Successful development of a vaccine against HIV will likely require the induction of both antibody and/or cellular immune responses sufficient to prevent infection or disease respectively following infectious challenge. While the induction of antibody responses for a variety of other infectious pathogens is readily achieved by a variety of vaccine formulations, live attenuated, recombinant viral vaccines or plasmid DNA vaccines only induce the induction of long-lived cellular immune responses, particularly CD8+ T cell responses. Moreover, since live attenuated HIV vaccines might be precluded from use due to safety concerns and DNA vaccines at present only induce modest CD8+ T cell responses in humans, there is an urgent need to develop ways to enhance the generation and maintenance of CD8+ T cell responses in humans in following immunization. This study focuses on how to optimize the magnitude and duration of CD8+ T cell responses following vaccination in rodents and primates using a variety of vaccine formulations. The data obtained over this past year have shown the following; 1. A comparative analysis of single or combination TLR ligands was done in NHP using SIV Gag protein and an oil/water emulsion. Amongst the adjuvants used, Poly IC and a TLR 7/8 agonist were the most potent for inducing SIV Gag specific CD4 and CD8+ T cell responses. 2. A non-human primate study showed that a non-targeted and targeted HIV Gag protein to DEC-205, a receptor specific for dendritic cells induced potent and comparable Th1 immunity following a series of immunizations. However the protein vaccine elicited higher avidity antibody responses while the DEC-205 targeted vaccine had higher CD8+ T cell responses. These data show that delivery of protein with Poly ICLC as an adjuvant can influence the type of adaptive immunity generated. Animals have been boosted with a pox viral vector encoding HIV Gag and the immune responses will be assessed. 3. A comparative analysis of adjuvants and formulation was recently completed in NHP using HIV Env protein. This study focused on two clinically approved adjuvants ( alum and MF-59) with or without TLR 4 or TLR 7 ligands as additional immune stimulators. The data generated so far show that MF-59 induces more potent humoral and cellular immunity than alum when given with HIV Env protein. Combining alum with a TLR 7 ligand strongly enhanced immunity compared to alum alone. By contrast, adding TLR 4 or TLR 7 ligands to MF 59 did increase immunity compared to alum alone. In terms of T cell immunity, MF 59 induced a mixed Th1 and Th2 cytokine response. Additional analysis in terms of durability, avidity and ADCC is being performed. 4. A comparative analysis of adenoviral or pox viral vectors encoding SIV Gag was initiated this year. The data show that the amount and duration of antigen has a dramatic influence on the strong CD8+ T cell immunity with rAd5 compared to other Ad serotypes. By contrast, there is minimal innate immunity induced by Ad5.

Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2011
Total Cost
$3,196,577
Indirect Cost
City
State
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