Efficacy and safety of a mosaic HIV-1 vaccine regimen in men who have sex with men and transgender individuals (HVTN 706/HPX3002/Mosaico): a global, randomised, double-blind, placebo-controlled, phase 3 trial.

backgroundThere is a high unmet need for effective HIV prevention options, including vaccines, for individuals at high risk of HIV acquisition who choose not to use pre-exposure prophylaxis or other prevention strategies. This study evaluated the efficacy and safety of an HIV-1 vaccine regimen consisting of tetravalent mosaic adenovirus serotype 26-based vaccine (Ad26.Mos4.HIV) and bivalent clade C glycoprotein (gp) 140-mosaic gp140 vaccine, in a population with high seroincidence.

methodsThis randomised, double-blind, phase 3 trial enrolled adult cisgender men and transgender individuals without HIV from 52 academic medical centres, health departments, and community-based clinics in Latin America, Europe, and the USA. Participants were randomly assigned (1:1) by use of a centrally prepared, computer-generated randomisation schedule to receive intramuscular injections of vaccine or saline placebo in stratified permuted blocks. Study participants, study site personnel (except for those with primary responsibility for study vaccine preparation and dispensing), and investigators were masked from vaccine allocation. The vaccine regimen consisted of Ad26.Mos4.HIV administered at months 0 and 3 followed by Ad26.Mos4.HIV administered concurrently with aluminium phosphate-adjuvanted clade C gp140-mosaic gp140 at months 6 and 12. The primary endpoint was vaccine efficacy in preventing HIV-1 acquisition between months 7 and 24 or between months 7 and 30 in the per-protocol population, which included all randomly assigned participants who received at least one study vaccination and who had not been diagnosed with HIV-1 4 weeks after the third vaccination, had received all planned vaccinations at the first three vaccination visits within the respective visit windows, and had no major protocol deviations linked to incorrect product administration. Safety outcomes were assessed in all randomised participants who received at least one study vaccination. The trial is registered with ClinicalTrials.gov (NCT03964415) and is complete.

findingsBetween Nov 4, 2019, and Aug 13, 2021, 3900 participants were enrolled and randomly assigned; 3887 received at least one study vaccination (1942 assigned to vaccine, 1945 to placebo). 3870 (99·6%) of 3887 participants were assigned male at birth, seven (0·2%) were assigned female, and one participant's sex at birth was undifferentiated; 3557 (91·5%) participants identified as male gender, 48 (1·2%) as female gender, and 278 (7·2%) as transgender or non-binary. The per-protocol population included 1525 participants in the vaccine group and 1494 in the placebo group. From month 7 to month 24 in the per-protocol population, HIV-1 incidence per 100 person-years was 3·63 (95% CI 2·77 to 4·67) in the vaccine group and 3·35 (2·53 to 4·36) in the placebo group, with an estimated vaccine efficacy (months 7-24) of -0·7% (95% CI -50·9 to 32·8; p=0·97). Vaccine efficacy (months 7-30) was -149·1% (-737·7 to 26·0; p=0·14). Most solicited local and systemic adverse events were mild or moderate and short-lived. Medically attended adverse events occurred in 999 (51·4%) of 1942 participants given vaccine and 1002 (51·5%) of 1945 participants given placebo; serious adverse events occurred in 82 (4·2%) of 1942 participants given vaccine and 77 (4·0%) of 1945 participants given placebo. No fatal adverse events considered related to the study vaccine occurred. Adverse events of special interest (thrombotic events or thrombocytopenia) occurred in four participants with vaccine and two with placebo; none had thrombosis with thrombocytopenia syndrome.

interpretationThe lack of efficacy in this and other HIV vaccine trials points to the importance of current efforts to develop vaccines that generate broadly neutralising antibodies.

fundingJohnson & Johnson; HIV Vaccine Trials Network; Division of AIDS, a division of National Institute of Allergy and Infectious Diseases; and US Army Medical Materiel Development Activity, a subordinate command of the US Army Medical Research and Development Command.