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.

Abstract

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.

• Authors: Ruth O Payne, Kathryn H Milne, Sean C Elias, Nick J Edwards, Alexander D Douglas, Rebecca E Brown, Sarah E Silk, Sumi Biswas, Kazutoyo Miura, Rachel Roberts, Thomas W Rampling, Navin Venkatraman, Susanne H Hodgson, Geneviève M Labbé, Fenella D Halstead, Ian D Poulton, Fay L Nugent, Hans de Graaf, Priya Sukhtankar, Nicola C Williams, Christian F Ockenhouse, April K Kathcart, Aziz N Qabar, Norman C Waters, Lorraine A Soisson, Ashley J Birkett, Graham S Cooke, Saul N Faust, Colleen Woods, Karen Ivinson, James S McCarthy, Carter L Diggs, Johan Vekemans, Carole A Long, Adrian V S Hill, Alison M Lawrie, Sheetij Dutta, Simon J Draper
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 213 Issue 11 Pg. 1743-51 (Jun 01 2016) ISSN: 1537-6613 [Electronic] United States
• PMID: 26908756 (Publication Type: Clinical Trial, Journal Article)
• Copyright: © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail [email protected].

Chemical References

• Antigens, Protozoan
• Malaria Vaccines
• Membrane Proteins
• Protozoan Proteins
• apical membrane antigen I, Plasmodium

Topics

• Adult
• Antigens, Protozoan (immunology)
• Enzyme-Linked Immunospot Assay
• Erythrocytes (parasitology)
• Female
• Humans
• Immunogenicity, Vaccine
• Life Cycle Stages
• Malaria Vaccines (immunology)
• Malaria, Falciparum (parasitology, prevention & control)
• Male
• Membrane Proteins (immunology)
• Middle Aged
• Models, Biological
• Plasmodium falciparum (immunology, physiology)
• Protozoan Proteins (immunology)
• Young Adult