Safety and tolerability of HIV-1 multiantigen pDNA vaccine given with IL-12 plasmid DNA via electroporation, boosted with a recombinant vesicular stomatitis virus HIV Gag vaccine in healthy volunteers in a randomized, controlled clinical trial

Abstract

Background: The addition of plasmid cytokine adjuvants, electroporation, and live attenuated viral vectors may further optimize immune responses to DNA vaccines in heterologous prime-boost combinations. The objective of this study was to test the safety and tolerability of a novel prime-boost vaccine regimen incorporating these strategies with different doses of IL-12 plasmid DNA adjuvant.

Methods: In a phase 1 study, 88 participants received an HIV-1 multiantigen (gag/pol, env, nef/tat/vif) DNA vaccine (HIV-MAG, 3000 μg) co-administered with IL-12 plasmid DNA adjuvant at 0, 250, 1000, or 1500 μg (N = 22/group) given intramuscularly with electroporation (Ichor TriGrid™ Delivery System device) at 0, 1 and 3 months; followed by attenuated recombinant vesicular stomatitis virus, serotype Indiana, expressing HIV-1 Gag (VSV-Gag), 3.4 ⊆ 107 plaque-forming units (PFU), at 6 months; 12 others received placebo. Injections were in both deltoids at each timepoint. Participants were monitored for safety and tolerability for 15 months.

Results: The dose of IL-12 pDNA did not increase pain scores, reactogenicity, or adverse events with the co-administered DNA vaccine, or following the VSV-Gag boost. Injection site pain and reactogenicity were common with intramuscular injections with electroporation, but acceptable to most participants. VSV-Gag vaccine often caused systemic reactogenicity symptoms, including a viral syndrome (in 41%) of fever, chills, malaise/fatigue, myalgia, and headache; and decreased lymphocyte counts 1 day after vaccination.

Conclusions: HIV-MAG DNA vaccine given by intramuscular injection with electroporation was safe at all doses of IL-12 pDNA. The VSV-Gag vaccine at this dose was associated with fever and viral symptoms in some participants, but the vaccine regimens were safe and generally well-tolerated.

Trial registration: Clinical Trials.gov NCT01578889.

Conflict of interest statement

The authors have read the journal policy and the authors of this manuscript have the following competing interests: MAA is employed by the National Institute of Allergy and Infectious Diseases (NIAID), the study sponsor. MLE, SSL, NKK, GJW, HVNT, IF, MES, KWC, BSP, JHE, MJM and CMH are recipients of NIAID funding, and this publication is a result of activities funded by NIAID. MAA is not involved with the process of funding these awards, nor in their administration of scientific aspects and, in accordance with NIAID policies, is deferred from decisions regarding funding of coauthors for a requisite period. TEL, DKC, JHE, RX, and AOS are employees and stakeholders of Profectus BioSciences, Inc. DKC is the principal author/inventor on a patent for the rVSVN4CT1 vector. At the time the study was conducted, MAE was an employee and stakeholder of Profectus BioSciences, Inc. and is now an employee of Takeda Pharmaceuticals, which has no affiliation with the study. DH is an employee and stakeholder of Ichor Medical Systems, Inc. IF serves on advisory boards for Gilead Sciences and ViiV Healthcare. HVNT has received research grant funding from Merck & Co. These affiliations do not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. HVTN 087 CONSORT flow diagram.

Fig 2. Visual analog scale pain scores after DNA/placebo and VSV-Gag/placebo vaccine delivery.

Participants rated their pain between 0 (no pain) and 10 (worst possible pain). The graph shows the mean and 95% CI of VAS scores at 3 timepoints indicating minutes after injection, shown by injection visits and treatment arms. The 95% CI was estimated using t-distribution with n-1 degrees of freedom. Pain scores were maximal at 0 minutes after electroporation, and significantly lower in T4 compared to other treatment arms at that timepoint.

Fig 3. Maximum local reactogenicity, prime vs boost, by treatment group.

Bar graphs show the percentage of participants in each treatment group reporting the specified maximum severity during the reactogenicity period. Left panels (Prime) indicate the maximum severity over all 3 priming injections. P values indicated are for comparisons across all treatment arms. The increased reactogenicity of the Prime compared to Boost is significant for T1-T4 (p

Fig 4. Maximum systemic reactogenicity, prime vs boost, by treatment group.

Bar graphs show the percentage of participants in each treatment group reporting the specified maximum severity during the reactogenicity period. Left panels (Prime) indicate the maximum severity over all 3 priming injections. P values indicated are for comparisons across all treatment arms. Maximum systemic symptoms were significantly more severe in T1-T4 groups than the placebo group following the VSV-Gag boost.

Fig 5. Decreases in peripheral blood absolute lymphocyte counts and absolute neutrophil counts after VSV-Gag.

Counts at 1 and 3 days after VSV-Gag boost were assessed for Groups 1 and 3 only. Placebo data from P1 and P3 are pooled, shown in blue. Data from T1 and T3 are displayed together, with T1 values in black and T3 in red. Bold lines represent median values for each treatment group, superimposed on the individual profiles.

Fig 6. Changes in numbers of cell populations assessed by Trucount™ after vaccination.

Absolute counts for CD3+ T cells (A), NK cells (B) and granulocytes (C) are shown. Placebo data from P1 and P3 are pooled, shown in blue. Data from T1 and T3 are displayed together, with T1 values in black and T3 in red. Bold lines represent median values for each treatment group, superimposed on the individual profiles.

Fig 7. Willingness to undergo electroporation, by treatment group.

Bar graphs show the percentage of participants in each treatment group reporting willingness to undergo EP, in response to these questions, as assessed 2 weeks after the last injection with EP: Left panel: How willing would you be to undergo electroporation if it were required for a new vaccine against a serious disease if you were at risk for that disease? Right panel: How willing would you be to undergo electroporation if it increased the effectiveness of a vaccine we already have, such as the influenza vaccine?