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40 Years of Pfs48/45 Research as a Transmission-Blocking Vaccine Target of Plasmodium falciparum Malaria
In the early 1980s, Richard Carter was among the first researchers to identify the sexual stage-specific Pfs48/45 protein, leading to the identification of target epitopes. Carter predicted its tertiary conformation while involved in a number of studies on naturally acquired sexual stage-specific antibodies. Pfs48/45 is a cysteine-rich surface protein of sexual stages of Plasmodium falciparum that plays a critical role in male gamete fertility. Antibodies against Pfs48/45 prevent parasite development in the mosquito vector, and therefore prevent the spread of malaria in the population. Since the gene was sequenced in the early 1990s, Pfs48/45 has been considered a prime target candidate for a malaria transmission-blocking vaccine. However, major manufacturing challenges—in particular, difficulty realizing satisfactory yields of a properly folded protein for the induction of functional antibodies—delayed clinical development significantly. These challenges were met roughly 20 years later. The first clinical trial with a Pfs48/45 subunit vaccine (R0.6C) was started in the Netherlands in early 2021. The excellent contributions to the long and winding path of Pfs48/45 research by Richard Carter are well recognized and are an integrated part of his seminal contributions to unraveling Plasmodium sexual stage biology.
Author Notes
Financial support: M. T. H. and J. L. P. were supported under a grant from the European and Developing Countries Clinical Trials Partnership (RIA2018SV-2311) for the continued development of R0.6C and ProC6C.
Authors’ addresses: Robert W. Sauerwein, TropIQ Health Sciences, Nijmegen, The Netherlands, E-mail: r.sauerwein@tropiq.nl. Jordan Plieskatt, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark, E-mail: jplieskatt@gmail.com. Michael Theisen, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark, and Centre for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark, E-mail: mth@ssi.dk.