期刊
INFECTION AND IMMUNITY
卷 81, 期 2, 页码 441-451出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/IAI.01107-12
关键词
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资金
- Ramalingaswami fellowship
- TATA innovation fellowship
- Department of Biotechnology (DBT), Government of India
- Grand Challenges Exploration grant from the Bill and Melinda Gates Foundation
- Bill and Melinda Gates Foundation through the Grand Challenges Explorations Initiative [GCE OPP1007027]
- DBT, Government of India, through the Ramalingaswami fellowship program [BT/HRD/35/02/14/2008]
- Vaccine Grant Challenges Program [ND/DBT/12/040]
- Indo-Australia Biotechnology Fund [BT/PR12677/ICD/55/14/2009]
- European Commission [242095]
- DBT
- senior research fellowships of the Council of Scientific and Industrial Research, Government of India
- junior and senior research fellowships of DBT
- [BT/PR13376/GBD/27/260/2009]
- [BT/01/CEIB/11/V/01]
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.
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