Evaluating the impact of malaria on immunogenicity of the Ebola virus vaccine

PROJECT SUMMARY Plasmodium parasites, the causative agents of malaria, continue to be major drivers of infectious disease-related morbidity and mortality. Plasmodium evades sterilizing immunity in part by inducing proinflammatory changes that interfere with the orchestration of humoral immunity targeted towards parasite-specific antigens. This is seemingly not limited to parasite-specific immunity, as malaria can interfere with the efficacy of other routine vaccinations; the underlying mechanism of these impairments is poorly understood. Plasmodium parasites are endemic throughout Central and West Africa, regions in which highly pathogenic Zaire Ebola virus (EBOV) episodically causes outbreaks. An FDA-approved, live-attenuated, recombinant vaccine called ERVEBO stimulates antibody responses directed against the EBOV glycoprotein (GP) and has shown promise during EBOV outbreaks in Guinea in 2016 and Democratic Republic of the Congo (DRC) in 2019. Recent studies in the DRC suggest that current ring vaccination with ERVEBO can be highly porous; ~30% of EBOV-infected participants in a recent antiviral trial in the DRC were prior recipients of the vaccine. A possible explanation for this vaccine failure is acute Plasmodium infection of vaccine recipients at the time of vaccination, resulting in reduced immune responses to the vaccine. Utilizing experimental Plasmodium infection and clinically relevant vaccine administration strategies in a mouse model, my preliminary data show that mice that are parasitemic at time of vaccination exhibit dramatically reduced levels of EBOV GP-specific antibodies, reduced vaccine-induced germinal center (GC) formation in the draining lymph node (LN), and reduced vaccine load in the draining LN. These data inform our hypothesis that Plasmodium impairs multiple steps in the generation of a robust humoral response to ERVEBO, which will be tested through the following specific aims: 1) determining the underlying mechanistic impact of Plasmodium infection on ERVEBO-induced GC responses in the draining LN, and 2) determining the impacts of Plasmodium on antibody producing plasma cells and the functionality of EBOV GP- specific antibodies. Success of these studies will reveal mechanisms through which Plasmodium can impair ERVEBO vaccine responses and provide clinically actionable approaches to overcome this impairment. The experiences, techniques, mentoring, and concepts in this proposal were specifically tailored to Mr. Jonah Elliff and his training goals. As a developing researcher interested in improving strategies to treat and prevent severe infectious disease, Mr. Elliff is performing these studies through the Medical Scientist Training Program (MSTP) at University of Iowa under the scientific mentorship of Drs. Wendy Maury and Noah Butler, who provide individualized training at the intersection of virology, immunology, and vaccinology. Longer term plans for Mr. Elliff will be to complete his MSTP training and pursue a research residency in internal medicine, followed by an infectious disease fellowship, and ultimately a faculty position at an academic research center to continue investigating virus-host interactions and immune responses that control viral infections.