Most candidate vaccines specific for HIV-1 are designed to stimulate cell-mediated immune responses. These include different viral and non-viral vectors and a combination of prime/boost protocols. Preliminary data already suggest that the immune responses elicited by these vaccines are limited and likely to be insufficient for protection. In this innovative project, we aim at enhancing both cell-mediated and neutralizing antibody responses by the use of two novel adjuvants that target innate and adaptive im munity, respectively: bacterial Flagellin via Toll-like receptor 5 signaling and polymeric (Mega) CD40 ligand via stimulation of CD40 on dendritic cells and lymphocytes. In addition, a new approach for adjuvant signaling will be developed with a novel alp havirus vaccine virus replicon vector of Semliki Forest virus, a virus, which recently has been shown to strongly target the innate immune pathways including Toll-like receptors. We will combine the novel adjuvant strategies to existing vaccines and analyz e whether such treatment can shape the immune responses into effective responses. Studies will be performed in human and murine settings (based amongst others on analysis of T and B cell memory responses) to get key comparative information for the develop ment of new formulation of HIV-specific vaccines. The effect of the adjuvants and vectors on innate immune signals will also be thoroughly characterized. Finally, vaccines and vaccine-adjuvant combinations also using alphavirus and poxvirus vectors will be evaluated in animal challenge models to obtain immune correlates of protection. This project will provide the basis for a more effective HIV vaccine.
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