Adjuvants for the Next Generation of Subunit TB Vaccines
Adjuvants for the Next Generation of Subunit TB Vaccines
Prof Angelo Izzo, Centenary Institute, Australia
Subunit vaccines comprising Mycobacterium tuberculosis (Mtb)-specific antigen(s) and adjuvant are likely to be a major factor in reducing the global tuberculosis (TB) burden. Our program is performing an in-depth head-to-head analysis of adjuvants that will be used for the next generation of TB vaccines. The study focuses on adjuvants that stimulate different innate immune pathways. A total of ten adjuvants will be examined. Targeted ligands thus far have included Toll-like receptor (TLR)4, TLR7/8, TLR9, macrophage-inducible C-type lectin (Mincle), CD40/CD40L, and stimulator of interferon genes (STING). The aim is to identify mechanisms of the adjuvants using the C57BL/6 mouse model, human dendritic cell–T cell assays, and eventually down-select to move specific candidates into non-human primates. In mice, adjuvants displayed varying degrees of reactogenicity at the site of inoculation and induced significant Th1 and/or Th1/Th17 responses in draining lymph nodes, lungs, and spleens. Single-cell RNA sequencing data demonstrated that there was significant upregulation of pro-inflammatory pathways associated with IFN-regulated genes in lymph node myeloid cells within 6 to 24 hours after intramuscular injection. Differences were also observed in other regulatory pathways. There was an associated recruitment of early dendritic cells, which over time were replaced by larger numbers of B and T cells. Memory responses were determined for each adjuvant/antigen formulation, and these data were then correlated to their ability to reduce the intra- and extra-pulmonary Mtb burden. TLR9, TLR4, and Mincle adjuvants, when formulated with the polypeptide Mtb antigen CysVac2 (Ag85B:CysD), resulted in a significant reduction of Mtb lung burden in a low-dose aerosol challenge mouse model. A cumulative summary of the data will be presented together with the factors associated with down-selection of candidates and the criteria used for selection for testing in non-human primates.
