Vaccinia virus recombinants engineered to express foreign genes have great potential as new live vaccines against infectious diseases. Modified vaccinia virus Ankara (MVA) is a promising human vaccine candidate due to its restricted host range, avirulence in animal models, excellent safety record as a smallpox vaccine and potent immunogenicity. This proposal intends to investigate various aspects of vaccinia virus in order to improve and develop MVA as a recombinant human vaccine.
Safety of recombinant vaccines. The molecular cell biology of MVA will be investigated and vaccinia virus proteins required for virus assembly and entry into cells will be characterised. This will lead to the identification of proteins that can be deleted from the viral genome and restrict even further the replication and dissemination of MVA in vivo. The role of vaccinia proteins that modulate the host immune response, such as soluble cytokine receptors or proteins that protect infected cells from interferon effects, will be investigated in the infected host. Deletion of these vaccinia genes may increase the susceptibility of vaccinia recomhinant to the attack of the immune system and also restlict virus spread.
Immunogenicity of recombinant vaccines. Vaccinia recombinants that may be used in human medicine will probably have deficient replication, thus the immunogenicity of the expressed foreign antigens will need to be enhanced. The research project will use different approaches: i) to display foreign antigens at the surface of virions; ii) to determine the inlluence of vaccinia immunomodulatory proteins; and iii) to express host cytokines that can promote immune responses.
These studies will lead to the development of safer and more immunogenic MVA recombinants, which will be tested as candidate vaccines against HIV, influenza and malaria parasite. Clinical trials with vaccinia MVA are being prepared, therefore there is an urgent need to understand at the molecular level the replication of vaccinia virus MVA and its interaction with the host immune system. This will not only improve MVA as a recombinant vaccine but will also allow us to control any problems that may arise in the field.
Funding SchemeCSC - Cost-sharing contracts
28130 Valdeolmos - Madrid
CB2 1QP Cambridge