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Randomized Controlled Trial
. 2023 Apr 17;41(16):2696-2706.
doi: 10.1016/j.vaccine.2023.03.015. Epub 2023 Mar 17.

Cellular and humoral responses to an HIV DNA prime by electroporation boosted with recombinant vesicular stomatitis virus expressing HIV subtype C Env in a randomized controlled clinical trial

Gregory J Wilson  1 , Benigno Rodriguez  2 , Shuying Sue Li  3 , Mary Allen  4 , Ian Frank  5 , Erika Rudnicki  3 , Meg Trahey  3 , Spyros Kalams  1 , Drew Hannaman  6 , David K Clarke  7 , Rong Xu  7 , Michael Egan  7 , John Eldridge  7 , Michael Pensiero  4 , Theresa Latham  7 , Guido Ferrari  8 , David C Montefiori  8 , Georgia D Tomaras  8 , Stephen C De Rosa  3 , Jeffrey M Jacobson  2 , Maurine D Miner  3 , Marnie Elizaga  3 ; HIV Vaccine Trials Network 112 Protocol Team
Affiliations
Randomized Controlled Trial

Cellular and humoral responses to an HIV DNA prime by electroporation boosted with recombinant vesicular stomatitis virus expressing HIV subtype C Env in a randomized controlled clinical trial

Gregory J Wilson et al. Vaccine. .

Abstract

Background: HIV subtypes B and C together account for around 60% of HIV-1 cases worldwide. We evaluated the safety and immunogenicity of a subtype B DNA vaccine prime followed by a subtype C viral vector boost.

Methods: Fourteen healthy adults received DNA plasmid encoding HIV-1 subtype B nef/tat/vif and env (n = 11) or placebo (n = 3) intramuscularly (IM) via electroporation (EP) at 0, 1, and 3 months, followed by IM injection of recombinant vesicular stomatitis virus encoding subtype C Env or placebo at 6 and 9 months. Participants were assessed for safety, tolerability of EP, and Env-specific T-cell and antibody responses.

Results: EP was generally well tolerated, although some device-related adverse events did occur, and vaccine reactogenicity was mild to moderate. The vaccine stimulated Env-specific CD4 + T-cell responses in greater than 80% of recipients, and CD8 + T-cell responses in 30%. Subtype C Env-specific IgG binding antibodies (bAb) were elicited in all vaccine recipients, and antibody-dependent cell-mediated cytotoxicity (ADCC) responses to vaccine-matched subtype C targets in 80%. Negligible V1/V2 and neutralizing antibody (nAb) responses were detected.

Conclusions: This prime/boost regimen was safe and tolerable, with some device-related events, and immunogenic. Although immunogenicity missed targets for an HIV vaccine, the DNA/rVSV platform may be useful for other applications.

Clinicaltrials: gov: NCT02654080.

Keywords: DNA vaccine; Electroporation; HIV vaccine; Vesicular stomatitis virus.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The following authors declare no conflicts of interest: MT, MDM, JE, DCM, JMJ, ME, DKC, GJW, GDT, GF, SK, ER, ME, TL, RX, SL. MA and MP are employed by NIAID but had no role in the funding decisions or grant oversight. DH is a full-time employee of Ichor Medical Systems, Inc. and receives a salary and equity for this work. SCDR reports funding from NIH, Bill & Melinda Gates Foundation for the work. IF gets research support from Moderna, Janssen, Pfizer and Sanofi, and is a consultant for Gilead, GlaxoSmithKline and Merck.

Figures

Figure 1.
Figure 1.. CONSORT diagram.
Participants were randomized into either vaccine or placebo group at a ratio of 4:1. The number of participants enrolled, randomized, followed up, and analyzed are shown for vaccine and placebo group. Arrows indicate time of vaccine/placebo administration and asterisks time blood samples were obtained from participants for immunogenicity analyses.
Figure 2.
Figure 2.. Visual analog scale (VAS) pain assessment scores.
Distributions for the magnitude of local injection/EP site pain as measured by the VAS are displayed by time postvaccination (0, 5-7 minutes, and 25-60 minutes), by visit and treatment arm. Graphs are displayed for the following scheduled visits: 1st, 2nd, and 3rd pDNA/placebo injections, 1st and 2nd rVSV/placebo injections. Each boxplot displays the 25th percentile, the median, and the 75th percentile. The whiskers extend from the 5th to 95th percentiles. The actual values that occurred at the scheduled visits chosen for the graphs are also plotted.
Figure 3.
Figure 3.. Vaccine-elicited CD4+ T-cell response rates and magnitudes.
Response rates (top bar graphs) and response magnitudes (bottom line graphs) of CD4+ T cells expressing IFN-γ and/or IL-2 at 2 weeks post the 3rd DNA/placebo, 1st and 2nd rVSV/placebo vaccinations to Env PTEg, gp120 C and gp41 C antigens. Statistically significant differences, if any, in response rates and magnitudes are indicated by the associated p-value. Each boxplot displays the 25th percentile, the median, and the 75th percentile among positive responders. The whiskers show the 5th to 95th percentile. Vaccine, blue; placebo, black. Filled circles indicate positive responses, open triangles indicate non-responders.
Figure 4.
Figure 4.. CD8+ T-cell response rates and magnitudes.
Response rates (top bar graphs) and response magnitudes (bottom line graphs) of CD8+ T cells expressing IFN-γ and/or IL-2 at 2 weeks post the 3rd pDNA/placebo, 1st and 2nd rVSV/placebo vaccinations to Env PTEg and gp120 C antigens. Statistically significant differences, if any, in response rates and magnitudes are indicated by the associated p-value. Each box plot displays the 25th percentile, the median, and the 75th percentile among positive responders. Whiskers show the 5th to 95th percentile. Vaccine, blue; placebo, black. Filled circles indicate positive responses, open triangles indicate non-responders.
Figure 5.
Figure 5.. IgG binding antibody response rates and magnitudes.
Response rates (top bar graphs) and response magnitudes (bottom line graphs) of binding IgG antibodies at 2 weeks post the 1st and 2nd rVSV/placebo vaccinations to gp120 C, gp140 C, gp140 B, and gp41 B antigens. Statistically significant differences, if any, in response rates and magnitudes are indicated by the associated p-value. Each boxplot displays the 25th percentile, the median, and the 75th percentile among positive responders. The whiskers show the 5th to 95th percentile. Vaccine, blue; placebo, black. Filled circles indicate positive responses, open triangles indicate non-responders. MFI = mean fluorescent intensity.
Figure 6.
Figure 6.. ADCC and neutralizing antibody response rates and magnitudes.
(A) ADCC activity measured by GTL assay of participant sera against gp120 C (C.1086) and gp120 B (B.MN) antigens at 2 weeks post 2nd rVSV/placebo vaccination. (B) ADCC activity measured by luciferase-based assay in HIV subtype C infected cells (HIV-Ce 1086 infectious molecular clone) at 2 weeks post 2nd rVSV/placebo vaccination. (C) Neutralizing antibody responses against MW965.26 (tier 1A, subtype C) at 2 weeks post the 1st and 2nd rVSV/placebo and 12 weeks post 2nd rVSV/placebo vaccinations. Response rates are depicted above graphs. Box plots are based on positive responders only (shown as filled circles); negative responders are shown as open triangles. Vaccine, blue; placebo, black.
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