Abstract
BackgroundRTS,S is the most advanced candidate malaria vaccine but it is only partially protective and the causes of inter-individual variation in efficacy are poorly understood. Here, we investigated whether peripheral blood monocyte-to-lymphocyte ratios (ML ratio), previously shown to correlate with clinical malaria risk, could account for differences in RTS,S efficacy among phase II trial participants in Africa.MethodsOf 11 geographical sites where RTS,S has been evaluated, pre-vaccination ML ratios were only available for trial participants in Kilifi, Kenya (N = 421) and Lambarene, Gabon (N = 189). Using time to first clinical malaria episode as the primary endpoint we evaluated the effect of accounting for ML ratio on RTS,S vaccine efficacy against clinical malaria by Cox regression modeling.ResultsThe unadjusted efficacy of RTS,S in this combined dataset was 47% (95% confidence interval (CI) 26% to 62%, P <0.001). However, RTS,S efficacy decreased with increasing ML ratio, ranging from 67% (95% CI 64% to 70%) at an ML ratio of 0.1 to 5% (95% CI -3% to 13%) at an ML ratio of 0.6. The statistical interaction between RTS,S vaccination and ML ratio was still evident after adjustment for covariates associated with clinical malaria risk in this dataset.ConclusionThe results suggest that stratification of study participants by ML ratio, easily measured from full differential blood counts before vaccination, might help identify children who are highly protected and those that are refractory to protection with the RTS,S vaccine. Identifying causes of low vaccine efficacy among individuals with high ML ratio could inform strategies to improve overall RTS,S vaccine efficacy.Trial registrationClinicalTrials.Gov numbers NCT00380393 and NCT00436007
Highlights
RTS,S is the most advanced candidate malaria vaccine but it is only partially protective and the causes of inter-individual variation in efficacy are poorly understood
We have previously shown that a high ratio of monocytes to lymphocytes (ML ratio) in peripheral blood at crosssectional survey correlates with increased susceptibility to clinical malaria in older children during follow-up [17]
The unadjusted efficacy of RTS,S against this primary endpoint of time to first clinical malaria episode in the combined dataset was 47%
Summary
RTS,S is the most advanced candidate malaria vaccine but it is only partially protective and the causes of inter-individual variation in efficacy are poorly understood. We investigated whether peripheral blood monocyte-to-lymphocyte ratios (ML ratio), previously shown to correlate with clinical malaria risk, could account for differences in RTS,S efficacy among phase II trial participants in Africa. We have previously shown that a high ratio of monocytes to lymphocytes (ML ratio) in peripheral blood at crosssectional survey correlates with increased susceptibility to clinical malaria in older children (median age 4.5 years) during follow-up [17]. This correlation between ML ratio and clinical malaria risk was evident even after accounting for inter-individual differences in the levels of antibody correlates of clinical immunity in the study population [17]. We here investigated whether ML ratio measured before vaccination could account for interindividual variation in RTS,S vaccine efficacy using published phase II data
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