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Human immunodeficiency virus type 1 (HIV-1)-specific monoclonal antibodies with extraordinary potency and breadth have recently been described. In humanized mice, combinations of monoclonal antibodies have been shown to suppress viraemia, but the therapeutic potential of these monoclonal antibodies has not yet been evaluated in primates with an intact immune system. Here we show that administration of a cocktail of HIV-1-specific monoclonal antibodies, as well as the single glycan-dependent monoclonal antibody PGT121, resulted in a rapid and precipitous decline of plasma viraemia to undetectable levels in rhesus monkeys chronically infected with the pathogenic simian–human immunodeficiency virus SHIV-SF162P3. A single monoclonal antibody infusion afforded up to a 3.1 log decline of plasma viral RNA in 7 days and also reduced proviral DNA in peripheral blood, gastrointestinal mucosa and lymph nodes without the development of viral resistance. Moreover, after monoclonal antibody administration, host Gag-specific T-lymphocyte responses showed improved functionality. Virus rebounded in most animals after a median of 56 days when serum monoclonal antibody titres had declined to undetectable levels, although, notably, a subset of animals maintained long-term virological control in the absence of further monoclonal antibody infusions. These data demonstrate a profound therapeutic effect of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys as well as an impact on host immune responses. Our findings strongly encourage the investigation of monoclonal antibody therapy for HIV-1 in humans., National Institutes of Health (U.S.) (AI055332), National Institutes of Health (U.S.) (AI060354), National Institutes of Health (U.S.) (AI078526), National Institutes of Health (U.S.) (AI084794), National Institutes of Health (U.S.) (AI095985), National Institutes of Health (U.S.) (AI096040), National Institutes of Health (U.S.) (AI100148), National Institutes of Health (U.S.) (AI10063), Bill & Melinda Gates Foundation (OPP1033091), Bill & Melinda Gates Foundation (OPP1033115), Bill & Melinda Gates Foundation (OPP1040741), Bill & Melinda Gates Foundation (OPP1040753), Ragon Institute of MGH, MIT, and Harvard, Stavros S. Niarchos Foundation, Howard Hughes Medical Institute (Investigator)

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, double-blinded, placebo-controlled, dose-escalation phase 1 study. Five groups of 12 subjects received 109–1011 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 (1011 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. Clinical Trials Registration. {"type":"clinical-trial","attrs":{"text":"NCT00618605","term_id":"NCT00618605"}}NCT00618605.