Pulmonary vaccines and immune responses to control tuberculosis

Abstract

Tuberculosis remains a staggering burden on global health, despite considerable research efforts toward preventative strategies. Subunit vaccines offer potential as safe generators of protective immunity, and there is growing interest in exploring delivery by the pulmonary route to enhance immunogenicity. In this study, novel subunit vaccines were designed and produced utilising a variety of adjuvants and protein antigens from Mycobacterium tuberculosis (Mtb), with a focus on formulation for pulmonary delivery. The immunogenicity and protective efficacy of these vaccines was assessed in a murine model of Mtb infection. First, the novel TLR2-ligand adjuvant, Lipokel®, was non-covalently conjugated to proteins from Mtb and formulated as dry powders for inhalation, delivering antigen into the lungs in a self-adjuvanting context. Second, immunodominant peptide epitopes from Mtb were covalently conjugated to Pam2Cys to provide stable lipopeptide vaccines. Third, strategies for covalent conjugation of full length recombinant proteins from Mtb to Pam2Cys are shown. Finally, the novel polysaccharide adjuvant AdvaxTM was tested in combination with fusion proteins as a pulmonary vaccine and this resulted in highly significant protection from Mtb challenge. A different approach used biodegradable poly(lactic-co-glycolic acid) particles as a carrier for MPT83 and adjuvants, formulated for pulmonary delivery. The protective efficacy of these particulate vaccines against Mtb was compared to the effect of DDA-liposome based vaccine formulations. Chemokine receptors play an important role in the recruitment of T-cells to the lungs following immunisation or infection. Therefore the role of CXCR6 was examined in early and chronic Mtb infection, and this was compared to the CD4+ T-cell responses induced by a recombinant influenza A virus vaccine. Paradoxically, CXCR6 deficiency increased protection against these pathogens and resulted in improved control of Mtb infection. These studies emphasise the critical nature of adjuvant choice and administration route on the efficacy of TB vaccines, and the novel effective vaccines developed in this study represent a new approach to prevent TB.