Lassa fever in African green monkeys: Clinical disease and fatal outcome are associated with systemic viral dissemination and inflammation.

Lassa virus (LASV) causes significant human morbidity and mortality in endemic areas of West Africa. Previous studies have shown that cynomolgus macaques of non-Mauritius Asian origin best reproduce clinical features of human Lassa fever (LF). Because of the shortage of macaques caused by the COVID-19 pandemic, research on high-consequence pathogens including LASV has been severely hindered.

Pathogenesis of Chapare virus in cynomolgus macaques.

Chapare virus (CHAPV) is an emerging New World arenavirus that is the causative agent of Chapare haemorrhagic fever (CHHF) responsible for recent outbreaks with alarmingly high case fatality rates in Bolivia near the Brazilian border. Here, we describe a nonhuman primate (NHP) model of CHHF infection which represents an essential tool to understand this emerging biological threat agent. Cynomolgus macaques challenged intravenously with CHAPV develop clinical disease, which recapitulates several key features of human CHHF.

Remdesivir, mAb114, REGN-EB3, and ZMapp partially rescue nonhuman primates infected with a low passage Kikwit variant of Ebola virus.

In 2018, a clinical trial of four investigational therapies for Ebola virus disease (EVD), known as the PALM trial, was conducted in the Democratic Republic of Congo. All patients received either the antiviral remdesivir (RDV) or a monoclonal antibody product: ZMapp, mAb114 (Ebanga), or REGN-EB3 (Inmazeb). The study concluded that both mAb114 and REGN-EB3 were superior to ZMapp and RDV in reducing mortality from EVD.

The oral drug obeldesivir protects nonhuman primates against lethal Ebola virus infection.

Obeldesivir (ODV; GS-5245) is an orally administered ester prodrug of the parent nucleoside GS-441524 that has broad spectrum antiviral activity inhibiting viral RNA-dependent RNA polymerases. We recently showed that ODV completely protects cynomolgus macaques against lethal infection with Sudan virus when given 24 hours after parenteral exposure. Here, we report that once daily oral ODV treatment of cynomolgus and rhesus macaques for 10 days confers 80 and 100% protection, respectively, against lethal Ebola virus infection when treatment is initiated 24 hours after mucosal (conjunctival) exposure.

Oral obeldesivir provides postexposure protection against Marburg virus in nonhuman primates.

The recent outbreak of Marburg virus (MARV) in Rwanda underscores the need for effective countermeasures against this highly fatal pathogen, with case fatality rates reaching 90%. Currently, no vaccines or approved treatments exist for MARV infection, distinguishing it from related viruses such as Ebola. Our study demonstrates that the oral drug obeldesivir (ODV), a nucleoside analog prodrug, shows promising antiviral activity against filoviruses in vitro and offers significant protection in animal models.

Therapeutic administration of a cross-reactive mAb targeting the fusion glycoprotein of Nipah virus protects nonhuman primates.

No licensed vaccines or therapies exist for patients infected with Nipah virus (NiV), although an experimental human monoclonal antibody (mAb) cross-reactive to the NiV and Hendra virus (HeV) G glycoprotein, m102.4, has been tested in a phase 1 trial and has been provided under compassionate use for both HeV and NiV exposures. NiV is a highly pathogenic zoonotic paramyxovirus causing regular outbreaks in humans and animals in South and Southeast Asia.

Oral administration of obeldesivir protects nonhuman primates against .

Obeldesivir (ODV, GS-5245) is an orally administered prodrug of the parent nucleoside of remdesivir (RDV) and is presently in phase 3 trials for COVID-19 treatment. In this work, we show that ODV and its circulating parent nucleoside metabolite, GS-441524, have similar in vitro antiviral activity against filoviruses, including Marburg virus, Ebola virus, and Sudan virus (SUDV). We also report that once-daily oral ODV treatment of cynomolgus monkeys for 10 days beginning 24 hours after SUDV exposure confers 100% protection against lethal infection.

Monoclonal antibody therapy protects nonhuman primates against mucosal exposure to Lassa virus.

Lassa fever (LF) is an acute viral illness that causes thousands of deaths annually in West Africa. There are currently no Lassa virus (LASV) vaccines or antivirals approved for human use. Recently, we showed that combinations of broadly neutralizing human monoclonal antibodies (BNhuMAbs) known as Arevirumab-2 or Arevirumab-3 protected up to 100% of cynomolgus macaques against challenge with diverse lineages of LASV when treatment was initiated at advanced stages of disease.

Monoclonal antibody therapy demonstrates increased virulence of a lineage VII strain of Lassa virus in nonhuman primates.

Lassa virus (LASV) is a World Health Organization (WHO) priority pathogen that causes high morbidity and mortality. Recently, we showed that a combination of three broadly neutralizing human monoclonal antibodies known as Arevirumab-3 (8.9F, 12.

The Therapeutic Monoclonal Antibody Bamlanivimab Does Not Enhance SARS-CoV-2 Infection by FcR-Mediated Mechanisms.

As part of the non-clinical safety package characterizing bamlanivimab (SARS-CoV-2 neutralizing monoclonal antibody), the risk profile for antibody-dependent enhancement of infection (ADE) was evaluated in vitro and in an African green monkey (AGM) model of COVID-19. In vitro ADE assays in primary human macrophage, Raji, or THP-1 cells were used to evaluate enhancement of viral infection. Bamlanivimab binding to C1q, FcR, and cell-based effector activity was also assessed.

A human monoclonal antibody combination rescues nonhuman primates from advanced disease caused by the major lineages of Lassa virus.

There are no approved treatments for Lassa fever (LF), which is responsible for thousands of deaths each year in West Africa. A major challenge in developing effective medical countermeasures against LF is the high diversity of circulating Lassa virus (LASV) strains with four recognized lineages and four proposed lineages. The recent resurgence of LASV in Nigeria caused by genetically distinct strains underscores this concern.

Long-term Prophylaxis Against Aerosolized Marburg Virus in Nonhuman Primates With an Afucosylated Monoclonal Antibody.

Marburg virus (MARV) causes a hemorrhagic fever disease in human and nonhuman primates with high levels of morbidity and mortality. Concerns about weaponization of aerosolized MARV have spurred the development of nonhuman primate (NHP) models of aerosol exposure. To address the potential threat of aerosol exposure, a monoclonal antibody that binds MARV glycoprotein was tested, MR186YTE, for its efficacy as a prophylactic.

Natural History of Nonhuman Primates After Oral Exposure to Ebola Virus Variant Makona.

Background: The primary route of infection by Ebola virus (EBOV) is through contact of mucosal surfaces. Few studies have explored infection of nonhuman primates (NHPs) via the oral mucosa, which is a probable portal of natural infection in humans.

Methods: To further characterize the pathogenesis of EBOV infection via the oral exposure route, we challenged cohorts of cynomolgus monkeys with low doses of EBOV variant Makona.

A Highly Attenuated Panfilovirus VesiculoVax Vaccine Rapidly Protects Nonhuman Primates Against Marburg Virus and 3 Species of Ebola Virus.

Background: The family Filoviridae consists of several virus members known to cause significant mortality and disease in humans. Among these, Ebola virus (EBOV), Marburg virus (MARV), Sudan virus (SUDV), and Bundibugyo virus (BDBV) are considered the deadliest. The vaccine, Ervebo, was shown to rapidly protect humans against Ebola disease, but is indicated only for EBOV infections with limited cross-protection against other filoviruses.

Pathogenesis of Aerosolized Ebola Virus Variant Makona in Nonhuman Primates.

Background: Highly pathogenic filoviruses such as Ebola virus (EBOV) hold capacity for delivery by artificial aerosols, and thus potential for intentional misuse. Previous studies have shown that high doses of EBOV delivered by small-particle aerosol cause uniform lethality in nonhuman primates (NHPs), whereas only a few small studies have assessed lower doses in NHPs.

Methods: To further characterize the pathogenesis of EBOV infection via small-particle aerosol, we challenged cohorts of cynomolgus monkeys with low doses of EBOV variant Makona, which may help define risks associated with small particle aerosol exposures.

Marburg and Ebola Virus Infections Elicit a Complex, Muted Inflammatory State in Bats.

The Marburg and Ebola filoviruses cause a severe, often fatal, disease in humans and nonhuman primates but have only subclinical effects in bats, including Egyptian rousettes, which are a natural reservoir of Marburg virus. A fundamental question is why these viruses are highly pathogenic in humans but fail to cause disease in bats. To address this question, we infected one cohort of Egyptian rousette bats with Marburg virus and another cohort with Ebola virus and harvested multiple tissues for mRNA expression analysis.

Recombinant vesicular stomatitis virus-vectored vaccine induces long-lasting immunity against Nipah virus disease.

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.

A recombinant VSV-vectored vaccine rapidly protects nonhuman primates against heterologous lethal Lassa fever.

Lassa virus (LASV) is recognized by the World Health Organization as one of the top five pathogens likely to cause a severe outbreak. A recent unprecedented resurgence of LASV in Nigeria caused by genetically diverse strains underscores the need for licensed medical countermeasures. Single-injection vaccines that can rapidly control outbreaks and confer long-term immunity are needed.

Natural history of infection in rhesus and cynomolgus macaques.

Due to its high mortality rate and continued re-emergence, Ebolavirus disease (EVD) continues to pose a serious threat to global health. A group of viruses within the genus causes this severe hemorrhagic disease in humans: Ebola virus (EBOV; species ), Sudan virus (SUDV; species ), Bundibugyo virus, and Taï Forest virus. EBOV and SUDV are associated with the highest case fatality rates.

Combination therapy with remdesivir and monoclonal antibodies protects nonhuman primates against advanced Sudan virus disease.

A major challenge in managing acute viral infections is ameliorating disease when treatment is delayed. Previously, we reported the success of a 2-pronged mAb and antiviral remdesivir therapeutic approach to treat advanced illness in rhesus monkeys infected with Marburg virus (MARV). Here, we explored the benefit of a similar combination therapy for Sudan ebolavirus (Sudan virus; SUDV) infection.

A recombinant VSV-vectored vaccine rapidly protects nonhuman primates against lethal Nipah virus disease.

SignificanceConcern has increased about the pandemic potential of Nipah virus (NiV). Similar to SARS-CoV-2, NiV is an RNA virus that is transmitted by respiratory droplets. There are currently no NiV vaccines licensed for human use.

Therapy for Argentine hemorrhagic fever in nonhuman primates with a humanized monoclonal antibody.

The COVID-19 pandemic has reemphasized the need to identify safe and scalable therapeutics to slow or reverse symptoms of disease caused by newly emerging and reemerging viral pathogens. Recent clinical successes of monoclonal antibodies (mAbs) in therapy for viral infections demonstrate that mAbs offer a solution for these emerging biothreats. We have explored this with respect to Junin virus (JUNV), an arenavirus classified as a category A high-priority agent and the causative agent of Argentine hemorrhagic fever (AHF).

Combination therapy protects macaques against advanced Marburg virus disease.

Monoclonal antibodies (mAbs) and remdesivir, a small-molecule antiviral, are promising monotherapies for many viruses, including members of the genera Marburgvirus and Ebolavirus (family Filoviridae), and more recently, SARS-CoV-2. One of the major challenges of acute viral infections is the treatment of advanced disease. Thus, extending the window of therapeutic intervention is critical.