Focusing HIV-1 Gag T cell responses to highly conserved regions by DNA vaccination in HVTN 119

BACKGROUND. An HIV-1 DNA vaccine composed of 7 highly conserved, structurally important elements (conserved elements, CE) of p24(Gag) was tested in a phase I randomized, double-blind clinical trial (HVTN 119, NCT03181789) in people without HIV. DNA vaccination of CE prime/CE+p55(Gag) boost was compared with p55(Gag). METHODS. Two groups (n = 25) received 4 DNA vaccinations (CE/CE+p55(Gag) or p55(Gag)) by intramuscular injection/electroporation, including IL-12 DNA adjuvant. The placebo group (n = 6) received saline. Participants were followed for safety and tolerability. Immunogenicity was assessed for T cell and antibody responses. RESULTS. Both regimens were safe and generally well tolerated. The p24CE vaccine was immunogenic and significantly boosted by CE+p55(Gag) (64% CD4(+), P = 0.037; 42% CD8(+), P = 0.004). CE+p55(Gag) induced responses to 5 of 7 CE, compared with only 2 CE by p55(Gag) DNA, with a higher response to CE5 in 30% of individuals (P = 0.006). CE+p55(Gag) induced significantly higher CD4(+) CE T cell breadth (0.68 vs. 0.22 CE; P = 0.029) and a strong trend for overall T cell breadth (1.14 vs. 0.52 CE; P = 0.051). Both groups developed high cellular and humoral responses. p24CE vaccine-induced CD4(+) CE T cell responses correlated (P = 0.007) with p24(Gag) antibody responses. CONCLUSION. The CE/CE+p55(Gag) DNA vaccine induced T cell responses to conserved regions in p24(Gag), increasing breadth and epitope recognition throughout p55(Gag) compared with p55(Gag) DNA. Vaccines focusing immune responses by priming responses to highly conserved regions could be part of a comprehensive HIV vaccine strategy.