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Complementary research action to support sars-related diagnostic, therapeutics and vaccin

Final Report Summary - SARS-DTV (Complementary research action to support SARS-related diagnostic, therapeutics and vaccine)

Severe acute respiratory syndrome (SARS) was a life-threatening form of pneumonia caused by a newly emerging coronavirus (SARS-CoV), which likely circulates in bats, together with a wide variety of other (recently discovered) coronaviruses. The prevention and / or containment of future outbreaks of these viruses, will depend on our understanding of their biology, pathogenesis, and evolution. To aid in designing an overall strategy, the SARS-DTV project focused its attention in particular on the development of reliable diagnostic tools, specific antiviral compounds, and a SARS-CoV vaccine.

With other coronaviruses, SARS-CoV employed a replicative machinery that is unique among RNA viruses because of the large number of enzymatic subunits and the use of several enzymes that are rare or lacking in other virus groups. Both individually expressed subunits and the integral enzyme complex in the living infected cell were studied. This resulted, for example, in two novel crystal structures of important SARS-CoV enzymes (NendoU and ADRP), in the discovery of a unique secondary RNA-dependent RNA polymerase activity (the nsp8 'primase'), in the more detailed description of several other viral enzymes, and in the ultrastructural characterisation of an elaborate network of modified membranes with which viral RNA synthesis is associated in the infected cell. Furthermore, an initial screening for antiviral lead compounds targeting SARS-CoV enzymes was performed. In addition, a 30 000 compound library was purchased for (ongoing and future) screening campaigns using biochemical assays developed during the characterisation of various enzymes. In a similar screening approach, but now targeting the viral life cycle as a whole, over 2 000 potential antiviral compounds were screened and several were found to show antiviral activity. Derivatives of selected anti-coronavirus compounds were synthesised to assess their antiviral activity in more detail. Furthermore, an animal model was used to study the in vivo activity of chloroquine against coronaviruses.

In our analysis of SARS-CoV Spike protein functions, the interactions with the ACE-2 receptor protein and the fusion process of viral envelope and cellular membrane were investigated. Efforts were made to obtain small molecules (e.g. peptides) that might be used to inhibit receptor-binding and entry of the virus.

In the immunological WP, antigenic sites on SARS-CoV proteins were characterised and the role of the humoral and cellular immune response in SARS infection was studied. Using an antibody-phage library approach, genes encoding neutralising human monoclonal antibodies were cloned and expressed as IgG molecules. Virus neutralisation epitopes and escape were studied using these reagents and transient expression systems required to rapidly produce anti-SARS-CoV antibodies were developed. In terms of cellular immunology, SARS-CoV T cell epitopes were defined and fine mapping was performed (55 new CD4 and CD8 epitopes). The magnitude of the responses to the novel epitopes in patient samples was determined.

Partners in the SARS-DTV 'Model systems' WP, successfully developed a vaccine virus-based reverse genetic systems for SARS-CoV and other coronaviruses. This important new research tool will enable the development (in progress) of biosafe, cell culture-based systems that can be used