-targeting adjuvants such as Escherichia coli double-mutant heat-labile toxin (dmLT), which binds to gangliosides on microfold (M) cells and dendritic cells, or α-galactosylceramide (α-GalCer), which can promote activation of invariant natural killer T (iNKT) cells locally and in draining lymph nodes via dendritic cell-mediated presentation, offer promise. Optimal formulations will address antigen design, adjuvanticity and antigen protection and targeting to address the unique challenges of intestinal delivery in the case of protein antigens (part a), whole cell vaccines (part b) and viral vector vaccines (part c). cDC, conventional dendritic cell; WCK, whole-cell killed.