Safety and immunogenicity of a polyvalent DNA-protein HIV vaccine with matched Env immunogens delivered as a prime-boost regimen or coadministered in HIV-uninfected adults in the USA (HVTN 124): a phase 1, placebo-controlled, double-blind randomised controlled trial

Abstract

Background: An effective HIV vaccine will most likely need to have potent immunogenicity and broad cross-subtype coverage. The aim of the HIV Vaccine Trials Network (HVTN) 124 was to evaluate safety and immunogenicity of a unique polyvalent DNA-protein HIV vaccine with matching envelope (Env) immunogens.

Methods: HVTN 124 was a randomised, phase 1, placebo-controlled, double-blind study, including participants who were HIV seronegative and aged 18-50 years at low risk for infection. The DNA vaccine comprised five plasmids: four copies expressing Env gp120 (clades A, B, C, and AE) and one gag p55 (clade C). The protein vaccine included four DNA vaccine-matched GLA-SE-adjuvanted recombinant gp120 proteins. Participants were enrolled across six clinical sites in the USA and were randomly assigned to placebo or one of two vaccine groups (ie, prime-boost or coadministration) in a 5:1 ratio in part A and a 7:1 ratio in part B. Vaccines were delivered via intramuscular needle injection. The primary outcomes were safety and tolerability, assessed via frequency, severity, and attributability of local and systemic reactogenicity and adverse events, laboratory safety measures, and early discontinuations. Part A evaluated safety. Part B evaluated safety and immunogenicity of two regimens: DNA prime (administered at months 0, 1, and 3) with protein boost (months 6 and 8), and DNA-protein coadministration (months 0, 1, 3, 6, and 8). All randomly assigned participants who received at least one dose were included in the safety analysis. The study is registered with ClinicalTrials.gov (NCT03409276) and is closed to new participants.

Findings: Between April 19, 2018 and Feb 13, 2019, 60 participants (12 in part A [five men and seven women] and 48 in part B [21 men and 27 women]) were enrolled. All 60 participants received at least one dose, and 14 did not complete follow-up (six of 21 in the prime-boost group and eight of 21 in the coadminstration group). 11 clinical adverse events deemed by investigators as study-related occurred in seven of 48 participants in part B (eight of 21 in the prime-boost group and three of 21 in the coadministration group). Local reactogenicity in the vaccine groups was common, but the frequency and severity of reactogenicity signs or symptoms did not differ between the prime-boost and coadministration groups (eg, 20 [95%] of 21 in the prime-boost group vs 21 [100%] of 21 in the coadministration group had either local pain or tenderness of any severity [p=1·00], and seven [33%] vs nine [43%] had either erythema or induration [p=0·97]), nor did laboratory safety measures. There were no delayed-type hypersensitivity reactions or vasculitis or any severe clinical adverse events related to vaccination. The most frequently reported systemic reactogenicity symptoms in the active vaccine groups were malaise or fatigue (five [50%] of ten in part A and 17 [81%] of 21 in the prime-boost group vs 15 [71%] of 21 in the coadministration group in part B), headache (five [50%] and 18 [86%] vs 12 [57%]), and myalgia (four [40%] and 13 [62%] vs ten [48%]), mostly of mild or moderate severity.

Interpretation: Both vaccine regimens were safe, warranting evaluation in larger trials.

Funding: US National Institutes of Health and US National Institute of Allergy and Infectious Diseases.

Figure 1.. Study diagram.

HVTN 124 was conducted in two parts. Part A focused on safety of the protein/GLA-SE vaccine. Part B compared DNA prime-protein boost with co-administration vaccine regimens, incorporating measures of immunogenicity as well as safety. The safety analysis was performed on the intent-to-treat population, while the immunogenicity analyses were restricted to per-protocol participants.

Figure 2.. gp120/gp140 antibody response.

IgG titres for Prime-Boost (blue), Co-Administration (red), and Placebo (grey) recipients against aggregated autologous gp120 antigens (A) (non-aggregated results are presented in Supplementary Table 1A, Appendix pages 4-7) and a heterologous gp120/gp140 panel (B). Response rates and relevant clades are summarized above each plot. Non-responders are shown as triangles (*p<0.05, precise p-values are reported in Supplementary Table 1A, Appendix pages 4-7).

Figure 3.. V1V2 antibody response.

IgG (A) and IgG3 (B) responses for Prime-Boost (blue) and Co-Administration (red) recipients against gp70-V1V2 panels (*p<0.05, precise p-values are reported in Supplementary Tables 1A, 1B, Appendix pages 4-11). Response rates and relevant clades are summarized above each plot. IgG (C) and IgG3 (D) responses against antigens common across HVTN 124 Prime-Boost (P-B), RV144, HVTN 702, and HVTN 705 are also provided to contextualize results with contemporary HIV vaccine trials (*p<0.05 compared to HVTN 124 Prime-Boost, ^&p<0.05 compared to RV144, precise p-values are reported in Supplementary Table 4, Appendix page 16).

Figure 4.. Neutralizing antibody activity.

Neutralizing antibody responses of Prime-Boost (blue), Co-Administration (red), and Placebo (grey) participants to tier 1A (A), tier 1B (B), and tier 2 (C) viruses (*p<0.05, precise p-values are reported in Supplementary Table 3, Appendix page 14-15). Response rates are summarized above each plot. Non-responders are shown as triangles. Neutralizing antibody responses to tier 1B virus TH023.6 are also shown and compared against comparable groups from other HVTN 096, HVTN 097, and HVTN 105 HIV vaccine trials (D) (*p<0.05 compared to HVTN 124 Prime-Boost, ^#p<0.05 compared to HVTN 124 Co-Administration, precise p-values are reported in Supplementary Table 6, Appendix page 18).

Figure 5.. CD4+ T cell response.

Response rates and magnitudes of CD4+ T cells expressing IFN-γ and/or IL-2 (A) and of CD4+ T cells expressing each function profile (B) from Prime-Boost (blue), Co-Administration (red), and Placebo (grey) recipients to Env peptides (*p<0.05, precise p-values are reported in Supplementary Table 7, Appendix page 19).