# Structure-guided design of a PfCyRPA-based vaccine against blood-stage malaria

## TL;DR

Researchers designed a new malaria vaccine candidate based on PfCyRPA that better elicits antibodies to block parasite growth.

## Contribution

A structure-guided, thermostable PfCyRPA-based immunogen (PfCyRPA-EM) was developed to elicit stronger growth-inhibitory antibodies.

## Key findings

- PfCyRPA-EM elicited antibodies that inhibited parasite growth more effectively than PfCyRPA.
- PfCyRPA-EM is more thermostable and easier to produce than PfCyRPA.
- The immunogen presents epitopes for growth-inhibitory antibodies using blades 1 and 2 of PfCyRPA.

## Abstract

Effective vaccines against malaria are urgently required. All components of the PfPCRCR complex are essential for erythrocyte invasion by Plasmodium falciparum and are potential vaccine immunogens against blood-stage malaria. Of these, PfRH5 has progressed furthest in clinical development, while PfCyRPA also induces parasite growth-inhibitory antibodies. Here, we used direct nanoparticle coupling and structure-guided design to generate improved PfCyRPA-based immunogens. PfCyRPA is a six-bladed β-propeller. Blades 1 and 2 are exposed in the PfPCRCR complex and contain the epitopes of the most potent known growth-inhibitory antibodies. We therefore performed structure-guided design to generate a correctly folded, thermostable epitope mimic, PfCyRPA-EM, containing blades 1 and 2. In a pre-clinical model, PfCyRPA-EM elicited antibodies that inhibited parasite growth at lower concentrations than those elicited by PfCyRPA. In addition, the higher thermostability of PfCyRPA-EM and its improved expression as an I53-50 nanoparticle fusion make it well-suited for clinical development, alone or with other immunogens.

PfCyRPA is required for the malaria parasite, Plasmodium falciparum, to enter blood cells and replicate. Structure-guided, rational immunogen design has been used to produce a novel PfCyRPA-based immunogen which specifically presents the epitopes for growth-inhibitory antibodies.

The most growth-inhibitory PfCyRPA-binding human monoclonal antibodies bind two blades of the β-propeller structure of PfCyRPA.Structure-guided design resulted in a synthetic immunogen, PfCyPRA-EM, which recapitulates the epitopes of growth-inhibitory antibodies.PfCyRPA-EM expresses to high levels, is easier to produce and is more stable than PfCyRPA.Immunisation with PfCyRPA-EM elicits a high-quality growth-inhibitory antibody response.

The most growth-inhibitory PfCyRPA-binding human monoclonal antibodies bind two blades of the β-propeller structure of PfCyRPA.

Structure-guided design resulted in a synthetic immunogen, PfCyPRA-EM, which recapitulates the epitopes of growth-inhibitory antibodies.

PfCyRPA-EM expresses to high levels, is easier to produce and is more stable than PfCyRPA.

Immunisation with PfCyRPA-EM elicits a high-quality growth-inhibitory antibody response.

PfCyRPA is required for the malaria parasite, Plasmodium falciparum, to enter blood cells and replicate. Structure-guided, rational immunogen design has been used to produce a novel PfCyRPA-based immunogen which specifically presents the epitopes for growth-inhibitory antibodies.