Tropical Medicine and Infectious Disease Review Evolution of Nipah Virus Infection: Past, Present, and Future Considerations Naomi Hauser 1 , Alexis C. Gushiken 2, Shivakumar Narayanan 2, Shyam Kottilil 2 and Joel V. Chua 2,* 1 Division of Infectious Diseases, University of California Davis Medical Center, Sacramento, CA 95817, USA; [email protected] 2 Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; [email protected] (A.C.G.); [email protected] (S.N.); [email protected] (S.K.) * Correspondence: [email protected]; Tel.: +1-410-706-5704 Abstract: Nipah virus (NiV) is a zoonotic paramyxovirus of the Henipavirus genus first identified in Malaysia in 1998. Henipaviruses have bat reservoir hosts and have been isolated from fruit bats found across Oceania, Asia, and Africa. Bat-to-human transmission is thought to be the primary mode of human NiV infection, although multiple intermediate hosts are described. Human infections with NiV were originally described as a syndrome of fever and rapid neurological decline following contact with swine. More recent outbreaks describe a syndrome with prominent respiratory symptoms and human-to-human transmission. Nearly annual outbreaks have been described since 1998 with case fatality rates reaching greater than 90%. The ubiquitous nature of the reservoir host, increasing deforestation, multiple mode of transmission, high case fatality rate, and lack of effective therapy or vaccines make NiV’s pandemic potential increasingly significant. Here we review the epidemiology and microbiology of NiV as well as the therapeutic agents and vaccines in development. Citation: Hauser, N.; Gushiken, A.C.; Keywords: Nipah virus; Nipah virus infection; zoonoses; emerging infection; henipaviruses Narayanan, S.; Kottilil, S.; Chua, J.V. Evolution of Nipah Virus Infection: Past, Present, and Future Considerations. Trop. Med. Infect. Dis. 2021, 6, 24. https://doi.org/10.3390/ 1. Introduction tropicalmed6010024 Nipah virus (NiV) is a member of the Henipavirus genus of the Paramyxoviridae family and is a zoonotic virus with a high case fatality rate [1]. Our knowledge of the geographic Academic Editor: Kathryn M. Jones distribution of NiV and the disease it causes, mode of pathogen transmission, and clinical manifestations of infection, have evolved over time. The first recognized human infection Received: 12 January 2021 was in the Malaysian village of Kampung Sungai Nipah in 1998, initiating a deadly outbreak Accepted: 9 February 2021 that lasted through 1999 [1,2]. Smaller sporadic outbreaks have since recurred nearly Published: 14 February 2021 annually within South Asia with case fatality rates reaching greater than 90% [3,4]. The original human NiV infections were found to be associated with contact with Publisher’s Note: MDPI stays neutral swine, and it was later confirmed that NiV could be isolated from the nose and oropharynx with regard to jurisdictional claims in of pigs [1,2,5,6]. Human infections were characterized by fever for up to 14 days, meningitis published maps and institutional affil- and/or encephalitis, with rapid neurological decline and progression to coma within 24 to iations. 48 h [5]. Later outbreaks outside the Malay peninsula have been characterized by different transmission dynamics and clinical presentation, including the development of severe respiratory symptoms in addition to neurological complications, with human infection traced to the consumption of horse meat, proximity to other infected humans, and ingestion Copyright: © 2021 by the authors. of raw date palm sap contaminated with the bodily fluids of bats [3,7–14]. Licensee MDPI, Basel, Switzerland. Similar to lyssaviruses, filoviruses, coronaviruses, and the related Hendra virus, NiV This article is an open access article is naturally hosted by pteropid bats [15,16]. Fruit bats found across Oceania, South and distributed under the terms and Southeast Asia, and sub-Saharan Africa are the natural reservoirs of NiV, and almost conditions of the Creative Commons yearly outbreaks of NiV infections continue to occur throughout South and Southeast Attribution (CC BY) license (https:// Asia [16,17]. The high case fatality rate associated with NiV infection, ubiquitous nature creativecommons.org/licenses/by/ 4.0/). of the reservoir host, increasing deforestation, and expanding modes of transmission Trop. Med. Infect. Dis. 2021, 6, 24. https://doi.org/10.3390/tropicalmed6010024 https://www.mdpi.com/journal/tropicalmed Trop. Med. Infect. Dis. 2021, 6, 24 2 of 12 Trop. Med. Infect. Dis. 2021, 6, 24 2 of 12 yearlycoupled outbreaks with a lackof NiV of rapidinfections diagnostics continue and to effectiveoccur throughout vaccine or South therapeutic and Southeast agents makeAsia [16,17].Nipah The virus’ high pandemic case fatality potential rate associated increasingly with relevant. NiV infection, The following ubiquitous is a nature review of of the the reservoirepidemiology host, andincreasing microbiology deforestation, of NiV asan welld expanding as the drugs modes and of vaccines transmission being evaluatedcoupled withfor thea lack treatment of rapid and diagnostics prevention and of NiVeffectiv infection.e vaccine or therapeutic agents make Nipah virus’ pandemic potential increasingly relevant. The following is a review of the epidemi- ology2. Epidemiology and microbiology of NiV as well as the drugs and vaccines being evaluated for the treatmentThe and original prevention NiV infection of NiV infection. cluster was first identified in September 1998 in Perak, Malaysia, followed by second and third clusters in the state of Negri Sembilan, with cases 2.occurring Epidemiology primarily among adult men in contact with swine [1,2,5]. In March 1999, a cluster of 11The similar original cases NiV was infection recognized cluster in Singapore was first amongidentified abattoir in September workers 1998 in contact in Perak, with Malaysia,pigs imported followed from by the second outbreak and regions third clusters of Malaysia, in the withstate NiVof Negri isolated Sembilan, from both with affected cases occurringpatients andprimarily the pigs among [1,2, adult6,17]. men Thereafter, in contact outbreaks with swine continued [1,2,5]. In to March spread 1999, throughout a clus- terMalaysia, of 11 similar leading cases to restrictions was recognized on swine in Singapore imports to among nearby abattoir Singapore, workers nationwide in contact NiV withtesting pigs among imported pigs from in Malaysia, the outbreak and ultimately regions of the Malaysia, mass culling with NiV of over isolated one million from both pigs affectedfrom any patients farm inand Malaysia the pigs with [1,2,6,17]. a confirmed Thereafter, infection. outb Together,reaks continued these interventions to spread throughoutultimately resultedMalaysia, in theleading end ofto therestrictions outbreak on nearly swine two imports years after to nearby initial discoverySingapore, [1 ,na-2,5]. tionwideSporadic NiV testing NiV outbreaks among pigs have in Malaysia, occurred inand multiple ultimately countries the mass throughout culling of South over one and millionSoutheast pigs Asia from since any itfarm was in first Malaysia discovered with (Figurea confirmed1), and infection. these recurrent Together, episodes these inter- differ ventionsfrom the ultimately large early resulted outbreaks in ofthe the end Malayan of the outbreak peninsula nearly with regardstwo years to clinicalafter initial presenta- dis- coverytion, case [1,2,5]. fatality rate, and mode of transmission (Table1). SporadicA new and NiV distinct outbreaks strain have of NiV, occurred with infectionin multiple characterized countries throughout largely by acute South severe and Southeastrespiratory Asia symptoms, since it was arose first indiscovered Bangladesh (Figure and 1), India and inthese 2000–2001. recurrent Epidemiological episodes differ fromstudies the revealedlarge early clustering outbreaks around of the household Malayan members peninsula and with hospital regards contacts to clinical without presen- clear tation,animal case exposure, fatality raisingrate, and suspicion mode of for transmission human-to-human (Table 1). transmission [7,9,11]. FigureFigure 1. 1. NipahNipah virus virus infection infection outbreak outbreak by by decade. decade. Il Illustrationlustration created created by by authors authors using using Esri. Esri. Trop. Med. Infect. Dis. 2021, 6, 24 3 of 12 Table 1. Nipah virus outbreaks listed in chronologic order with case fatality rates, exposure history, and clinical features. Legend—ARDS: acute respiratory distress syndrome; CFR: case fatality rate; CSF: cerebrospinal fluid; MODS: multiorgan dysfunction syndrome. Cases Fatalities Exposure History, Transmission, Country Year(s) Reference N (% CFR) Clinical Features • Close contact with pigs (i.e., pig farmers) • Preceded by symptomatic Chua 2000 [1] Malaysia Sep 1998–Dec 1999 265 105 (38.5%) infection in pigs Goh et al., 2000 [18] • Febrile encephalitis • Incubation period: 4 days to 2 months (90% in ≤ 2 weeks) • Abattoir workers • Pigs imported from a Malaysian farm affected by the virus Singapore March 1999 11 1 (9.1%) Paton et al., 1999 [6] • Encephalitis and atypical pneumonia • Nipah virus positive in CSF and tissue • Almost annual outbreaks since 2001 • Direct consumption of fruit bat-contaminated date Luby et al., 2006 [13] Jan 2001–Feb 2015 palm sap Bangladesh 261 19 (75.9%) Gurley et al., 2017 [10] (17 outbreaks) • Human-to-human Nikolay et