Protection Against Marburg Virus Using a Recombinant VSV-Vaccine Depends on T and B Cell Activation

Abstract

Marburg virus (MARV) is the causative agent of hemorrhagic fever outbreaks with high case fatality rates. Closely related to Ebola virus, MARV is a filamentous virus with a negative-sense, single-stranded RNA genome. Although extensive studies on filovirus countermeasures have been conducted, there are no licensed treatments against MARV infections. An experimental vaccine based on the recombinant vesicular stomatitis virus (VSV) expressing the MARV-Musoke glycoprotein demonstrated complete protection when a single dose was administered 28 days and up to 14 months prior to MARV challenge. Here, we analyzed the protective efficacy of an updated vaccine expressing the MARV-Angola glycoprotein (VSV-MARV). A single dose of VSV-MARV given 5 weeks before challenge provided uniform protection with no detectable viremia. The vaccine induced B and T cell proliferation and, importantly, antigen-specific IgG production. Transcriptomic signatures confirm these findings and suggest innate immunity engendered by VSV-MARV may direct the development of protective humoral immunity.

Immune correlates of postexposure vaccine protection against Marburg virus

“…Survival data, viremia, clinical findings, and antibody titers for the untreated controls (N = 3), vector control (N = 1) and a cohort of ∆G-treated subjects (N = 4) were published previously ( Fig. S1b and (8,9), mild to moderate petechial rash (8,9,10,11), lymphopenia (6), ALT + (21) +++ (10,14), AST + (14) +++ (10), ALP ++ (10), GGT + (14,21) +++ (10), CRP increase (10), tPA ++ (10), PAI-1 ++ (14) +++ (10), factor IX + (3) ++ (21) +++ (6,10,14) 1600 (10), 800 (14), 200 (21), 100 (28) 100 6 (12,13,14), anorexia (12), mild to moderate petechial rash (13,14), mild dyspnea (14), lymphopenia (10), granulocytosis (10,14), thrombocytopenia (10,14), BUN ++ (14), CRE + (14), ALT + (10) +++ (14), AST ++ (10) +++ (14), ALP ++ (14), GGT + (14), CRP increase (10,14), p-selectin + (6), d-dimer + (6,10,14), tPA +++ (14), PAI-1 + (3) ++ (10) +++ (14), factor IX + (14) (6,10,14) 100 (6), 100 (10), 100…”

“…A single intramuscular (i.m.) injection of an rVSV expressing the Musoke variant GP (rVSV∆G/MARV-Musoke-GP; ~5e 7 plaque-forming units (PFU)) or Angola variant GP (rVSV∆G/MARV-Angola-GP; ~5e 7 PFU) was 100% effective in cynomolgus macaques against a 1000 PFU uniformly lethal MARV challenge when administered within 28 days before challenge 12,13 . A ~2e 7 PFU dose of the rVSV∆G/MARV-Musoke-GP vaccine also provided cross-protection against the Angola variant and related Ravn virus at the same challenge dose 14 .…”

“…While total antibody level against the GP is a reliable predictor of protection, neutralizing ability does not appear to be a necessity 12,14,[16][17][18][19][20] . In contrast, cellular responses are not considered critical according to the limited descriptions that exist [12][13][14]16,[18][19][20] . Early investigations of the rVSV-based immune mechanisms of protection against EBOV have primarily been examined via antibody-mediated immune cell depletion.…”

“…Paradoxically, transcriptomic analyses revealed a previously unrecognized role of T-cell immunity in rVSV vaccine protection against EBOV and MARV in the macaque model 13,22 . Likewise, results from clinical trials show rVSV immunization elicited GP-specific T helper cells and cytotoxic T-cell lymphocytes (CTLs) in human subjects 23 .…”

To B or Not to B: Mechanisms of Protection Conferred by rVSV-EBOV-GP and the Roles of Innate and Adaptive Immunity

“…Intramuscular vaccination with 10 million PFU of rVSV-EBOV-GP results in complete protection and no detectable viremia [ 56 , 61 ]. Although a large increase in the number of proliferating central and effector memory CD4 and CD8 T cells was noted 7–14 DPV, the frequencies of interferon (IFN)-γ-secreting EBOV-GP-specific T cells were low [ 61 , 101 ]. Increases in the frequencies of proliferating marginal-zone, antibody-producing B cells and memory B cells are also noted at 14–21 DPV, correlating with the increased levels of neutralizing and non-neutralizing EBOV-GP-specific IgG [ 61 ].…”