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bioRxiv · 10.1101/2025.09.10.675493

Acute malaria dysregulates specialized lymph node macrophages to suppress vaccine-elicited protection against Ebola virus

Elliff, J.·Grady, L.·O'Donnell, K. L.·Messingham, C. O.·Rogers, K. J.·Akther, J.·Thurman, A.·Vijay, R.·Pezzulo, A. A.·Randall, T.·Marzi, A.·Butler, N.·Maury, W.
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Abstract

The filovirus, Ebola virus (EBOV), causes outbreaks of Ebola virus disease (EVD) throughout equatorial Africa. ERVEBO(R) (rVSV/EBOV) is a replication-competent, recombinant vesicular stomatitis virus (rVSV)-vectored vaccine licensed to control EVD outbreaks. EVD outbreaks occur in regions endemic for Plasmodium-caused malaria. Plasmodium infections persist due in part to the parasites ability to evade sterilizing immunity which also dampens immune responses to heterologous vaccines. Acute murine Plasmodium infection at the time of rVSV/EBOV vaccination reduced vaccine-mediated protection against mouse-adapted EBOV (ma-EBOV) challenge. Decreased protection was associated with a Plasmodium-induced interferon gamma (IFN-{gamma})-mediated decrease of rVSV/EBOV replication in lymph node (LN) macrophages, resulting in reduced primary anti-EBOV glycoprotein antibody responses. Higher doses of rVSV/EBOV partially overcame the antibody deficits and elicited protective responses. Evidence of the negative impact of Plasmodium on the efficacy of low dose rVSV/EBOV vaccine protocols supports the use of high antigen loads in effective management of EVD outbreaks. IMPORTANCEWe show that blood-stage murine Plasmodium infections negatively impacts the primary antibody response elicited by low dose rVSV/EBOV vaccination and results in reduced protection against a lethal dose of ma-EBOV. This defect occurs within the draining lymph node due to the elevation of IFN-{gamma} elicted in Py-infected mice. The Py-imposed decrease in vaccine-mediated protection can be overcome with higher doses of rVSV/EBOV. While the strong protection conferred by rVSV/EBOV and significant side effects known to be associated with this vaccine have led to the suggestion that the vaccine dosage be reduced19, our studies provide a rationale for maintaining a higher dose.

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Elliff, J., Grady, L., O'Donnell, K. L., Messingham, C. O., Rogers, K. J., Akther, J., Thurman, A., Vijay, R., Pezzulo, A. A., Randall, T., Marzi, A., Butler, N., Maury, W.. 2025-09-11. Acute malaria dysregulates specialized lymph node macrophages to suppress vaccine-elicited protection against Ebola virus. https://doi.org/10.1101/2025.09.10.675493

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