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

Abstract

Background: Live, 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.

Methods: Healthy 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.

Results: We 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.

Conclusions: The 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 registration: ClinicalTrials.gov NCT02366013.

Fig 1. Trial profile.

HC, household contact.

Fig 2. Oral, replicating adenovirus 26 vector vaccine for HIV-1.

(A) Schematic showing the construction of the replication competent adenovirus serotype 26 (Ad26) vaccine vector from wild-type Ad26. A transgene cassette consisting of a mosaic HIV-1 Env gene (Mos1 Env) was inserted to create the rcAd26.MOS1.HIV-Env (rcAd26) vaccine. lITR, left inverted terminal repeat; rITR, right inverted terminal repeat[3]. (B) Intact rcAd26 vaccine from dissolved lyophilized capsule as seen by electron microscopy.

Fig 3. Vaccine safety.

(A) Frequency of possibly, probably and definitely related (“Related”) unsolicited adverse events from the signing of the informed consent form until Study Day 112. Multiple adverse events could be reported per participant. (B) Number of participants who reported reactogenicity symptoms from the day of study product administration (Day 0) through Day 9. The National Institute of Allergy and Infectious Diseases Division of AIDS Toxicity Table was used to grade severity of adverse events and reactogenicity.

Fig 4. Vaccine-specific immune responses.

(A) Mos1 Env-specific binding antibody responses, (B) Mos1 Env-specific T cell responses, and (C) Ad26 vector-specific neutralizing antibody responses by dose group. Individual responses from participant by day and dose group are shown. Dots show individual titers at a given time point. Summaries of responses are presented with geometric mean titers (GMTs), all with associated 95% confidence intervals (CIs). Dotted lines indicate threshold for positivity.

Fig 5. Viral shedding.

Number of adenovirus serotype 26 (Ad26) hexon copies/ml detected by real-time (rt)PCR in rectal secretions collected on Day -2, 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 17, 21, and 28 for all groups. Arrow indicates day of study product administration. All samples with detectable Ad26 by PCR were negative by adenovirus culture.