Paper

Development of an improved blood-stage malaria vaccine targeting the essential RH5-CyRPA-RIPR invasion complex

Mchugh, Kirsty, Draper, Simon J, Alanine, Daniel Gw, Illingworth, Joseph K, King, Crichter, Silk, Sarah E, Miura, Kazutoyo, Christen, Jayne M, Lyth, Oliver R, Li An Cowley, Noe, Amy R, Carnot, Cecilia, Long, Carole A, Ragotte, Robert J, Williams, Barnabas G, Soisson, Lorraine A, King, Lloyd Dw, Kotraiah, Vinayaka, Barfod, Lea, Quinker, Doris, Pattinson, David J, Pulido, David, Davies, Hannah, Shea, Michael W, Lias, Amlia M, Birkett, Ahsley J, Rigby, Cassandra A, Douglas, Alexander D, Jin, Jing, Dabbs, Rebecca A, Barrett, Jordan R, Skinner, Katherine, Macgill, Randall S, Higgins, Matthew K

2024

Overview

In recent years, reticulocyte-binding protein homologue 5 (RH5) has emerged as a leading blood-stage Plasmodium falciparum malaria vaccine antigen. The most advanced blood-stage vaccine candidate in a Phase 2b clinical trial, RH5.1/Matrix-M[TM], is based on a full-length soluble protein-with-adjuvant formulation. RH5 interacts with cysteine-rich protective antigen (CyRPA) and RH5-interacting protein (RIPR) to form an essential heterotrimeric RCR-complex. Here, we investigated whether a vaccine candidate based on the ternary RCR-complex could substantially improve upon the leading clinical candidate RH5.1/Matrix-M[TM] in preclinical studies. Using a panel of monoclonal antibodies (mAbs) we confirm that parasite growth-inhibitory epitopes on each antigen are exposed on the surface of the RCR-complex and that mAb pairs binding to different antigens can function additively or synergistically to mediate parasite growth inhibition activity (GIA) in vitro. However, immunisation of rats with the RCR-complex consistently fails to outperform RH5.1 alone. We show this is due to immuno-dominance of RIPR coupled with the inferior potency of anti-full length RIPR polyclonal IgG antibodies as compared to the anti-RH5 and anti-CyRPA response. To address this, we identified the growth-inhibitory antibody epitopes of RIPR are clustered within C-terminal EGF-like domains of RIPR. A fusion of these EGF domains to CyRPA, called R78C, combined with RH5.1, provided a new vaccination strategy that improves upon the levels of in vitro GIA seen with RH5.1 alone. Superiority of the combination antigen vaccine candidate was achieved by the induction of a quantitatively higher, but qualitatively similar, polyclonal antibody response that demonstrated additive GIA across the three antigen targets. These preclinical data justified the advancement of the RH5.1+R78C/Matrix-M[TM] combination vaccine to a Phase 1 clinical trial.Competing Interest StatementSJD is an inventor on patent applications relating to RH5 or RCR-complex malaria vaccines and antibodies and is a co-founder of and shareholder in SpyBiotech. AMM has an immediate family member who is an inventor on patent applications relating to RH5 or R78C malaria vaccines and antibodies and is a co-founder of and shareholder in SpyBiotech. BGW, LDWK, DP, DQ, AML, SES, JRB, KMc, DGWA, ADD, JJI, MKH are inventors on patent applications relating to RH5 and/or RCR-complex malaria vaccines and/or antibodies.JJ is an inventor on patent applications relating to vaccines made using spontaneous amide bond formation and is a co-founder of and shareholder in SpyBiotech. RAD is an inventor on patent applications relating to vaccines made using spontaneous amide bond formation and shareholder in SpyBiotech. All other authors have declared that no conflict of interest exists.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Antibodies / Antibody response / Antigens / Blood / Clinical trials / Epidermal growth factor / Epitopes / Immunization / Immunoglobulin G / Immunology / Inventors / Malaria / Monoclonal antibodies / Patent applications / Plasmodium falciparum / Polyclonal antibodies / Protective antigen / Proteins / Reticulocyte-binding protein / Stockholders / Vaccines