Comparative Immunogenicity in Rhesus Monkeys of DNA Plasmid, Recombinant Vaccinia Virus, and Replication-Defective Adenovirus Vectors Expressing a Human Immunodeficiency Virus Type 1 gag Gene

Abstract

Cellular immune responses, particularly those associated with CD3؉ CD8 ؉ cytotoxic T lymphocytes (CTL), play a primary role in controlling viral infection, including persistent infection with human immunodeficiency virus type 1 (HIV-1). Accordingly, recent HIV-1 vaccine research efforts have focused on establishing the optimal means of eliciting such antiviral CTL immune responses. We evaluated several DNA vaccine formulations, a modified vaccinia virus Ankara vector, and a replication-defective adenovirus serotype 5 (Ad5) vector, each expressing the same codon-optimized HIV-1 gag gene for immunogenicity in rhesus monkeys. The DNA vaccines were formulated with and without one of two chemical adjuvants (aluminum phosphate and CRL1005). The Ad5-gag vector was the most effective in eliciting anti-Gag CTL. The vaccine produced both CD4؉ and CD8 ؉ T-cell responses, with the latter consistently being the dominant component. To determine the effect of existing antiadenovirus immunity on Ad5-gag-induced immune responses, monkeys were exposed to adenovirus subtype 5 that did not encode antigen prior to immunization with Ad5-gag. The resulting anti-Gag T-cell responses were attenuated but not abolished. Regimens that involved priming with different DNA vaccine formulations followed by boosting with the adenovirus vector were also compared. Of the formulations tested, the DNA-CRL1005 vaccine primed T-cell responses most effectively and provided the best overall immune responses after boosting with Ad5-gag. These results are suggestive of an immunization strategy for humans that are centered on use of the adenovirus vector and in which existing adenovirus immunity may be overcome by combined immunization with adjuvanted DNA and adenovirus vector boosting.

Neutralizing Antibodies to Adenovirus Serotype 5 Vaccine Vectors Are Directed Primarily against the Adenovirus Hexon Protein

“…A major limitation of this approach, however, is the high prevalence of pre-existing anti-Ad5 immunity in human populations. Anti-Ad5 immunity has been shown to suppress substantially the immunogenicity of rAd5 vaccines in studies in mice (7)(8)(9)(10), rhesus monkeys (11), and humans in phase 1 clinical trials (12).…”

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.…”

HIV-189.6 Gag expressed from a replication competent HSV-1 vector elicits persistent cellular immune responses in mice

“…Nevertheless, since the significance of the CTL responses as a correlate of protection is not entirely clear, a large Phase III trial is underway to measure the efficacy of a canarypox vector as part of an HIV vaccine regimen. While awaiting the canarypox Phase III results, modified Vaccinia Ankara (MVA) [62][63][64] and adenovirus vaccine vectors [24,65] are being evaluated in both preclinical and Phase I and II patient trials. Both vectors stimulate potent CMI responses in primates and a majority of human subjects.…”

“…Herpes simplex virus type-1 (HSV-1) with deletions in the Δγ 1 34.5 gene is replication-competent but is aneurovirulent [23]. Attenuated HSV-1 recombinants are attractive as HIV-1 vaccine vectors for multiple reasons: i) herpesvirus vectors can infect dendritic cells and stimulate potent, longlasting CMI responses [24][25][26][27][28]; ii) attenuated HSV can establish latency and reactivate with the potential to prolong an immune response [29,30]; iii) several nonessential genes can be deleted and replaced with multiple foreign gene inserts (up to 30 kb) [31]; vi) HSV Δγ 1 34.5 viruses have been safe during human use in clinical trials, including intracranial injection at high doses [32][33][34][35]; and v) although prior immunity to HSV has a variable effect on vector efficacy in gene therapy applications, it does not impair either antibody or CMI responses elicited against immunogens expressed from HSV vectors [36][37][38][39].…”