Harnessing innate-like T cells as adjuvants for mucosal vaccines that enhance anti-viral humoral immunity
Authors:   , Pankhurst Theresa 
Published: February 2025

<p dir="ltr">Vaccination represents one of the greatest medical advancements in human history, responsible for preventing millions of death every year, and the complete eradication of deadly pathogens such as smallpox. Improving vaccine design to continue eradicating deadly pathogens is essential, displayed by the ongoing devastating global burden imparted by pandemic viruses. Viruses such as influenza and seasonal acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infect their host through the respiratory mucosa, therefore the initiation of mucosal immune responses in the lung have potential to neutralize invading viruses before they have the opportunity to infect the individual. Vaccines that are administered systemically, such as needle injection into the arm, do not induce mucosal immune responses, in contrast to mucosally-delivered vaccines that can induce both mucosal and systemic immune responses. Therefore, mucosal vaccines have the potential to provide a double layer of protection against pandemic-causing respiratory viruses, and may advance vaccinology in the quest to eradicate such pathogens. Mucosal vaccine development is currently hampered by a lack of available adjuvants, which are substances added to a vaccine that enhances immune responses towards a small fragment, or antigen derived from the target pathogen. This thesis has explored the potential to harness our own immune cells that are abundant in the lung mucosa, namely mucosal-associated invariant T (MAIT) and natural killer T (NKT) cells, as cellular mucosal adjuvants.</p><p dir="ltr">This thesis was able to show that intranasal vaccination of MAIT cell agonist 5-(-2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU) could augment mucosal and systemic production of antibodies against co-delivered protein antigens. Mechanistically, it was determined that MAIT cells in the lung became activated and licensed dendritic cells (DCs) in a CD40L signalling dependent fashion. Licensed DC were then able to prime antigen-specific follicular helper T (T<sub>FH</sub>) cells via ICOSL signalling, which in turn, provided help to B cells in the germinal centre. Functionally, the antibodies that were augmented by MAIT cell agonists displayed protective potential when challenged with live influenza virus. Moreover, this capacity potentiated by mucosal 5-OP-RU vaccination provided superior protection to that of currently licensed adjuvants that are delivered systemically.</p><p dir="ltr">In addition, this thesis was able to show that intranasal vaccination of NKT cell agonist α-galactosylceramide (αGC) could augment production of antibodies against conjugated B cell peptides. It was determined that when epitopes for NKT cells, B cells and T<sub>FH</sub> were conjugated, long-lived antibodies and advantageous isotype-switching could be induced at optimal levels. Although these antibodies were unable to generate significant protection when challenged with live influenza, mucosal vaccination of αGC delivered in combination with protein antigen displayed substantial ability to neutralize target proteins derived from SARS-CoV-2.</p><p dir="ltr">In summary, this thesis provides evidence for two promising adjuvants that could be employed for mucosal vaccination, and suggests that, with the appropriate antigen and supply of helper signals, there may be a therapeutic advantage for these adjuvants in the future of influenza and SARS-CoV-2 mucosal vaccine design.</p>