Potent antibody lineage against malaria transmission elicited by human vaccination with Pfs25

Brandon Mcleod,Stephen W Scally,Sebastian Rämisch,Jean-Philippe Julien,Colleen Woods,Dongkyoon Kim,William R Schief,Alexandre Bosch,C Richter King,Stephen Streatfield,Ngan Nguyen,Kazutoyo Miura,Hanjun Shin,Daniel Emerling,Wayne Volkmuth,Jessica A Chichester

doi:10.1038/s41467-019-11980-6

Abstract

Transmission-blocking vaccines have the potential to be key contributors to malaria elimination. Such vaccines elicit antibodies that inhibit parasites during their development in Anopheles mosquitoes, thus breaking the cycle of transmission. To date, characterization of humoral responses to Plasmodium falciparum transmission-blocking vaccine candidate Pfs25 has largely been conducted in pre-clinical models. Here, we present molecular analyses of human antibody responses generated in a clinical trial evaluating Pfs25 vaccination. From a collection of monoclonal antibodies with transmission-blocking activity, we identify the most potent transmission-blocking antibody yet described against Pfs25; 2544. The interactions of 2544 and three other antibodies with Pfs25 are analyzed by crystallography to understand structural requirements for elicitation of human transmission-blocking responses. Our analyses provide insights into Pfs25 immunogenicity and epitope potency, and detail an affinity maturation pathway for a potent transmission-blocking antibody in humans. Our findings can be employed to guide the design of improved malaria transmission-blocking vaccines.

Highlights

Transmission-blocking vaccines have the potential to be key contributors to malaria elimination
From a collection of monoclonal antibodies with transmission-blocking activity, we identify the most potent transmission-blocking antibody yet described against Pfs25; 2544
One of the most attractive transmission-blocking vaccines (TBVs) targets is Pfs[25], a glycophosphotidylinositol-linked protein expressed on the surface of ookinetes, which develop from the fertilized zygote[12,13]

Summary

Introduction

Transmission-blocking vaccines have the potential to be key contributors to malaria elimination. Our analyses provide insights into Pfs[25] immunogenicity and epitope potency, and detail an affinity maturation pathway for a potent transmission-blocking antibody in humans. We determine the co-crystal structures of four human antibodies bound to Pfs[25], and describe three novel protective epitopes on Pfs[25], including the most potent mAb yet described from any organism.

Results

Conclusion