Abstract
Proteins Pfs230 and Pfs48/45 are Plasmodium falciparum transmission-blocking (TB) vaccine candidates that form a membrane-bound protein complex on gametes. The biological role of Pfs230 or the Pfs230-Pfs48/45 complex remains poorly understood. Here, we present the crystal structure of recombinant Pfs230 domain 1 (Pfs230D1M), a 6-cysteine domain, in complex with the Fab fragment of a TB monoclonal antibody (mAb) 4F12. We observed the arrangement of Pfs230 on the surface of macrogametes differed from that on microgametes, and that Pfs230, with no known membrane anchor, may exist on the membrane surface in the absence of Pfs48/45. 4F12 appears to sterically interfere with Pfs230 function. Combining mAbs against different epitopes of Pfs230D1 or of Pfs230D1 and Pfs48/45, significantly increased TB activity. These studies elucidate a mechanism of action of the Pfs230D1 vaccine, model the functional activity induced by a polyclonal antibody response and support the development of TB vaccines targeting Pfs230D1 and Pfs230D1-Pfs48/45.
Highlights
Proteins Pfs[230] and Pfs48/45 are Plasmodium falciparum transmission-blocking (TB) vaccine candidates that form a membrane-bound protein complex on gametes
Pfs25-ExoProtein A (EPA) conjugates formulated with AlhydrogelTM, an aluminum based adjuvant, in phase 1 trials conducted in the United States[11] and in Mali, West Africa[12] have required four doses to generate antibody titers that significantly reduced parasite transmission as assessed by an ex vivo standard membrane feeding assay (SMFA)[11,12]
We previously reported that the monoclonal antibody (mAb) 4F12 (Fig. 1), which recognizes a conformational epitope within Pfs230D1, blocked or reduced parasite transmission in the SMFA assay[16]
Summary
Proteins Pfs[230] and Pfs48/45 are Plasmodium falciparum transmission-blocking (TB) vaccine candidates that form a membrane-bound protein complex on gametes. Combining mAbs against different epitopes of Pfs230D1 or of Pfs230D1 and Pfs48/45, significantly increased TB activity These studies elucidate a mechanism of action of the Pfs230D1 vaccine, model the functional activity induced by a polyclonal antibody response and support the development of TB vaccines targeting Pfs230D1 and Pfs230D1-Pfs48/45. Efforts to develop a vaccine that disrupts mosquito infection, known as a malaria transmission-blocking (TB) vaccine, have been ongoing since the reporting of induced TB immunity in chickens against Plasmodium gallinaceum in 19766. Pfs25-EPA conjugates formulated with AlhydrogelTM, an aluminum based adjuvant, in phase 1 trials conducted in the United States[11] and in Mali, West Africa[12] have required four doses to generate antibody titers that significantly reduced parasite transmission as assessed by an ex vivo standard membrane feeding assay (SMFA)[11,12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
