First-in-human evaluation of a hexon chimeric adenovirus vector expressing HIV-1 Env (IPCAVD 002).

Development of a preventive human immunodeficiency virus 1 (HIV-1) vaccine is a global health priority, but to our knowledge only 4 vaccine concepts have been evaluated in field trials to date [1–7]. Adenoviruses are potent vectors [8], and although recombinant adenovirus (Ad) serotype 5 (rAd5) vectors have been studied as preventative HIV-1 vaccines both alone and in conjunction with DNA priming, they have not been efficacious [1, 7]. Potential limitations of Ad serotype 5 (Ad5) vectors include the high level of preexisting antivector immunity, particularly in the developing world [9, 10], as well as qualitative features of the immune responses elicited [11]. To overcome these potential limitations, adenoviruses with lower seroprevalence have been proposed as vectors [12]. Alternative serotype Ad vectors have notable biologic differences from rAd5 in terms of baseline seroepidemiologic findings, receptor usage, tropism, innate immune profile, adaptive immune phenotype, and protective efficacy in the simian immunodeficiency virus (SIV)/macaque model [13–16]. Several alternative serotype Ad vectors, including Ad26 and Ad35, have advanced into clinical trials as potential vaccine vectors [17–20]. An alternative approach to retain favorable immunologic features of Ad5 vectors while reducing the potential impact of preexisting Ad5 antibodies is to develop chimeric recombinant Ad vectors in which the key Ad5 neutralization epitopes have been removed. Because Ad5-specific neutralizing antibodies (nAbs) are directed primarily against the Ad5 hexon major capsid protein [21], specifically against the 7 hexon hypervariable regions on the hexon surface, we developed chimeric rAd5 vectors in which the hexon hypervariable regions were swapped with the corresponding regions from the rare Ad serotype 48 (Ad48) [22]. These chimeric vectors use the same cellular receptor as Ad5 and effectively circumvented dominant Ad5-specific nAbs directed against the hexon hypervariable regions [22]. Furthermore, a single injection of an Ad5HVR48 chimeric vaccine expressing SIV Env/Gag/Pol/Nef was immunogenic and led to improved peak and plateau viral loads after SIV challenge in macaques [23]. In this study, we report the first-in-human safety and immunogenicity evaluation of an Ad5HVR48 vectored HIV-1 vaccine, and we evaluated the capacity of this chimeric vector to induce nAbs against both Ad5 and Ad48.