A polyvalent DMA prime-protein boost vaccine (DP6-001), consisting of codon optimized HIV-1 env (A, B, C, E) and gag (C) genes and homologous gp120 proteins in QS-21 adjuvant, was evaluated by our team in both preclinical studies and in a Phase I clinical trial. Data from the clinical trial demonstrated that DNA priming enhanced the anti-Env antibody (Ab) response following Env protein boost (see Preliminary Studies). This was the first time that this vaccine strategy for eliciting Ab, termed 'DNA prime/protein boost,'was demonstrated in humans for HIV vaccine development. Especially encouraging was the detection of neutralizing antibodies (NAbs) against both homologous and heterologous primary isolates. In addition, T cell responses against Gag and Env were also induced by DP6-001 vaccination, indicating that the DNA prime-protein boost strategy has the potential to elicit both anti-HIV NAbs and cellular immunity. While these results were exciting, the human trial also revealed unanticipated reactogenic complications that were not seen in either the preclinical, IND-enabling safety/toxicology testing in rabbits or the nonhuman primate studies. A single case of leukocytoclastic vasculitis (LCV) that transiently occurred in a subject who received the highest DNA priming dose (7.2 mg intramuscularly) followed by a single protein immunization. Similarly, all of the other five subjects from this high dose DNA priming group also exhibited reactogenic AEs as evidenced by self-reported myalgias, low grade fever and headaches following the single protein boost. These results have made us aware of a boundary condition for an acceptable HIV vaccine: while strong immunogenicity is good, excessive reactogenicity could limit the widespread deployment of such a vaccine. As a result of this experience, we have reconfigured our studies in Project 2 in an effort to minimize reactogenicity as we optimize immunogenicity.
Aim 1 will use mice to compare the cytokine profile and TLR responses between mice receiving low and high DNA prime when protein boost includes QS-21 which was included in DP6-001.
Aim 2 will use the information learned from Aim 1 to test the effect of other adjuvants (monophosphoryl lipid A, Montanide ISA 51 and alum) that may have lower potential for reactogenicity while maintaining the high immunogenicity.
Aim 3 will examine the reactogenicity of the candidate vaccines in mice when DNA vaccine is delivered by electroporation.
Aim 4 will test the next generation of polyvalent Env formulation (including optimized adjuvant and DNA delivery method) in rhesus macaques to assess their immunogenicity, safety, and ability to protect from a viral challenge.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI082676-04
Application #
8377354
Study Section
Special Emphasis Panel (ZAI1-ESB-A)
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$22,629
Indirect Cost
$8,873
Name
University of Massachusetts Medical School Worcester
Department
Type
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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Costa, Matthew R; Pollara, Justin; Edwards, Regina Whitney et al. (2016) Fc Receptor-Mediated Activities of Env-Specific Human Monoclonal Antibodies Generated from Volunteers Receiving the DNA Prime-Protein Boost HIV Vaccine DP6-001. J Virol 90:10362-10378
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Buglione-Corbett, Rachel; Pouliot, Kimberly; Marty-Roix, Robyn et al. (2014) Reduced MyD88 dependency of ISCOMATRIXâ„¢ adjuvant in a DNA prime-protein boost HIV vaccine. Hum Vaccin Immunother 10:1078-90
Chen, Yuxin; Vaine, Michael; Wallace, Aaron et al. (2013) A novel rabbit monoclonal antibody platform to dissect the diverse repertoire of antibody epitopes for HIV-1 Env immunogen design. J Virol 87:10232-43

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