Abstract
BACKGROUNDHVTN 098, a randomized, double-blind, placebo-controlled trial, evaluated the safety, tolerability, and immunogenicity of PENNVAX-GP HIV DNA vaccine, administered with or without plasmid IL-12 (pIL-12), via intradermal (ID) or intramuscular (IM) electroporation (EP) in healthy, HIV-uninfected adults. The study tested whether PENNVAX-GP delivered via ID/EP at one-fifth the dose could elicit equivalent immune responses to delivery via IM/EP and whether inclusion of pIL-12 provided additional benefit.METHODSParticipants received DNA encoding HIV-1 env/gag/pol in 3 groups: 1.6 mg ID (ID no IL-12 group, n = 20), 1.6 mg ID + 0.4 mg pIL-12 (ID + IL-12 group, n = 30), 8 mg IM + 1 mg pIL-12 (IM + IL-12 group, n = 30), or placebo (n = 9) via EP at 0, 1, 3, and 6 months. Results of cellular and humoral immunogenicity assessments are reported.RESULTSFollowing vaccination, the frequency of responders (response rate) to any HIV protein based on CD4+ T cells expressing IFN-γ or IL-2 was 96% for both the ID + IL-12 and IM + IL-12 groups; CD8+ T cell response rates were 64% and 44%, respectively. For ID delivery, the inclusion of pIL-12 increased CD4+ T cell response rate from 56% to 96%. The frequency of responders was similar (≥90%) for IgG binding antibody to gp140 consensus Env across all groups, but the magnitude was higher in the ID + IL-12 group compared with the IM + IL-12 group.CONCLUSIONPENNVAX-GP DNA induced robust cellular and humoral immune responses, demonstrating that immunogenicity of DNA vaccines can be enhanced by EP route and inclusion of pIL-12. ID/EP was dose sparing, inducing equivalent, or in some aspects superior, immune responses compared with IM/EP.TRIAL REGISTRATIONClinicalTrials.gov NCT02431767.FUNDINGThis work was supported by National Institute of Allergy and Infectious Diseases (NIAID), U.S. Public Health Service grants, an HIV Vaccine Design and Development Team contract, Integrated Preclinical/Clinical AIDS Vaccine Development Program, and an NIH award.
Highlights
DNA has been included as part of the vaccine regime for several candidate HIV vaccines contributing to robust immunogenicity
We focused on increasing the magnitude and breadth of Env-specific immune responses in HIV Vaccine Trials Network (HVTN) 098 by designing and including 2 env plasmids encoding both RNA- and codon-optimized clade A and C consensus Env immunogens
The majority (82%) of both IM/EP and ID/EP participants reported that the level of discomfort was acceptable, and all but 2 said they would be willing to undergo EP vaccination for a serious disease
Summary
DNA has been included as part of the vaccine regime for several candidate HIV vaccines contributing to robust immunogenicity (e.g., refs. 1–3). There were initial concerns about the feasibility and tolerability of EP vaccination in vivo, several trials have shown acceptability of EP among study participants and enhanced immune responses when delivered by the intramuscular (IM) [5,6,7,8] and intradermal (ID) [9, 10] routes. The HIV Vaccine Trials Network (HVTN) 098 study, reported here, explored improvements in plasmid and construct design, formulation, as well as delivery in healthy, HIV-1–uninfected study participants in a multicenter clinical trial. HVTN 098, a randomized, double-blind, placebo-controlled trial, evaluated the safety, tolerability, and immunogenicity of PENNVAX-GP HIV DNA vaccine, administered with or without plasmid IL-12 (pIL-12), via intradermal (ID) or intramuscular (IM) electroporation (EP) in healthy, HIV-uninfected adults. The study tested whether PENNVAX-GP delivered via ID/EP at onefifth the dose could elicit equivalent immune responses to delivery via IM/EP and whether inclusion of pIL-12 provided additional benefit
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