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Nonhuman Primate Models for Nipah and Hendra Virus Countermeasure Evaluation

Mire CE, Satterfield BA, Geisbert TW

Methods Mol Biol, 2023;2682:159-173.
PMID: 37610581 DOI: 10.1007/978-1-0716-3283-3_12

Hendra and Nipah viruses are henipaviruses that have caused lethal human disease in Australia and Malaysia, Bangladesh, India, and the Philippines, respectively. These viruses are considered Category C pathogens by the US Centers for Disease Control. Nipah virus was recently placed on the World Health Organization Research and Development Blueprint Roadmaps for vaccine and therapeutic development. Given the infrequent and unpredictable nature of henipavirus outbreaks licensure of vaccines and therapeutics will likely require an animal model to demonstrate protective efficacy against henipavirus disease. Studies have shown that nonhuman primates are the most accurate model of human henipavirus disease and would be an important component of any application for licensure of a vaccine or antiviral drug under the US FDA Animal Rule. Nonhuman primate model selection and dosing are discussed regarding vaccine and therapeutic studies against henipaviruses.
Fulltext Single injection recombinant vesicular stomatitis virus vaccines protect ferrets against lethal Nipah virus disease

Mire CE, Versteeg KM, Cross RW, Agans KN, Fenton KA, Whitt MA, et al.

Virol J, 2013 Dec 13;10:353.
PMID: 24330654 DOI: 10.1186/1743-422X-10-353

BACKGROUND: Nipah virus (NiV) is a highly pathogenic zoonotic agent in the family Paramyxoviridae that is maintained in nature by bats. Outbreaks have occurred in Malaysia, Singapore, India, and Bangladesh and have been associated with 40 to 75% case fatality rates. There are currently no vaccines or postexposure treatments licensed for combating human NiV infection.
METHODS AND RESULTS: Four groups of ferrets received a single vaccination with different recombinant vesicular stomatitis virus vectors expressing: Group 1, control with no glycoprotein; Group 2, the NiV fusion protein (F); Group 3, the NiV attachment protein (G); and Group 4, a combination of the NiV F and G proteins. Animals were challenged intranasally with NiV 28 days after vaccination. Control ferrets in Group 1 showed characteristic clinical signs of NiV disease including respiratory distress, neurological disorders, viral load in blood and tissues, and gross lesions and antigen in target tissues; all animals in this group succumbed to infection by day 8. Importantly, all specifically vaccinated ferrets in Groups 2-4 showed no evidence of clinical illness and survived challenged. All animals in these groups developed anti-NiV F and/or G IgG and neutralizing antibody titers. While NiV RNA was detected in blood at day 6 post challenge in animals from Groups 2-4, the levels were orders of magnitude lower than animals from control Group 1.
CONCLUSIONS: These data show protective efficacy against NiV in a relevant model of human infection. Further development of this technology has the potential to yield effective single injection vaccines for NiV infection.
Fulltext A treatment for and vaccine against the deadly Hendra and Nipah viruses

Broder CC, Xu K, Nikolov DB, Zhu Z, Dimitrov DS, Middleton D, et al.

Antiviral Res, 2013 Oct;100(1):8-13.
PMID: 23838047 DOI: 10.1016/j.antiviral.2013.06.012

Hendra virus and Nipah virus are bat-borne paramyxoviruses that are the prototypic members of the genus Henipavirus. The henipaviruses emerged in the 1990s, spilling over from their natural bat hosts and causing serious disease outbreaks in humans and livestock. Hendra virus emerged in Australia and since 1994 there have been 7 human infections with 4 case fatalities. Nipah virus first appeared in Malaysia and subsequent outbreaks have occurred in Bangladesh and India. In total, there have been an estimated 582 human cases of Nipah virus and of these, 54% were fatal. Their broad species tropism and ability to cause fatal respiratory and/or neurologic disease in humans and animals make them important transboundary biological threats. Recent experimental findings in animals have demonstrated that a human monoclonal antibody targeting the viral G glycoprotein is an effective post-exposure treatment against Hendra and Nipah virus infection. In addition, a subunit vaccine based on the G glycoprotein of Hendra virus affords protection against Hendra and Nipah virus challenge. The vaccine has been developed for use in horses in Australia and is the first vaccine against a Biosafety Level-4 (BSL-4) agent to be licensed and commercially deployed. Together, these advances offer viable approaches to address Hendra and Nipah virus infection of livestock and people.
A Lethal Aerosol Exposure Model of Nipah Virus Strain Bangladesh in African Green Monkeys

Prasad AN, Agans KN, Sivasubramani SK, Geisbert JB, Borisevich V, Mire CE, et al.

J Infect Dis, 2020 05 11;221(Suppl 4):S431-S435.
PMID: 31665351 DOI: 10.1093/infdis/jiz469

The high case-fatality rates and potential for use as a biological weapon make Nipah virus (NiV) a significant public health concern. Previous studies assessing the pathogenic potential of NiV delivered by the aerosol route in African green monkeys (AGMs) used the Malaysia strain (NiVM), which has caused lower instances of respiratory illness and person-to-person transmission during human outbreaks than the Bangladesh strain (NiVB). Accordingly, we developed a small particle aerosol model of NiVB infection in AGMs. Consistent with other mucosal AGM models of NiVB infection, we achieved uniform lethality and disease pathogenesis reflective of that observed in humans.
Fulltext Use of Single-Injection Recombinant Vesicular Stomatitis Virus Vaccine to Protect Nonhuman Primates Against Lethal Nipah Virus Disease

Mire CE, Geisbert JB, Agans KN, Versteeg KM, Deer DJ, Satterfield BA, et al.

Emerg Infect Dis, 2019 Jun;25(6):1144-1152.
PMID: 31107231 DOI: 10.3201/eid2506.181620

Nipah virus (NiV) is a zoonotic pathogen that causes high case-fatality rates (CFRs) in humans. Two NiV strains have caused outbreaks: the Malaysia strain (NiVM), discovered in 1998-1999 in Malaysia and Singapore (≈40% CFR); and the Bangladesh strain (NiVB), discovered in Bangladesh and India in 2001 (≈80% CFR). Recently, NiVB in African green monkeys resulted in a more severe and lethal disease than NiVM. No NiV vaccines or treatments are licensed for human use. We assessed replication-restricted single-injection recombinant vesicular stomatitis vaccine NiV vaccine vectors expressing the NiV glycoproteins against NiVB challenge in African green monkeys. All vaccinated animals survived to the study endpoint without signs of NiV disease; all showed development of NiV F Ig, NiV G IgG, or both, as well as neutralizing antibody titers. These data show protective efficacy against a stringent and relevant NiVB model of human infection.
Fulltext Pathogenic Differences between Nipah Virus Bangladesh and Malaysia Strains in Primates: Implications for Antibody Therapy

Mire CE, Satterfield BA, Geisbert JB, Agans KN, Borisevich V, Yan L, et al.

Sci Rep, 2016 08 03;6:30916.
PMID: 27484128 DOI: 10.1038/srep30916

Nipah virus (NiV) is a paramyxovirus that causes severe disease in humans and animals. There are two distinct strains of NiV, Malaysia (NiVM) and Bangladesh (NiVB). Differences in transmission patterns and mortality rates suggest that NiVB may be more pathogenic than NiVM. To investigate pathogenic differences between strains, 4 African green monkeys (AGM) were exposed to NiVM and 4 AGMs were exposed to NiVB. While NiVB was uniformly lethal, only 50% of NiVM-infected animals succumbed to infection. Histopathology of lungs and spleens from NiVB-infected AGMs was significantly more severe than NiVM-infected animals. Importantly, a second study utilizing 11 AGMs showed that the therapeutic window for human monoclonal antibody m102.4, previously shown to rescue AGMs from NiVM infection, was much shorter in NiVB-infected AGMs. Together, these data show that NiVB is more pathogenic in AGMs under identical experimental conditions and suggests that postexposure treatments may need to be NiV strain specific for optimal efficacy.
Fulltext Resistance of Cynomolgus Monkeys to Nipah and Hendra Virus Disease Is Associated With Cell-Mediated and Humoral Immunity

Prasad AN, Woolsey C, Geisbert JB, Agans KN, Borisevich V, Deer DJ, et al.

J Infect Dis, 2020 05 11;221(Suppl 4):S436-S447.
PMID: 32022850 DOI: 10.1093/infdis/jiz613

BACKGROUND: The henipaviruses, Hendra virus (HeV) and Nipah virus (NiV), are capable of causing severe and often lethal respiratory and/or neurologic disease in animals and humans. Given the sporadic nature of henipavirus outbreaks, licensure of vaccines and therapeutics for human use will likely require demonstration of efficacy in animal models that faithfully reproduce the human condition. Currently, the African green monkey (AGM) best mimics human henipavirus-induced disease.
METHODS: The pathogenic potential of HeV and both strains of NiV (Malaysia, Bangladesh) was assessed in cynomolgus monkeys and compared with henipavirus-infected historical control AGMs. Multiplex gene and protein expression assays were used to compare host responses.
RESULTS: In contrast to AGMs, in which henipaviruses cause severe and usually lethal disease, HeV and NiVs caused only mild or asymptomatic infections in macaques. All henipaviruses replicated in macaques with similar kinetics as in AGMs. Infection in macaques was associated with activation and predicted recruitment of cytotoxic CD8+ T cells, Th1 cells, IgM+ B cells, and plasma cells. Conversely, fatal outcome in AGMs was associated with aberrant innate immune signaling, complement dysregulation, Th2 skewing, and increased secretion of MCP-1.
CONCLUSION: The restriction factors identified in macaques can be harnessed for development of effective countermeasures against henipavirus disease.
Fulltext A Hendra virus G glycoprotein subunit vaccine protects African green monkeys from Nipah virus challenge

Bossart KN, Rockx B, Feldmann F, Brining D, Scott D, LaCasse R, et al.

Sci Transl Med, 2012 Aug 08;4(146):146ra107.
PMID: 22875827 DOI: 10.1126/scitranslmed.3004241

In the 1990s, Hendra virus and Nipah virus (NiV), two closely related and previously unrecognized paramyxoviruses that cause severe disease and death in humans and a variety of animals, were discovered in Australia and Malaysia, respectively. Outbreaks of disease have occurred nearly every year since NiV was first discovered, with case fatality ranging from 10 to 100%. In the African green monkey (AGM), NiV causes a severe lethal respiratory and/or neurological disease that essentially mirrors fatal human disease. Thus, the AGM represents a reliable disease model for vaccine and therapeutic efficacy testing. We show that vaccination of AGMs with a recombinant subunit vaccine based on the henipavirus attachment G glycoprotein affords complete protection against subsequent NiV infection with no evidence of clinical disease, virus replication, or pathology observed in any challenged subjects. Success of the recombinant subunit vaccine in nonhuman primates provides crucial data in supporting its further preclinical development for potential human use.