Development of Shielded Adenovirus Vector as a Vaccine Strategy For Anthrax

DESCRIPTION (provided by applicant): The emerging threat of bio-terrorism provides a major challenge to protect the civilian population through standard prophylactic vaccine means. The recent anthrax attacks highlighted the urgent need to develop vaccine strategies that act rapidly to the threat of the biological pathogen, and which can be produced in an economically effective manner. In the context of anthrax, the protective antigen (PA) of this pathogen elicits a strong immune response and is used in the current prophylactic vaccine. However, due to the protracted protocol of the current vaccine, an alternative delivery system of PA, one of which rapidly induces the immune system to produce antibodies, in a sustained manner is necessary. One such mechanism would be gene delivery of PA using adenovirus (Ad) gene delivery vectors, which provide an ideal platform to meet both economic and vaccination requirements. Ad vectors are employed in a wide range of gene therapy and vaccine applications and have an established broad safety record in humans, with attractive features such as high titer production, structural stability, broad infectivity, established protocols for genetic manipulation and high levels of transgene expression with lack of host genome integration. Importantly, these vectors are efficient at evoking immunity against the transgene they carry. However, development of these vectors in the clinical context has highlighted that vector efficacy may be limited by the host humoral responses due to pre-existing titers of neutralizing antibodies, in humans, against the vector itself. On the basis of this caveat we have a novel strategy, termed shielding, in which we have technology to genetically modify the virion capsid to provide an uniformly shielded Ad vector. We have identified the pIX capsid protein as an ideal locale for genetic incorporation of shielding ligands, in particular self-proteins such as albumin, to conceal the Ad vector from pre-existing neutralizing antibodies. In this SBIR proposal the basic feasibility of employing a shielding protein, albumin, in the Ad capsid in a defined manner utilizing a specific capsid protein will be established in in vitro [and in vivo models and] the ability of the vector to retain PA expression will be established in vitro. We envision the creation of our shielded Ad vectors as a major progress in the development of clinically and commercially feasible [Ad drug candidates] that can be dosed multiple times for maximum effectiveness to prevent bio-terrorism provoked illness in humans. There are currently no prophylactic vaccines, which act rapidly to protect the population against the emerging threat of bio-terrorism, and this was highlighted by recent anthrax attacks. It is clear that new options are needed. The development of the proposed shielded Ad vector technology can provide an efficient, cost-effective and creative approach to combat anthrax attacks. In addition, the development of the immunologically shielded vector system approach would have further application for many biological threats such as plague and botulism.