Defining molecular and cellular mechanisms of protection from malaria infection by PfCSP-targeting antibodies

Malaria is a globally devastating, mosquito-borne disease which infects hundreds of millions of people each year, resulting in ~435,000 deaths. The continual emergence of resistance to frontline antimalarials, due to the considerable genetic plasticity of the malaria parasite P. falciparum, has made development of a highly effective malaria vaccine an important part of the global eradication campaign. However, efforts to date have been largely unsuccessful, likely owing to the extraordinarily high threshold for protection. Thus in order to develop a vaccine which confers both robust and durable immunity, it is necessary to understand both the immune mechanisms required to induce a protective response, and the mechanisms by which this response confers protection. The humoral immune response to malaria parasites is dominated by antibodies (Abs) against the central repeat region of an intrinsically disordered P. falciparum surface protein PfCSP, and a small percentage of these repeat- targeting Abs confer potent, sterile protection in animal models. 

To achieve this, this proposal outlines an interdisciplinary approach utilizing in vivo protection assays and a synthesis of low and high resolution light and electron microscopy. These experiments will test the overall hypothesis that protective PfCSP repeat-targeting Abs induce a structural phenotype on PfCSP which is both correlated with and underlies the mechanism of protection. I have solved a number of high-resolution cryo-EM structures of protective Abs bound to PfCSP, which form multivalent helical structures stabilized by affinity-matured Ab-Ab contacts. 

Overall, these experiments will greatly enhance our understanding the mechanism by which Abs protect from malaria infection, and may revolutionize our understanding of basic P. falciparum biology. This work will also inform rational vaccine design by uncovering novel, and more precise correlates of Ab-mediated inhibition and protection.

NIH project details

Enabling Technologies & Assays
Vaccines (Immune Correlates)

Jun 2021 — Jun 2022

$66,390

United States