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.

Conflict of interest statement

Competing Interests: Dr. Ballou and Dr. Cohen report being employees of and owning shares in the GSK group of companies. Dr. Vekemans was an employee of the GSK group of companies at the time of study conduct. GSK did not play a role in data collection and analysis, or decision to publish, but the GSK authors did contribute to the study design and provided edits to the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Dr. Dutta and Dr. Lanar report being listed as inventors of patents covering the FMP 2.1 malaria vaccine candidate, which includes United States Patent numbers 7029685 and 7060276. No other potential conflict of interest relevant to this article was reported.

Figures

Fig 1. Mean 3D7 growth inhibition assay results by study day and group with 95% confidence intervals.

Fig 2. Mean FVO growth inhibition assay results by study day and group with 95% confidence intervals.