title: Strain-specific Plasmodium falciparum growth inhibition among Malian children immunized with a blood-stage malaria vaccine.
abstract: The blood-stage malaria vaccine FMP2.1/AS02A, comprised of recombinant Plasmodium falciparum apical membrane antigen 1 (AMA1) and the adjuvant system AS02A, had strain-specific efficacy against clinical malaria caused by P. falciparum with the vaccine strain 3D7 AMA1 sequence. To evaluate a potential correlate of protection, we measured the ability of participant sera to inhibit growth of 3D7 and FVO strains in vitro using high-throughput growth inhibition assay (GIA) testing. Sera from 400 children randomized to receive either malaria vaccine or a control rabies vaccine were assessed at baseline and over two annual malaria transmission seasons after immunization. Baseline GIA against vaccine strain 3D7 and FVO strain was similar in both groups, but more children in the malaria vaccine group than in the control group had 3D7 and FVO GIA activity ≥15% 30 days after the last vaccination (day 90) (49% vs. 16%, p<0.0001; and 71.8% vs. 60.4%, p = 0.02). From baseline to day 90, 3D7 GIA in the vaccine group was 7.4 times the mean increase in the control group (p<0.0001). In AMA1 vaccinees, 3D7 GIA activity subsequently returned to baseline one year after vaccination (day 364) and did not correlate with efficacy in the extended efficacy time period to day 730. In Cox proportional hazards regression models with time-varying covariates, there was a slight suggestion of an association between 3D7 GIA activity and increased risk of clinical malaria between day 90 and day 240. We conclude that vaccination with this AMA1-based malaria vaccine increased inhibition of parasite growth, but this increase was not associated with allele-specific efficacy in the first malaria season. These results provide a framework for testing functional immune correlates of protection against clinical malaria in field trials, and will help to guide similar analyses for next-generation malaria vaccines. Clinical trials registry: This clinical trial was registered on clinicaltrials.gov, registry number NCT00460525.
authors.affiliation: Division of Malaria Research, Institute for Global Health, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Matthew B
authors.identifier: http://orcid.org/0000-0003-3874-581X
authors.initials: MB
authors.lastname: Laurens
authors.affiliation: Malaria Research and Training Center, Bamako, Mali.
authors.forename: Bourema
authors.initials: B
authors.lastname: Kouriba
authors.affiliation: U.S. Military Malaria Vaccine Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Elke
authors.initials: E
authors.lastname: Bergmann-Leitner
authors.affiliation: U.S. Military Malaria Vaccine Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Evelina
authors.initials: E
authors.lastname: Angov
authors.affiliation: Malaria Research and Training Center, Bamako, Mali.
authors.forename: Drissa
authors.initials: D
authors.lastname: Coulibaly
authors.affiliation: Malaria Research and Training Center, Bamako, Mali.
authors.forename: Issa
authors.initials: I
authors.lastname: Diarra
authors.affiliation: Malaria Research and Training Center, Bamako, Mali.
authors.forename: Modibo
authors.initials: M
authors.lastname: Daou
authors.affiliation: Malaria Research and Training Center, Bamako, Mali.
authors.forename: Amadou
authors.initials: A
authors.lastname: Niangaly
authors.affiliation: Division of Malaria Research, Institute for Global Health, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: William C
authors.initials: WC
authors.lastname: Blackwelder
authors.affiliation: Division of Malaria Research, Institute for Global Health, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Yukun
authors.initials: Y
authors.lastname: Wu
authors.affiliation: GSK Vaccines, Rixensart, Belgium.
authors.forename: Joe
authors.initials: J
authors.lastname: Cohen
authors.affiliation: GSK Vaccines, Rixensart, Belgium.
authors.forename: W Ripley
authors.initials: WR
authors.lastname: Ballou
authors.affiliation: GSK Vaccines, Rixensart, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Vekemans
authors.affiliation: U.S. Military Malaria Vaccine Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: David E
authors.initials: DE
authors.lastname: Lanar
authors.affiliation: U.S. Military Malaria Vaccine Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Sheetij
authors.initials: S
authors.lastname: Dutta
authors.affiliation: Malaria Vaccine Development Program, U.S. Agency for International Development, Washington, DC, United States of America.
authors.forename: Carter
authors.initials: C
authors.lastname: Diggs
authors.affiliation: Malaria Vaccine Development Program, U.S. Agency for International Development, Washington, DC, United States of America.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Soisson
authors.affiliation: U.S. Military Malaria Vaccine Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: D Gray
authors.initials: DG
authors.lastname: Heppner
authors.affiliation: Malaria Research and Training Center, Bamako, Mali.
authors.forename: Ogobara K
authors.initials: OK
authors.lastname: Doumbo
authors.affiliation: Division of Malaria Research, Institute for Global Health, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Plowe
authors.affiliation: Malaria Research and Training Center, Bamako, Mali.
authors.forename: Mahamadou A
authors.initials: MA
authors.lastname: Thera
mesh_terms: D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002648:Child; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D017780:Malaria Vaccines / Q000276:immunology*; D016778:Malaria, Falciparum / Q000469:parasitology / Q000517:prevention & control*; D008302:Mali; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010963:Plasmodium falciparum / Q000254:growth & development* / Q000276:immunology / Q000302:isolation & purification; D016016:Proportional Hazards Models; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000276:immunology / Q000302:isolation & purification
chemical_list: D000953:Antigens, Protozoan; D017780:Malaria Vaccines; D008565:Membrane Proteins; D015800:Protozoan Proteins; D011994:Recombinant Proteins; C090077:apical membrane antigen I, Plasmodium