title: Identification of a potent combination of key Plasmodium falciparum merozoite antigens that elicit strain-transcending parasite-neutralizing antibodies.
abstract: Blood-stage malaria vaccines that target single Plasmodium falciparum antigens involved in erythrocyte invasion have not induced optimal protection in field trials. Blood-stage malaria vaccine development has faced two major hurdles, antigenic polymorphisms and molecular redundancy, which have led to an inability to demonstrate potent, strain-transcending, invasion-inhibitory antibodies. Vaccines that target multiple invasion-related parasite proteins may inhibit erythrocyte invasion more efficiently. Our approach is to develop a receptor-blocking blood-stage vaccine against P. falciparum that targets the erythrocyte binding domains of multiple parasite adhesins, blocking their interaction with their receptors and thus inhibiting erythrocyte invasion. However, with numerous invasion ligands, the challenge is to identify combinations that elicit potent strain-transcending invasion inhibition. We evaluated the invasion-inhibitory activities of 20 different triple combinations of antibodies mixed in vitro against a diverse set of six key merozoite ligands, including the novel ligands P. falciparum apical asparagine-rich protein (PfAARP), EBA-175 (PfF2), P. falciparum reticulocyte binding-like homologous protein 1 (PfRH1), PfRH2, PfRH4, and Plasmodium thrombospondin apical merozoite protein (PTRAMP), which are localized in different apical organelles and are translocated to the merozoite surface at different time points during invasion. They bind erythrocytes with different specificities and are thus involved in distinct invasion pathways. The antibody combination of EBA-175 (PfF2), PfRH2, and PfAARP produced the most efficacious strain-transcending inhibition of erythrocyte invasion against diverse P. falciparum clones. This potent antigen combination was selected for coimmunization as a mixture that induced balanced antibody responses against each antigen and inhibited erythrocyte invasion efficiently. We have thus demonstrated a novel two-step screening approach to identify a potent antigen combination that elicits strong strain-transcending invasion inhibition, supporting its development as a receptor-blocking malaria vaccine.
authors.affiliation: Malaria Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India.
authors.forename: Alok K
authors.initials: AK
authors.lastname: Pandey
authors.forename: K Sony
authors.initials: KS
authors.lastname: Reddy
authors.forename: Tajali
authors.initials: T
authors.lastname: Sahar
authors.forename: Sonal
authors.initials: S
authors.lastname: Gupta
authors.forename: Hina
authors.initials: H
authors.lastname: Singh
authors.forename: E Jyotheeswara
authors.initials: EJ
authors.lastname: Reddy
authors.forename: Mohd
authors.initials: M
authors.lastname: Asad
authors.forename: Faiza A
authors.initials: FA
authors.lastname: Siddiqui
authors.forename: Pankaj
authors.initials: P
authors.lastname: Gupta
authors.forename: Bijender
authors.initials: B
authors.lastname: Singh
authors.forename: Kunal R
authors.initials: KR
authors.lastname: More
authors.forename: Asif
authors.initials: A
authors.lastname: Mohmmed
authors.forename: Chetan E
authors.initials: CE
authors.lastname: Chitnis
authors.forename: Virander S
authors.initials: VS
authors.lastname: Chauhan
authors.forename: Deepak
authors.initials: D
authors.lastname: Gaur
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000913:Antibodies, Protozoan / Q000276:immunology; D000953:Antigens, Protozoan / Q000276:immunology*; D004912:Erythrocytes / Q000276:immunology / Q000469:parasitology; D006790:Host-Parasite Interactions / Q000276:immunology*; D008024:Ligands; D017780:Malaria Vaccines / Q000276:immunology*; D016778:Malaria, Falciparum / Q000276:immunology; D052940:Merozoites / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010963:Plasmodium falciparum / Q000276:immunology*; D011485:Protein Binding / Q000276:immunology; D054730:Protein Interaction Domains and Motifs / Q000276:immunology; D015800:Protozoan Proteins / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D008024:Ligands; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D011994:Recombinant Proteins