Mucosally Targeted Prime‐Boost Vaccination Approaches for Tuberculosis Based on the TLR2/4 Ligand OprI Adjuvant

Gartner, T.; Baeten, M.; De Baetselier, P.; Huygen, K.; Revets, H.

Immunity against tuberculosis (TB), caused by Mycobacterium tuberculosis, depends largely on activation and maintenance of strong cell‐mediated immune responses involving both CD4(+) and CD8(+) T cells and the ability to respond with Th1‐type cytokines, particularly IFN‐γ. Recent studies suggested that BCG, the only licensed vaccine against M. tuberculosis, may fail to induce T‐cell responses in the lung mucosa and may therefore not protect against pulmonary TB. A decrease in TB mortality may be achieved by enhancing immunity in the lung. The present study evaluated the induction of antigen‐specific immunity in the lung by intranasal (i.n.) delivery of the lipoprotein I (OprI) from Pseudomonas aeruginosa. OprI has shown to be a Toll‐like receptor 2/4 agonist that, when given subcutaneously, induces Type‐1 immune responses against heterologous antigens. Here, a fusion of OprI to Ag85A of Mtb (OprI‐Ag85A) was used as a subunit vaccine in homologous prime‐boost immunizations. In addition, OprI‐Ag85A was combined with an Ag85A‐encoding DNA vaccine (Ag85A DNA) or with BCG in heterologous prime‐boost vaccinations. Intranasal and parenteral delivery with OprI‐Ag85A elicited comparable T‐cell responses in the spleen; in addition, i.n. delivery elicited specific T‐cell responses in the lung lymph nodes (LLNs). Intramuscular delivery of Ag85A DNA induced significant systemic Th1 immune responses. Intranasal boosting with OprI‐Ag85A enhanced this response and in addition induced an antigen‐specific IFN‐γ response in LLN. OprI may therefore be an efficient adjuvant for mucosal boosting. We continue to evaluate the protection induced by OprI‐based prime‐boost vaccinations against pulmonary TB. Results on the immunogenicity and protection against intravenous Mtb H37Rv infection will be presented.