Assessment of the Safety and Immunogenicity of 2 Novel Vaccine Platforms for HIV-1 Prevention

Abstract

Background A prophylactic HIV-1 vaccine is a global health priority. Objective To assess a novel vaccine platform as a prophylactic HIV-1 vaccine regimen. Design/Setting This randomized, double-blind, placebo-controlled trial assessed two candidate HIV-1 vaccines (Ad26.EnvA and Ad35-Env both at 5×1010 vp) in homologous and heterologous combinations in three geographic regions (US, East and South Africa). Both subjects and study personnel were blinded to treatment allocation. (NCT 01215149). Patients Healthy HIV uninfected adults. Measurements Safety and immunogenicity were assessed and the impact of baseline vector immunity was analyzed. Results 217 subjects received at least 1 vaccination and 210 (>96%) completed follow-up, No vaccine-associated serious adverse events occurred. All regimens were generally well tolerated though more vaccine recipients had transient moderate or severe systemic reactions (36.5%) compared to placebo recipients (20.5%). All regimens elicited humoral and cellular immune responses in nearly all volunteers. There was no impact of pre-existing Ad26 or Ad35 neutralizing antibody titers on vaccine safety and little on immunogenicity. In both homologous and heterologous regimens the second vaccination significantly increased EnvA antibody titers (~20 fold from median ELISA titers of 30–300 to 3000). The heterologous regimen Ad26-Ad35 elicited significantly higher EnvA antibody titers than Ad35-Ad26. T cell responses were modest and lower in East Africa than in South Africa and the United States. Conclusions Both vaccines elicited significant immune responses in all populations. Baseline vector immunity did not have a significant impact on immune responses. Second vaccinations in all regimens significantly boosted EnvA titers though vaccine order in the heterologous regimen had a modest effect on the immune response. Primary Funding IAVI, NIAID/NIH, and the Ragon Institute in collaboration with Crucell Holland BV.

Progress in HIV vaccine development

“…Furthermore, preexisting Ad26 or Ad35 neutralizing antibody had no effect on vaccine safety and no significant impact on immunogenicity. 125 Replication competent, enteric-coated, Ad4 has been used to prevent acute respiratory disease from adenoviruses by the US military. 126 Two phase I trials of replication competent, rAd4 HIV-1 vaccine, NCT01989533 (Ad4 Mosaic Gag/Ad4 clade C Env150 via intranasal or oral routes) and NCT02771730 (Ad4 Mosaic Gag or Ad4 clade C Env150 or both prime, AIDSVAX Ò B/E/aluminum hydroxide boost) are currently underway (Table 2).…”

“…120,121 Ad26 and Ad35 studies have shown potential in phase I/II human vaccine trials. [122][123][124][125] A recent randomized, double-blind, placebo-controlled trial in 218 healthy adults using Ad26. EnvA.01 and Ad35.Env vectors in both homologous and heterologous combinations elicited humoral and cellular immune responses in nearly all participants.…”

The complete genome sequence of human adenovirus 84, a highly recombinant new Human mastadenovirus D type with a unique fiber gene

“…Candidate novel HAdV genotypes are currently evaluated, approved and assigned names by the Human Adenovirus Working Group (hadvwg.gmu.edu) to reduce conflicts and confusion with designation. Human adenoviruses are causative agents of respiratory, gastrointestinal, urinary and ocular diseases, but adenovirus-based vectors are also being developed for cancer treatment, prevention of infectious diseases, and/or to correct genetic disorders (Alonso-Padilla et al, 2016;Baden et al, 2016;Majhen et al, 2014;Zhang and Seto, 2015). As part of our effort seeking to identify new potential vector candidates, we obtained the complete genomic sequence for a respiratory isolate originally identified as a unique intertypic recombinant of species HAdV-D strains.…”

Safety and Immunogenicity of a rAd35-EnvA Prototype HIV-1 Vaccine in Combination with rAd5-EnvA in Healthy Adults (VRC 012)

“…When rAd26/rAd35 heterologous regimens, employing a different rAd35 vector and EnvA insert, were evaluated in the presence or absence of pre-existing vector immunity, using rAd26 as the prime proved more effective than priming with rAd35 at producing EnvA binding ELISA titers. Both heterologous regimens produced higher EnvA ELISA titers than homologous regimens, and there were no significant differences noted between vector-naïve and vector pre-immune individuals [56]. A unique strategy to circumvent pre-existing Ad5 immunity but still reap the immunological benefits of the Ad5 response involved creating a chimeric Ad5/Ad48 HIV EnvA immunogen [57].…”