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 7

p24Gag antibody responses.

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p24Gag antibody responses. The binding antibody multiplex assay (BAMA) t...
The binding antibody multiplex assay (BAMA) to p24Gag was performed at M6.5. (A) Response rates (upper panel) listing number of responders, number of samples analyzed, and response rate in percentage points. P values are from Wilcoxon rank-sum tests. The lower panel shows the area under the curve (AUTC) from responders in color and nonresponders in gray with box plots based on data from responders superimposed on the distribution. The midline of the box denotes the median, and the boundaries of the box denote the 25th and 75th percentiles. 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. (B and C) Correlation between p24Gag antibody level (AUTC, from panel A) and p24Gag-specific IFN-γ+ CD4+ T cell response at M6.5 in (B) T1 and (C) T2 (data from Figure 6). Spearman’s r and P values are given.