TBV - Pf48/45 (EMVI call 2003)

Inventor:                                       Prof Henk Stunnenberg, RUNMC University of Nijmegen

The rational for this approach is based on the observation hat antibodies that target sexual stage antigens expressed in the mid-gut of the mosquito can block transmission of the parasite from mosquito to man. The Pfs 48/45 protein was identified as a target antigen some time ago, the main justification for this choice being:
• Its role in fertilisation
• Its surface location
• Antibodies against Pfs48/45 block transmission in a membrane feeder assay
• Serum from malaria infected populations exhibit transmission blocking activity

The main challenge in this project has been producing a recombinant protein that is correctly folded and in sufficient quantities to envisage clinical assessment. Initial experimentation indicated that the recombinant protein was not capable of inducing TB antibodies in mice. Many different fragments were expressed in E. coli but with poor results in general. In a best case scenario (fragment 10 C) only 20% of the protein was considered to be in the correct conformation, as assessed by its ability to be recognised by functional TB antibodies. Other fragments (10N and 6N) did not show significantly improved profiles.
The SAC portfolio review in October 2006 concluded that the situation would need to be improved dramatically in order to envisage moving on to GMP production, and SAC recommended the project be terminated. However, the project was re-evaluated by SAC in November 2007 on the receipt of a Progress Report submitted by Profs. Stunnenberg and Sauerwein. SAC recommended that the project continue, albeit with specific deliverables. This recommendation was approved by the Board at their meeting on 9 January 2008. A new contract has not been signed and a Settlement Agreement to terminate the contract is pending signatures.