There are two major components of effective vaccines: adjuvants and antigens. The adjuvant for a vaccine must induce the immune responses that are protective, while the antigens must be those against which an immune response can provide protection from infection or disease. Most currently available adjuvants for humans, of which there are very few, induce antibody responses and primarily Th2 T cell responses. For many infections, including M. tuberculosis, Th1 CD4 T cell response and a cytotoxic or cytokine-producing CD8 T cell response are needed. Adjuvants that can induce such responses against subunit proteins and are also safe are urgently needed to tackle the most stubborn infectious diseases. Here, we propose to optimize a promising new adjuvant developed by Statens Serum Institute (SSI), CAF09, which builds on the CAF platform of cationic nanoparticles composed of bioactive lipids. This adjuvant induces both CD4 (Th1, Th17) and CD8 T cells. Optimization of CAF09 formulation and route of vaccination will be performed, using an established subunit vaccine, H56, which was developed by SSI and has been demonstrated to provide protection in several animal models, including non-human primates. Following optimization, the best candidates, based on mouse studies, will be tested for immunogenicity in non-human primates, to provide better translation to humans. The best formulation of CAF09/H56 will be scaled up and toxicity and stability studies will be performed. Finally, one formulation of CAF09/H56, as determined by the iterative studies in mice and monkeys, will be tested in a rigorous non-human primate M. tuberculosis challenge model. These studies will provide the crucial pre-clinical data for moving CAF09/H56 forward into human clinical trials as an improved TB vaccine candidate.
Development of adjuvants that are safe and can induce both CD4 and CD8 T cells is very challenging. However, there are many infectious diseases for which vaccine-induced quality immune responses that include both CD4 and CD8 T cells would improve protection. Tuberculosis, which kills almost 2 million people per year, is exacerbated in the absence of either CD4 or CD8 T cells in non-human primate models. The current vaccines going forward in clinical trials primarily induce only CD4 T cells. Here, we propose to build on exciting data with a unique adjuvant CAF09 to develop this adjuvant for use with a subunit fusion protein (H56) that has previously been demonstrated to provide protection in several animal models. CAF09 induces both CD4 and CD8 T cell responses in mice. We propose to optimize formulation of CAF09, scale-up production, and do toxicity testing. Immunogenicity of H56 formulated with CAF09 will be tested in cynomolgus macaques. Finally, efficacy of H56/CAF09 will be determined in a well-established, rigorous cynomolgus macaque model of tuberculosis. This is a collaboration between Peter Andersen and the Statens Serum Institute, which has a history of adjuvant and vaccine development, and the JoAnne Flynn at University of Pittsburgh School of Medicine who has extensive experience in non-human primate models of tuberculosis.
