# Nanobody-mediated targeting of Plasmodium falciparum PfPIMMS43 can block malaria transmission in mosquitoes

## TL;DR

Scientists developed nanobodies that target a key malaria parasite protein, reducing mosquito infection and proposing gene drive mosquitoes to spread this trait for malaria elimination.

## Contribution

High-affinity nanobodies targeting PfPIMMS43 are developed and shown to block malaria transmission in mosquitoes.

## Key findings

- Nanobodies bind PfPIMMS43 and reduce infection in Anopheles mosquitoes.
- Epitopes are conserved and accessible in PfPIMMS43.
- Gene drive mosquitoes expressing nanobodies could block malaria transmission.

## Abstract

The transition from ookinete to oocyst is a critical step in the Plasmodium falciparum lifecycle and an important target for malaria transmission-blocking strategies. PfPIMMS43, a surface protein of P. falciparum ookinetes and sporozoites, is critical for this transition and aids the parasite in evading mosquito immune responses. Previous studies demonstrated that polyclonal PfPIMMS43 antibodies reduced P. falciparum infection in Anopheles mosquitoes. Here, building on these findings, we have developed high-affinity single-domain VHH antibodies (nanobodies) derived from llama heavy-chain-only antibodies. We have shown that these nanobodies bind both recombinant and endogenous PfPIMMS43 produced by P. falciparum ookinetes in the mosquito midgut. Importantly, they significantly reduce infection intensity and prevalence of laboratory and field strains of P. falciparum in An. coluzzii and An. gambiae, respectively. Epitope mapping has revealed that the nanobodies target conserved regions in the second half of PfPIMMS43, with homology modelling confirming epitope accessibility. These findings establish PfPIMMS43 as a promising transmission-blocking target. To enhance malaria control and elimination efforts, we propose an innovative strategy in which genetically modified mosquitoes express PfPIMMS43-specific nanobodies in their midguts and spread this trait in wild mosquito populations via gene drive technology.

Nanobodies targeting the ookinete and sporozoite surface protein PIMMS43 block mosquito infection by African Plasmodium falciparum field isolates. Gene drive mosquitoes expressing these nanobodies could be deployed to eliminate malaria transmission.