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296 A Novel Vaccine to HIV-1 Gag Based on a Replication-Defective Adenovirus Recombinant of the Chimpanzee Serotype 68
J. Fitzgerald1, J. Wilson2, and H. Ertl*1
1The Wistar Inst., Philadelphia, PA, USA and 2Univ. of Pennsylvania, Philadelphia, USA
Replication-defective E1-deleted adenoviral recombinants to HIV-1 based on the human strain 5 (Adhu5) induce HIV-1-specific B- and T-cell responses with high efficiency in experimental animals. Nevertheless, nearly all humans repeatedly encounter Adhu5 virus, and a significant proportion thus has neutralizing antibodies expected to interfere with the efficacy of recombinant vaccines based on Adhu5 virus. To circumvent this interference while preserving the known advantages of adenoviral recombinants we developed a novel vector system for expression of a codon-optimized truncated form of gag of HIV-1. The vaccine is based on an E1-deleted adenovirus recombinant derived from the chimpanzee serotype 68. This virus does not circulate in the human population and fails to carry neutralizing B-cell epitopes that cross-react with the most common serotypes of human adenoviruses. The CD8+ T-cell response to gag was tested in mice immunized with the Adchimp68 recombinant or an Adhu5 recombinant expressing the same transgene product. Both recombinants induced CD8+ T-cell responses to gag in Balb/c mice. Gag-specific CD8+ T-cell activity was superior upon immunization with the Adchimp68 construct, which achieved CD8+ T-cell frequencies to gag of ~16(19% of the entire splenic CD8+ cell population. The response to gag presented by the Adhu5gag37 virus peaked 2 to 4 days earlier than the CD8+ T-cell response to the Adchimp68gag37 recombinant. Frequencies of CD8+ T cells to gag as well as primary target cell lysis could be augmented further to ~40% by boosting with a heterologous vaccine carrier. Mice preimmune to Adhu5 virus failed to respond to a subsequent vaccination with the Adhu5gag37 vaccine. In contrast, the CD8+ T-cell response to gag was only slightly reduced in Adhu5-immune mice vaccinated with the Adchimp68gag37 construct. Priming or booster immunization with a heterologous vaccine construct failed to restore the CD8+ T-cell response to gag presented by the Adhu5 recombinant vaccine.
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