1015. Induction of Protective Immunity to Anthrax Lethal Toxin with a Chimpanzee Adenovirus-Based Vaccine Carrier in the Presence of Pre-Existing Anti-Human Adenovirus Immunity
Authors: Masahiko Hashimoto, Julie L. Boyer, Neil R. Hackett, James M. Wilson, Ronald G. Crystal
Journal: Molecular Therapy (2004)

An intentional release of anthrax spores could result in widespread inhalational anthrax and a socioeconomic disaster, and thus development of a effective, rapidly acting vaccine is essential to protect susceptible individuals. The current vaccine licensed for use in the US has limited availability and requires multiple administrations for full protection. We have recently demonstrated (Tan et al, Hum Gene Ther. 2003, 14:1673) that a single intramuscular administration of a recombinant serotype 5 adenovirus (Ad) vector expressing protective antigen (PA), a component of anthrax lethal toxin, provides rapid protection against lethal toxin challenge in BALB/c mice. However, approximately 35 to 50% of humans have pre-existing neutralizing antibodies against Ad5 and this may limit the utility of the Ad5-based vaccine. Based on the concept that “seroswitch” of an Ad vector could circumvent pre-existing anti-Ad5 immunity, this study assesses the hypothesis that a recombinant adenoviral vector based on the chimpanzee-derived serotype AdC7 expressing the secreted form of PA (AdC7secPA) will protect against anthrax lethal toxin in the presence of pre-existing anti-Ad5 immunity. BALB/c mice (n=5/group) were immunized intramuscularly with 109 particle units (pu) AdC7secPA, Ad5secPA (a human serotype Ad5-based vector expressing a secreted form of PA) or AdNull (an Ad5 vector with no transgene). At 4 wk post-administration, anti-PA reciprocal titers were assessed by ELISA. Serum anti-PA antibody titers for Ad5secPA-immunized mice were 8800 ± 1600 (mean ± standard error). Serum antibody titers in response to AdC7secPA immunization were 130 ± 62 at a dose of 109 pu, 3000 ± 1300 at 1010 pu, and 14,000 ± 3400 at 1011 pu. No anti-PA titers were detectable for the AdNull control group. To assess the effect of pre-existing anti-Ad5 immunity on anti-PA antibody titers, mice were injected intramuscularly with 1010 pu of a control Ad5 vector to induce anti-Ad immunity. At 4 wk post-administration, with anti-Ad5 neutralizing titers of 84 ± 13, the pre-immunized mice received 1010 pu AdC7secPA. Four wk later, the reciprocal anti-PA antibody titers in Ad5 pre-immunized mice were 1300 ± 490, demonstrating the efficacy of AdC7secPA at stimulating anti-PA titers in the presence of anti-Ad5 immunity. To assess protection in vivo, AdC7secPA- and Ad5secPA-immunized mice were challenged with a lethal intravenous dose of B. anthracis lethal toxin. After 6 wk, 100% of Ad5sechPA (109 pu)-immunized mice survived, whereas 100% of naive control mice died. A dose of 109 pu AdC7secPA protected 60% of immunized mice and a dose of 1010 pu resulted in 100% survival. In Ad5 pre-immunized, AdC7secPA-vaccinated mice, survival after lethal toxin challenge was 100%. These data demonstrate that in the presence of pre-existing anti-Ad5 immunity, the chimpanzee based vector AdC7secPA is an effective vaccine for the development of protective immunity against PA.