Twenty Years of Nipah Virus Research: Where Do We Go From Here?

Twenty years ago, the world had only just discovered Nipah virus, a new zoonotic paramyxovirus closely related to Hendra virus. A concurrent disease outbreak in pigs and humans in Malaysia led to the discovery of this virus in 1999 [1]. Through the intermediate host involved in this outbreak—domestic pigs—the outbreak spread to Singapore, resulting in a total of 276 reported cases with 106 deaths; the outbreak ended with the culling of more than 1 000 000 pigs [1, 2].

Nipah virus has caused fewer than 700 diagnosed human cases in the 20 years since its discovery, and, so far, outbreaks have been contained within a few chains of transmission. However, Nipah virus is among the most lethal viruses currently known. Because of this, even isolated cases can enormously impact families, healthcare workers, communities, and healthcare systems. Moreover, the potential involvement of intermediate, agricultural hosts can have significant economic consequences. In this study, we summarize the major scientific advances in Nipah virus epidemiology and biology made in the past 20 years to identify important gaps in our knowledge that must be filled to effectively prevent Nipah virus infections and deaths.

MAJOR ADVANCES

Nipah Virus Epidemiology

Over the past 20 years, our understanding of the epidemiology of Nipah virus has grown substantially, thanks to increased capacity and efforts to identify and study human Nipah virus infections. The development of diagnostics tests after the outbreak in Malaysia offered a significant leap in our capability to identify cases. In 2001, just 1 year after the development of these tests, 2 outbreaks of Nipah virus occurred in India and Bangladesh, almost simultaneously [3, 4]. The geographical range of detected human cases of Nipah virus infection has continued to grow with outbreaks identified in the Philippines in 2014 and in Kerala, India, in 2018 [5, 6].

Scientists and public health officials quickly learned that Nipah virus had the ability to spread from person to person [3, 7]. Outbreaks on the Indian subcontinent were smaller in size than the outbreak in Malaysia, but they have been continuously reported, almost yearly, since 2001, suggesting that the virus may have been infecting humans for many years, undetected. Although the case fatality rate of Nipah virus infections in Malaysia was high, it has been even higher in South Asia, at approximately 70%.

After outbreaks in 2001, 2003, 2004, and 2005, Bangladesh established targeted, hospital-based surveillance in 2006 (1) to identify and proactively respond to outbreaks of Nipah virus and (2) to identify isolated cases so that the mechanism of viral spillover from bats to humans could be identified. As a result, we know that multiple Nipah virus spillover events occur there each year (Nikolay et al, this supplement), primarily through human consumption of raw or fermented date palm sap contaminated with the urine or saliva of infected fruit bats [8]. Effective interventions to interrupt transmission have been developed but are not routinely used [9, 10].

Since 2015, the World Health Organization has listed Nipah virus as one of the most dangerous emerging viruses, due in large part to its capacity to transmit from person to person [11]. Although only ~10% of Nipah patients transmit the virus to others, transmission is highly heterogeneous and super-spreaders have infected dozens of people [12]. Close caregivers, typically family members but also sometimes healthcare workers, are at highest risk for infection, which most likely occurs through contact with infectious respiratory secretions from the patient [12]. Prevention of human-to-human transmission through quick diagnosis and infection prevention measures are among the best prevention strategies currently available.

Animal Models

Animal models have been developed that reasonably recapitulate human disease as it is currently understood, providing valuable insights into pathogenesis and creating necessary platforms to test the efficacy of potential therapeutics and vaccines. Syrian hamsters and ferrets develop severe neurological and respiratory disease [13–15], whereas African green monkeys develop severe respiratory disease [16, 17]. African green monkeys are currently considered the gold standard model for assessing the efficacy of Nipah virus disease countermeasures. A model of experimental Nipah virus infection of pigs has also been developed [18], providing a crucial pathway to developing vaccines for pigs to reduce the future risk to commercial industry and to humans working closely with these animals.

Reverse Genetics

The development of reverse genetics systems to produce recombinant Nipah viruses provides an important tool for studying Nipah virus in vitro and in vivo [19–21]. The ability to introduce reporter genes, knock out protein functions, or introduce specific mutations has already been used to study Nipah virus spread in a host, functions of individual viral proteins, and specific elements of the virus replication cycle [21–24], and will undoubtedly lead to many more discoveries on molecular determinants of pathogenesis and transmission in the years to come.

Vaccines and Antivirals

Increasing concerns about Nipah virus have spurred investment in vaccines. Several vaccine candidates, which have been efficacious in animals models, have been selected by the Coalition of Epidemic Preparedness Innovation (CEPI) to progress through phase I and II clinical trials (https://cepi.net/research_dev/priority-diseases/).

Many antivirals have been tested in the quest for Nipah virus therapeutics, but only 2 have shown good therapeutic efficacy in non-human primates: the monoclonal antibody m102.4 and the nucleotide prodrug remdesivir [17, 25, 26]. Efficacy data for m102.4 are most promising, with protection from both lethal Nipah virus strains Malaysia and Bangladesh when administered at 5 (Malaysia strain) or 3 days (Bangladesh strain) after challenge.

A Growing Family

New henipaviruses continue to be discovered, including Cedar, Mojiang, and Ghanaian bat viruses [27–29]. Cedar virus lacks essential pathogenicity factors [30, 31] and is considered non-pathogenic to humans, but the risk posed by the other viruses remains unknown. These newly discovered henipaviruses have radically expanded our understanding of the geographic range of henipaviruses, which now extends into the Far East and Africa.

KNOWLEDGE GAPS

Nipah Virus Strain Variation

The vast majority of experimental Nipah virus research in the past 20 years has been performed with a single isolate obtained from a patient during the Nipah virus outbreak in Malaysia. More recent work has expanded to include an isolate from a patient in Bangladesh. However, this still means that all experimental knowledge on Nipah virus has been derived from work with only 2 virus strains, limiting inferences and interpretations about the impact of strain variation on pathogenicity, virus shedding, transmission, and efficacy of countermeasures.

Zoonotic Transmission

Infection dynamics in bats are largely unknown, as are the biotic and abiotic factors that may affect these dynamics and, most importantly, virus shedding. The number of spillover events varies drastically from year to year in Bangladesh (Nikolay et al, this supplement), but it is unclear whether this variation is due to changes in viral shedding in the fruit bat reservoir, changes in human behavior, or other factors. Furthermore, the information about Nipah virus spillovers comes almost exclusively from Bangladesh, and these spillover pathways may not be representative of other areas where Nipah virus is prevalent in fruit bats. Indeed, the virus has been detected in bats in many countries that have not reported human Nipah cases. This lack of human cases could reflect a gap in surveillance or may indicate that necessary drivers of zoonotic transmission are missing in these regions.

Human Infection and Pathogenesis

The pathogenesis of Nipah virus in humans remains poorly understood. Disease progression is rapid, and delays in seeking care coupled with lack of rapid diagnostics means that only rarely are patients diagnosed with Nipah virus infection before death, severely limiting opportunities to collect biological samples. Furthermore, outbreaks have occurred in areas where diagnostic autopsy is not the standard of care, due to religious and cultural concerns or to limited capacity, further limiting samples available for analysis. Data on tissue and cell tropism, replication kinetics in these cells, virus shedding, host factors affecting human-to-human transmission, and the role of the innate and adaptive immune responses in the disease process are critical for a thorough understanding of Nipah virus pathogenesis and for bridging data from animal models to humans. More data on Nipah virus disease in patients are indispensable for clinical testing and licensing of vaccines and antivirals, and collection of these difficult-to-obtain data should be a priority now that vaccines and antivirals are scheduled to be tested for efficacy in humans soon. Indeed, until and unless we gain the ability to quickly diagnose patients, clinical trials will remain impractical.

Quest for Survival

Nipah virus patients are as likely to succumb to infection today as they were 20 years ago. Encephalitis and acute respiratory distress, 2 common features of Nipah infection, are notoriously difficult to treat, and the absence of any best practice guidelines for supportive care further complicates patient care. However, a lack of funding for development of countermeasures also has resulted in limited progress; although CEPI is funding clinical trials of vaccine candidates, a similar effort for Nipah virus therapeutics is not in place.

CONCLUSIONS

In the past 20 years, Nipah virus has been just one of many emerging bat-borne zoonotic virus threats to global health security, along with severe acute respiratory syndrome-coronavirus (CoV) that emerged in 2003, Ebola virus, and, most recently, the novel coronavirus that emerged in Wuhan, China, in late 2019. Growing concerns about these pathogens have led to increased investments in vaccine development. These efforts are welcome, and licensing of effective candidate vaccines would dramatically improve our ability to mitigate the impact of the emergence of a more transmissible Nipah virus strain. Despite commitments to vaccine development, many basic facts about Nipah virus epidemiology, biology, and ecology remain unknown. Until we better understand the basics of Nipah virus, our ability to prevent spillovers and cure the disease will not improve.

Notes

Disclaimer. The findings and conclusions in this report are those of the authors and do not necessarily represent those of the Centers for Disease Control and Prevention.

Financial support. E. S. G. is supported by the Preventing Emerging Pathogenic Threats (PREEMPT) program from the Defense Advanced Research Projects Agency; C. F. S. is supported by core funding at the Centers for Disease Control and Prevention; E. d. W. is supported by the Intramural Research Program of National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) and the NIH Distinguished Scholars Program.

Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.