Comparison of shortened mosaic HIV-1 vaccine schedules: a randomised, double-blind, placebo-controlled phase 1 trial (IPCAVD010/HPX1002) and a preclinical study in rhesus monkeys (NHP 17-22)

Abstract

Background: Current efficacy studies of a mosaic HIV-1 prophylactic vaccine require four vaccination visits over one year, which is a complex regimen that could prove challenging for vaccine delivery at the community level, both for recipients and clinics. In this study, we evaluated the safety, tolerability, and immunogenicity of shorter, simpler regimens of trivalent Ad26.Mos.HIV expressing mosaic HIV-1 Env/Gag/Pol antigens combined with aluminium phosphate-adjuvanted clade C gp140 protein.

Methods: We did this randomised, double-blind, placebo-controlled phase 1 trial (IPCAVD010/HPX1002) at Beth Israel Deaconess Medical Center in Boston, MA, USA. We included healthy, HIV-uninfected participants (aged 18-50 years) who were considered at low risk for HIV infection and had not received any vaccines in the 14 days before study commencement. We randomly assigned participants via a computer-generated randomisation schedule and interactive web response system to one of three study groups (1:1:1) testing different regimens of trivalent Ad26.Mos.HIV (5 × 1010 viral particles per 0·5 mL) combined with 250 μg adjuvanted clade C gp140 protein. They were then assigned to treatment or placebo subgroups (5:1) within each of the three main groups. Participants and investigators were masked to treatment allocation until the end of the follow-up period. Group 1 received Ad26.Mos.HIV alone at weeks 0 and 12 and Ad26.Mos.HIV plus adjuvanted gp140 at weeks 24 and 48. Group 2 received Ad26.Mos.HIV plus adjuvanted gp140 at weeks 0, 12, and 24. Group 3 received Ad26.Mos.HIV alone at week 0 and Ad26.Mos.HIV plus adjuvanted gp140 at weeks 8 and 24. Participants in the control group received 0·5 mL of 0·9% saline. All study interventions were administered intramuscularly. The primary endpoints were Env-specific binding antibody responses at weeks 28, 52, and 72 and safety and tolerability of the vaccine regimens for 28 days after the injection. All participants who received at least one vaccine dose or placebo were included in the safety analysis; immunogenicity was analysed using the per-protocol population. The IPCAVD010/HPX1002 trial is registered with ClinicalTrials.gov, NCT02685020. We also did a parallel preclinical study in rhesus monkeys to test the protective efficacy of the shortened group 3 regimen.

Findings: Between March 7, 2016, and Aug 19, 2016, we randomly assigned 36 participants to receive at least one dose of study vaccine or placebo, ten to each vaccine group and two to the corresponding placebo group. 30 (83%) participants completed the full study, and six (17%) discontinued it prematurely because of loss to follow-up, withdrawal of consent, investigator decision, and an unrelated death from a motor vehicle accident. The two shortened regimens elicited comparable antibody titres against autologous clade C Env at peak immunity to the longer, 12-month regimen: geometric mean titre (GMT) 41 007 (95% CI 17 959-93 636) for group 2 and 49 243 (29 346-82 630) for group 3 at week 28 compared with 44 590 (19 345-102 781) for group 1 at week 52). Antibody responses remained increased (GMT >5000) in groups 2 and 3 at week 52 but were highest in group 1 at week 72. Antibody-dependent cellular phagocytosis, Env-specific IgG3, tier 1A neutralising activity, and broad cellular immune responses were detected in all groups. All vaccine regimens were well tolerated. Mild-to-moderate pain or tenderness at the injection site was the most commonly reported solicited local adverse event, reported by 28 vaccine recipients (93%) and two placebo recipients (33%). Grade 3 solicited systemic adverse events were reported by eight (27%) vaccine recipients and no placebo recipients; the most commonly reported grade 3 systemic symptoms were fatigue, myalgia, and chills. The shortened group 3 regimen induced comparable peak immune responses in 30 rhesus monkeys as in humans and resulted in an 83% (95% CI 38·7-95, p=0·004 log-rank test) reduction in per-exposure acquisition risk after six intrarectal challenges with SHIV-SF162P3 at week 54, more than 6 months after final vaccination.

Interpretation: Short, 6-month regimens of a mosaic HIV-1 prophylactic vaccine elicited robust HIV-specific immune responses that were similar to responses elicited by a longer, 12-month schedule. Preclinical data showed partial protective efficacy of one of the short vaccine regimens in rhesus monkeys. Further clinical studies are required to test the suitability of the shortened vaccine regimens in humans. Such shortened regimens would be valuable to increase vaccine delivery at the community level, particularly in resource-limited settings.

Funding: Ragon Institute (Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University; Cambridge, MA, USA) and Janssen Vaccines & Prevention (Leiden, Netherlands).

Copyright © 2020 Elsevier Ltd. All rights reserved.

Figures

Figure 1:. Trial profile

IPCAVD010/HPX1002 clinical study.

Figure 2:. Humoral and cellular immune responses against clade C HIV-1 Env following vaccination.

(A) Binding antibody clade C gp140-specific titers by enzyme-linked immunosorbent assays. Dotted line is the LLOQ threshold. Left panel, the symbol reflects the group geometric mean. Middle and right panels, the line reflects the group geometric mean. (B) Clade C gp140-specific antibody-dependent cellular phagocytic score. Dotted line is the LOD. Left panel, the symbol reflects the group geometric mean. Middle and right panels, the line reflects the group geometric mean. (C) T cell responses by interferon-gamma (IFNγ) enzyme-linked immunospot (ELISPOT) assays against Env PTE peptide pools. Dotted line is positivity threshold. Vaccine response was defined as value more than threshold (if baseline is

Figure 3:. Antibody epitope mapping.

(A) The pattern of antibody binding to linear Env peptides is shown for each group at week 28 (all groups) and week 52 (Group 1 only, after late boost). Each dot represents the average signal intensity per peptide within each group. Baseline responses are plotted on the y axis in the downward direction. Week 28 and 52 responses are plotted on the y axis in the upward direction. The amino acid start position of each peptide (aligned to HXB2 HIV strain) is plotted along the x axis. V3=variable loop 3 region. C4=constant region 4. C5=constant region 5. (B) The depth of antibody binding to linear Env peptides is shown for each participant within each group at week 28 and 52. Each dot represents the total number of positive peptide responses per participant for each peptide set (e.g., all Env (4031 peptides), variable loop (1559 peptides), constant region (1205 peptides) and gp41 (1237 peptides). The threshold for positivity was >5× noise distribution of the sample slide. The line reflects the group median. G1=group 1. G2=group 2. G3=group 3. Wk=Week. Endpoints for placebo recipients from Groups 1–3 were pooled into a single “Placebo” group.

Figure 4:. Humoral and cellular immune responses in rhesus monkeys and comparison to humans.

(A) Binding antibody clade C gp140-specific titers determined by enzyme-linked immunosorbent assays (ELISA). Dotted line is the LLOQ threshold. (B) T cell responses by interferon-gamma (IFN-γ) enzyme-linked immunospot (ELISPOT) assays against Env PTE peptide pools. Dotted line reflects the positivity threshold. (C) Clade C gp140-specific antibody-dependent cellular phagocytic (ADCP) score. Horizontal lines indicate geometric mean titers for ELISA and ADCP and medians for ELISPOT responses. LLOQ=lower limit of quantification. SFU=spot-forming units. PBMC=peripheral blood mononuclear cells. Error bars depict the 95% confidence interval.

Figure 5:. Protective efficacy in rhesus monkeys and correlates of risk reduction.

Six weekly intrarectal challenges were administered to rhesus monkeys at weeks 1, 2, 3, 4, 5 and 6. (A) Kaplan-Meier plot of the level of protection the short vaccine regimen offered to the 15 rhesus monkeys at risk per group, assessed one week after each challenge. No animals were censored. (B) Mean predicted infection frequency compared to observed infection frequency per time point (vaccine group only). Predictions are based on a model that was generated with historic data using peak immunogenicity Clade C ELISA and PTE Env ELISPOT data. Error bars depict the 95% confidence interval. (C) Humoral and cellular immune responses measured by clade C ELISA and PTE Env ELISPOT at week 28, the week following each of six challenges (at weeks 54–59) of monkeys from the vaccine group. Blue dots represent uninfected monkeys per timepoint, and red dots indicate monkeys that were infected following each challenge. The diagonal lines display model-derived probabilities of infection, modeled on ELISA and ELISPOT responses.