Antibody targeting of a specific region of Pfs47 blocks Plasmodium falciparum malaria transmission

• Published in: npj vaccines 2018-07, Vol.3 (1), p.26-26, Article 26
• Main Authors: Canepa, Gaspar E., Molina-Cruz, Alvaro, Yenkoidiok-Douti, Lampouguin, Calvo, Eric, Williams, Adeline E., Burkhardt, Martin, Peng, Fangni, Narum, David, Boulanger, Martin J., Valenzuela, Jesus G., Barillas-Mury, Carolina
• Format: Article
• Language: English
• Subjects: 631/250/590; 631/326/590; Antigens; Biomedical and Life Sciences; Biomedicine; E coli; Immunoglobulins; Infectious Diseases; Malaria; Medical Microbiology; Mosquitoes; Proteins; Public Health; Vaccine; Vaccines; Virology
• ISSN: 2059-0105; 2059-0105
• DOI: 10.1038/s41541-018-0065-5

Transmission-blocking vaccines are based on eliciting antibody responses in the vertebrate host that disrupt parasite development in the mosquito vector and prevent malaria transmission. The surface protein Pfs47 is present in Plasmodium falciparum gametocytes and female gametes. The potential of Pfs47 as a vaccine target was evaluated. Soluble full-length recombinant protein, consisting of three domains, was expressed in E. coli as a thioredoxin fusion (T-Pfs47). The protein was immunogenic, and polyclonal and monoclonal antibodies (mAb) were obtained, but they did not confer transmission blocking activity (TBA). All fourteen mAb targeted either domains 1 or 3, but not domain 2 (D2), and immune reactivity to D2 was also very low in polyclonal mouse IgG after T-Pfs47 immunization. Disruption of the predicted disulfide bond in D2, by replacing cysteines for alanines (C230A and C260A), allowed expression of recombinant D2 protein in E. coli . A combination of mAbs targeting D2, and deletion proteins from this domain, allowed us to map a central 52 amino acid (aa) region where antibody binding confers strong TBA (78-99%). This 52 aa antigen is immunogenic and well conserved, with only seven haplotypes world-wide that share 96–98% identity. Neither human complement nor the mosquito complement-like system are required for the observed TBA. A dramatic reduction in ookinete numbers and ookinete-specific transcripts was observed, suggesting that the antibodies are interacting with female gametocytes and preventing fertilization. Malaria vaccines: Targeting transmission Transmission blocking activity (TBA) of malaria vaccines can potentially target parasite stages either within the human host or the mosquito vector. A team led by Carolina Barillas-Mury at the National Institutes of Health, USA, engineered a vaccine targeting the protein Pfs47 which is present mainly on the surface of Plasmodium falciparum gametocytes. Full-length Pfs47 elicits no TBA; however, an antigen based on a modified version of the central region of Pfs47’s domain 2 generates antibodies with potent TBA in mice. This TBA is independent of human complement or a mosquito complement-like system. Instead, such TBA antibodies likely function by interfering with female gametocytes and preventing fertilization. The Pfs47 region eliciting potent TBA is highly conserved in P. falciparum , suggesting the possibility of a broadly-effective vaccine or synergy with other vaccine target antigens.