Immunogenicity of Heterologous Prime-Boost Regimens Involving Recombinant Adenovirus Serotype 11 (Ad11) and Ad35 Vaccine Vectors in the Presence of Anti-Ad5 Immunity

Abstract

The high prevalence of preexisting immunity to adenovirus serotype 5 (Ad5) in human populations will likely limit the immunogenicity and clinical utility of recombinant Ad5 (rAd5) vector-based vaccines for human immunodeficiency virus type 1 and other pathogens. A potential solution to this problem is to utilize rAd vaccine vectors derived from rare Ad serotypes such as Ad35 and Ad11. We have previously reported that rAd35 vectors were immunogenic in the presence of anti-Ad5 immunity, but the immunogenicity of heterologous rAd prime-boost regimens and the extent that cross-reactive anti-vector immunity may limit this approach have not been fully explored. Here we assess the immunogenicity of heterologous vaccine regimens involving rAd5, rAd35, and novel rAd11 vectors expressing simian immunodeficiency virus Gag in mice both with and without anti-Ad5 immunity. Heterologous rAd prime-boost regimens proved significantly more immunogenic than homologous regimens, as expected. Importantly, all regimens that included rAd5 were markedly suppressed by anti-Ad5 immunity. In contrast, rAd35-rAd11 and rAd11-rAd35 regimens elicited high-frequency immune responses both in the presence and in the absence of anti-Ad5 immunity, although we also detected clear cross-reactive Ad35/Ad11-specific humoral and cellular immune responses. Nevertheless, these data suggest the potential utility of heterologous rAd prime-boost vaccine regimens using vectors derived from rare human Ad serotypes.Preexisting anti-vector immunity represents a major hurdle in the development of vector-based vaccines for human immunodeficiency virus type 1 (HIV-1) and other pathogens. Recombinant adenovirus serotype 5 (rAd5) vectors have been shown to elicit high-frequency immune responses and to afford protective efficacy in a variety of animal models (24,30,31). These vectors are therefore being advanced into large-scale clinical trials (14,25). However, the high prevalence of antiAd5 immunity in human populations will likely limit the immunogenicity and clinical utility of rAd5 vector-based vaccines, particularly in the developing world (13,25,32). Anti-Ad5 immunity has already been shown to suppress substantially the immunogenicity of rAd5 vaccines for HIV-1 in studies in mice (2, 3, 6, 29, 34), rhesus monkeys (4), and humans in phase 1 clinical trials (26).A potential solution to this problem is to develop rAd vectors from alternative Ad serotypes. One approach is to develop rAd vectors from species other than humans. For example, ovine (10), porcine (21), bovine (22), and chimpanzee (5, 33) Ads have been constructed. Of these vector systems, chimpanzee rAd vaccine vectors in particular have been shown to be immunogenic and only marginally affected by anti-Ad5 immunity in preclinical studies (6,20). However, a potential hurdle for the use of nonhuman rAd vaccine vectors is their unknown clinical disease associations in humans, which may raise substantial safety and regulatory concerns.Another approach is to develop rAd vectors from rare human Ad serotypes ...

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