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 the multistage 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.
Highlights
Tuberculosis (TB) remains a major cause of morbidity and mortality worldwide, with 10 million new cases and 1.5 million deaths per year[1]
Previous studies of intramuscular (i.m.) vaccination of mice with CysVac2/AdvaxCpG demonstrated substantially enhanced systemic CD4+ T cell responses composed of multifunctional Th1 polarized cells, which correlated with protection against aerosol M. tuberculosis infection[16]
When the vaccinespecific T cell response was examined in the blood prior to M. tuberculosis challenge, a higher level of circulating polyfunctional CD4+ T cells expressing IFN-γ was present after i.m. vaccination (Fig. 1b and Supplementary Fig 2a), with the most prominent phenotype identified as multi-cytokine-secreting CD44+ CD4+ T cells (Fig. 1c)
Summary
Tuberculosis (TB) remains a major cause of morbidity and mortality worldwide, with 10 million new cases and 1.5 million deaths per year[1]. Mycobacterium bovis bacillus Calmette–Guérin (BCG) is currently the only licensed vaccine against TB, its efficacy varies greatly, especially against the adult pulmonary form of the disease[2]. The 2015 WHO End TB Strategy identified the development of a more effective and administered vaccine for controlling TB and halting the global epidemic[3]. Extensive research has resulted in many new TB vaccine candidates, 14 of which are currently in human vaccine trials and are reviewed in detail elsewhere[4]. A Phase IIb clinical trial of the fusion protein vaccine M72/AS01E showed protective efficacy of 50% in M. tuberculosis-infected adults after 3 years[5,6]. Vaccines with higher efficacy are considered necessary to reduce TB incidence to the targets outlined in the End TB Strategy objectives[3]
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