Immune correlates of postexposure vaccine protection against Marburg virus

Abstract

Postexposure immunization can prevent disease and reduce transmission following pathogen exposure. The rapid immunostimulatory properties of recombinant vesicular stomatitis virus (rVSV)-based vaccines make them suitable postexposure treatments against the filoviruses Ebola virus and Marburg virus (MARV); however, the mechanisms that drive this protection are undefined. Previously, we reported 60-75% survival of rhesus macaques treated with rVSV vectors expressing MARV glycoprotein (GP) 20-30 minutes after a low dose exposure to the most pathogenic variant of MARV, Angola. Survival in this model was linked to production of GP-specific antibodies and lower viral load. To confirm these results and potentially identify novel correlates of postexposure protection, we performed a similar experiment, but analyzed plasma cytokine levels, frequencies of immune cell subsets, and the transcriptional response to infection in peripheral blood. In surviving macaques (80-89%), we observed induction of genes mapping to antiviral and interferon-related pathways early after treatment and a higher percentage of T helper 1 (Th1) and NK cells. In contrast, the response of non-surviving macaques was characterized by hypercytokinemia; a T helper 2 signature; recruitment of low HLA-DR expressing monocytes and regulatory T-cells; and transcription of immune checkpoint (e.g., PD-1, LAG3) genes. These results suggest dysregulated immunoregulation is associated with poor prognosis, whereas early innate signaling and Th1-skewed immunity are important for survival. Members of the genera Marburgvirus (MARV) and Ebolavirus (EBOV) are pathogens in the family Filoviridae that cause a similar life-threatening hemorrhagic disease in humans and non-human primates (NHPs) 1. More than 30,000 people have been infected with EBOV, whereas 469 cumulative cases and 376 recorded deaths are attributed to Marburg virus disease (MVD) 2-4. Although fewer cases are recorded for MARV, future outbreaks and spread of the virus into non-endemic regions are of great concern. MVD has an overall mortality rate of 81% and imported cases have occurred in Germany, the former Yugoslavia (presently Serbia), the Netherlands, and the United States 1-4. Moreover, the Egyptian fruit bat host reservoir has a wide geographic distribution 5. While MARV is thought to be limited to equatorial Africa, a research group that surveyed a large South African bat colony found that ~53% of these animals were seropositive for the virus, and recently MARV was isolated from bats in West Africa for the first time 6,7. Surveillance in the latter region also revealed serological evidence of filoviruses (MARV and EBOV) circulating in human subjects prior to the 2013-2016 EBOV outbreak 8,9. The likelihood of spillover events and spread into human populations emphasizes the need for adequate countermeasures against this deadly virus. One of the most promising vaccine candidates against MARV and EBOV uses a live, attenuated recombinant vesicular stomatitis virus (rVSV) platform to express filovirus ...

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