TBV - Pf48/45

Transmission Blocking Vaccine - Plasmodium falciparum 48/45
The rationale for this approach is based on the observation that 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

Background

Full background information can be found in the proposal submitted in response to a European Vaccine Initiaitive (EMVI) now European Vaccine Initiaitve call in 2003. The proposal was recommended by the independent Scientific Advisory Committee (SAC) and subsequently approved by the Board.

Product Deveopment

A contract was signed with Stichting Katholieke Universiteit, Universal Medical Centre Nijmegen late in 2004 for the "Pharmaceutical development of a Plasmodium falciparum 48/45 transmission blocking malaria vaccine".

Statens Serum Institut expressed an interest in this project, and a contract was signed in 2005 for "demonstrating that the L. lactis system can be used for expressing Pfs48/45 and potentially to produce a limited amount of (non-Good Manufacturing Practice) recombinant Pfs48/45".

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 review of EMVI portfolio in October 2006 concluded that the situation would need to be improved dramatically in order to envisage moving on to Good Manufacturing Practice 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. The original contract was terminated, and a new contract issued. However, legal issues arose over the termination of the contract and a Settlement Agreement to terminate the contract was signed in 2009.