First-in-Human Randomized, Controlled Trial of Mosaic HIV-1 Immunogens Delivered via a Modified Vaccinia Ankara Vector

Abstract

Background: Mosaic immunogens are bioinformatically engineered human immunodeficiency virus type 1 (HIV-1) sequences designed to elicit clade-independent coverage against globally circulating HIV-1 strains.

Methods: This phase 1, double-blinded, randomized, placebo-controlled trial enrolled healthy HIV-uninfected adults who received 2 doses of a modified vaccinia Ankara (MVA)-vectored HIV-1 bivalent mosaic immunogen vaccine or placebo on days 0 and 84. Two groups were enrolled: those who were HIV-1 vaccine naive (n = 15) and those who had received an HIV-1 vaccine (Ad26.ENVA.01) 4-6 years earlier (n = 10). We performed prespecified blinded cellular and humoral immunogenicity analyses at days 0, 14, 28, 84, 98, 112, 168, 270, and 365.

Results: All 50 planned vaccinations were administered. Vaccination was safe and generally well tolerated. No vaccine-related serious adverse events occurred. Both cellular and humoral cross-clade immune responses were elicited after 1 or 2 vaccinations in all participants in the HIV-1 vaccine-naive group. Env-specific responses were induced after a single immunization in nearly all subjects who had previously received the prototype Ad26.ENVA.01 vaccine.

Conclusions: No safety concerns were identified, and multiclade HIV-1-specific immune responses were elicited.

Clinical trials registration: NCT02218125.

Figure 1.

Local and systemic reactogenicity. Solicited adverse events (AEs) were collected for 8 days following each vaccination. Shown are the proportions of vaccinees experiencing local reactogenicity (including pain and/or tenderness, erythema, pruritus, warmth, swelling, or induration; A) or systemic symptoms (fatigue, myalgia, headache, chills, nausea, or vomiting; B) following the first or second vaccination by dose group. See Methods for descriptions of group 1, group 2, and placebo recipients.

Figure 2.

Interferon γ enzyme-linked immunospot responses measured using peptide pools corresponding to the potential T-cell epitope Env (A), Gag (B), and Pol (C) sets. Median responses at each time point are indicated with a solid line, and the dashed line indicates the positive threshold of 55 spot-forming cells (SFCs) per 10⁶ peripheral blood mononuclear cells (PBMCs). Arrows indicate the injection time points. Statistical significance was determined by the Mann-Whitney-Wilcoxon test. All subjects were either naive to a prior human immunodeficiency virus type 1 (HIV-1) vaccine or had received 2 or 3 doses of a prototype HIV-1 vaccine (Ad26.ENVA.01) containing only an EnvA insert. See Methods for descriptions of group 1, group 2, and placebo recipients.

Figure 3.

Cellular immune responses measured by intracellular cytokine staining. The percentage of CD4⁺ T cells (A, C, and E) and CD8⁺ T cells (B, D, and F) producing interleukin 2 and or interferon γ in response to stimulation with potential T-cell epitope Env (A and B), Gag Mos1 (C and D), and Gag Mos2 (E and F) peptide pools are shown. Median responses at each time point are indicated with a solid line, and the dashed line indicates the lower limit of detection of the assay. Arrows indicate the injection time points. All subjects were either naive to a prior human immunodeficiency virus type 1 (HIV-1) vaccine or had received 2 or 3 doses of a prototype HIV-1 vaccine (Ad26.ENVA.01) containing only an EnvA insert. See Methods for descriptions of group 1, group 2, and placebo recipients.

Figure 4.

Humoral immune responses measured against EnvA (A), EnvB (B), EnvC (C), and Mos1 Env (D) by an enzyme-linked immunosorbent assay. Median responses at each time point are indicated with a solid line and the dashed line indicates the lower limit of detection of the assay. Arrows indicate the injection time points. Statistical significance was determined by the Mann-Whitney-Wilcoxon test. All subjects were either naive to a prior human immunodeficiency virus type 1 (HIV-1) vaccine or had received 2 or 3 doses of a prototype HIV-1 vaccine (Ad26.ENVA.01) containing only an EnvA insert. See Methods for descriptions of group 1, group 2, and placebo recipients.

Figure 5.

Neutralizing antibody activity was measured using pseudoviruses expressing Env derived from tier 1A viruses MN3 (clade B; A), SF162 (clade B; B), and MW965 (clade C; C). Median responses at each time point are indicated with a solid line, and the dashed line indicates the lower limit of detection of the assay. Arrows indicate the injection time points. All subjects were either naive to a prior human immunodeficiency virus type 1 (HIV-1) vaccine or had received 2 or 3 doses of a prototype HIV-1 vaccine (Ad26.ENVA.01) containing only an EnvA insert. See Methods for descriptions of group 1, group 2, and placebo recipients.

Figure 6.

Env binding antibodies as measured by surface plasmon resonance. Binding antibodies were measured against the cyclic V2 loop (A) and the cyclic V3 loop (B) peptides of 92TH023 (clade AE). Median responses at each time point are indicated with a solid line. Arrows indicate the injection time points. All subjects were either naive to a prior human immunodeficiency virus type 1 (HIV-1) vaccine or had received 2 or 3 doses of a prototype HIV-1 vaccine (Ad26.ENVA.01) containing only an EnvA insert. See Methods for descriptions of group 1, group 2, and placebo recipients.

Figure 7.

Antibody-dependent cellular phagocytosis responses measured using beads coated with Env from clade A (A1.con; A), clade B (SF162; B), or clade C (1086C [C] or ZA [D]). Median responses at each time point are indicated with a solid line. Arrows indicate the injection time points. Statistical significance was determined by the Wilcoxon signed rank test. All subjects were either naive to a prior human immunodeficiency virus type 1 (HIV-1) vaccine or had received 2 or 3 doses of a prototype HIV-1 vaccine (Ad26.ENVA.01) containing only an EnvA insert. See Methods for descriptions of group 1, group 2, and placebo recipients.