Abstract
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.
Highlights
Malaria, a life-threatening disease caused by Plasmodium parasites, is transmitted by anopheline mosquitoes
The global malaria mortality rate decreased by 48% between 2000–2015, with an estimated 4.2 million lives saved as a result of scale-up of malaria control interventions, there were still 212 million new cases and an estimated 429,000 malaria-related deaths in 2015.1 These gains are threatened as Plasmodium parasites around the world exhibit growing resistance to anti-malarial drugs and as mosquitoes become resistant to insecticides.[1]
We explored the potential of Pfs[47] as vaccine target, and used a combination of polyclonal and monoclonal antibodies (mAb) and protein deletions to search for targets to block P. falciparum infection in A. gambiae mosquitoes
Summary
A life-threatening disease caused by Plasmodium parasites, is transmitted by anopheline mosquitoes. These antibodies interact with proteins present on the surface of sexual and sporogonic stages of Plasmodium or on the surface of the mosquito midgut, and disrupt molecular interactions, such as fertilization, critical for malaria transmission.[3] Pre-clinical studies led to the development of several P. falciparum transmissionblocking vaccine candidates, of which Pfs[230], Pfs[25], and Pfs48/45 are the best characterized antigens.[4] Pfs[25] protein, expressed on the surface of female gametes in the mosquito midgut, persists throughout the zygote, ookinete, and early oocyst stages.[5] Pfs[230] and Pfs48/45, members of the 6-cysteine family of proteins, are expressed on the surface of both male and female gametocytes in
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