Rational Design of Coronavirus Vaccines
Prevention of virus diseases by vaccination aims for controlled induction of protective immune responses against viral pathogens. Live virus vaccines consist of attenuated, replication-competent viruses that are believed to be superior in the induction of broad immune responses, including cell-mediated immunity. The recent proceedings in the area of virus reverse genetics allows for the rational design of recombinant vaccines by targeting, i.e., inactivating, viral pathogenicity factors. Attenuated virus vaccines can be generated by targeting essential pathogenicity factors.
The effect of coronavirus non-structural protein 1 (nsp1) on pathogenicity was analyzed in a murine model of coronavirus infection. By deleting a part of this protein, a recombinant virus was generated that is greatly attenuated in vivo, while retaining immunogenicity. In particular, the mutant virus retained the ability to replicate in professional antigen-presenting cells and fulfilled an important requirement of a promising vaccine candidate: the induction of a protective long-lasting, antigen-specific cellular immune response.
The mutant grew normally in tissue culture, but was severely attenuated in vivo. Replication and spread of the nsp1 mutant virus was restored almost to wild-type levels in type I interferon (IFN) receptor-deficient mice, indicating that nsp1 interferes efficiently with the type I IFN system. Importantly, replication of nsp1 mutant virus in professional antigen-presenting cells such as conventional dendritic cells and macrophages, and induction of type I IFN in plasmacytoid dendritic cells, was not impaired. Furthermore, even low doses of the nsp1 mutant elicited potent cytotoxic T cell responses and protected mice against homologous and heterologous virus challenge.
This study has implications for the rational design of live attenuated coronavirus vaccines aimed at preventing coronavirus-induced diseases of veterinary and medical importance, including the potentially lethal severe acute respiratory syndrome. Taken together, the presented attenuation strategy provides a paradigm for the development of highly efficient coronavirus vaccines.
what size is this image? very cool.