Functional genomics of vaccine relevant and naturally occurring orthopoxviruses

Arinze S. Okoli
Arinze Okoli is the project leader

Orthopoxviruses, in particular Vaccinia and Cowpox viruses, are good candidates for live virus vaccine vectors. Several live virus vaccines have been developed using the Vaccinia virus strain – Modified Vaccinia virus Ankara (MVA) as vector. However, none of the live virus-vectored vaccines have been licensed for human use due to their inability to pass requisite clinical trials and/or biosafety evaluations. The most recent example is the failure at phase IIB clinical trial of MVA85a, being unable to provide protection in preventing tuberculosis in infants. This underscores the crucial need for better understanding of the basic biology underpinning this technology.

The current empirical approach to transgenic vaccines development ignores the impacts of genetic modifications on the characteristics of the expressed virus. Thus, the mechanistic events by which MVA vaccines could confer protections in humans are presently unknown; safety concerns such as transgenes instabilities, pre-existing immunity, vaccine strains with altered host specificity and host’s response to replication competent virus-based vaccines have not been clarified.

The aim of this project is to comprehensively and systematically identify affected key molecular factors of virus and host in cells infected with transgenic MVA derived vaccines using innovative and high impact new methods in system biology including proteomics, molecular biology and RNAi technologies.

Specific investigations include: (1) effects of transgenic modification on the genetics and physiology of MVA in comparison to the parental strains; (2) pathways of host cell response to MVA-based vaccines; (3) roles of antigenic factors of MVA in MVA-based vaccines; (4) factors associated with transgenes instability in transgenic MVA-based vaccines; (5) host tropism determinant of MVA.