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Background: HVTN 120 is a phase 1/2a randomized double-blind placebo-controlled human immunodeficiency virus (HIV) vaccine trial that evaluated the safety and immunogenicity of ALVAC-HIV (vCP2438) and MF59- or AS01B-adjuvanted bivalent subtype C gp120 Env protein at 2 dose levels in healthy HIV-uninfected adults., Methods: Participants received ALVAC-HIV (vCP2438) alone or placebo at months 0 and 1. At months 3 and 6, participants received either placebo, ALVAC-HIV (vCP2438) with 200 μg of bivalent subtype C gp120 adjuvanted with MF59 or AS01B, or ALVAC-HIV (vCP2438) with 40 μg of bivalent subtype C gp120 adjuvanted with AS01B. Primary outcomes were safety and immune responses., Results: We enrolled 160 participants, 55% women, 18-40 years old (median age 24 years) of whom 150 received vaccine and 10 placebo. Vaccines were generally safe and well tolerated. At months 6.5 and 12, CD4+ T-cell response rates and magnitudes were higher in the AS01B-adjuvanted groups than in the MF59-adjuvanted group. At month 12, HIV-specific Env-gp120 binding antibody response magnitudes in the 40 μg gp120/AS01B group were higher than in either of the 200 μg gp120 groups., Conclusions: The 40 μg dose gp120/AS01B regimen elicited the highest CD4+ T-cell and binding antibody responses. Clinical Trials Registration . NCT03122223., Competing Interests: Potential conflicts of interest. S. G. is an employee of Sanofi Pasteur and C. A. D. G. was employed by Sanofi Pasteur at the time of the study. M. Ko. and O. V. D. M. are employees of GSK and hold shares in GSK. All other authors report no potential conflicts. Funding to pay the Open Access publication charges for this article was provided by the NIH. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Adjuvants are widely used to enhance and/or direct vaccine-induced immune responses yet rarely evaluated head-to-head. Our trial directly compared immune responses elicited by MF59 versus alum adjuvants in the RV144-like HIV vaccine regimen modified for the Southern African region. The RV144 trial of a recombinant canarypox vaccine vector expressing HIV env subtype B (ALVAC-HIV) prime followed by ALVAC-HIV plus a bivalent gp120 protein vaccine boost adjuvanted with alum is the only trial to have shown modest HIV vaccine efficacy. Data generated after RV144 suggested that use of MF59 adjuvant might allow lower protein doses to be used while maintaining robust immune responses. We evaluated safety and immunogenicity of an HIV recombinant canarypox vaccine vector expressing HIV env subtype C (ALVAC-HIV) prime followed by ALVAC-HIV plus a bivalent gp120 protein vaccine boost (gp120) adjuvanted with alum (ALVAC-HIV+gp120/alum) or MF59 (ALVAC-HIV+gp120/MF59) or unadjuvanted (ALVAC-HIV+gp120/no-adjuvant) and a regimen where ALVAC-HIV+gp120 adjuvanted with MF59 was used for the prime and boost (ALVAC-HIV+gp120/MF59 coadministration)., Methods and Findings: Between June 19, 2017 and June 14, 2018, 132 healthy adults without HIV in South Africa, Zimbabwe, and Mozambique were randomized to receive intramuscularly: (1) 2 priming doses of ALVAC-HIV (months 0 and 1) followed by 3 booster doses of ALVAC-HIV+gp120/MF59 (months 3, 6, and 12), n = 36; (2) 2 priming doses of ALVAC-HIV (months 0 and 1) followed by 3 booster doses of ALVAC-HIV+gp120/alum (months 3, 6, and 12), n = 36; (3) 4 doses of ALVAC-HIV+gp120/MF59 coadministered (months 0, 1, 6, and 12), n = 36; or (4) 2 priming doses of ALVAC-HIV (months 0 and 1) followed by 3 booster doses of ALVAC-HIV+gp120/no adjuvant (months 3, 6, and 12), n = 24. Primary outcomes were safety and occurrence and mean fluorescence intensity (MFI) of vaccine-induced gp120-specific IgG and IgA binding antibodies at month 6.5. All vaccinations were safe and well-tolerated; increased alanine aminotransferase was the most frequent related adverse event, occurring in 2 (1.5%) participants (1 severe, 1 mild). At month 6.5, vaccine-specific gp120 IgG binding antibodies were detected in 100% of vaccinees for all 4 vaccine groups. No significant differences were seen in the occurrence and net MFI of vaccine-specific IgA responses between the ALVAC-HIV+gp120/MF59-prime-boost and ALVAC-HIV+gp120/alum-prime-boost groups or between the ALVAC-HIV+gp120/MF59-prime-boost and ALVAC-HIV+gp120/MF59 coadministration groups. Limitations were the relatively small sample size per group and lack of evaluation of higher gp120 doses., Conclusions: Although MF59 was expected to enhance immune responses, alum induced similar responses to MF59, suggesting that the choice between these adjuvants may not be critical for the ALVAC+gp120 regimen., Trial Registration: HVTN 107 was registered with the South African National Clinical Trials Registry (DOH-27-0715-4894) and ClinicalTrials.gov (NCT03284710)., Competing Interests: MK and OVDM are employed by GSK and hold shares in the company. MK reports grants from Bill & Melinda Gates Foundation and grants from NIH during the conduct of the study. NKT was an employee of GSK Biologicals and Novartis Vaccines & Diagnostics during the time of the trial. All other authors have nothing to declare., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: Eliciting durable humoral immunity with sufficient breadth and magnitude is important for HIV-1 vaccine design. The HVTN 114 vaccine trial evaluated different boost regimens administered after a 7-year rest period in participants previously enrolled in HVTN 205, who received either three MVA/HIV62B (MMM) or two DNA and two MVA/HIV62B (DDMM) injections; both vaccines expressed multiple HIV-1 antigens in non-infectious virus-like-particles. The primary objective of HVTN 114 was to assess the impact of a heterologous gp120 protein AIDSVAX B/E boost on the magnitude, breadth and durability of vaccine-induced immune responses., Methods: We enrolled 27 participants from HVTN 205 into five groups. Eight participants who previously received MMM were randomized and boosted with either MVA/HIV62B alone (T1; n = 4) or MVA/HIV62B and AIDSVAX B/E (T2; n = 4). Nineteen participants who received DDMM were randomized and boosted with MVA/HIV62B alone (T3; n = 6), MVA/HIV62B and AIDSVAX B/E (T4; n = 6), or AIDSVAX B/E alone (T5; n = 7). Boosts were at months 0 and 4. Participants were followed for safety and immunogenicity for 10 months and were pooled for analysis based on the regimen: MVA-only (T1 + T3), MVA + AIDSVAX (T2 + T4), and AIDSVAX-only (T5)., Results: All regimens were safe and well-tolerated. Prior to the boost vaccination, binding antibody and CD4+T-cell responses were observed 7 years after HVTN 205 vaccinations. Late boosting with AIDSVAX, with or without MVA, resulted in high binding antibody responses to gp120 and V1V2 epitopes, with increased magnitude and breadth compared to those observed in HVTN 205. Late boosting with MVA, with or without AIDSVAX, resulted in increased gp140 and gp41 antibody responses and higher CD4+T-cell responses to Env and Gag., Conclusions: Late boosting with AIDSVAX, alone or in combination with MVA, can broaden binding antibody responses and increase T-cell responses even years following the original MVA/HIV62B with or without DNA-priming vaccine., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [The authors of this manuscript have read the journal's policy and have the following competing interests: YH, CY, MDM, CP, SCD, KC, MJM, PG, JM, MK, MS, LRB, DM are recipients of funding from The National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health, and this publication is a result of activities funded by the NIAID. HLR was a co-founder of GeoVax, Inc. and is an inventor on patents that GeoVax licensed from Emory University and the NIAID for commercial development of the MVA/HIV62B and JS7 DNA vaccines. CFK receives research grants to her institution from NIH, CDC, Gilead Sciences, ViiV, Moderna, and Novavax. GDT received research grants to her institution from NIAID, BMGF, GSK and Macrogenics, has patent applications for HIV vaccine design and incidence testing, and has consulted for Axon Advisors. KES has a patent application for HIV incidence testing. SB receives research grants to her institution from NIH, Gilead Sciences, Merck, and Viiv. The rest of the authors have no conflicts., (Published by Elsevier Ltd.)

BACKGROUNDHVTN 098, a randomized, double-blind, placebo-controlled trial, evaluated the safety, tolerability, and immunogenicity of PENNVAX-GP HIV DNA vaccine, administered with or without plasmid IL-12 (pIL-12), via intradermal (ID) or intramuscular (IM) electroporation (EP) in healthy, HIV-uninfected adults. The study tested whether PENNVAX-GP delivered via ID/EP at one-fifth the dose could elicit equivalent immune responses to delivery via IM/EP and whether inclusion of pIL-12 provided additional benefit.METHODSParticipants received DNA encoding HIV-1 env/gag/pol in 3 groups: 1.6 mg ID (ID no IL-12 group, n = 20), 1.6 mg ID + 0.4 mg pIL-12 (ID + IL-12 group, n = 30), 8 mg IM + 1 mg pIL-12 (IM + IL-12 group, n = 30), or placebo (n = 9) via EP at 0, 1, 3, and 6 months. Results of cellular and humoral immunogenicity assessments are reported.RESULTSFollowing vaccination, the frequency of responders (response rate) to any HIV protein based on CD4+ T cells expressing IFN-γ or IL-2 was 96% for both the ID + IL-12 and IM + IL-12 groups; CD8+ T cell response rates were 64% and 44%, respectively. For ID delivery, the inclusion of pIL-12 increased CD4+ T cell response rate from 56% to 96%. The frequency of responders was similar (≥90%) for IgG binding antibody to gp140 consensus Env across all groups, but the magnitude was higher in the ID + IL-12 group compared with the IM + IL-12 group.CONCLUSIONPENNVAX-GP DNA induced robust cellular and humoral immune responses, demonstrating that immunogenicity of DNA vaccines can be enhanced by EP route and inclusion of pIL-12. ID/EP was dose sparing, inducing equivalent, or in some aspects superior, immune responses compared with IM/EP.TRIAL REGISTRATIONClinicalTrials.gov NCT02431767.FUNDINGThis work was supported by National Institute of Allergy and Infectious Diseases (NIAID), U.S. Public Health Service grants, an HIV Vaccine Design and Development Team contract, Integrated Preclinical/Clinical AIDS Vaccine Development Program, and an NIH award.