First-in-human randomized controlled trial of an oral, replicating adenovirus 26 vector vaccine for HIV-1

Abstract

BackgroundLive, attenuated viral vectors that express HIV-1 antigens are being investigated as an approach to generating durable immune responses against HIV-1 in humans. We recently developed a replication-competent, highly attenuated Ad26 vector that expresses mosaic HIV-1 Env (rcAd26.MOS1.HIV-Env, “rcAd26”). Here we present the results of a first-in-human, placebo-controlled clinical trial to test the safety, immunogenicity and mucosal shedding of rcAd26 given orally.MethodsHealthy adults were randomly assigned to receive a single oral dose of vaccine or placebo at 5:1 ratio in a dosage escalation of 10^8 to 10^11 rcAd26 VP (nominal doses) at University of Rochester Medical Center, Rochester, NY, USA. Participants were isolated and monitored for reactogenicity for 10 days post-vaccination, and adverse events were recorded up to day 112. Rectal and oropharyngeal secretions were evaluated for shedding of the vaccine. Humoral and cellular immune responses were measured. Household contacts were monitored for secondary vaccine transmission.ResultsWe enrolled 22 participants and 11 household contacts between February 7 and June 24, 2015. 18 participants received one dose of HIV-1 vaccine and 4 participants received placebo. The vaccine caused only mild to moderate adverse events. No vaccine-related SAEs were observed. No infectious rcAd26 viral particles were detected in rectal or oropharyngeal secretions from any participant. Env-specific ELISA and ELISPOT responses were undetectable. No household contacts developed vaccine-induced HIV-1 seropositivity or vaccine-associated illness.ConclusionsThe highly attenuated rcAd26.MOS1.HIV-Env vaccine was well tolerated up to 10^11 VP in healthy, HIV-1-uninfected adults, though the single dose was poorly immunogenic suggesting the replicative capacity of the vector was too attenuated. There was no evidence of shedding of infectious virus or secondary vaccine transmission following the isolation period. These data suggest the use of less attenuated viral vectors in future studies of live, oral HIV-1 vaccines.Trial registrationClinicalTrials.gov NCT02366013.

COVID-19 Vaccines: “Warp Speed” Needs Mind Melds, Not Warped Minds

“…The median NAb endpoint titer measured in the macaques was ∼40. Taken together, in both mice and macaques, the antibody responses to this live recombinant virus vector seem very weak, which is consistent with how adenovirus-based HIV-1 vaccines perform in macaques and humans unless a protein boost is given ( 90 , 91 ). All 6 of the ChAdOx1-vaccinated macaques became infected after SARS-CoV-2 challenge, although with fewer symptoms, including reduced lung damage compared to that of the control group.…”

“…In the HIV-1 vaccine arena, adenovirus vaccines induce only weak antibody responses in animals and humans compared to those from recombinant proteins, even when the endpoint is only nonneutralizing antibodies (non-NAbs) ( 82 , 90 ). Indeed, an adenovirus-based vaccine from Janssen that is now in phase 2b trials for HIV-1 prevention includes a recombinant spike-derived protein boost component that is specifically intended to increase non-NAb titers (it is unable to elicit NAbs in a meaningful way) ( 90 , 91 ). This adenovirus vector seems conceptually similar to the one that is the basis of the same company’s SARS-CoV-2 vaccine program.…”

“…An animal study is summarized below ( 98 ). Like the viral vector vaccines, DNA vaccines against HIV-1 are often used in the prime-boost mode, in which a recombinant protein is administered to increase the generally weak response to several earlier immunizations with its DNA plasmid-delivered counterpart ( 82 , 90 ). Inovio’s INO-4800 SARS-CoV-2 DNA vaccine has now been tested in mice and guinea pigs ( 71 ).…”

Longitudinal quantification of adenovirus neutralizing responses in Zambian mother-infant pairs: Impact of HIV-1 infection and its treatment

“…Adenoviruses are large double stranded DNA viruses that, through deletion of genetic content and propagation to high titers, can be used as gene-delivery tools or vaccine vectors [5]. Historically, Ad vaccines and vectors were replication competent and thus had some risk of causing an Adenoviral infection [6,7]. Modern Ad constructs are typically replication incompetent or produce single cycle infections where no new Ad particles are produced but an inserted transgene of interest is efficiently expressed [8].…”

Comparative Evaluation of the Vaccine Efficacies of Three Adenovirus-Based Vector Types in the Friend Retrovirus Infection Model

“…Of the more than 70 known AdV types, only a small number have been tested in preclinical studies (6,7,9,(12)(13)(14)(15), and apart from Ad5, only vectors based on human AdV types 4, 6, 26, and 35 and chimpanzee AdV types 3 and 63 have been advanced into clinical studies as vaccine candidates against Ebola virus (16,17), Plasmodium falciparum (18,19), Mycobacterium tuberculosis (20), influenza virus (21), hepatitis C virus (22), or human immunodeficiency virus (HIV) (23)(24)(25)(26). For most of the rare AdV-based vectors, it has been shown that their immunogenicity is inferior to that of Ad5, resulting in reduced immune responses upon immunization with these vectors, although their efficacy in Ad5-preimmune mice is superior to the efficacy of an Ad5-based vaccine (7,9,12,14,15).…”