Abstract
The development of effective vaccines against bacterial lung infections requires the induction of protective, pathogen-specific immune responses without deleterious inflammation within the pulmonary environment. Here, we made use of a polysaccharide-adjuvanted vaccine approach to elicit resident pulmonary T cells to protect against aerosol Mycobacterium tuberculosis infection. Intratracheal administration of M. tuberculosis fusion protein CysVac2 and the delta-inulin adjuvant Advax™ (formulated with a TLR9 agonist) provided superior protection against aerosol M. tuberculosis infection in mice, compared to parenteral delivery. Surprisingly, removal of the TLR9 agonist did not impact vaccine protection despite a reduction in cytokine-secreting T cell subsets, particularly CD4+ IFN-γ+IL-2+TNF+ multifunctional T cells. CysVac2/Advax-mediated protection was associated with the induction of lung-resident, antigen-specific memory CD4+ T cells that expressed IL-17 and RORγt, the master transcriptional regulator of Th17 differentiation. IL-17 was identified as a key mediator of vaccine efficacy, with blocking of IL-17 during M. tuberculosis challenge reducing phagocyte influx, suppressing priming of pathogen-specific CD4+ T cells in local lymph nodes and ablating vaccine-induced protection. These findings suggest that tuberculosis vaccines such as CysVac2/Advax that are capable of eliciting Th17 lung-resident memory T cells are promising candidates for progression to human trials.
Author summary Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), kills more individuals each year than any other single pathogen and a more effective vaccine is critical for global control of the disease. TB is an airborne disease, and the only available vaccine, BCG, administered intradermally, is unreliable in protecting against the pulmonary form of the disease. Vaccination in the lung would be a rational way of inducing a local memory immune response to TB, however vaccine platforms would need to deliver antigens to delicate mucosal surfaces without inducing deleterious inflammatory responses. In this report we used pulmonary delivery of TB antigens combined with non-reactogenic polysaccharide adjuvants to induce protection against TB lung infection in mice. The vaccine formulation induced high levels of T cells that resided in the lung and notably expressed the cytokine IL-17. Removal of IL-17 limited the influx of immune cells recruited to the lung and completely ablated protection afforded by the vaccine. This study provides new insights into mechanisms of protection against M. tuberculosis and provides a promising candidate to protect against TB in humans.