Immune correlates of postexposure vaccine protection against Marburg virus

Theresa E Latham,Chad E Mire,Demetrius Matassov,Thomas W Geisbert,Joan B Geisbert,John H Eldridge,Viktoriya Borisevich,Robert W Cross,Daniel J Deer,Courtney Woolsey,Karla A Fenton,Krystle N Agans,Allen Jankeel,Ilhem Messaoudi,Cheryl S Gerardi

doi:10.1038/s41598-020-59976-3

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.

Highlights

Postexposure immunization can prevent disease and reduce transmission following pathogen exposure
The ∆G vector expresses a Marburg virus (MARV)-Angola-GP from the site of the native Vesicular stomatitis virus (VSV) glycoprotein (G) gene, whereas the N2 vector expresses the MARV-Angola-GP from the first open reading frame
Provided Tregs negatively regulate immune and T-effector responses by upregulating inhibitory receptors, such as PD-1, lymphocyte activation gene 3 (LAG-3), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), we examined the expression of these immune checkpoint molecules[46]

Summary

Introduction

Postexposure immunization can prevent disease and reduce transmission following pathogen exposure. 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. Investigations of the rVSV-based immune mechanisms of protection against EBOV have primarily been examined via antibody-mediated immune cell depletion These studies revealed that CD4+ T-cell depletion during vaccination, unlike CD4+ depletion during challenge, rescinded production of GP-specific IgG and protection against a subsequent EBOV challenge[21]. CD8+ T-cells were dispensable against EBOV during rVSV vaccination indicating cellular responses are less essential mediators of rVSV-induced immunity These reports are based on protection following vaccination 28 days before challenge, not postexposure

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