Pfs48/45, a protein important for male gamete fertility, is in advanced stages of development as a Plasmodium falciparum transmission blocking vaccine. The Plasmodium vivax counterpart Pvs 48/45 is likewise expected to be an important vaccine candidate. In spite of significant sequence identify and presumed conserved biological function not much is known about the transmission blocking efficacy of antibodies against Pvs48/45 and if it will be similar to functional antibodies against Pfs48/45 as no cross-blocking reactivity has been observed. Several impediments to developing a transmission blocking vaccine for P. vivax malaria have delayed progress for this long term goal. These have included availability of conformationally suitable recombinant protein, lack of an in vivo challenge model and the inability to produce P. vivax gametocytes in the lab to test biological function of antibodies. In this application, we propose to develop certain much needed reagents to move the field forward capitalizing on success with Pfs48/45 in the co-investigator's lab.
In Aim 1 we propose to generate monoclonal antibodies directed against Pvs48/45 and characterize their binding parameters and functionality through in vitro membrane feeding assays.
Aim 2 will focus on examining the polymorphisms of Pvs48/45 in natural isolates and identification of epitopes recognized by antibodies elicited by natural infection.
The third aim will determine the functional domains in Pvs48/45 using fragments of the protein to identify protein domains involved in forming conformational epitopes of relevance to transmission. The development of the mAb reagents against Pvs48/45 will greatly aid in understanding the biology of the protein and assist in the development of a transmission blocking vaccine based on Pvs48/45 for P. vivax malaria. While the objectives of the proposed work may appear routine, the generation of these reagents and characterization of epitopes are critical for more significant gains as discussed above as well as use of mAbs with transmission blocking potential in developing and establishing a murine model based on transgenic parasites (which is outside the scope of this application).
The Pfs48/45 gametocyte surface protein in Plasmodium falciparum has been established as a potent transmission blocking antigen and vaccine candidate. Transmission blocking vaccines against malaria provide a complementing role along with other candidates as potential means of eliminating and/or eradicating the disease. Plasmodium vivax is prevalent in a greater portion of the world and is being increasingly recognized as causing severity of disease and mortality and it appears that the two Plasmodium species are distinct and cross protection has not been established. Reagents such as monoclonal antibodies are critical to develop a vaccine against Plasmodium vivax. Development of critical reagents is the major focus of this application.
| Cao, Yi; Hart, Robert J; Bansal, Geetha P et al. (2018) Functional Conservation of P48/45 Proteins in the Transmission Stages of Plasmodium vivax (Human Malaria Parasite) and P. berghei (Murine Malaria Parasite). MBio 9: |
