Targeting PTRAMP-CSS potently inhibits P. falciparum across blood, liver and mosquito stages

2026 · doi:10.64898/2026.05.10.724175
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This paper studied whether targeting the Plasmodium falciparum PTRAMP-CSS heterodimer, a component of the essential PCRCR invasion complex, can inhibit parasite invasion across the parasite’s liver, blood, and mosquito lifecycle stages. Using anti-PTRAMP-CSS nanobodies and supporting structural analyses, the authors found that inhibitory nanobodies blocked merozoite invasion of erythrocytes, reduced mosquito infection in membrane-feeding assays, and inhibited sporozoite invasion of primary human hepatocytes, with crystal structures identifying conserved inhibitory epitopes and informing bispecific Fc-construct design to improve potency. As a caveat, the functional and vaccine-relevant efficacy evidence is presented through in vitro/in vivo-relevant assay systems and associated semi-immune Kenyan CHMI antibody correlations rather than a single unified clinical outcome measure. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

Malaria, caused by Plasmodium falciparum spans liver, blood, and mosquito stages, limiting the effectiveness of single-stage vaccines. The PTRAMP-CSS heterodimer, a core component of the essential PCRCR invasion complex, is expressed on merozoites, mature gametocytes, and salivary gland sporozoites, enabling single-antigen targeting across multiple lifecycle stages. Nanobodies against PTRAMP-CSS block merozoite invasion of erythrocytes, reduce mosquito infection in membrane-feeding assays, and inhibit sporozoite invasion of primary human hepatocytes. High-resolution crystal structures of inhibitory and non-inhibitory nanobody-antigen complexes identify conserved inhibitory epitopes and guide the design of bispecific nanobody Fc constructs with enhanced potency. In semi-immune Kenyan CHMI samples, higher baseline IgG to PTRAMP-CSS and Ripr is associated with improved parasite control. By demonstrating conserved vulnerability across all three major lifecycle stages, PTRAMP-CSS offers a realistic path to single-antigen, multistage vaccines and biologics that aim to prevent disease and block transmission.
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Abstract Malaria, caused by Plasmodium falciparum spans liver, blood, and mosquito stages, limiting the effectiveness of single-stage vaccines. The PTRAMP-CSS heterodimer, a core component of the essential PCRCR invasion complex, is expressed on merozoites, mature gametocytes, and salivary gland sporozoites, enabling single-antigen targeting across multiple lifecycle stages. Nanobodies against PTRAMP-CSS block merozoite invasion of erythrocytes, reduce mosquito infection in membrane-feeding assays, and inhibit sporozoite invasion of primary human hepatocytes. High-resolution crystal structures of inhibitory and non-inhibitory nanobody-antigen complexes identify conserved inhibitory epitopes and guide the design of bispecific nanobody Fc constructs with enhanced potency. In semi-immune Kenyan CHMI samples, higher baseline IgG to PTRAMP-CSS and Ripr is associated with improved parasite control. By demonstrating conserved vulnerability across all three major lifecycle stages, PTRAMP-CSS offers a realistic path to single-antigen, multistage vaccines and biologics that aim to prevent disease and block transmission. Competing Interest Statement The authors have declared no competing interest.

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