Drug Resistant HIV: Novel Target Validation and Small Molecule Lead Discovery

DESCRIPTION (provided by applicant): HIV/AIDS remains a major health problem and there is a need for effective and durable HIV vaccines. Establishing potent and durable antibodies (Ab) that have neutralizing and non-neutralizing mechanisms can contribute to the prevention of mucosal HIV infection. Findings from the recent RV144 trial have highlighted a significant role for protective non-neutralizing Ab mechanisms. It was also observed in the RV144 trial, that vaccine efficacy diminished as Ab responses waned thus underlining the importance of developing HIV vaccines that are also durable. Therefore our main goal is to improve the magnitude while maintaining the durability and quality of the Ab responses elicited by the GeoVax HIV vaccines that are currentlyundergoing Phase 1/2a clinical testing. GeoVax HIV vaccines are designed using plasmid DNA and Modified Vaccinia Ankara (MVA) vectors to express proteins that form non-infectious virus like-particles (VLP) displaying trimeric gp160 envelope (DNA vaccines)or trimeric gp150 envelope (MVAVLP). To augment vaccine potency, Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) is co-expressed as an adjuvant with VLPs by the DNA prime (DNAGM). Our SIV prototype vaccine with GM-CSF enhanced the avidity, binding titers of anti-envelope (Env) Ab and protected 71% of vaccinated macaques against 12 repeat rectal exposures to SIVsmE660, whereas a matched vaccine without co-expressed GM-CSF provided only 25% protection. While this adjuvanted vaccine represents a significant step toward achieving a protective HIV vaccine, data from our clinical trials indicate that much lower levels of Env-specific Ab are elicited by our HIV vaccines in humans than our SIV prototype vaccines in macaques. The RV144 Thai trial showed moderate protection against infection by combining a protein with a poxvirus boost. Thus, we are working to identify conditions that will achieve higher titer of protective Env Ab responses in humans. Here, we are proposing to 1) add a soluble oligomeric gp140 Env to our current MVA boost regimen or 2) substitute our current MVA boost with an MVA that secretes soluble gp140, to enhance the magnitude and maintain the durability and quality, of Ab elicited by our DNAGM/MVA vaccine. Our collaborators are Drs Xiaoying Shen, David Montefiori, Bernard Moss, Linda Wyatt and Hanne Elyard who are experts in the field of HIV vaccines, humoral immunity, MVA recombinants. Our goal is to achieve at least a 10-fold enhancement of anti-Env binding Ab titers in Phase I. Withsuccess, we plan to submit a Phase II proposal testing protection against SHIV with the best vaccine regimen. The data gained from this study will be of great importance in providing the initial safety and efficacy data needed for an IND submission and thework to be carried out in clinical trials. With our experience in clinical trials and MVA manufacture, we are well positioned with the capability to move these vaccine components into clinical testing, apply for IND approval and ramp into commercialization. We highly stress the importance of eliciting higher titers and durable protective Ab responses for HIV vaccines and that enhancing our DNAGM/MVAVLP vaccine is a critical step forward to achieving an effective HIV vaccine. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: HIV/AIDS remains a major health problem and there is a need for effective and durable HIV vaccines. An estimated 2.5 million HIV infections occur each year with ~55,000 new infections per year in the United States. The averagecost for antiretroviral therapies until death is 500,000. Infected individuals in developing nations can afford only minimal ART, much of which is donated or heavily subsidized. The development of an efficacious HIV vaccine is a global priority and if successful will bear a tremendous impact on global health and economies. One practical strategy is to focus on enhancing humoral responses elicited by current HIV vaccines showing promise or success in SIV macaque studies, and are safe for use in humans.