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Demonstration of the blood-stage Plasmodium falciparum controlled human malaria infection model to assess the efficacy of the P. falciparum membrane antigen 1 vaccine, FMP2.1/AS01

Demonstration of the blood-stage Plasmodium falciparum controlled human malaria infection model to assess the efficacy of the P. falciparum membrane antigen 1 vaccine, FMP2.1/AS01
Demonstration of the blood-stage Plasmodium falciparum controlled human malaria infection model to assess the efficacy of the P. falciparum membrane antigen 1 vaccine, FMP2.1/AS01
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 Trial Registration:?NCT02044198.
0022-1899
1-9
Payne, R.O.
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Milne, K.H.
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Elias, S.C.
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Edwards, N.J.
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Silk, S.E.
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Biswas, S.
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Hodgson, S.H.
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Labbe, G.M.
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Halstead, F.D.
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De Graaf, H.
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Sukhtankar, P.
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Williams, N.C.
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Ockenhouse, C.F.
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Waters, N.C.
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Soisson, L.A.
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Vekemans, J.
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Payne, R.O.
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Milne, K.H.
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Elias, S.C.
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Edwards, N.J.
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Douglas, A.D.
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Brown, R.E.
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Silk, S.E.
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Biswas, S.
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Miura, K.
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Roberts, R.
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Rampling, T.W.
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Venkataraman, N.
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Hodgson, S.H.
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Lawrie, A.M.
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Payne, R.O., Milne, K.H., Elias, S.C., Edwards, N.J., Douglas, A.D., Brown, R.E., Silk, S.E., Biswas, S., Miura, K., Roberts, R., Rampling, T.W., Venkataraman, N., Hodgson, S.H., Labbe, G.M., Halstead, F.D., Poulton, I.D., Nugent, F.L., De Graaf, H., Sukhtankar, P., Williams, N.C., Ockenhouse, C.F., Kathcart, A.K., Qabar, A.N., Waters, N.C., Soisson, L.A., Birkett, A.J., Cooke, G.S., Faust, S.N., Woods, C., Ivinson, K., McCarthy, J.S., Diggs, C.L., Vekemans, J., Long, C.A., Hill, A.V.S., Lawrie, A.M., Dutta, S. and Draper, S.J. (2016) Demonstration of the blood-stage Plasmodium falciparum controlled human malaria infection model to assess the efficacy of the P. falciparum membrane antigen 1 vaccine, FMP2.1/AS01. The Journal of Infectious Diseases, 1-9. (doi:10.1093/infdis/jiw039). (PMID:26908756)

Record type: Article

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 Trial Registration:?NCT02044198.

Full text not available from this repository.

More information

Accepted/In Press date: 21 January 2016
e-pub ahead of print date: 4 February 2016
Organisations: Faculty of Medicine

Identifiers

Local EPrints ID: 391300
URI: http://eprints.soton.ac.uk/id/eprint/391300
ISSN: 0022-1899
PURE UUID: d45ab3ee-8dca-4913-8cfc-bb88038caddc
ORCID for S.N. Faust: ORCID iD orcid.org/0000-0003-3410-7642

Catalogue record

Date deposited: 11 Apr 2016 12:58
Last modified: 18 Feb 2021 17:07

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Contributors

Author: R.O. Payne
Author: K.H. Milne
Author: S.C. Elias
Author: N.J. Edwards
Author: A.D. Douglas
Author: R.E. Brown
Author: S.E. Silk
Author: S. Biswas
Author: K. Miura
Author: R. Roberts
Author: T.W. Rampling
Author: N. Venkataraman
Author: S.H. Hodgson
Author: G.M. Labbe
Author: F.D. Halstead
Author: I.D. Poulton
Author: F.L. Nugent
Author: H. De Graaf
Author: P. Sukhtankar
Author: N.C. Williams
Author: C.F. Ockenhouse
Author: A.K. Kathcart
Author: A.N. Qabar
Author: N.C. Waters
Author: L.A. Soisson
Author: A.J. Birkett
Author: G.S. Cooke
Author: S.N. Faust ORCID iD
Author: C. Woods
Author: K. Ivinson
Author: J.S. McCarthy
Author: C.L. Diggs
Author: J. Vekemans
Author: C.A. Long
Author: A.V.S. Hill
Author: A.M. Lawrie
Author: S. Dutta
Author: S.J. Draper

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