Demonstration of the Blood-Stage Plasmodium falciparum Controlled Human Malaria Infection Model to Assess Efficacy of the P. falciparum Apical Membrane Antigen 1 Vaccine, FMP2.1/AS01

• Published in: The Journal of infectious diseases Vol. 213; no. 11; pp. 1743 - 1751
• Main Authors: Payne, Ruth O., Milne, Kathryn H., Elias, Sean C., Edwards, Nick J., Douglas, Alexander D., Brown, Rebecca E., Silk, Sarah E., Biswas, Sumi, Miura, Kazutoyo, Roberts, Rachel, Rampling, Thomas W., Venkatraman, Navin, Hodgson, Susanne H., Labbé, Geneviève M., Halstead, Fenella D., Poulton, Ian D., Nugent, Fay L., de Graaf, Hans, Sukhtankar, Priya, Williams, Nicola C., Ockenhouse, Christian F., Kathcart, April K., Qabar, Aziz N., Waters, Norman C., Soisson, Lorraine A., Birkett, Ashley J., Cooke, Graham S., Faust, Saul N., Woods, Colleen, Ivinson, Karen, McCarthy, James S., Diggs, Carter L., Vekemans, Johan, Long, Carole A., Hill, Adrian V. S., Lawrie, Alison M., Dutta, Sheetij, Draper, Simon J.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.06.2016
• Subjects: Adult; Antigens, Protozoan - immunology; Enzyme-Linked Immunospot Assay; Erythrocytes - parasitology; Female; Humans; Immunogenicity, Vaccine; Life Cycle Stages; Major and Brief Reports; Malaria Vaccines - immunology; Malaria, Falciparum - parasitology; Malaria, Falciparum - prevention & control; Male; Membrane Proteins - immunology; Middle Aged; Models, Biological; PARASITES; Plasmodium falciparum; Plasmodium falciparum - immunology; Plasmodium falciparum - physiology; Protozoan Proteins - immunology; Young Adult; AMA1; vaccine; blood stage; malaria; CHMI
• DOI: 10.1093/infdis/jiw039
• ISSN: 0022-1899

Background. Models of controlled human malaria infection (CHMI) initiated by mosquito bite have been widely used to assess efficacy of preerythrocytic vaccine candidates in small proof-of-concept phase 2a clinical trials. Efficacy testing of blood-stage malaria parasite vaccines, however, has generally relied on larger-scale phase 2b field trials in malaria-endemic populations. We report the use of a blood-stage P. falciparum CHMI model to assess blood-stage vaccine candidates, using their impact on the parasite multiplication rate (PMR) as the primary efficacy end point. Methods. Fifteen healthy United Kingdom adult volunteers were vaccinated with FMP2.1, a protein vaccine that is based on the 3D7 clone sequence of apical membrane antigen 1 (AMA1) and formulated in Adjuvant System 01 (AS01). Twelve vaccinees and 15 infectivity controls subsequently underwent blood-stage CHMI. Parasitemia was monitored by quantitative real-time polymerase chain reaction (PCR) analysis, and PMR was modeled from these data. Results. FMP2.1/AS01 elicited anti-AMA1 T-cell and serum antibody responses. Analysis of purified immunoglobulin G showed functional growth inhibitory activity against P. falciparum in vitro. There were no vaccine- or CHMI-related safety concerns. All volunteers developed blood-stage parasitemia, with no impact of the vaccine on PMR. Conclusions. FMP2.1/AS01 demonstrated no efficacy after blood-stage CHMI. However, the model induced highly reproducible infection in all volunteers and will accelerate proof-of-concept testing of future blood-stage vaccine candidates. Clinical Trials Registration. NCT02044198.