Comparative Seroprevalence and Immunogenicity of Six Rare Serotype Recombinant Adenovirus Vaccine Vectors from Subgroups B and D

Abstract

Recombinant adenovirus serotype 5 (rAd5) vector-based vaccines are currently being developed for both human immunodeficiency virus type 1 and other pathogens. The potential limitations associated with rAd5 vectors, however, have led to the construction of novel rAd vectors derived from rare Ad serotypes. Several rare serotype rAd vectors have already been described, but a detailed comparison of multiple rAd vectors from subgroups B and D has not previously been reported. Such a comparison is critical for selecting optimal rAd vectors for advancement into clinical trials. Here we describe the construction of three novel rAd vector systems from Ad26, Ad48, and Ad50. We report comparative seroprevalence and immunogenicity studies involving rAd11, rAd35, and rAd50 vectors from subgroup B; rAd26, rAd48, and rAd49 vectors from subgroup D; and rAd5 vectors from subgroup C. All six rAd vectors from subgroups B and D exhibited low seroprevalence in a cohort of 200 individuals from sub-Saharan Africa, and they elicited Gag-specific cellular immune responses in mice both with and without preexisting anti-Ad5 immunity. The rAd vectors from subgroup D were also evaluated using rhesus monkeys and were shown to be immunogenic after a single injection. The rAd26 vectors proved the most immunogenic among the rare serotype rAd vectors studied, although all rare serotype rAd vectors were still less potent than rAd5 vectors in the absence of anti-Ad5 immunity. These studies substantially expand the portfolio of rare serotype rAd vectors that may prove useful as vaccine vectors for the developing world.Replication-incompetent, recombinant adenovirus serotype 5 (rAd5) vectors have been demonstrated to elicit potent antigen-specific cellular immune responses in both preclinical and clinical studies (2,7,25,26,28). In particular, rAd5 vectorbased vaccines for human immunodeficiency virus type 1 (HIV-1) and other pathogens are currently being advanced into large-scale clinical studies. However, the immunogenicity and clinical utility of rAd5 vectors may be limited by the high prevalence of preexisting anti-Ad5 immunity in human populations, particularly in the developing world (13,19,25,30,31,33,35). Preexisting anti-Ad5 immunity has already been shown to suppress the immunogenicity of rAd5 vector-based vaccines in mice (3,14,15,22,30,36), rhesus monkeys (6, 22), and humans (7, 25). Moreover, immunization with rAd5 vectors generates potent antivector immunity that substantially inhibits the utility of homologous vector readministration (3,6,24).The generation of novel rAd vectors that circumvent antiAd5 immunity is therefore an important research priority. Strategies that are currently being explored include constructing hexon-chimeric rAd5 vectors (22), generating rAd vectors from nonhuman Ad serotypes (8,11,21,34), and developing rAd vectors from rare human Ad serotypes (12,14,25,35). Such novel rAd vectors may prove useful as vaccine vectors in populations in the developing world with high levels of preexisting anti-Ad5 immunity. Nov...

Genetic immunization in the lung induces potent local and systemic immune responses

“…As we showed, the induction of local cellular responses and systemic humoral responses is largely unaffected by preexisting antivector antibodies. This ability to overcome preexisting immunity is important, because populations targeted for vaccination often have high rates of adenoviral seroprevalence, particularly in the developing world (17). Ad5 seroprevalence has raised concerns that the utility of adenoviral vectors in humans may be limited (12).…”

Wild-type adenoviruses from groups A–F evoke unique innate immune responses, of which HAd3 and SAd23 are partially complement dependent

“…15 Because the spleen houses a variety of professional immune response cell types, high levels of HAd37 accumulation in the spleen may help to explain why HAd26, also a rare group D Ad serotype, efficiently stimulates a high level, antigen-specific CD8+ T-cell response even in the presence of HAd5 antibodies. 20 Although both SAd23 and HAd31 were detected at both 6 and 24 h.p.i. in the CAR expressing murine liver and the spleen, the relative low abundance of their genomes detected in these tissues (relative to HAd5) suggests sequestration of these serotypes in tissues not tested in this study.…”

“…These alternative serotype vectors have been demonstrated to show altered cell-type tropisms, retain their ability to avoid neutralizing antibodies to other Ad serotypes and can also stimulate antigen-specific CD8+ T-cell responses to transgenes they encode. 20,21 However, little is known about the acute toxicities and biodistribution profiles that these alternative Ad serotypes might engender, relative to the HAd5 platform. Furthermore, there are simian, ovine, bovine, porcine, avian and canine Ads that are also potentially amenable for use as gene transfer or vaccine vectors.…”

Impact of Recombinant Adenovirus Serotype 35 Priming versus Boosting of aPlasmodium falciparumProtein: Characterization of T- and B-Cell Responses to Liver-Stage Antigen 1

“…The immunogenicity of rAd, together with the availability of a highly efficient and scalable production platform (17,21), has fuelled interest in pursuing Ad vectors as a vaccine platform. The preexisting neutralizing immunity limits the use of highly prevalent serotypes, such as Ad serotype 5 (Ad5) (2,10,11,14,19,28,31,42,57,58,60); however, the development of novel vectors based on low-seroprevalence serotypes that are not influenced by the preexisting immunity toward Ad5, such as Ad35 (1,4,60), open new avenues for the use Ad vectors as vaccine vehicles.…”