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The filoviruses -- Ebola virus and Marburg virus -- cause lethal haemorrhagic fever in humans and non-human primates (NHPs). Filoviruses present a global health threat both as naturally acquired diseases and as potential agents of bioterrorism. In the recent 2013-2016 outbreak of Ebola virus, the most promising therapies for post-exposure use with demonstrated efficacy in the gold-standard NHP models of filovirus disease were unable to show statistically significant protection in patients infected with Ebola virus. This Review briefly discusses these failures and what has been learned from these experiences, and summarizes the current status of post-exposure medical countermeasures in development, including antibodies, small interfering RNA and small molecules. We outline how our current knowledge could be applied to the identification of novel interventions and ways to use interventions more effectively.

The search for a universal filovirus vaccine that provides protection against multiple filovirus species has been prompted by sporadic but highly lethal outbreaks of Ebolavirus and Marburgvirus infections. A good prophylactic vaccine should be able to provide protection to all known filovirus species and as an upside potentially protect from newly emerging virus strains. We investigated the immunogenicity and protection elicited by multivalent vaccines expressing glycoproteins (GP) from Ebola virus (EBOV), Sudan virus (SUDV), Taï Forest virus (TAFV) and Marburg virus (MARV). Immune responses against filovirus GP have been associated with protection from disease. The GP antigens were expressed by adenovirus serotypes 26 and 35 (Ad26 and Ad35) and modified Vaccinia virus Ankara (MVA) vectors, all selected for their strong immunogenicity and good safety profile. Using fully lethal NHP intramuscular challenge models, we assessed different vaccination regimens for immunogenicity and protection from filovirus disease. Heterologous multivalent Ad26-Ad35 prime-boost vaccination regimens could give full protection against MARV (range 75%-100% protection) and EBOV (range 50% to 100%) challenge, and partial protection (75%) against SUDV challenge. Heterologous multivalent Ad26-MVA prime-boost immunization gave full protection against EBOV challenge in a small cohort study. The use of such multivalent vaccines did not show overt immune interference in comparison with monovalent vaccines. Multivalent vaccines induced GP-specific antibody responses and cellular IFNγ responses to each GP expressed by the vaccine, and cross-reactivity to TAFV GP was detected in a trivalent vaccine expressing GP from EBOV, SUDV and MARV. In the EBOV challenge studies, higher humoral EBOV GP-specific immune responses (p = 0.0004) were associated with survival from EBOV challenge and less so for cellular immune responses (p = 0.0320). These results demonstrate that it is feasible to generate a multivalent filovirus vaccine that can protect against lethal infection by multiple members of the filovirus family.

Ebola-virus-targeting short interfering RNAs (siRNAs) encapsulated in lipid nanoparticles are adapted to the current outbreak strain of the virus, and the siRNA cocktail is shown to protect nonhuman primates fully when administered 3 days after challenge with the current West African Ebola virus isolate; upon viral sequence data availability, the drug can be adapted to the new virus and produced in as little as 8 weeks. Treating the current Ebola outbreak Ebola virus-targeting siRNAs encapsulated in lipid nanoparticles (TKM-Ebola) have been shown previously to provide post-exposure protection of nonhuman primates against lethal Ebola virus challenge. The therapy has also been used on compassionate grounds in a number of human patients in the current outbreak, although the efficacy in humans is not known. Here, Thomas Geisbert and colleagues rapidly adapt the TKM-Ebola cocktail to the current outbreak strain of the virus and show that it is able to fully protect nonhuman primates when administered 3 days after challenge with the current West African EBOV isolate. Once viral sequence data becomes available, the drug can be adapted to the new virus and produced in as little as 8 weeks. The current outbreak of Ebola virus in West Africa is unprecedented, causing more cases and fatalities than all previous outbreaks combined, and has yet to be controlled 1 . Several post-exposure interventions have been employed under compassionate use to treat patients repatriated to Europe and the United States 2 . However, the in vivo efficacy of these interventions against the new outbreak strain of Ebola virus is unknown. Here we show that lipid-nanoparticle-encapsulated short interfering RNAs (siRNAs) rapidly adapted to target the Makona outbreak strain of Ebola virus are able to protect 100% of rhesus monkeys against lethal challenge when treatment was initiated at 3 days after exposure while animals were viraemic and clinically ill. Although all infected animals showed evidence of advanced disease including abnormal haematology, blood chemistry and coagulopathy, siRNA-treated animals had milder clinical features and fully recovered, while the untreated control animals succumbed to the disease. These results represent the first, to our knowledge, successful demonstration of therapeutic anti-Ebola virus efficacy against the new outbreak strain in nonhuman primates and highlight the rapid development of lipid-nanoparticle-delivered siRNA as a countermeasure against this highly lethal human disease.

Ebola virus (EBOV) causes severe and often fatal hemorrhagic fever in humans and nonhuman primates (NHPs). Currently, there are no licensed vaccines or therapeutics for human use. Recombinant vesicular stomatitis virus (rVSV)-based vaccine vectors, which encode an EBOV glycoprotein in place of the VSV glycoprotein, have shown 100% efficacy against homologous Sudan ebolavirus (SEBOV) or Zaire ebolavirus (ZEBOV) challenge in NHPs. In addition, a single injection of a blend of three rVSV vectors completely protected NHPs against challenge with SEBOV, ZEBOV, the former Côte d'Ivoire ebolavirus, and Marburg virus. However, recent studies suggest that complete protection against the newly discovered Bundibugyo ebolavirus (BEBOV) using several different heterologous filovirus vaccines is more difficult and presents a new challenge. As BEBOV caused nearly 50% mortality in a recent outbreak any filovirus vaccine advanced for human use must be able to protect against this new species. Here, we evaluated several different strategies against BEBOV using rVSV-based vaccines. Groups of cynomolgus macaques were vaccinated with a single injection of a homologous BEBOV vaccine, a single injection of a blended heterologous vaccine (SEBOV/ZEBOV), or a prime-boost using heterologous SEBOV and ZEBOV vectors. Animals were challenged with BEBOV 29-36 days after initial vaccination. Macaques vaccinated with the homologous BEBOV vaccine or the prime-boost showed no overt signs of illness and survived challenge. In contrast, animals vaccinated with the heterologous blended vaccine and unvaccinated control animals developed severe clinical symptoms consistent with BEBOV infection with 2 of 3 animals in each group succumbing. These data show that complete protection against BEBOV will likely require incorporation of BEBOV glycoprotein into the vaccine or employment of a prime-boost regimen. Fortunately, our results demonstrate that heterologous rVSV-based filovirus vaccine vectors employed in the prime-boost approach can provide protection against BEBOV using an abbreviated regimen, which may have utility in outbreak settings.

Over 40 years since the discovery of Ebola virus, the anti-Ebola virus vaccine efforts of the past 2 decades have culminated in over 12 different vaccine candidates that have been placed into a number of clinical trial phases, past and present. Of these 12 vaccines, four candidates are up to or in phase II clinical trials, and only one has completed the phase III clinical trial stage. While remarkable progress toward a national regulatory agency-approved vaccine for Ebola virus has been made, there remain unanswered questions on issues such as, but not limited to, vaccine protective immunity and duration of that immunity, and the appropriate vaccination strategy for those at risk of Ebola virus infection.

Crimean-Congo hemorrhagic fever virus (CCHFV), a tick-borne bunyavirus, can cause a life-threatening hemorrhagic syndrome in humans but not in its animal host. The virus is widely distributed throughout southeastern Europe, the Middle East, Africa, and Asia. Disease management has proven difficult and there are no broadly licensed vaccines or therapeutics. Recombinant vesicular stomatitis viruses (rVSV) expressing foreign glycoproteins (GP) have shown promise as experimental vaccines for several viral hemorrhagic fevers. Here, we developed and assessed a replication competent rVSV vector expressing the CCHFV glycoprotein precursor (GPC), which encodes CCHFV structural glycoproteins. This construct drives strong expression of CCHFV-GP, in vitro . Using these vectors, we vaccinated STAT-1 knock-out mice, an animal model for CCHFV. The vector was tolerated and 100% efficacious against challenge from a clinical strain of CCHFV. Anti-CCHFV-GP IgG and neutralizing antibody titers were observed in surviving animals. This study demonstrates that a rVSV expressing only the CCHFV-GP has the potential to serve as a replication competent vaccine platform against CCHF infections.

Thomas Geisbert and colleagues show that a cocktail of monoclonal antibodies protects cynomolgus monkeys from lethal Lassa fever virus infection, including when administration is delayed by more than a week after viral challenge. There are no approved treatments for Lassa fever, which is endemic to the same regions of West Africa that were recently devastated by Ebola. Here we show that a combination of human monoclonal antibodies that cross-react with the glycoproteins of all four clades of Lassa virus is able to rescue 100% of cynomolgus macaques when treatment is initiated at advanced stages of disease, including up to 8 d after challenge.

Lassa virus is a member of the Arenaviridae family, which causes human infections ranging from asymptomatic to severe hemorrhagic disease with a high case fatality rate. We have designed and generated lipid nanoparticle encapsulated, modified mRNA vaccines that encode for the wild-type Lassa virus strain Josiah glycoprotein complex or the prefusion stabilized conformation of the Lassa virus glycoprotein complex. Hartley guinea pigs were vaccinated with two 10 µg doses, 28 days apart, of either construct. Vaccination induced strong binding antibody responses, specific to the prefusion conformation of glycoprotein complex, which were significantly higher in the prefusion stabilized glycoprotein complex construct group and displayed strong Fc-mediated effects. However, Lassa virus-neutralizing antibody activity was detected in some but not all animals. Following the challenge with a lethal dose of the Lassa virus, all vaccinated animals were protected from death and severe disease. Although the definitive mechanism of protection is still unknown, and assessment of the cell-mediated immune response was not investigated in this study, these data demonstrate the promise of mRNA as a vaccine platform against the Lassa virus and that protection against Lassa virus can be achieved in the absence of virus-neutralizing antibodies. Lassa virus infections in humans can result in severe disease, including hemorrhagic fever. Here the authors describe an mRNA-based Lassa virus vaccine that shows protection without requirement for neutralizing antibody in a guinea pig model of infection.

When arthropod-borne viruses (arboviruses) are delivered to vector mosquitoes in infectious bloodmeals, viral components interact with host proteins to hijack cells and initiate replication. The extent to which arbovirus infection alters mosquito host transcriptional regulatory processes is currently unknown. We hypothesized that histone modifications would be altered in mosquitoes exposed to Rift Valley fever virus (RVFV MP12). H3K27ac and H3K9me3 marks were interrogated using CUT&RUN in a mosquito species that has a predicted dissemination barrier, Aedes aegypti . Global H3K27ac peaks showed progressive depletion over time compared to bloodfed controls. Gene set enrichment analysis revealed that immune response transcripts were enriched at 1 and 3 days post-feeding (dpf). For virus-exposed samples, the highest proportion of DEGs proximal to histone marks occurred with depletion of repressive H3K9me3 peaks at 3 dpf. Associated DEGs included transcription factors, secondary messengers and processes affecting cell polarization. Analysis of midguts after a non-infectious bloodmeal versus sugar-fed controls revealed global changes to H3K27ac and H3K9me3 marks, as well. Differential H3K27ac marks were proximal to one quarter of all DEGs at 1 dpf, consistent with an important role of H3K27ac in bloodmeal digestion. Together, these results demonstrate that H3K27ac and H3K9me3 patterns are altered upon virus exposure in a complex interplay that could be due to viral manipulation or host defense.

The viral determinants that contribute to Nipah virus (NiV)-mediated disease are poorly understood compared with other paramyxoviruses. Here we use recombinant NiVs (rNiVs) to examine the contributions of the NiV V and W proteins to NiV pathogenesis in a ferret model. We show that a V-deficient rNiV is susceptible to the innate immune response in vitro and behaves as a replicating non-lethal virus in vivo . Remarkably, rNiV lacking W expression results in a delayed and altered disease course with decreased respiratory disease and increased terminal neurological disease associated with altered in vitro inflammatory cytokine production. This study confirms the V protein as the major determinant of pathogenesis, also being the first in vivo study to show that the W protein modulates the inflammatory host immune response in a manner that determines the disease course. Nipah virus (NiV) can be transmitted from bats and other animals to humans, causing severe encephalitis and respiratory disease. Here, Satterfield et al. show that the W protein of NiV modulates the host immune response and determines disease course in a ferret model of infection.