Rapid protection of nonhuman primates against Marburg virus disease using a single low-dose VSV-based vaccine.

BACKGROUND: Marburg virus (MARV) is the causative agent of Marburg virus disease (MVD) which has a case fatality rate up to ∼90% in humans. Recently, there were cases reported in Guinea and Ghana highlighting this virus as a high-consequence pathogen potentially threatening global public health. There are no licensed treatments or vaccines available today. We used a vesicular stomatitis virus (VSV)-based vaccine expressing the MARV-Angola glycoprotein (VSV-MARV) as the viral antigen. Previously, a single dose of 1 × 107 plaque-forming units (PFU) administered 7 days before challenge resulted in uniform protection from disease in cynomolgus macaques. METHODS: As we sought to lower the vaccination dose to achieve a higher number of vaccine doses per vial, we administered 1 × 105 or 1 × 103 PFU 14 days or 1 × 103 PFU 7 days before challenge to cohorts of cynomolgus macaques and investigated immunity as well as protective efficacy. RESULTS: Vaccination resulted in uniform protection with no detectable viremia. Antigen-specific IgG responses were induced by both vaccine concentrations and were sustained until the study endpoint. Neutralizing antibody responses and antibody-dependent cellular phagocytosis were observed. The cellular response after vaccination was characterized by an early induction of NK cell activation. Additionally, antigen-specific memory T cell subsets were detected in all vaccination cohorts indicating that while the primary protective mechanism of VSV-MARV is the humoral response, a functional cellular response is also induced. INTERPRETATION: Overall, this data highlights VSV-MARV as a viable and fast-acting MARV vaccine candidate suitable for deployment in emergency outbreak situations and supports its clinical development. FUNDING: This work was funded by the Intramural Research Program NIAID, NIH.

Single Dose of a VSV-Based Vaccine Rapidly Protects Macaques From Marburg Virus Disease.

Marburg virus (MARV) is a member of the filovirus family that causes hemorrhagic disease with high case fatality rates. MARV is on the priority list of the World Health Organization for countermeasure development highlighting its potential impact on global public health. We developed a vesicular stomatitis virus (VSV)-based vaccine expressing the MARV glycoprotein (VSV-MARV) and previously demonstrated uniform protection of nonhuman primates (NHPs) with a single dose. Here, we investigated the fast-acting potential of this vaccine by challenging NHPs with MARV 14, 7 or 3 days after a single dose vaccination with VSV-MARV. We found that 100% of the animals survived when vaccinated 7 or 14 days and 75% of the animal survived when vaccinated 3 days prior to lethal MARV challenge. Transcriptional analysis of whole blood samples indicated activation of B cells and antiviral defense after VSV-MARV vaccination. In the day -14 and -7 groups, limited transcriptional changes after challenge were observed with the exception of day 9 post-challenge in the day -7 group where we detected gene expression profiles indicative of a recall response. In the day -3 group, transcriptional analysis of samples from surviving NHPs revealed strong innate immune activation. In contrast, the animal that succumbed to disease in this group lacked signatures of antiviral immunity. In summary, our data demonstrate that the VSV-MARV is a fast-acting vaccine suitable for the use in emergency situations like disease outbreaks in Africa.

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

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.