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Background Marburg virus (MARV) has caused numerous sporadic outbreaks of severe hemorrhagic fever in humans. Human case fatality rates of Marburg virus disease (MVD) outbreaks range from 20% to 90%. Viral genotypes of MARV can differ by over 20%, suggesting variable virulence between lineages may accompany this genetic divergence. Comparison of existing animal models of MVD employing different strains of MARV support differences in virulence across MARV genetic lineages; however, there are few systematic comparisons in models that recapitulate human disease available. Methods We compared features of disease pathogenesis in uniformly lethal hamster models of MVD made possible through serial adaptation in rodents. Results No further adaptation from a previously reported guinea pig-adapted (GPA) isolate of MARV-Angola was necessary to achieve uniform lethality in hamsters. Three passages of GPA MARV-Ci67 resulted in uniform lethality, where 4 passages of a GPA Ravn virus was 75% lethal. Hamster-adapted MARV-Ci67 demonstrated delayed time to death, protracted weight loss, lower viral burden, and slower histologic alteration compared to GPA MARV-Angola. Conclusions These data suggest isolate-dependent virulence differences are maintained even after serial adaptation in rodents and may serve to guide choice of variant and model used for development of vaccines or therapeutics for MVD. [ABSTRACT FROM AUTHOR]

Background: Marburg virus (MARV), an Ebola-like virus, remains an eminent threat to public health as demonstrated by its high associated mortality rate (23–90%) and recent emergence in West Africa for the first time. Although a recombinant vesicular stomatitis virus (rVSV)-based vaccine (Ervebo) is licensed for Ebola virus disease (EVD), no approved countermeasures exist against MARV. Results from clinical trials indicate Ervebo prevents EVD in 97.5–100% of vaccinees 10 days onwards post-immunization. Methodology/Findings: Given the rapid immunogenicity of the Ervebo platform against EVD, we tested whether a similar, but highly attenuated, rVSV-based Vesiculovax vector expressing the glycoprotein (GP) of MARV (rVSV-N4CT1-MARV-GP) could provide swift protection against Marburg virus disease (MVD). Here, groups of cynomolgus monkeys were vaccinated 7, 5, or 3 days before exposure to a lethal dose of MARV (Angola variant). All subjects (100%) immunized one week prior to challenge survived; 80% and 20% of subjects survived when vaccinated 5- and 3-days pre-exposure, respectively. Lethality was associated with higher viral load and sustained innate immunity transcriptional signatures, whereas survival correlated with development of MARV GP-specific antibodies and early expression of predicted NK cell-, B-cell-, and cytotoxic T-cell-type quantities. Conclusions/Significance: These results emphasize the utility of Vesiculovax vaccines for MVD outbreak management. The highly attenuated nature of rVSV-N4CT1 vaccines, which are clinically safe in humans, may be preferable to vaccines based on the same platform as Ervebo (rVSV "delta G" platform), which in some trial participants induced vaccine-related adverse events in association with viral replication including arthralgia/arthritis, dermatitis, and cutaneous vasculitis. Author summary: Marburg virus (MARV) is one of the deadliest viruses known to man. One of the most effective vaccines against this pathogen uses a recombinant vesicular stomatitis virus (rVSV) platform to express MARV glycoprotein (GP) immunogen. As rVSV-based vaccines may be used as medical interventions to mitigate or prevent outbreaks of MARV, defining the time window needed to elicit protection is vital. Here, a rVSV vector expressing MARV glycoprotein (rVSV-N4CT1-MARV-GP) fully protected nonhuman primates from lethality and disease when given as soon as 1 week prior to exposure. At 5- and 3-days pre-exposure, partial protection (80% and 20% survival, respectively) was achieved. Vaccination with rVSV-N4CT1-MARV-GP appears to "jump-start" the immune system to allow sufficient time for MARV-specific adaptive responses to form. This fast-acting vaccine is based on a similar platform as Ervebo, the only FDA- and EMA-approved vaccine for preventing Ebola virus infection. The rVSV-N4CT1-MARV-GP vaccine features additional attenuations in the rVSV backbone that may contribute to a more acceptable safety profile in vaccinees, as Ervebo in some recipients induced vaccine-related adverse events including rashes and joint pain. [ABSTRACT FROM AUTHOR]

Background: Phylogenetic comparisons of known Marburg virus (MARV) strains reveal 2 distinct genetic lineages: Ravn and the Lake Victoria Marburg complex (eg, Musoke, Popp, and Angola strains). Nucleotide variances of >20% between Ravn and other MARV genomes suggest that differing virulence between lineages may accompany this genetic divergence. To date, there exists limited systematic experimental evidence of pathogenic differences between MARV strains., Methods: Uniformly lethal outbred guinea pig models of MARV-Angola (MARV-Ang) and MARV-Ravn (MARV-Rav) were developed by serial adaptation. Changes in genomic sequence, weight, temperature, histopathologic findings, immunohistochemical findings, hematologic profiles, circulating biochemical enzyme levels, coagulation parameters, viremia levels, cytokine levels, eicanosoid levels, and nitric oxide production were compared between strains., Results: MARV-Rav infection resulted in delayed increases in circulating inflammatory and prothrombotic elements, notably lower viremia levels, less severe histologic alterations, and a delay in mean time to death, compared with MARV-Ang infection. Both strains produced more marked coagulation abnormalities than previously seen in MARV-infected mice or inbred guinea pigs., Conclusions: Although both strains exhibit great similarity to pathogenic markers of human and nonhuman primate MARV infection, these data highlight several key differences in pathogenicity that may serve to guide the choice of strain and model used for development of vaccines or therapeutics for Marburg hemorrhagic fever., (Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: The procoagulant tissue factor (TF) is thought to play a role in the coagulation disorders that characterize filoviral infections. In this study, we evaluated the pathogenesis of lethal infection with the Angola strain of Marburg virus (MARV-Ang) in rhesus macaques and tested the efficacy of recombinant nematode anticoagulant protein c2 (rNAPc2), an inhibitor of TF/factor VIIa, as a potential treatment., Methods: Twelve rhesus macaques were challenged with a high dose (1000 pfu) of MARV-Ang. Six macaques were treated with rNAPc2, and 6 macaques served as control animals., Results: All 6 control animals succumbed to MARV-Ang challenge by day 8 (mean, 7.3 days), whereas 5 of 6 rNAPc2-treated animals died on day 9 and 1 rNAPc2-treated animal survived. The disease course for MARV-Ang infection appeared to progress more rapidly in rhesus macaques than has been previously reported for other strains of MARV. In contrast to Ebola virus (EBOV) infection in macaques, up-regulation of TF was not as striking, and deposition of fibrin was a less prominent pathologic feature of disease in these animals., Conclusions: These data show that the pathogenicity of MARV-Ang infection appears to be consistent with the apparent increased human virulence attributed to this strain. The apparent reduced efficacy of rNAPc2 against MARV-Ang infection, compared with its efficacy against EBOV infection, appears to be associated with differences in TF induction and fibrin deposition.

Marburg (MARV) and Ebola viruses (EBOV) emerged from the rainforests of Central Africa more than 30 years ago causing outbreaks of severe and, usually, fatal hemorrhagic fever. EBOV has garnered the lion's share of the attention, fueled by the higher frequency of EBOV outbreaks, high mortality rates and importation into the USA, documented in such popular works as the best-selling novel 'The Hot Zone'. However, recent large outbreaks of hundreds of cases of MARV infection in the Democratic Republic of the Congo and Angola with case fatalities approaching 90% dramatically highlight its lethal potential. Although no vaccines or antiviral drugs for MARV are currently available, remarkable progress has been made over the last few years in developing potential countermeasures against MARV in nonhuman primate models. In particular, a vaccine based on attenuated recombinant vesicular stomatitis virus was recently shown to have both preventive and postexposure efficacy.