Strain-specific Plasmodium falciparum growth inhibition among Malian children immunized with a blood-stage malaria vaccine

PLoS One. 2017 Mar 10;12(3):e0173294. doi: 10.1371/journal.pone.0173294. eCollection 2017.

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.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial

MeSH terms

  • Antigens, Protozoan / genetics
  • Antigens, Protozoan / immunology
  • Antigens, Protozoan / metabolism
  • Child
  • Erythrocytes / parasitology
  • Humans
  • Malaria Vaccines / immunology*
  • Malaria, Falciparum / parasitology
  • Malaria, Falciparum / prevention & control*
  • Mali
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism
  • Plasmodium falciparum / growth & development*
  • Plasmodium falciparum / immunology
  • Plasmodium falciparum / isolation & purification
  • Proportional Hazards Models
  • Protozoan Proteins / genetics
  • Protozoan Proteins / immunology
  • Protozoan Proteins / metabolism
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / immunology
  • Recombinant Proteins / isolation & purification

Substances

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

Associated data

  • ClinicalTrials.gov/NCT00460525

Grant support

Supported by a contract (N01AI85346) and a cooperative agreement (U19AI065683) from the National Institute of Allergy and Infectious Diseases, a grant (D43TW001589) from the Fogarty International Center, National Institutes of Health, and a contract (W81XWH-06-1-0427) from the Department of Defense and the U.S. Agency for International Development for site development and the conduct of the trial; by a contract (HHSN272200800013C) from the National Institute of Allergy and Infectious Diseases for data management and statistical support; by grants from the U.S. Agency for International Development and the Military Infectious Diseases Research Program, Fort Detrick, MD, for vaccine production and laboratory assays; and by the Doris Duke Charitable Foundation Distinguished Clinical Scientist Award and an award from the Howard Hughes Medical Institute (to Dr. Plowe). The funder provided support in the form of salaries for authors [ML, DC, BK, ID, AN, WCB, OD, CP, MT], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.