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The emergence of the novel henipavirus, Langya virus, received global attention after the virus sickened over three dozen people in China. There is heightened concern that henipaviruses, as respiratory pathogens, could spark another pandemic, most notably the deadly Nipah virus (NiV). NiV causes near-annual outbreaks in Bangladesh and India and induces a highly fatal respiratory disease and encephalitis in humans. No licensed countermeasures against this pathogen exist. An ideal NiV vaccine would confer both fast-acting and long-lived protection. Recently, we reported the generation of a recombinant vesicular stomatitis virus-based (rVSV-based) vaccine expressing the NiV glycoprotein (rVSV-[DELTA]G-[NiV.sub.B]G) that protected 100% of nonhuman primates from NiV-associated lethality within a week. Here, to evaluate the durability of rVSV-[DELTA]G- [NiV.sub.B]G, we vaccinated African green monkeys (AGMs) one year before challenge with an uniformly lethal dose of NiV. The rVSV- [DELTA]G-[NiV.sub.B]G vaccine induced stable and robust humoral responses, whereas cellular responses were modest. All immunized AGMs (whether receiving a single dose or prime-boosted) survived with no detectable clinical signs or NiV replication. Transcriptomic analyses indicated that adaptive immune signatures correlated with vaccine-mediated protection. While vaccines for certain respiratory infections (e.g., COVID-19) have yet to provide durable protection, our results suggest that rVSV-[DELTA]G- [NiV.sub.B]G elicits long-lasting immunity., Introduction Nipah virus (NiV) causes encephalitis and severe respiratory disease in humans with case-fatality rates (CFRs) ranging from 40% to 100% (1). Inherent features of NiV engender concern that the [...]

Lassa fever (LF) is an acute viral hemorrhagic fever endemic to West Africa, where [approximately equal to] 300,000-500,000 cases/year occur and mortality rates are high (1). Humans primarily are infected [...]

Recent occurrences of filoviruses and the arenavirus Lassa virus (LASV) in overlapping endemic areas of Africa highlight the need for a prophylactic vaccine that would confer protection against all of these viruses that cause lethal hemorrhagic fever (HF). We developed a quadrivalent formulation of VesiculoVax that contains recombinant vesicular stomatitis virus (rVSV) vectors expressing filovirus glycoproteins and that also contains a rVSV vector expressing the glycoprotein of a lineage IV strain of LASV. Cynomolgus macaques were vaccinated twice with the quadrivalent formulation, followed by challenge 28 days after the boost vaccination with each of the 3 corresponding filoviruses (Ebola, Sudan, Marburg) or a heterologous contemporary lineage II strain of LASV. Serum IgG and neutralizing antibody responses specific for all 4 glycoproteins were detected in all vaccinated animals. A modest and balanced cell-mediated immune response specific for the glycoproteins was also detected in most of the vaccinated macaques. Regardless of the level of total glycoprotein-specific immune response detected after vaccination, all immunized animals were protected from disease and death following lethal challenges. These findings indicate that vaccination with attenuated rVSV vectors each expressing a single HF virus glycoprotein may provide protection against those filoviruses and LASV most commonly responsible for outbreaks of severe HF in Africa., Introduction Viral hemorrhagic fevers are a group of infectious diseases with symptoms that are similar among humans (1). The causative viruses affect the vascular system and can cause a hemorrhagic [...]

Nipah virus (NiV) and Hendra virus (HeV) are highly pathogenic zoonotic agents in the paramyxovirus genus Henipavirus. Human case-fatality rates (CFRs) for these viruses historically have ranged from 40% to [...]

Ebolaviruses and marburgviruses belong to the family Filoviridae and cause high lethality in infected patients. There are currently no licensed filovirus vaccines or antiviral therapies. The development of broad-spectrum therapies against members of the Marburgvirus genus, including Marburg virus (MARV) and Ravn virus (RAVV), is difficult because of substantial sequence variability. RNAi therapeutics offer a potential solution, as identification of conserved target nucleotide sequences may confer activity across marburgvirus variants. Here, we assessed the therapeutic efficacy of lipid nanoparticle (LNP) delivery of a single nucleoprotein-targeting (NP-targeting) siRNA in nonhuman primates at advanced stages of MARV or RAVV disease to mimic cases in which patients begin treatment for fulminant disease. Sixteen rhesus monkeys were lethally infected with MARV or RAVV and treated with NP siRNA-LNP, with MARV-infected animals beginning treatment four or five days after infection and RAVV-infected animals starting treatment three or six days after infection. While all untreated animals succumbed to disease, NP siRNA-LNP treatment conferred 100% survival of RAVV-infected macaques, even when treatment began just 1 day prior to the death of the control animals. In MARV-infected animals, day-4 treatment initiation resulted in 100% survival, and day-5 treatment resulted in 50% survival. These results identify a single siRNA therapeutic that provides broad-spectrum protection against both MARV and RAVV., Introduction From 1967 until late 2013, members of the 2 genera of filoviruses, Marburgvirus and Ebolavirus, have caused periodic occurrences of hemorrhagic fever (HF) in Central Africa, resulting in severe [...]

Author(s): Chad E Mire [1, 2]; Robert W Cross [1, 2]; Joan B Geisbert [1, 2]; Viktoriya Borisevich [1, 2]; Krystle N Agans [1, 2]; Daniel J Deer [1, 2]; [...]

For those fortunate enough to have survived a deadly disease, a vital question remains: how long does their hard-earned immunity last? Tracking of antibodies in Ebola survivors reveals a surprising pattern. A surprising pattern of changes in antibody levels in Ebola survivors., Author(s): Courtney Woolsey, Thomas W. Geisbert Author Affiliations: Antibodies periodically wax and wane in survivors of Ebola The West African Ebola epidemic in 2013-16 was unprecedented in its size, affecting [...]

Direct delivery of aerosolized vaccines to the respiratory mucosa elicits both systemic and mucosal responses. This vaccine strategy has not been tested for Ebola virus (EBOV) or other hemorrhagic fever viruses. Here, we examined the immunogenicity and protective efficacy of an aerosolized human parainfluenza virus type 3-vectored vaccine that expresses the glycoprotein (GP) of EBOV (HPIV3/EboGP) delivered to the respiratory tract. Rhesus macaques were vaccinated with aerosolized HPIV3/EboGP, liquid HPIV3/EboGP, or an unrelated, intramuscular, Venezuelan equine encephalitis replicon vaccine expressing EBOV GP. Serum and mucosal samples from aerosolized HPIV3/EboGP recipients exhibited high EBOV-specific IgG, IgA, and neutralizing antibody titers, which exceeded or equaled titers observed in liquid recipients. The HPIV3/EboGP vaccine induced an EBOV-specific cellular response that was greatest in the lungs and yielded polyfunctional [CD8.sup.+] T cells, including a subset that expressed CD103 (αE integrin), and [CD4.sup.+] T helper cells that were predominately type 1. The magnitude of the [CD4.sup.+] T cell response was greater in aerosol vaccinees. The HPIV3/EboGP vaccine produced a more robust cell-mediated and humoral immune response than the systemic replicon vaccine. Moreover, 1 aerosol HPIV3/EboGP dose conferred 100% protection to macaques exposed to EBOV. Aerosol vaccination represents a useful and feasible vaccination mode that can be implemented with ease in a filovirus disease outbreak situation., Introduction Ebola virus (EBOV) is a member of the family Filoviridae, which causes in humans and nonhuman primates (NHPs) the most severe hemorrhagic fever known, with a case fatality rate [...]

Author(s): Chad E. Mire [1, 2]; Demetrius Matassov [3]; Joan B. Geisbert [1, 2]; Theresa E. Latham [3]; Krystle N. Agans [1, 2]; Rong Xu [4]; Ayuko Ota-Setlik [4]; Michael [...]

Vaccine-induced immunity to Ebola virus infection in nonhuman primates (NHPs) is marked by potent antigen-specific cellular and humoral immune responses (1,2); however, the immune mechanism of protection remains unknown. Here we define the immune basis of protection conferred by a highly protective recombinant adenovirus virus serotype 5 (rAd5) encoding Ebola virus glycoprotein (GP) (1,3) in NHPs. Passive transfer of high-titer polyclonal antibodies from vaccinated Ebola virus-immune cynomolgus macaques to naive macaques failed to confer protection against disease, suggesting a limited role of humoral immunity. In contrast, depletion of [CD3.sup.+] T cells in vivo after vaccination and immediately before challenge eliminated immunity in two vaccinated macaques, indicating a crucial requirement for T cells in this setting. The protective effect was mediated largely by [CD8.sup.+] cells, as depletion of [CD8.sup.+] cells in vivo using the cM-T807 monoclonal antibody (mAb), which does not affect [CD4.sup.+] T cell or humoral immune responses, abrogated protection in four out of five subjects. These findings indicate that [CD8.sup.+] cells have a major role in rAd5-GP-induced immune protection against Ebola virus infection in NHPs. Understanding the immunologic mechanism of Ebola virus protection will facilitate the development of vaccines for Ebola and related hemorrhagic fever viruses in humans., Viral vector vaccines have shown efficacy for the delivery of Ebola virus genes and immune protection against infection in NHPs, but the mechanism of immune protection has not been defined [...]

Viral hemorrhagic fevers (VHFs) are caused by a group of genetically distinct zoonotic viruses, which include [greater than or equal to] 4 virus families (Filoviridae, Arenaviridae, Bunyaviridae, and Flaviviridae). Because [...]

Construction of several new Biosafety Level 4 (BSL-4) laboratories and expansion of existing operations have created an increased international demand for well-trained staff and facility leaders. Directors of most North [...]

To facilitate rapid, unbiased, differential diagnosis of infectious diseases, we designed GreeneChipPm, a panmicrobial microarray comprising 29,455 sixty-mer oligonucleotide probes for vertebrate viruses, bacteria, fungi, and parasites. Methods for nucleic [...]

ABSTRACT Background Ebola virus causes a hemorrhagic fever syndrome that is associated with high mortality in humans. In the absence of effective therapies for Ebola virus infection, the development of [...]

Viral hemorrhagic fevers are associated with high rates of illness and death. Although therapeutic options are limited, early differential diagnosis has implications for containment and may aid in clinical management. [...]

Author(s): Steven M Jones [1, 2, 9]; Heinz Feldmann (corresponding author) [1, 3, 9]; Ute Stroher [1, 3]; Joan B Geisbert [4]; Lisa Fernando [1]; Allen Grolla [1]; Hans-Dieter Klenk [...]

Smallpox has played ~n unparalleled role in human history and remains a significant potential threat to public health. Despite the historical significance of this disease, we know little about the underlying pathophysiology or the virulence mechanisms of the causative agent, variola virus. To improve our understanding of variola pathogenesis and variola-host interactions, we examined the molecular and cellular features of hemorrhagic smallpox in cynomolgus macaques. We used cDNA microarrays to analyze host gene expression patterns in sequential blood samples from each of 22 infected animals. Variola infection elicited striking and temporally coordinated patterns of gene expression in peripheral blood. Of particular interest were features that appear to represent an IFN response, cell proliferation, immunoglobulin gene expression, viral dose-dependent gene expression patterns, and viral modulation of the host immune response. The virtual absence of a tumor necrosis factor [alpha]/NF-[kappa]B-activated transcriptional program in the face of an overwhelming systemic infection suggests that variola gene products may ablate this response. These results provide a detailed picture of the host transcriptional response during smallpox infection, and may help guide the development of diagnostic, therapeutic, and prophylactic strategies.

A previously undescribed coronavirus (COY) is the etiologic agent responsible for severe acute respiratory syndrome (SARS). Using a panel of contiguous cDNAs that span the entire genome, we have assembled a full-length cDNA of the SARS-CoV Urbani strain, and have rescued molecularly cloned SARS viruses (infectious clone SARS-CoV) that contained the expected marker mutations inserted into the component clones. Recombinant viruses replicated as efficiently as WT virus and both were inhibited by treatment with the cysteine proteinase inhibitor (2S,3S)-transepoxysuccinyl-L-leucylamido-3-methylbutane ethyl ester. In addition, subgenomic transcripts were initiated from the consensus sequence ACGAAC in both the WT and infectious clone SARS-CoV. Availability of a SARS-CoV full-length cDNA provides a template for manipulation of the viral genome, allowing for the rapid and rational development and testing of candidate vaccines and therapeutics against this important human pathogen.

Author(s): Nancy J. Sullivan [1]; Thomas W. Geisbert [2]; Joan B. Geisbert [2]; Ling Xu [1]; Zhi-yong Yang [1]; Mario Roederer [1]; Richard A. Koup [1]; Peter B. Jahrling [2]; [...]

Ebola virus (EBOV) causes acute hemorrhagic fever that is fatal in up to 90% of cases in both humans and nonhuman primates. No vaccines or treatments are available for human [...]

Author(s): Emily P. Thi [1]; Chad E. Mire [2, 3]; Amy C. H. Lee [1]; Joan B. Geisbert [2, 3]; Joy Z. Zhou [1]; Krystle N. Agans [2, 3]; Nicholas [...]

A global outbreak of severe acute respiratory syndrome (SARS) caused by a novel coronavirus began in March 2003. The rapid emergence of SARS and the substantial illness and death it [...]

A blend of three monoclonal antibodies has completely protected monkeys against a lethal dose of Ebola virus. Unlike other post-infection therapies, the treatment works even at advanced stages of the [...]