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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. 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. 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. No safety concerns were identified, and multiclade HIV-1-specific immune responses were elicited. NCT02218125.

We evaluated the safety and immunogenicity of (i) an intradermal HIV-DNA regimen given with/without intradermal electroporation (EP) as prime and (ii) the impact of boosting with modified vaccinia virus Ankara (HIV-MVA) administered with or without subtype C CN54rgp140 envelope protein adjuvanted with Glucopyranosyl Lipid A (GLA-AF) in volunteers from Tanzania and Mozambique. Healthy HIV-uninfected adults (N = 191) were randomized twice; first to one of three HIV-DNA intradermal priming regimens by needle-free ZetaJet device at weeks 0, 4 and 12 (Group I: 2x0.1mL [3mg/mL], Group II: 2x0.1mL [3mg/mL] plus EP, Group III: 1x0.1mL [6mg/mL] plus EP). Second the same volunteers received 108 pfu HIV-MVA twice, alone or combined with CN54rgp140/GLA-AF, intramuscularly by syringe, 16 weeks apart. Additionally, 20 volunteers received saline placebo. Vaccinations and electroporation did not raise safety concerns. After the last vaccination, the overall IFN-γ ELISpot response rate to either Gag or Env was 97%. Intradermal electroporation significantly increased ELISpot response rates to HIV-DNA-specific Gag (66% group I vs. 86% group II, p = 0.026), but not to the HIV-MVA vaccine-specific Gag or Env peptide pools nor the magnitude of responses. Co-administration of rgp140/GLA-AF with HIV-MVA did not impact the frequency of binding antibody responses against subtype B gp160, C gp140 or E gp120 antigens (95%, 99%, 79%, respectively), but significantly enhanced the magnitude against subtype B gp160 (2700 versus 300, p<0.001) and subtype C gp140 (24300 versus 2700, p<0.001) Env protein. At relatively low titers, neutralizing antibody responses using the TZM-bl assay were more frequent in vaccinees given adjuvanted protein boost. Intradermal electroporation increased DNA-induced Gag response rates but did not show an impact on Env-specific responses nor on the magnitude of responses. Co-administration of HIV-MVA with rgp140/GLA-AF significantly enhanced antibody responses.

We administered Ad26, modified vaccinia Ankara vectors containing mosaic HIV-1 antigens or placebo in 26 individuals who initiated antiretroviral therapy during acute human immunodeficiency virus infection as an exploratory study to determine the safety and duration of viremic control after treatment interruption. The vaccine was safe and generated robust immune responses, but delayed time to viral rebound compared to that in placebo recipients by only several days and did not lead to viremic control after treatment interruption (clinical trial NCT02919306). Test of therapeutic mosaic vaccines in HIV-infected individuals shows no control of virus after treatment interruption.

Background. Clade B DNA and recombinant modified vaccinia Ankara (MVA) vaccines producing virus-like particles displaying trimeric membrane-bound envelope giycoprotein (Env) were tested in a phase 2a trial in human immunodeficiency virus (HIV)-uninfected adults for safety, immunogenicity, and 6-month durability of immune responses. Methods. A total of 299 individuals received 2 doses of JS7 DNA vaccine and 2 doses of MVA/HIV62B at 0, 2, 4, and 6 months, respectively (the DDMM regimen); 3 doses of MVA/HIV62B at 0, 2, and 6 months (the regimen); or placebo injections. Results. At peak response, 93.2% of the DDMM group and 98.4% of the group had binding antibodies for Env. These binding antibodies were more frequent and of higher magnitude for the transmembrane subunit (gp41) than the receptor-binding subunit (gpl20) of Env. For both regimens, response rates were higher for CD4⁺ T cells (66.4% in the DDMM group and 43.1% in the group) than for CD8⁺ T cells (21.8% in the DDMM group and 14.9% in the group). Responding CD4⁺ and CD8⁺ T cells were biased toward Gag, and > 70% produced 2 or 3 of the 4 cytokines evaluated (ie, interferon γ, interleukin 2, tumor necrosis factor α, and granzyme B). Six months after vaccination, the magnitudes of antibodies and T-cell responses had decreased by <3-fold. Conclusions. DDMM and MMM vaccinations with virus-like particle-expressing immunogens elicited durable antibody and T-cell responses.

Background. The Step Study tested whether an adenovirus serotype 5 (Ad5)-vectored human immunodeficiency virus (HIV) vaccine could prevent HIV acquisition and/or reduce viral load set-point after infection. At the first interim analysis, nonefficacy criteria were met. Vaccinations were halted; participants were unblinded. In post hoc analyses, more HIV infections occurred in vaccinees vs placebo recipients in men who had Ad5-neutralizing antibodies and/or were uncircumcised. Follow-up was extended to assess relative risk of HIV acquisition in vaccinees vs placebo recipients over time. Methods. We used Cox proportional hazard models for analyses of vaccine effect on HIV acquisition and vaccine effect modifiers, and nonparametric and semiparametric methods for analysis of constancy of relative risk over time. Results. One hundred seventy-two of 1836 men were infected. The adjusted vaccinees vs placebo recipients hazard ratio (HR) for all follow-up time was 1.40 (95% confidence interval [CI], 1.03—1.92; P = .03). Vaccine effect differed by baseline Ad5 or circumcision status during first 18 months, but neither was significant for all follow-up time. The HR among uncircumcised and/or Ad5-seropositive men waned with time since vaccination. No significant vaccine-associated risk was seen among circumcised, Ad5-negative men (HR, 0.97; P = 1.0) over all follow-up time. Conclusions. The vaccine-associated risk seen in interim analysis was confirmed but waned with time from vaccination. Clinical Trials Registration. NCT00095576.

Observational data and non-human primate challenge studies suggest that cell-mediated immune responses might provide control of HIV replication. The Step Study directly assessed the efficacy of a cell-mediated immunity vaccine to protect against HIV-1 infection or change in early plasma HIV-1 levels. We undertook a double-blind, phase II, test-of-concept study at 34 sites in North America, the Caribbean, South America, and Australia. We randomly assigned 3000 HIV-1-seronegative participants by computer-generated assignments to receive three injections of MRKAd5 HIV-1 gag/pol/nef vaccine (n=1494) or placebo (n=1506). Randomisation was prestratified by sex, adenovirus type 5 (Ad5) antibody titre at baseline, and study site. Primary objective was a reduction in HIV-1 acquisition rates (tested every 6 months) or a decrease in HIV-1 viral-load setpoint (early plasma HIV-1 RNA measured 3 months after HIV-1 diagnosis). Analyses were per protocol and modified intention to treat. The study was stopped early because it unexpectedly met the prespecified futility boundaries at the first interim analysis. This study is registered with ClinicalTrials.gov, number NCT00095576. In a prespecified interim analysis in participants with baseline Ad5 antibody titre 200 or less, 24 (3%) of 741 vaccine recipients became HIV-1 infected versus 21 (3%) of 762 placebo recipients (hazard ratio [HR] 1·2 [95% CI 0·6–2·2]). All but one infection occurred in men. The corresponding geometric mean plasma HIV-1 RNA was comparable in infected male vaccine and placebo recipients (4·61 vs 4·41 log10 copies per mL, one tailed p value for potential benefit 0·66). The vaccine elicited interferon-γ ELISPOT responses in 75% (267) of the 25% random sample of all vaccine recipients (including both low and high Ad5 antibody titres) on whose specimens this testing was done (n=354). In exploratory analyses of all study volunteers, irrespective of baseline Ad5 antibody titre, the HR of HIV-1 infection between vaccine and placebo recipients was higher in Ad5 seropositive men (HR 2·3 [95% CI 1·2–4·3]) and uncircumcised men (3·8 [1·5–9·3]), but was not increased in Ad5 seronegative (1·0 [0·5–1·9]) or circumcised (1·0 [0·6–1·7]) men. This cell-mediated immunity vaccine did not prevent HIV-1 infection or reduce early viral level. Mechanisms for insufficient efficacy of the vaccine and the increased HIV-1 infection rates in subgroups of vaccine recipients are being explored. Merck Research Laboratories; the Division of AIDS, National Institute of Allergy and Infectious Diseases, in the US National Institutes of Health (NIH); and the NIH-sponsored HIV Vaccine Trials Network (HVTN).

In an efficacy trial, 2504 persons at high risk for HIV-1 acquisition received either a DNA prime–recombinant adenovirus type 5 boost (DNA/rAd5) vaccine or placebo. The vaccine regimen did not reduce either HIV-1 acquisition or viral load. The epidemic infection caused by the human immunodeficiency virus type 1 (HIV-1) is now in its fourth decade, with an estimated 2.5 million new infections occurring annually worldwide. 1 The number of newly infected persons, although diminishing, outpaces the number of patients who initiate antiretroviral therapy. Despite a number of successful prevention interventions that have been reported, including preexposure prophylaxis and treatment as prevention, 2 – 9 ultimate control of the HIV epidemic will most likely come only with the development of a safe and effective preventive vaccine. This goal has proved to be elusive. Of the efficacy trials of HIV vaccines that . . .

Building on results from the AELIX-002 trial with HIVACAT T-cell immunogen (HTI)-based vaccines, the AELIX-003 (NCT04364035) trial tested the safety of the combination of ChAdOx1.HTI (C) and MVA.HTI (M), with the TLR7 agonist vesatolimod (VES), in a double-blind, placebo-controlled, randomized clinical trial in 50 virally suppressed early-treated men with HIV-1 infection. Secondary objectives included immunogenicity and effects on viral rebound kinetics during a 24-week antiretroviral treatment interruption (ATI). The most common treatment-related adverse events were mild-to-moderate injection-site pain, influenza-like illness, headache, and fatigue. Strong, broad, and HTI-focused T-cell responses were induced by vaccination. All participants experienced viral rebound in ATI; 33.3% and 23.5% ( P  = 0.4494) of CCMM + VES and placebo recipients, respectively, remained off antiretroviral therapy for 24 weeks. Post hoc analysis confirmed a correlation between levels of HTI-specific T cells and prolonged time off antiretroviral therapy. The combination of HTI vaccines and VES was safe and elicited robust T-cell responses. Here the authors report results from a randomized clinical trial testing a combination of ChAOx1/MVA.HTI vaccines and the TLR7 agonist vesatolimod in men living with HIV-1. While the treatment showed a good safety profile and induction of HTI-focused T-cell responses, viral rebound was similar in treatment arm and placebo arm.

► A phase I/II HIV vaccine trial has been conducted in Tanzania employing priming with HIV-1 DNA and boosting HIV-1 MVA. ► It has demonstrated excellent safety and immunogenicity by eliciting cell-mediated as well as antibody responses to Env. ► The superiority of low dose intradermal over high dose intramuscular HIV-DNA vaccination has been found. ► The capacity built paves the way for further HIV vaccine trials in Tanzania by collaboration between the North and South. We conducted a phase I/II randomized placebo-controlled trial with the aim of exploring whether priming with a low intradermal dose of a multiclade, multigene HIV-1 DNA vaccine could improve the immunogenicity of the same vaccine given intramuscularly prior to boosting with a heterologous HIV-1 MVA among healthy adults in Dar es Salaam, Tanzania. Sixty HIV-uninfected volunteers were randomized to receive DNA plasmid vaccine 1mg intradermally (id), n=20, or 3.8mg intramuscularly (im), n=20, or placebo, n=20, using a needle-free injection device. DNA plasmids encoding HIV-1 genes gp160 subtype A, B, C; rev B; p17/p24 gag A, B and Rtmut B were given at weeks 0, 4 and 12. Recombinant MVA (108pfu) expressing HIV-1 Env, Gag, Pol of CRF01_AE or placebo was administered im at month 9 and 21. The vaccines were well tolerated. Two weeks after the third HIV-DNA injection, 22/38 (58%) vaccinees had IFN-γ ELISpot responses to Gag. Two weeks after the first HIV-MVA boost all 35 (100%) vaccinees responded to Gag and 31 (89%) to Env. Two to four weeks after the second HIV-MVA boost, 28/29 (97%) vaccinees had IFN-γ ELISpot responses, 27 (93%) to Gag and 23 (79%) to Env. The id-primed recipients had significantly higher responses to Env than im recipients. Intracellular cytokine staining for Gag-specific IFN-γ/IL-2 production showed both CD8+ and CD4+ T cell responses. All vaccinees had HIV-specific lymphoproliferative responses. All vaccinees reacted in diagnostic HIV serological tests and 26/29 (90%) had antibodies against gp160 after the second HIV-MVA boost. Furthermore, while all of 29 vaccinee sera were negative for neutralizing antibodies against clade B, C and CRF01_AE pseudoviruses in the TZM-bl neutralization assay, in a PBMC assay, the response rate ranged from 31% to 83% positives, depending upon the clade B or CRF01_AE virus tested. This vaccine approach is safe and highly immunogenic. Low dose, id HIV-DNA priming elicited higher and broader cell-mediated immune responses to Env after HIV-MVA boost compared to a higher HIV-DNA priming dose given im. Three HIV-DNA priming immunizations followed by two HIV-MVA boosts efficiently induced Env-antibody responses.

Background. We report the first-in-human safety and immunogenicity assessment of a prototype Ad26 vector-based human immunodeficiency virus (HIV) vaccine in humans. Methods. Sixty Ad26-seronegative, healthy, HIV-uninfected subjects were enrolled in a randomized, doubleblinded, placebo-controlled, dose-escalation phase 1 study. Five groups of 12 subjects received 10 9 -10 11 vp of the Ad26-EnvA vaccine (N = 10/group) or placebo (N = 2/group) at weeks 0 and 24 or weeks 0, 4, and 24. Safety and immunogenicity were assessed. Results. Self-limited reactogenicity was observed after the initial immunization at the highest (IO 11 vp) dose. No product-related SAEs were observed. All subjects who received the Ad26-EnvA vaccine developed Ad26 NAb titers, EnvA-specific enzyme-linked immunosorbent assays (ELISA) titers, and EnvA-specific enzyme-linked immunospot assays (ELISPOT) responses. These responses persisted at week 52. At week 28 in the 10⁹, 10¹⁰, 10¹¹ vp 3-dose and the 10¹⁰ and 5 × 10¹⁰ vp 2-dose groups, geometric mean EnvA ELISA titers were 6113, 12 470, 8545, 3470, and 9655 and mean EnvA ELISPOT responses were 397, 178, 736, 196, and 1311 SFC/10⁶ peripheral blood mononuclear cells, respectively. Conclusion. This Ad26 vectored vaccine was generally safe and immunogenic at all doses tested. Reactogenicity was minimal with doses of 5 × 10¹⁰ vp or less. Ad26 is a promising new vaccine vector for HIV-1.