Phase 1 Human Immunodeficiency Virus (HIV) Vaccine Trial to Evaluate the Safety and Immunogenicity of HIV Subtype C DNA and MF59-Adjuvanted Subtype C Envelope Protein

Abstract

Background: The Pox-Protein Public-Private Partnership is performing a suite of trials to evaluate the bivalent subtype C envelope protein (TV1.C and 1086.C glycoprotein 120) vaccine in the context of different adjuvants and priming agents for human immunodeficiency virus (HIV) type 1 (HIV-1) prevention.

Methods: In the HIV Vaccine Trials Network 111 trial, we compared the safety and immunogenicity of DNA prime followed by DNA/protein boost with DNA/protein coadministration injected intramuscularly via either needle/syringe or a needle-free injection device (Biojector). One hundred thirty-two healthy, HIV-1-uninfected adults were enrolled from Zambia, South Africa, and Tanzania and were randomized to 1 of 6 arms: DNA prime, protein boost by needle/syringe; DNA and protein coadministration by needle/syringe; placebo by needle/syringe; DNA prime, protein boost with DNA given by Biojector; DNA and protein coadministration with DNA given by Biojector; and placebo by Biojector.

Results: All vaccinations were safe and well tolerated. DNA and protein coadministration was associated with increased HIV-1 V1/V2 antibody response rate, a known correlate of decreased HIV-1 infection risk. DNA administration by Biojector elicited significantly higher CD4+ T-cell response rates to HIV envelope protein than administration by needle/syringe in the prime/boost regimen (85.7% vs 55.6%; P = .02), but not in the coadministration regimen (43.3% vs 48.3%; P = .61).

Conclusions: Both the prime/boost and coadministration regimens are safe and may be promising for advancement into efficacy trials depending on whether cellular or humoral responses are desired.

Clinical trials registration: South African National Clinical Trials Registry (application 3947; Department of Health [DoH] no. DOH-27-0715-4917) and ClinicalTrials.gov (NCT02997969).

Keywords: Biojector; DNA prime/protein boost; HIV vaccine; subtype C.

Figure 1.

HIV Vaccine Trials Network (HVTN) 111 CONSORT diagram, showing enrollment and follow-up of participants in HVTN 111, including availability of samples for immunological testing. Abbreviations: bAb, binding antibody; CONSORT, consolidated standards of reporting trials; HIV, human immunodeficiency virus; ICS, intracellular cytokine staining; nAb, neutralizing antibody.

Figure 2.

Reactogenicity in HIV Vaccine Trials Network (HVTN) 111. Local reactogenicity symptoms according to treatment arm and severity grade. Abbreviation: HIV, human immunodeficiency virus.

Figure 3.

Binding antibody responses. BAMA response rates (bar charts) and magnitudes (box plots) by treatment arm for the following antigens: 96ZM651.C glycoprotein (gp) 140 (A), CaseA2_gp70_V1V2.B (B), and 1086.C V1V2 (C). Bar charts show positive response rates. Box plots show responses and are based on positive responders only (shown as colored circles); negative responders are shown as gray triangles. *P ≤ .05; †P ≤ .01; ‡P ≤ .001. Abbreviations: B, Biojector; BAMA, binding-antibody multiplex assay; MFI, mean fluorescence intensity; S, needle/syringe.

Figure 4.

Neutralizing antibody (nAb) responses. Response rates (bar charts) and nAb titers (box plots) against TV1c8.2.C (A) and MW965.26.C (B) are shown by treatment arm. Bar charts show positive response rates. Box plots show responses and are based on positive responders only (shown as colored circles); negative responders are shown as gray triangles. *P ≤ .05; †P ≤ .01; ‡P ≤ .001. Abbreviations: B, Biojector; ID50, 50% infectious dose; S, needle/syringe.

Figure 5.

CD4⁺ T-cell responses, as measured by intracellular cytokine staining. Response rate (bar charts) and magnitude (box plots) 2 weeks after the final vaccination by treatment arm are shown for the following vaccine-matched peptide pools: any human immunodeficiency virus (HIV) (A), Any envelope (Env) (B), Env.1086.C (C), and Env-1-ZM96.C (D). Any HIV is the sum of any Pol, any Env, Nef-CN54, and Gag-ZM96.C, where any Pol is the sum of Pol-1-CN54 and Pol-2-CN54. Any Env is the maximum of Env ZM96, Env.1086.C, and Env.TV1.C, where Env ZM96 is the sum of Env-1-ZM96.C and Env-2-ZM96.C. Bar charts show positive response rates. Box plots show responses and are based on positive responders only (shown as colored circles); negative responders are shown as gray triangles. *P ≤ .05; †P ≤ .01; ‡P ≤ .001. Abbreviations: B, Biojector; IFN, interferon; IL-2, interleukin; S, needle/syringe; Pol, polyfunctionality.

Figure 6.

Functionality and polyfunctionality according to study arm. A, Functionality and polyfunctionality scores of CD4⁺ T-cell subsets to any envelope (Env) ZM96 2 weeks after the final vaccination. To determine scores for Env ZM96, data for Env-1-ZM96.C and Env-2-ZM96.C were combined before fitting the Combinatorial Polyfunctionality Analysis of Single Cells (COMPASS) model. B, Heat map of mean COMPASS posterior probabilities for CD4⁺ T-cell responses to any Env ZM96 among vaccine and placebo recipients. Rows correspond to mean posterior probabilities of participants in each treatment group. Each cell shows the probability (ranging from white [0] to purple [1]) that the corresponding cell subset (column) demonstrates an antigen-specific response in the corresponding treatment group (row). Abbreviations: B, Biojector; Co-ad, coadministration; GzB, granzyme B; IFN, interferon; IL-2, IL-4, and IL-17, interleukin 2, 4, and 17; P, Placebo; Prime/bst, prime/boost; S, needle/syringe; TNF, tumor necrosis factor.