{"doi":"10.1101/2024.02.08.579322","title":"Development of an improved blood-stage malaria vaccine targeting the essential RH5-CyRPA-RIPR invasion complex","abstract":"ABSTRACT 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™, 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™ 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™ combination vaccine to a Phase 1 clinical trial.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":489964,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.957,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":734432,"name":"Lloyd D. W. King","orcid":null,"position":1,"is_corresponding":false},{"id":626106,"name":"David Pulido","orcid":"0000-0003-3422-0434","position":2,"is_corresponding":false},{"id":626100,"name":"Doris Quinkert","orcid":"0000-0003-4135-6452","position":3,"is_corresponding":false},{"id":1036105,"name":"Amelia M. Lias","orcid":"0000-0003-2939-7761","position":4,"is_corresponding":false},{"id":251516,"name":"Sarah E. Silk","orcid":"0000-0003-0563-4814","position":5,"is_corresponding":false},{"id":838651,"name":"Robert J. Ragotte","orcid":"0000-0002-6463-1595","position":6,"is_corresponding":false},{"id":1162401,"name":"H. Dele Davies","orcid":"0000-0002-2917-9062","position":7,"is_corresponding":false},{"id":626095,"name":"Jordan R. Barrett","orcid":"0000-0003-0746-1945","position":8,"is_corresponding":false},{"id":1162404,"name":"Kirsty McHugh","orcid":"0000-0002-5411-7883","position":9,"is_corresponding":false},{"id":1162882,"name":"Cassandra A. Rigby","orcid":null,"position":10,"is_corresponding":false},{"id":734433,"name":"Daniel G. W. Alanine","orcid":null,"position":11,"is_corresponding":false},{"id":626102,"name":"Lea Barfod","orcid":"0000-0001-6510-495X","position":12,"is_corresponding":false},{"id":1212764,"name":"Michael W. Shea","orcid":null,"position":13,"is_corresponding":false},{"id":1212204,"name":"Li An Cowley","orcid":"0000-0002-5468-1820","position":14,"is_corresponding":false},{"id":467983,"name":"Rebecca A. Dabbs","orcid":"0000-0001-6227-7329","position":15,"is_corresponding":false},{"id":1212205,"name":"David J. Pattinson","orcid":"0000-0003-0806-6832","position":16,"is_corresponding":false},{"id":626107,"name":"Alexander D. Douglas","orcid":"0000-0002-5410-7562","position":17,"is_corresponding":false},{"id":1212765,"name":"Oliver Lyth","orcid":null,"position":18,"is_corresponding":false},{"id":1212766,"name":"Joseph J. Illingworth","orcid":null,"position":19,"is_corresponding":false},{"id":467984,"name":"Jing Jin","orcid":"0000-0002-3250-9173","position":20,"is_corresponding":false},{"id":1207515,"name":"Cecilia Carnrot","orcid":"0009-0000-3495-8119","position":21,"is_corresponding":false},{"id":253145,"name":"Vinayaka Kotraiah","orcid":null,"position":22,"is_corresponding":false},{"id":196246,"name":"Jayne M. Christen","orcid":null,"position":23,"is_corresponding":false},{"id":251514,"name":"Amy R. Noe","orcid":"0000-0002-5230-9742","position":24,"is_corresponding":false},{"id":860981,"name":"Randall S. MacGill","orcid":"0000-0002-4566-1481","position":25,"is_corresponding":false},{"id":414016,"name":"C. Richter King","orcid":"0000-0002-8860-0419","position":26,"is_corresponding":false},{"id":612955,"name":"Ashley J. 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Williams","orcid":"0000-0002-3078-8076","position":0,"is_corresponding":true}],"reference_count":61,"raw_metadata":null,"created_at":"2026-07-19T02:08:32.775003Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}