Cytokines associated with moderate and severe adverse events during a controlled human malaria infection trial

Background: Ensuring the safety and efficacy of candidate vaccines is critical. Although mechanisms underpinning protective immune responses to malaria vaccines are frequently investigated, immune responses correlating with moderate and severe adverse events (AEs) have not been examined.Methods: In order to determine which cytokines were associated with moderate and severe AEs, we measured the concentration of 41 different cytokines in serum samples from multiple participants at different timepoints throughout the trial. Each measurement was then assigned to a clinical group depending on if the individual was experiencing an AE and/or if they had evidence of parasitemia at the time of the measurement (e.g. None, AE without Parasitemia, Parasitemia without AE, or Parasitemia with AE). We then performed Principal Component Analysis, individual univariate cytokine comparisons using Wilcoxon rank sum tests, and a mixed effects logistic regression to determine if cytokine profiles varied across these clinical groups.

Results: The Principal Component Analysis revealed that observations clustered based on similarity in cytokine signatures and that the principal components were associated with both AEs and parasitemia. We also found that Interleukin (IL)-6 was elevated in individuals with Parasitemia with AE but not Parasitemia without AE in both the univariate comparisons and the mixed effects logistic regression. Multiple other cytokines were associated with Parasitemia without AE and Parasitemia with AE (e.g. Interferon gamma-inducible protein (IP)-10, Macrophage inflammatory protein (MIP)-1a, Tumor necrosis factor (TNF)-Ã ).

Conclusions: This is the first study to characterize real-time cytokine profiles associated with moderate and severe AEs in a human vaccine candidate trial. More research on immune responses associated with moderate and severe AEs, the mechanisms underpinning these immune responses, and their relationship to vaccine efficacy is warranted.