Effect of preexisting immunity to adenovirus human serotype 5 antigens on the immune responses of nonhuman primates to vaccine regimens based on human- or chimpanzee-derived adenovirus vectors.

In this study we compared a prime-boost regimen with two serologically distinct replication-defective adenovirus (Ad) vectors derived from chimpanzee serotypes C68 and C1 expressing Gag, Pol, gp140, and Nef of human immunodeficiency virus type 1 with a regimen in which replication-defective Ad vectors of the human serotype 5 (AdHu5) were given twice. Experiments were conducted in rhesus macaques that had or had not been preexposed to antigens of AdHu5. There was no significant difference in T-cell responses tested from peripheral blood of the different groups, although responses were overall highest in nonpreexposed animals immunized with the chimpanzee Ad vectors. Preexisting immunity to AdHu5 completely inhibited induction of transgene product-specific antibodies by the AdHu5 vectors without affecting antibody responses to the chimpanzee vectors. Upon euthanasia, T-cell responses were tested from a number of tissues. Preexisting immunity to AdHu5, commonly found in humans, changed the homing pattern of vaccine-induced T cells. In AdHu5-preexposed animals vaccinated with the chimpanzee Ad vectors, frequencies of transgene-specific T cells were higher in spleens than in blood, and in most preexposed animals vaccinated either with AdHu5 vectors or chimpanzee adenovirus vectors, frequencies of such T cells were exceptionally high in livers. The latter results indicate that analysis of T-cell responses solely from blood mononuclear cells of vaccine recipients may not suffice to compare the potencies of different vaccine regimens.

A CD46-binding chimpanzee adenovirus vector as a vaccine carrier.

A replication-defective chimeric vector based on the chimpanzee adenovirus serotype C1 was developed and tested as a vaccine carrier in mice. The AdC1 virus is closely related to human adenoviruses of subgroup B2 and uses CD46 for cell attachment. To overcome poor growth of E1-deleted AdC1 vectors on cell lines that provide the E1 of adenovirus of the human serotype 5 (AdHu5) virus in trans, the inverted terminal repeats and some of the early genes of AdC1 were replaced with those from AdC5, a chimpanzee origin adenovirus of subfamily E. The chimeric AdC1/C5 vector efficiently transduces CD46-expressing mouse dendritic cells (DCs) in vitro and initiates their maturation. Transduction of DCs in vivo is inefficient in CD46 transgenic mice. The AdC1/C5 vector induces transgene product-specific B- and CD8(+) T-cell responses in mice. Responses are slightly higher in wild-type mice than in CD46 transgenic mice. Transgene product-specific T-cell responses elicited by the AdC1/C5 vector can be increased by priming or boosting with a heterologous adenovirus vector. Pre-existing immunity to adenovirus of the common human serotype 5 does not affect induction of cell-mediated immune responses by the AdC1/C5 vector. This vector provides an additional tool in a repertoire of adenovirus-based vaccine vectors.

Type I interferon inhibits antibody responses induced by a chimpanzee adenovirus vector.

Recent studies have indicated that type I interferon (IFN) enhances antibody responses and promotes isotype switching. In this study, we analyzed the role of type I IFN signaling during the generation of transgene product-specific antibody responses elicited by recombinant adenovirus (Ad) vectors. A vector derived from a human Ad serotype (AdHu5) induced low levels of type I IFN following infection of dendritic cells (DCs) and stimulated normal transgene product-specific antibody responses in mice that have a defective type I IFN receptor (IFNAR(-/-)). A vector derived from a chimpanzee Ad serotype (AdC68) induced very high levels of type I IFN following infection of DCs, and surprisingly, primed stronger transgene product-specific antibody responses in IFNAR(-/-) mice compared to wild-type mice. The increased antibody response in IFNAR(-/-) mice vaccinated with the AdC68 vector was mainly due to the generation of IgG1 antibodies that were not elicited in wild-type mice. The induction of IgG1 antibodies correlated with an increase in transgene product expression in IFNAR(-/-) mice and was not associated with an increase in T helper 2 responses. We conclude that type I IFN, when induced at high levels, can downregulate transgene product expression of Ad vectors and inhibit the formation of optimal antibody responses.

Chimpanzee adenovirus antibodies in humans, sub-Saharan Africa.

Human sera from the United States, Thailand, and sub-Saharan Africa and chimpanzee sera were tested for neutralizing antibodies to 3 chimpanzee adenoviruses. Antibodies were more common in humans residing in sub-Saharan Africa than in humans living in the United States or Thailand. This finding suggests cross-species transmission of chimpanzee adenoviruses.

A chimpanzee-origin adenovirus vector expressing the rabies virus glycoprotein as an oral vaccine against inhalation infection with rabies virus.

Rabies has the highest fatality rate of all human viral infections and the virus could potentially be disseminated through aerosols. Currently licensed vaccines to rabies virus are highly effective but it is unknown if they would provide reliable protection to rabies virus transmitted through inhalation, which allows rapid access to the central nervous system upon entering olfactory nerve endings. Here we describe preclinical data with a novel vaccine to rabies virus based on a recombinant replication-defective chimpanzee-origin adenovirus vector expressing the glycoprotein of the Evelyn Rokitniki Abelseth strain of rabies virus. This vaccine, termed AdC68rab.gp, induces sustained central and mucosal antibody responses to rabies virus after oral application and provides complete protection against rabies virus acquired through inhalation even if given at a moderate dose.