Ndungu, F. M. | bioRxiv Science

bioRxiv2026

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

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.

microbiology↗

bioRxiv2020

Atypical B cells are a normal component of immune responses to vaccination and infection in humans

The full diversity of the circulating human B cell compartment is unknown. Flow cytometry analysis suggests that in addition to naive and memory B cells, there exists a population of CD11c+, CD27- CD21- "atypical" B cells, that are associated with chronic or recurrent infection and autoimmunity. We used single cell RNA-seq approaches to examine the diversity of both antigen-specific B cells and total B cells in healthy subjects and individuals naturally-exposed to recurrent malaria infections. This analysis revealed two B cell lineages: a classical lineage of activated and resting memory B cells, and an atypical-like lineage. Surprisingly, the atypical lineage was common in both malaria exposed individuals and non-exposed healthy controls. Using barcoded antibodies in conjunction with our transcriptomic data, we found that atypical lineage cells in healthy individuals lack many atypical B markers and thus represent an undercounted cryptic population. We further determined using antigen specific probes that atypical cells can be induced by primary vaccination in humans and can be recalled upon boosting. Collectively these data suggest that atypical cells are not necessarily pathogenic but can be a normal component of B responses to antigen.

immunology↗