The acquired immunodeficiency syndrome caused by HIV-1 is the leading cause of death in Africa and the fourth leading cause of death woridwide. The recent RV144 phase-3 trial (Thai trial) testing the efficacy of an AIDS vaccine consisting of a poxvirus vector (ALVAC) prime and protein boost demonstrated a modest efficacy where 25% ofthe vaccinated individuals were protected from HIV-1 infection. These results are highly encouraging, however the immune correlates for this protection are yet to be identified but suggest a role for non-neutralizing Ab in protection. Furthermore, the protection in the Thai trial appeared to be short lived (for the first six months) and there is a need for developing approaches that sustain immunological memory of vaccineelicited responses. Our ongoing studies in rhesus macaques demonstrated a similar protection from heterologous repetitive mucosal SIV challenges by a DNA prime and poxvirus (modified vaccinia Ankara) boost vaccine (DNA/MVA). In addition, co-delivery of granulocyte and macrophage colony stimulating factor (GM-CSF) DNA with our vaccine DNA significantly enhanced the protection mediated by the DNA/MVA vaccine from 25% to 70%. GM-CSF did not adjuvant the anti-viral CD8 T cell responses but enhanced the avidity of binding Ab specific to the Env and promoted generation of anti-viral IgA in rectal secretions. Importantly, the avidity of binding Ab against the challenge virus Env strongly correlated with enhanced protection against acquisition of SIV infection. These and results from other studies highlight an important role for other non-neutralizing activities of antibody in protection. The overall goals of this project are to identify the mechanisms of GM-CSF-mediated enhancement of protection against a mucosal SIV challenge and to test the effect of a protein boost for enhancing this protection against acquisition of heterologous repetitive intravaginal SIV challenges in rhesus macaques. In our specific aim 1, we will investigate the immune correlates for GM-CSF mediated enhanced protection. Here we will test the hypothesis that GM-CSF enhances the breadth, avidity, cytolytic activity and mucosal homing of anti-Env binding Ab in serum and mucosal secretions by modulating function of antigen presenting cells and T helper responses. In our specific aim 2, we will test whether addition of a protein boost, adjuvated with either alum or a combination of toll-like receptor ligands encapsulated in nanoparticles, to the GM-CSF-adjuvanted DNA/MVA vaccine will further enhance the longevitiy of protective immunity against acquisition of heterologous repetitive intravaginal SIV challenge.

Public Health Relevance

The acquired immunodeficiency caused by HIV-1 is the leading cause of death in Africa and the fourth leading cause of death woridwide. The overall goal of this project is to develop an effective vaccine to control HIV/AIDS world wide.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI096187-04
Application #
8681318
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Emory University
Department
Type
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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