Safety and Immunogenicity Study of Multiclade HIV-1 Adenoviral Vector Vaccine Alone or as Boost following a Multiclade HIV-1 DNA Vaccine in Africa

Walter Jaoko,Martin Ho,Susan Allen,Claudia Schmidt,Helen Thomson,Jill Gilmour,Tony Tarragona-Fiol,Richard A Koup,Soe Than,Len Dally,Omu Anzala,Josephine H Cox,Gary J Nabel,Barney S Graham,Kayitesi Kayitenkore,Peter Hayes,Bashir Farah,Elizabeth M Adams,Etienne Karita,Robert T Bailer,Gwynneth Stevens,Gloria Omosa-Manyonyi,Kelley Loughran,Carol Smith,Wendy Komaroff,Jean De Dieu Bizimana ,Mark Boaz ,Philip Bergin ,Claude Mambo Muvunyi ,Patricia E Fast ,Job J Bwayo

doi:10.1371/journal.pone.0012873

Abstract

BackgroundWe conducted a double-blind, randomized, placebo-controlled Phase I study of a recombinant replication-defective adenovirus type 5 (rAd5) vector expressing HIV-1 Gag and Pol from subtype B and Env from subtypes A, B and C, given alone or as boost following a DNA plasmid vaccine expressing the same HIV-1 proteins plus Nef, in 114 healthy HIV-uninfected African adults.Methodology/Principal FindingsVolunteers were randomized to 4 groups receiving the rAd5 vaccine intramuscularly at dosage levels of 1×1010 or 1×1011 particle units (PU) either alone or as boost following 3 injections of the DNA vaccine given at 4 mg/dose intramuscularly by needle-free injection using Biojector® 2000. Safety and immunogenicity were evaluated for 12 months. Both vaccines were well-tolerated. Overall, 62% and 86% of vaccine recipients in the rAd5 alone and DNA prime - rAd5 boost groups, respectively, responded to the HIV-1 proteins by an interferon-gamma (IFN-γ) ELISPOT. The frequency of immune responses was independent of rAd5 dosage levels. The highest frequency of responses after rAd5 alone was detected at 6 weeks; after DNA prime - rAd5 boost, at 6 months (end of study). At baseline, neutralizing antibodies against Ad5 were present in 81% of volunteers; the distribution was similar across the 4 groups. Pre-existing immunity to Ad5 did not appear to have a significant impact on reactogenicity or immune response rates to HIV antigens by IFN-γ ELISPOT. Binding antibodies against Env were detected in up to 100% recipients of DNA prime - rAd5 boost. One volunteer acquired HIV infection after the study ended, two years after receipt of rAd5 alone.Conclusions/SignificanceThe HIV-1 rAd5 vaccine, either alone or as a boost following HIV-1 DNA vaccine, was well-tolerated and immunogenic in African adults. DNA priming increased the frequency and magnitude of cellular and humoral immune responses, but there was no effect of rAd5 dosage on immunogenicity endpoints.Trial RegistrationClinicalTrials.gov NCT00124007

Highlights

In a Phase IIb/III community-based clinical trial in Thailand, prevention from HIV infection was demonstrated for the first time with a combination of ALVAC-HIV and AIDSVAX B/E [1]
A recombinant multiclade adenovirus type 5 vectorbased vaccine expressing HIV-1 subtype B Gag and Pol and subtypes A, B and C Env (VRC HIV-1 replicationdefective adenovirus type 5 (rAd5)), and a recombinant DNA vaccine encoding the same proteins plus subtype B Nef (VRC HIV-1 DNA), developed by the Vaccine Research Center (VRC) at the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH), have been evaluated previously either alone or in a DNA prime - rAd5 boost combination in healthy, HIV-uninfected volunteers; both vaccines were well-tolerated and immunogenic [2,3,4,5,6,7]. To further develop these vaccines, three clinical studies were conducted simultaneously: i) the V001 study - presented here - sponsored by the International AIDS Vaccine Initiative (IAVI) in collaboration with the Division of AIDS (DAIDS)/NIAID/NIH, conducted in Kenya and Rwanda, ii) the HIV Vaccine Trials Network (HVTN) 204 study sponsored by DAIDS, NIAID, conducted in the US, Latin America, the Caribbean and South Africa and iii) the US Military HIV Research Program (USMHRP) sponsored RV172 study supported by DAIDS, NIAID, conducted in Kenya, Uganda and Tanzania [8]
The two vaccines are currently being tested in a Phase II safety and effectiveness trial in the US in HIV-uninfected, circumcised men who have sex with men and who are negative for neutralizing antibodies against Ad5 at baseline. (HVTN 505; http://clinicaltrials.gov/ct2/show/ NCT00865566)

Summary

Introduction

In a Phase IIb/III community-based clinical trial in Thailand, prevention from HIV infection was demonstrated for the first time with a combination of ALVAC-HIV (canarypox vectored HIV vaccine) and AIDSVAX B/E (recombinant protein-based HIV vaccine) [1]. A recombinant multiclade adenovirus type 5 (rAd5) vectorbased vaccine expressing HIV-1 subtype B Gag and Pol and subtypes A, B and C Env (VRC HIV-1 rAd5), and a recombinant DNA vaccine encoding the same proteins plus subtype B Nef (VRC HIV-1 DNA), developed by the Vaccine Research Center (VRC) at the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH), have been evaluated previously either alone or in a DNA prime - rAd5 boost combination in healthy, HIV-uninfected volunteers; both vaccines were well-tolerated and immunogenic [2,3,4,5,6,7]. We conducted a double-blind, randomized, placebo-controlled Phase I study of a recombinant replicationdefective adenovirus type 5 (rAd5) vector expressing HIV-1 Gag and Pol from subtype B and Env from subtypes A, B and C, given alone or as boost following a DNA plasmid vaccine expressing the same HIV-1 proteins plus Nef, in 114 healthy HIVuninfected African adults

Objectives

Methods

Conclusion