Focusing HIV-1 Gag T cell responses to highly conserved regions by DNA vaccination in HVTN 119
Spyros A. Kalams, Barbara K. Felber, James I. Mullins, Hyman M. Scott, Mary A. Allen, Stephen C. De Rosa, Jack Heptinstall, Georgia D. Tomaras, Jiani Hu, Allan C. DeCamp, Margherita Rosati, Jenifer Bear, Michael N. Pensiero, John Eldridge, Michael A. Egan, Drew Hannaman, M. Juliana McElrath, George N. Pavlakis, HIV Vaccine Trials Network 119(HVTN 119) Study Team
Spyros A. Kalams, Barbara K. Felber, James I. Mullins, Hyman M. Scott, Mary A. Allen, Stephen C. De Rosa, Jack Heptinstall, Georgia D. Tomaras, Jiani Hu, Allan C. DeCamp, Margherita Rosati, Jenifer Bear, Michael N. Pensiero, John Eldridge, Michael A. Egan, Drew Hannaman, M. Juliana McElrath, George N. Pavlakis, HIV Vaccine Trials Network 119(HVTN 119) Study Team
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Clinical Research and Public Health AIDS/HIV Clinical trials

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

Abstract

BACKGROUND An HIV-1 DNA vaccine composed of 7 highly conserved, structurally important elements (conserved elements, CE) of p24Gag was tested in a phase I randomized, double-blind clinical trial (HVTN 119, NCT03181789) in people without HIV. DNA vaccination of CE prime/CE+p55Gag boost was compared with p55Gag.METHODS Two groups (n = 25) received 4 DNA vaccinations (CE/CE+p55Gag or p55Gag) 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+p55Gag (64% CD4+, P = 0.037; 42% CD8+, P = 0.004). CE+p55Gag induced responses to 5 of 7 CE, compared with only 2 CE by p55Gag DNA, with a higher response to CE5 in 30% of individuals (P = 0.006). CE+p55Gag 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 p24Gag antibody responses.CONCLUSION The CE/CE+p55Gag DNA vaccine induced T cell responses to conserved regions in p24Gag, increasing breadth and epitope recognition throughout p55Gag compared with p55Gag DNA. Vaccines focusing immune responses by priming responses to highly conserved regions could be part of a comprehensive HIV vaccine strategy.TRIAL REGISTRATION Clinical Trials.gov NCT03181789FUNDING HVTN, NIAID/NIH

Authors

Spyros A. Kalams, Barbara K. Felber, James I. Mullins, Hyman M. Scott, Mary A. Allen, Stephen C. De Rosa, Jack Heptinstall, Georgia D. Tomaras, Jiani Hu, Allan C. DeCamp, Margherita Rosati, Jenifer Bear, Michael N. Pensiero, John Eldridge, Michael A. Egan, Drew Hannaman, M. Juliana McElrath, George N. Pavlakis, HIV Vaccine Trials Network 119(HVTN 119) Study Team

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Figure 2

Flow cytometric analysis of cellular immune responses to CE and full-length Gag.

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Flow cytometric analysis of cellular immune responses to CE and full-len...
Intracellular cytokine staining (ICS) was performed at M0, and 2 weeks after the second (M1.5) and fourth (M6.5) vaccinations, measuring antigen-specific T cell response rates (bar graphs in upper panels) and magnitudes (box-line plots in lower panels) in PBMCs against CE (A and B) and p55Gag (C and D). Response rates and the percentage of CD4+ and CD8+ T cells expressing cytokines were plotted by T cell subset, HIV peptide pool, visit, and treatment group. Samples scoring positive by Fisher’s test (see Methods) were plotted in color (coded for group) and the cases reported negative in gray. The distribution of the background-adjusted magnitude of IFN-γ+ and/or IL-2+ T cell response is displayed graphically on the log scale y axis, which is truncated at 0.025%; any values below this level were censored. Data points for each participant are connected by a gray line. The whiskers extend to the most extreme data points that are no more than 1.5 times the interquartile range (i.e., height of the box) or, if no value meets this criterion, to the data extremes. The CE peptide pool comprised 15-mer peptides overlapping by 11 AA and 10-mer peptides overlapping by 9 AA spanning all 7 CE. The Gag (HXB2 strain) peptide pool comprised 15-mer peptides overlapping by 11 AA spanning full-length p55Gag.