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

Abstract

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.

A Cloned Recombinant Vesicular Stomatitis Virus-Vectored Marburg Vaccine, PHV01, Protects Guinea Pigs from Lethal Marburg Virus Disease

“…Together, PHV01 MVS and FDS elicited significant IgG and neutralizing antibody responses that reduced or eliminated MARV replication in most vaccinated animals. These conclusions were not unexpected given previous studies performed with rVSV∆G-MARV/Ang and rVSV∆G-MARV/Mus in NHPs [12,13,[17][18][19]24,25]. Nevertheless, this study represents the first published evaluation of an rVSV-based MARV vaccine in a rodent, and it attests to the predictive value of the MARV guinea pig model in countermeasure evaluation.…”

A highly attenuated Vesiculovax vaccine rapidly protects nonhuman primates against lethal Marburg virus challenge

“…Here, vaccination of macaques with a single 10 million PFU dose of rVSV-N4CT1-MARV-GP one week prior to MARV-Angola challenge resulted in lack of detectable viremia in these animals with protection from clinical disease and lethality. [ 27 ]. However, we detected changes in bloodwork of surviving subjects indicative of very mild disease in the absence of clinical signs.…”

“…The specific mechanisms of rapid rVSV-elicited protection are not fully elucidated but are thought to involve stimulation of both innate and adaptive immunity [ 13 , 27 , 50 – 52 ]. Resistance to disease was strongly tied to early control of MARV replication.…”

“…Thus, early NK cell differentiation status may dictate Fc-mediated activation of NK cells. This finding may be of relevance as antibody neutralizing capacity is not highly correlative of protection against MVD, and only low levels of neutralizing antibodies are typically detected following rVSV-MARV vaccination [ 13 , 27 ]. Previously, we’ve specifically measured the capacity of rVSV-N4CT1-MARV-GP to induce neutralizing antibodies against MARV [ 14 ].…”

“…While preclinical studies have demonstrated the ability of rVSV-based vaccines to rapidly combat Marburgviruses including the Angola variant [ 13 , 14 ], the exact prophylactic window remains undefined. Recently, Marzi et al reported that a “delta G” rVSV-based vaccine (rVSVΔG-MARV-GP-Angola) similar to Ervebo fully protected NHPs when vaccinated at 7 or 14 days prior to exposure [ 27 ]. Partial protection (75%) was observed when NHPs were vaccinated 3 days before exposure.…”