In November 2002 in China, an outbreak of atypical pneumonia occurred in which a proportion of cases were very severe or fatal, and a high lethality was seen among elderly patients. The clinical syndrome began with fever, dry cough, myalgia and sore throat and progressed to atypical pneumonia. Outbreaks followed thereafter in 2003 in Vietnam, Hong Kong, Singapore, Canada, and Taiwan. Extraordinary characteristics of this global epidemic of """"""""Severe Acute Respiratory Syndrome"""""""" (SARS) include the rapid isolation of the etiologic agent (a novel coronavirus; SARS-CoV), elucidation of the complete sequence of the viral genome, accelerated development of diagnostic tests, and rapid global exchange of clinical, epidemiologic and microbiologic information via the Internet by scientists and health officials in many countries. Investigators in the USA and Hong Kong were first to isolate from patients the novel coronavirus that is distinct from previously recognized groups of coronavirus. The underlying hypothesis of this research plan is that by appropriate manipulation of attenuated Salmonella enterica serovar Typhi (S. Typhi) and Shigella live vectors it will be possible to develop a mucosally-administered """"""""prime-boost"""""""" vaccination strategy to prevent SARS. We will utilize attenuated S. Typhi or Shigella flexneri 2a live vector vaccine strains to deliver (via mucosal immunization) a Sindbis eukaryotic DNA replicon encoding the S (spike) and M (membrane) glycoproteins and the N nucleocapsid protein of the Urbani strain of the SARS-CoV to prime the immune system to recognize these coronavirus antigens. We will then boost the immune response by mucosally administering proteosomes (meningococcal outer membrane protein vesicles) to which the same SARS proteins are adsorbed (along with a lipopolysaccharide adjuvant). Virus-like Particles and attenuated S. Typhi expressing SARS peptide epitopes will serve as back-up boosting strategies. We will study whether these constructs can elicit the relevant immune responses, first in mice, then in cynomolgus monkeys, and finally in clinical trials in humans (the latter under separate funding). The induction of B and T cell memory pools will also be examined in monkeys. This approach aims to mimic the strong and broad immunity elicited by live virus vaccines with the inherent safety factor of not having to use putative attenuated live SARS virus derivatives. If the proposed vaccination strategy can indeed elicit broad, balanced and long-lasting immune responses in cynomolgus monkeys, these studies can be followed by a challenge (under respiratory pathogen biosafety level 3 containment) to assess the efficacy of the vaccine against wild type SARS-CoV.
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