411. Does an Early Cytokine Response During Ebola Virus Disease Improve the Duration of Survival in Rhesus Macaques?

Abstract

BackgroundEbola virus disease results in a severe cytokine release resulting in organ failure and disseminated intravascular coagulation, often leading to death. An early post-exposure immune response may improve outcomes but that remains poorly characterized. Therefore, we evaluated select serum cytokine markers of immune activation in nonhuman primates (NHPs) for their association with duration of survival.MethodsThis was a post-hoc analysis of an interventional supportive care NHP study in which 13 rhesus macaques were inoculated intramuscularly with a target dose of 1000 PFU Zaire ebolavirus (Kikwit). We measured cytokines with a Luminex MAGPIX panel at baseline and daily starting day 3 post-exposure until euthanasia. Based on human clinical data, 10 cytokines and proteins were included in our analysis: IL-1ra, IL-6, IL-10, GM-CSF, MCP-1, MIP-1α, MIP-1β, IFN-γ, TNF-α, and C-reactive protein levels. After NHPs were divided into two groups by k-means clustering, we developed Kaplan–Meier curves for time to death (Figure 1). We visually explored Pearson’s correlation and kinetics of serum cytokines and log10viral load (Figure 1; Figure 2). We fitted cox regression models with each cytokine to evaluate the risk of early disease for each cytokine log10 level or log2-fold change. We performed a sensitivity analysis for MIP-1β centering the data at dpe 0.ResultsAmong NHPs with temperature data, 83% (N = 10) developed fevers (>3 SD baseline) from dpe 3 to 4.The macrophage markerMIP-1β was associated with an increased risk of early death (per log10pg/mL increase, HR= 52.83 at dpe 3, adjusted P = 0.045). Surprisingly, this association was also observed at dpe 0 (HR= 36.88 at dpe 0, adjusted P = 0.044). Other cytokine levels or changes were not associated with an increased hazard of death.ConclusionOur findings did not support a role for early systemic cytokine release in improving survival. However, elevated baseline levels of the MIP-1β may predispose NHPs to early death from EVD. This finding could represent a target for therapeutic strategies and should be further researched. Disclosures All authors: No reported disclosures.