Nipah virus: epidemiology, pathogenesis, treatment, and prevention

Abstract

Nipah virus (NiV) is a zoonotic paramyxovirus that has recently emerged as a crucial public health issue. It can elicit severe encephalitis and respiratory diseases in animals and humans, leading to fatal outcomes, exhibiting a wide range of host species tropism, and directly transmitting from animals to humans or through an intermediate host. Human-to-human transmission associated with recurrent NiV outbreaks is a potential global health threat. Currently, the lack of effective therapeutics or licensed vaccines for NiV necessitates the primary utilization of supportive care. In this review, we summarize current knowledge of the various aspects of the NiV, including therapeutics, vaccines, and its biological characteristics, epidemiology, pathogenesis, and clinical features. The objective is to provide valuable information from scientific and clinical research and facilitate the formulation of strategies for preventing and controlling the NiV.

Keywords

Nipah virus / epidemiology / pathogenesis / treatment / prevention

1 Introduction

The emergence of viral diseases in recent years has considerably impacted human health. In late August, another outbreak of the Nipah virus (NiV) emerged in the southern Indian state of Kerala, resulting in six confirmed cases, two of which were fatal [1]. Over 700 individuals, including healthcare workers, were tested for infection, and schools, offices, and public transportation networks were closed [2]. This outbreak marks the fourth occurrence within Kerala over the past five years since 2018 [3, 4]. Notably, NiV outbreaks have been consistently reported annually across the other countries of South and Southeast Asia, such as Malaysia, Singapore, Bangladesh, India, and Philippines, since 1998 [5–8]. Despite typically exhibiting localized impact geographically, these outbreaks showed heightened lethality due to NiV’s high pathogenicity and mammal’s high capacity for zoonotic and human-to-human transmission. Consequently, increased human-to-human transmission potentially enhances contagion levels, and the NiV has attracted considerable interest in recent decades.

As an emerging zoonotic virus transmitted by bats, the NiV was initially isolated and characterized in Malaysia in 1998 [9]. The spread of infection remained uncontrolled because measures were primarily focused on managing the Japanese Encephalitis (JE) outbreak until the NiV was isolated from the cerebrospinal fluid of a victim two months after NiV infection [10]. The name “Nipah virus” was derived from Kampung Sungai Nipah (Nipah River village) in Negeri Sembilan State, Malaysia, where the virus was first confirmed in patient serum samples exhibiting encephalitis symptoms [11, 12]. The NiV belongs to the RNA virus group Mononegavirales along with other commonly known viruses, such as the Hendra, Ebola, measles, mumps, rabies, and Marburg viruses [13]. Two major genetic lineages of the NiV cause diseases in humans: NiV Malaysia (NiV-MY) and NiV Bangladesh (NiV-BD) [14]. The two strains are largely indistinguishable in function but may substantially differ in pathogenicity and transmissibility. Notably the NiV-BD is more pathogenic than the NiV-MY [15–19]. The primary modes of transmission of the NiV to humans include direct contact with infected animals, particularly fruit bats of the Pteropus genus [20], or consumption of contaminated food, such as raw date palm sap. The initial outbreak occurred in India in 2001 mainly through close human-to-human contact [21, 22]. NiV infection can result in various clinical manifestations ranging from mild flu-like symptoms to severe respiratory distress and encephalitis. Additionally, it can cause serious diseases in animals, leading to substantial economic losses affecting farmers [23].

In 2018, the World Health Organization (WHO) acknowledged NiV infection as a global health concern and designated it as a priority disease, underscoring the urgent need for research on the epidemiology, modes of transmission, and potential prevention of the disease and corresponding control strategies [12, 24]. Owing to its high mortality rate in humans and zoonotic nature, the NiV is classified as a biosafety level 4 pathogen. However, many countries have limited access to NiV samples, and research on NiV infection has been impeded by the limited number of cases and diagnostic challenges. Despite the increasing risk of a global pandemic, comprehensive studies that integrate data from NiV infections in pigs, bats, and humans remain scarce. Currently, no specific therapeutic intervention for NiV infection is available, symptomatic supportive care remains the primary approach, and a vaccine against NiV is yet to be developed [25, 26].

Here, we conducted a comprehensive review of this highly pathogenic microorganism, encompassing its biological characteristics, epidemiology, pathogenesis and clinical manifestations. Additionally, we examined therapeutic approaches and vaccine strategies, focusing on the unconventional outbreak patterns linked to modified transmission methods. Furthermore, we analyzed the current situation and proposed multidisciplinary approaches from clinical and scientific perspectives to effectively address this public health concern.

2 Epidemiology

2.1 NiV infection outbreaks in Southeast Asian countries

The initial documentation of NiV outbreak originated from Malaysia, where the 1998 outbreak has been extensively documented in the literature [27, 28]. Notably, an earlier outbreak occurred in Malaysia in 1997. A herd of pigs on a farm in the Ampang district of Malaysia experienced an unprecedented mass mortality event [10]. Simultaneously, a veterinarian working on the farm developed encephalitis. In 1998, the Kinta district, which is near the site of the previous outbreak, had a series of reported cases in pig farmers, who exhibited symptoms, such as fever, headache, and impaired consciousness [10, 27, 28]. The authorities declared a JE outbreak after the detection of JE IgM antibodies in four patients, and then the local government implemented intensive fogging with insecticides in the outbreak area and vaccinated people with JE vaccines imported from Japan. However, the containment of the epidemic remains elusive [10, 29, 30]. From 1998 to 1999, a large-scale outbreak occurred in Malaysia, predominantly affecting adults and deviating from the typical epidemic characteristics associated with JE [10, 30]. Thus, a virus sample was sent to the Centers for Disease Control and Prevention (CDC) on March 12, 1999. The virus’s nucleocapsid resembled a “human bone” structure, which indicated that it is a novel type of paramyxovirus [10]. Upon receiving the results on March 15, 1999, authorities in Malaysia adjusted their strategies and successfully contained the outbreak [31, 32]. All pigs in the areas were declared infected and culled by shooting either in burial pits or within pens. The carcasses were buried after quick lime was applied. All pig farm workers and abattoir workers and veterinary staff who were in contact with infected animals were required to use goggles, face shield, mask, rubber boots, thick rubber gloves, long apron, long sleeved shirt, and long pants. Other precautions included the use of a separate needle for each pig, washing with detergent or soap and water after handling pigs, avoiding contact with blood, urine, or feces of pigs, proper disinfecting of abattoir and knives, disinfecting dead or sacrificed animals prior to burial, and spraying of trucks with disinfectant [31, 32]. In April 1999, the virus was initially isolated from the cerebrospinal fluids of patients in Malaysia [9]. The NiV was named from its first isolation site: Sungei Nipah Village [33, 34]. Between September 1998 and December 1999, a total of 283 NiV infection cases were reported in Malaysia, resulting in 109 deaths [34] (Fig.1).

Fig.1 NiV outbreaks and consequences.

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Given that the NiV emerged in Malaysia, it quickly spread to Singapore due to the importation of live pigs from Malaysia. Between March 9 and March 19, 1999, a total of 11 abattoir workers in Singapore were hospitalized because of encephalitis followed by pneumonia, and one died [35]. The slaughterhouse that employed these workers had imported pigs from an NiV-affected farm in Malaysia, and all patients had close contact with infected pigs [35, 36]. Further testing confirmed the genetic identity between the virus that caused the outbreak in Malaysia [30, 36] and the virus involved in Singapore’s outbreak. A case-control study of the epidemic in Singapore showed that exposure to urine or feces from infected live pigs is a risk factor for human NiV infection [36]. After the NiV outbreak, Chan et al. [37] tested 1469 Singaporean residents at risk of exposure for serological antibodies and found that 22 out of 1469 (1.5%) indicated NiV infection, and all antibody-positive individuals have had direct contact with pigs. However, only 12 (54.6%) infected patients had respiratory and neurological symptoms, whereas 10 (45.4%) had no clinical symptoms, suggesting asymptomatic NiV infections. The importation of pigs from NiV-affected areas in Malaysia was banned in Singapore, and contaminated slaughterhouses were closed [38]. The ban effectively controlled the outbreak. Since then, no new cases associated with NiV have been reported in the country.

From April to May in 2001, the village in Meherpur District, Bangladesh, had 13 cases of encephalitis with nine fatalities. Preliminary investigations by the Bangladesh Ministry of Health and the WHO excluded a diagnosis of JE, dengue fever, or malaria, but two of the 42 serum specimens obtained from village residents in May 2001 showed reactive antibodies to NiV antigen in tests performed at the US CDC [39]. This report was the first NiV infection in the history of Bangladesh. Since then, NiV infections have been reported in Bangladesh annually and are often associated with high mortality [14, 39]. In January 2003, additional 12 patients contracted NiV infection in Naogaon district, which was located approximately 150 km away from Meherpur District, and eight patients reportedly died [14, 39]. In 2004, an NiV outbreak occurred in the Faridpur District of Bangladesh, resulting in 36 confirmed cases and a fatality rate of 75% [40]. Emily et al. identified potential human-to-human transmission in this outbreak through a case-control study [40]. The subsequent NiV outbreak in Thakurgaon in 2007 provided further evidence of NiV transmission between humans potentially through close contact with the patient’s respiratory secretions and body fluids [41–43]. A total of 208 patients and 161 deaths were reported in Bangladesh from 2001 to 2012 [14], and 242 cases of NiV in Bangladesh were reported as of March 2019 [14, 44].

In January 2023, another NiV outbreak reoccurred in Bangladesh. A team of experts, led by the Institute of Epidemiology, Disease Control and Research, conducted investigations. From January 4 to March 2, 2023, three clusters and seven sporadic NiV outbreaks were identified from seven districts of Bangladesh. A total of 14 Nipah cases were reported, which included 86% (12/14) laboratory-confirmed and 14% (2/14) probable cases. There were 11 cases of primary infection, all with the history of raw date palm sap consumption prior to symptom onset. During the investigations, 675 contacts were identified; among them, three individuals were infected with the NiV, indicating human-to-human transmission. As of March 4, there were 14 new cases with 10 deaths, resulting in a fatality rate as high as 71% [45, 46].

The NiV virus has caused multiple outbreaks in India for nearly two decades. In early 2001, an outbreak of febrile central nervous system occurred in Siliguri, which is near the border between India and Bangladesh, resulting in 66 infections and 45 fatalities [6, 47]. This event marks the first occurrence of NiV infection in India. Subsequently, Mandeep et al. conducted a retrospective analysis on clinical data from 19 patients involved in the outbreak, of which nine exhibited NiV-specific antibodies [6, 48]. Sequence analysis suggested that the NiV strain from Siliguri, India, was more closely related to NiV isolates from Bangladeshi patients than to NiV isolates from Malaysian patients [6]. This outbreak primarily affected healthcare personnel in hospital settings potentially because of direct exposure to patients’ bodily fluids. Subsequent investigation unveiled the presence of viral RNA in patients’ urine, indicating a potential risk for human-to-human NiV transmission [6]. In April 2007, India experienced its second NiV outbreak in West Bengal, resulting in the death of five patients [49, 50]. The first patient was a 35-year-old male farmer with a strong preference for consuming palm wine, which may have been contaminated by fruit bats [50]. Three patients were relatives of the index patient, and one patient was a healthcare worker who had close contact with the index patient [50]. In May 2018, the largest NiV outbreak occurred in southern India [4, 51]. The index case was a 27-year-old man, and other patients had direct or indirect contact with him. A total of 23 suspected cases, out of which 18 were confirmed, resulting in 21 deaths reported [4]. NiV RNA was detected in all the confirmed cases, and NiV-specific antibodies were detected in 13 of these patients [4]. In 2019, another NiV outbreak occurred in Ernakulam District, Kerala, India, and the index case was a 21-year-old man [52]. The outbreak was swiftly contained through the strict isolation of the index case and close monitoring of 300 contacts [3]. The death of a 12-year-old boy in Kozhikode District in 2021 was attributed to NiV infection caused by the consumption of wild fruit [12, 53, 54]. In September 2023, another NiV outbreak occurred in the district, resulting in six confirmed cases and two deaths [55, 56]. The index case was a 49-year-old man, and the remaining cases had close contact with him [55, 56].

In 2014, an outbreak of NiV infection occurred in the Philippines and was associated with horse consumption and contact. Unusually fatal human cases were reported on April 2, 2014 in two villages on the island of Mindanao [57, 58]. A joint team from the Philippine government and the WHO investigated the outbreak from May 22 to 24, identifying 17 suspected cases including two deaths [57, 58]. Anti-NiV IgM antibodies were detected in specimens from three patients, and subsequent single-sequence reading of the P gene of NiV revealed that the responsible strain was more similar to the Malaysian strain [57]. Epidemiologic investigations showed that 10 of 17 infected individuals had been involved in horse slaughter or consumption, and seven, including two healthcare workers, had contact with patients [57].

2.2 Animal reservoirs

The role of hosts is crucial to the transmission and emergence of the NiV. According to a comprehensive case-control trial, the 1998–1999 Malaysian outbreak demonstrated a robust correlation between patient infection and close contact with infected pigs [11]. This finding is supported the effectiveness of controlling the outbreak after culling more than 1 million pigs and treating and disinfecting their carcasses and living environments [59, 60]. Notably, infected pigs usually present with respiratory and neurological symptoms, but most pigs may develop mild illness from infection without being detected [11]. Epidemiological investigations have demonstrated that bats serve as the primary reservoirs for transmitting NiV to pigs, which subsequently infect humans through close contact with pig feed or drinking water contaminated with urine and saliva [29]. The migration of forest fruit bats to human pig farms may be due to anthropogenic factors, such as deforestation and wildlife trade [20, 34, 61]. In Bangladesh, most NiV outbreaks occurred mainly in the central and northwestern regions of the country [14, 47, 58]. The natural habitats of flying foxes, which have been identified as the primary natural animal reservoirs for NiV, are predominantly located within these areas [58, 62]. A case-control study in Bangladesh identified the consumption of raw date palm juice contaminated with fruit bats as a major cause of illness [22]. Given that outbreaks primarily occur during the date palm picking season, it suggests a potential link between flying foxes frequently ingesting date palm juice and subsequently contaminating jars with urine or feces [7, 63]. In the 2018 NiV outbreak in India, Yadav et al. used PCR and sequencing to compare patient specimens with bat-borne viruses and found a similarity of 99.7 to 100%, strongly suggesting that bats are the source of the outbreak [64].

The NiV had caused numerous outbreaks, exhibiting a diverse host range, from bats as natural reservoirs [65] to other animals, and wide geographical distribution (Tab.1). The diversity of NiV hosts may be attributed to the utilization of highly conserved ephrinB2/B3 receptor molecules by NiV, which are present in all mammals [66, 67]. During the NiV outbreak in Malaysia in 1998–1999, epidemic-related deaths were reported early in pigs, dogs, and cats, and the NiV antigen was found in the lung and kidney tissues of infected pigs [11]. Dogs were also tested positive for NiV antibodies [68] or were infected through immunohistochemistry during the Malaysian outbreak [69]. Further, nucleotide sequencing of kidney and liver tissues from a dead dog confirmed NiV infection [70]. Multiple NiV outbreaks in Bangladesh have demonstrated the involvement of domestic animals (such as cattle, pigs, and goats) [39, 41, 71]. Sukant et al. identified soluble attachment glycoproteins (sG) of henipaviruses (NiV and Hendra virus (HeV)) in the sera of cattle, goats, and pigs in a study based on serological investigations; however, these antibodies did not neutralize NiV [71]. In the NiV outbreak in the Philippines, horses, dogs, and cats died due to NiV infection [57]. However, NiV-neutralizing antibodies were not detected in the animal samples, except in the sera of four dogs [57]. These animals contracted the infection through ingestion of food contaminated with bat saliva or urine [41,71], and NiV infected various animals in experiments, including guinea pigs, hamsters, ferrets, squirrel monkeys, and African green monkeys [14, 72–74]. Although NiV can infect a variety of animals, only infected pigs are highly contagious to humans [68, 75], and evidence of the spread of NiV infection in other animals and the transmission of NiV from animals to humans is lacking.

Tab.1 NiV-infected animal hosts

Category	Animal	Geographic location/country	Association to human cases (yes/no)	Infection route and outcome	Method of detection	Reference
Natural host	Fruit bat	Malaysia, Bangladesh, India, Indonesia, Thailand, Cambodia, Vietnam, Madagascar, Ghana, etc.	Yes	IW/RNS	EI, PCR and NiV antibodies	[29, 50, 63, 65, 77–82]
Reservoir host	Pig	Malaysia, Singapore, Bangladesh,	Yes	IW, IL/RNS, Death	EI and NiV antibodies	[11, 36, 71]
	Horse	Philippines	Yes	IW/RNS, Death	EI	[57]
	Dog	Philippines, Malaysia	No	IW, IL/RNS, Death	Immunohistochemistry, NiV antibodies and EI	[11, 68, 69, 72]
	Cat	Philippines	No	IW, IL/RNS	EI and AI	[11, 72]
	Squirrel monkey	_	No	IL/RNS	AI	[14, 73]
	Golden hamster	_	No	IL/RNS, Death	AI	[14, 74]
	Cattle	Bangladesh	Suspect	IW/RNS	NiV antibodies	[71]
	Goat	Bangladesh	Suspect	IW/RNS	NiV antibodies	[71]
	Guinea pig	_	No	IL/Unknown	AI	[14]
	Ferret	_	No	IL/Unknown	AI	[14]
	Rat	Malaysia	Suspect	IW/Unknown	EI	[11]
	African green monkey	_	No	IL/Unknown	AI	[14]

Abbreviation: PCR, polymerase chain reaction; EI, epidemiological investigation; AI, artificial infection; IL, infections in laboratory; IW, infections in wild; NS: no obvious symptoms; RNS, respiratory neurological symptoms.

The NiV is widely distributed across many countries geographically. Fruit bats, the natural host of NiV, are mainly found in tropical and subtropical regions of Asia, East Africa, mainland Australia, and some oceanic islands [3, 76]. A survey conducted in Thailand found that the recovery rate of NiV RNA in bats was the highest in May [77]. NiV antibodies were detected positive in Pteropus lylei species [78]. A restaurant in Cambodia detected NiV antibodies in the sera of bats served as food [79]. This finding suggests that the local population is at a high risk of NiV infection [79]. NiV positive host animals have also been reported in Vietnam [80], Madagascar [81], Ghana [82], and other Asian and African countries.

3 Biological characteristics

NiV is a nonsegmented negative-sense single-stranded RNA virus that belongs to the family Paramyxoviridae and genus henipavirus, which also includes HeV, Ghanaian bat virus, Cedar virus, Mojiang virus, Gamak virus, Daeryong virus, and Langya virus that was identified in patients from China [83–85]. The most striking unusual biological characteristics of henipaviruses are their zoonotic potential and broad host tropism including pigs, dogs, cats, horses, guinea pigs, hamsters, bats, and humans [61, 86–88]. NiV is highly similar to HeV, showing 68.0%–92.0% and 40.0%–67.0% homology in protein-coded regions and non-translated regions, respectively [47, 89].

Similar to other paramyxoviruses, NiV particles are enveloped, pleomorphic, and spherical to filamentous [9, 90]. The viral envelope is a lipid bilayer derived from the infected host cell during virus assembly and budding that contains a single layer of surface projections with an average length of 17 ± 1 nm [14, 91]. NiV is larger in diameter (500 nm) than typical paramyxoviruses (150–400 nm), with extreme variations in size ranging from 40 nm to 1900 nm [92, 93]. It has reticular cytoplasmic inclusions close to the endoplasmic reticulum, unlike other paramyxoviruses [21].

Among the NiVs known to cause disease in humans, there are two major genetic lineages, NiV-MY and NiV-BD [14]. The NiV-MY genome is 18 246 nucleotides (nt) in length, whereas NiV-BD genome is 18 252 nt long [94]. The amino acid homology between the proteins expressed by NiV-MY and NiV-BD is 92.0%, and the nucleotide sequences show 91.8% similarity [95]. Compared with Bangladesh NiV strains, the NiV strains prevalent in India exhibit ~4% nucleotide and amino acid disparity [96]. Functionally, the two strains are largely indistinguishable but may considerably differ in pathogenicity and transmissibility [15]. Studies on African green monkeys reported that NiV-BD is more pathogenic than NiV-MY [15–19], and ferret infection study showed that NiV-BD infection increased oral shedding and had more rapid onset and higher levels of virus replication in the respiratory tract than NiV-MY infection [97, 98]. These differences may explain why the cases in Bangladesh and India have shorter incubation periods, more severe respiratory symptoms (disease), greater human-to-human transmission, and higher case fatality rates than cases in other countries; meanwhile, NiV-MY cases are mostly associated with neuroinvasive infections [99, 100].

The genome RNA of NiV consists of six structural genes, the nucleocapsid (N), the phosphoprotein (P), the matrix protein (M), the fusion glycoprotein (F), the surface attachment glycoprotein (G), and long polymerase or RNA-dependent RNA polymerase (L), flanked by 3′ leader and 5′ trailer regions (Fig.2) [86, 101]. The N protein complexes with P and L proteins and forms ribonucleoproteins (RNPs), which are responsible for encapsidating the genome RNA of NiV in a ratio of one N to six nucleotides [102]. The RNP is responsible for the initial transcription of viral mRNAs [103]. Given the exact nucleotide-N match at the RNA 3′-end is required for the formation of an active replication promoter, the NiV genome must conform to the “rule of six” and count 6n + 0 nucleotides, similar to the genomes of all the viruses in the subfamily Paramyxovirinae [102, 104, 105].

Fig.2 NiV structure and its genetics.

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The NiV P protein encoded by the P gene is a multitasking protein. That is not only an essential component of the viral RNA transcription/replication complex but also a component of the viral arsenal that hijacks cellular components and counteracts host immune responses [106]. The P gene encodes three nonstructural proteins (C, V, and W) from overlapping open reading frames in infected cells [14, 107, 108]. The V and C proteins are localized in the cytoplasm, and the nuclear localization of W is cell type specific [108–111]. NiV C, V, and W proteins can inhibit NiV minigenome transcription and replication in a dose-dependent manner [112], which is consistent with observations for other paramyxoviruses [113–116]. All four P gene products have IFN antagonist activity when the proteins were transiently expressed. Studies that used recombinant NiVs lacking V, C, or W protein to analyze the functions of these proteins in infected cells indicated that the lack of each accessory protein does not considerably contribute to the inhibition of IFN signaling in infected cells and V and C proteins play key roles in NiV pathogenicity; these roles are independent of IFN–antagonist activity [117].

The M protein mediates the assembly and release of NiV particles [111]. Late domain motifs found in numerous viral matrix proteins recruit specific host factors to viral assembly sites and facilitate virus release [118]. Potential late domain motifs (YMYL and YPLGVG) have been identified in the NiV M protein, and mutagenizing any of these motifs drastically reduces virus-like particle budding and skews the subcellular localization of the M protein toward the nucleus [119, 120]. In addition, the ubiquitination of the M protein is closely correlated with NiV viral particle budding [121].

The NiV G and F proteins are surface glycoproteins and facilitate viral attachment and host cell infection [86, 122]. The G protein is a receptor-binding protein and engages host cell membrane proteins, known as ephrin B2 and ephrin B3, as entry receptors. Ephrin B2 expression is prominent in arteries, arterioles, and capillaries in multiple organs and tissues, whereas ephrin B3 is predominantly found in the nervous system and the vasculature [123]. Ephrin B2 and B3 are highly conserved across susceptible hosts, including humans, horses, pigs, cats, dogs, mice, and bats, with amino acid identities of 95%–96% and 95%–98%, respectively [66, 124]. The receptor distribution correlates well with the broad species tropism of the NiV and the specific distribution of viral antigen observed in hosts susceptible to NiV infection, which may account for some of the pathology in the central nervous system in NiV patients [86].

The F protein is a fusion protein. After receptor binding, it facilitates the fusion of viral and host cell membranes that finally deliver the viral nucleocapsid into the cytoplasm [125]. Similar to many paramyxovirus fusion proteins, the NiV F protein is synthesized as an inactive precursor F0, which is proteolytically cleaved by a host cell protease (endosomal cathepsin L) into mature disulfide-linked active F1 and F2 subunits [126]. In an NiV infection, this process occurs after initial expression at the cell surface and a subsequent internalisation event [127]. The disulfide-linked subunits are then transported back to the cell surface to be incorporated into budding virions or to facilitate the cell-to-cell spread of virus, forming multinucleated syncytia, which are characteristic features of many paramyxovirus infections [127–129].

The NiV L protein has many different enzymatic functions, catalyzing initiation, elongation, and the termination of mRNA transcription and genome replication [105]. The GDNQ motif contained in the L protein is a putative polymerase catalytic site in most paramyxoviruses [130]. Conversely, the NiV L protein has GDNE in this position. The site-directed mutagenesis of the glutamate residue in the motif GDNE indicated a robust ability of the NiV L protein to tolerate different substitutions in this motif without completely losing its activity, suggesting that this residue is not crucial for the catalytic polymerase activity of the NiV L protein [131].

The NiV can survive for up to 3 days in fruit juice or mango fruit and for at least 7 days in artificial date palm sap (13.0% sucrose and 0.2% BSA in water, pH 7.0) kept at 22 °C [132]. The virus has a half-life of 18 h in the urine of fruit bats [132]. The NiV is relatively stable and remains viable at 70 °C for 1 h (only the viral concentration will be reduced). It can be completely inactivated by 15 min of heating at 100 °C [58]. However, the viability of the virus in its natural environment may vary under different conditions. NiV can be readily inactivated by soaps, detergents, and commercially available disinfectants, such as sodium hypochlorite [133].

4 Pathogenesis

The presence of NiV in the upper respiratory tract epithelial cells of patients during the early stage of the disease indicates potential transmission through contact with respiratory secretions or aerosols [43]. The sensitivity of the respiratory tract epithelium to the NiV indicates that it is the primary site of initial infection [134]. Research on histopathological changes in fatal human cases of NiV suggests that endothelial cells play a crucial role as primary targets, but evidence of this role remains lacking [135]. The NiV employs G protein as an attachment protein to bind ephrin B2/B3 receptors, triggering F-mediated fusion and enabling viral entry into host cells [136] (Fig.3).

Fig.3 NiV pathogenesis in humans [148, 149]. 1: NiV entry into human body. 2a: Via the upper respiratory tract, NiV enters the lower respitroy tract and lung. 2b: Via the upper respiratory tract, NiV enters the olfactory nerve. 2c: Via the olfactory nerve, NiV enters the CNS. 3: NiV uses F and G proteins to attach ephrin B2/B3 epithelial cell surface receptors and enter epithelial cells. 4: NiV replicates itself in the epithelial cells. 5: NiV is released from the epithelial cells and attaches to endothelial cells. 6: NiV uses F and G proteins to attach ephrin B2/B3 endothelial cell surface receptors and enter endothelial cells. In the endothelial cells, NiV replication occurs (synthesis structural, nonstructural protein, replication of the NiV genome, and assembly of viruses occur). 7: NiV enters the blood vessels and forms viremia. 8(a, b, c): NiV enters various organs, such as the heart, kidneys, and spleen. 9(a, b): NiV transcends the blood–brain barrier and infiltrates the central nervous system.

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In the later stages of the disease, viral replication occurs in the respiratory epithelium and subsequently spreads to the vascular endothelial cells of the lungs [137]. In response to small respiratory tract infection, inflammatory cytokines, such as IL-6, IL-4, TNF-α, IFN-γ, IFN-λ, and IFN-β, are upregulated [138–140]. Subsequently, immune cells are recruited to the respiratory tract and lungs, ultimately leading to the manifestation of clinical presentation characterized by respiratory distress [138]. The severe damage and fatal consequences of the NiV are attributed to the inhibition of IFN-dependent antiviral signaling mediated by P proteins and the attenuation of an innate immune response [141–143].

NiV infection trigger vasculitis in small blood vessels and capillaries, while large and medium blood vessels are often unaffected [137]. The NiV enters the bloodstream through damaged capillaries and causes viremia [135]. By binding with heparin sulfate, NiV adheres to circulating leukocytes but does not infect them [144]. Thus, NiV reveals a remarkable capacity to hijack leukocytes as cargo for dissemination within a host [145] (Fig.3).

The NiV disseminates throughout the body via the bloodstream, resulting in the infection of various organs. NiV infection lacks distinctive macroscopic pathological characteristics while usually inducing vasculitis in the brain, lungs, heart, kidneys, and spleen [137] and is characterized by endothelial cell necrosis and inflammatory cell infiltration [146]. The presence of vasculitis was observed in 62% of cases, whereas fibrinoid necrosis was detected in 59% of cases within the lungs [137]. The spleen exhibited white medullary loss and acute necrotizing inflammation of the periarterial sheath [137]. No pathology was observed in the liver, skeletal muscles, and other tissues [137].

The inflammatory factors induce a disruption of the blood–brain barrier integrity, leading to the manifestation of CNS symptoms in patients [14]. NiV infects T cells that express CD16, a potent receptor for the activated leukocyte cell adhesion molecule ALCAM (CD166), which is highly expressed in the microvascular endothelial cells constituting the blood–air and blood–brain barriers. This finding suggests the predilection of NiV to infect small blood vessels in the lungs and brain [147].

Although the central nervous system (CNS) is the most severely affected, the main pathological manifestations include vasculitis, thrombosis, parenchymal necrosis, and viral inclusions [137]. Vasculitis primarily affects small arteries in the brain rather than middle and large arteries. Cerebral hernia has been observed in a few cases [137]. Lastly, NiV can rapidly enter the central nervous system via the olfactory route [148] (Fig.3).

Well-established animal models of NiV infection provide valuable insights into the pathogenesis of the disease [150]. The initial experiments on NiV infection were conducted in 1999, involving pigs, cats, and bats [151]. Pteropid bats as natural hosts of NiV did not exhibit any clinical sign of the disease after they were inoculated with NiV under experimental conditions [76, 152]. Pigs played a crucial role as amplifying and intermediate hosts during NiV outbreaks, reproducing nervous and respiratory diseases accompanied by fever [153, 154]. A hamster model was developed to simulate acute human infections caused by the NiV [74], which has been widely utilized for drug evaluation and vaccine development [155–158]. Additionally, the efficacy of a neutralizing human monoclonal antibody (mAb) against lethal NiV infection was assessed using a ferret model [16]. Acute and highly pathogenic nonhuman primate models were established using squirrel monkeys [73] and African green monkeys [159]. These models have revealed that persistent NiV infection can lead to late-onset encephalitis with relapses in humans [160]. Furthermore, cats inoculated subcutaneously or intranasally/orally with NiV exhibited broncho-interstitial pneumonia and meningitis symptoms [72]. The clinical outcome of NiV infection is correlated with the route and level of virus infection in a hamster model [138].

5 Clinical presentation

NiV primarily causes acute encephalitis and respiratory illness and is highly fatal, ranging from 40% to 75% [49, 161, 162]. In the early stages of NiV infection, patients often have nonspecific symptoms, such as fever, headache, vomiting, dizziness, and myalgia. As the disease progresses, patients may develop severe pneumonia or fatal encephalitis [163]. Neurologic sequelae are frequently observed in acute NiV encephalitis survivors who may have suffered substantial long-term neurologic and functional morbidity [164]. NiV-BD infections are more likely to present with respiratory symptoms than NiV-MY infections [5, 165].

The incubation period for NiV infection ranges from a few days to two months, with an average period of 5–7 days [166, 167]. During this period, 8%–15% of infected people remain asymptomatic [11, 168], whereas others initially exhibit mild flu-like symptoms, including body aches, fatigue, nausea and vomiting [169]. These symptoms may sometimes be indistinguishable from other common upper respiratory infections, posing a diagnostic challenge [6, 166, 167, 170]. Severe cases may progress to pneumonia and ARDS, requiring mechanical ventilation (Fig.4).

Fig.4 Clinical presentation of NiV infection.

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Neurological symptoms are common in reported cases. Patients may experience severe headaches, confusion, drowsiness, and disorientation. As the disease progresses, more severe neurological symptoms, including seizures, coma, and focal neurological deficits, may occur [137, 167]. In a case series composed of 160 patients, more than 10% had either encephalitis relapse or late-onset encephalitis [171]. The clinical features of late-onset and relapse NiV encephalitis are similar to the acute episode of encephalitis and includes seizures and focal neurological signs. Clinical signs include unilateral eyelid ptosis, dysphonia, periodic muscle spasm, tendon reflex loss, decreased muscle tone, neck stiffness, elevated blood pressure, and tachycardia, indicating brain stem and upper neck spinal cord damage; signs of lower motor neuron damage were also detected, such as nystagmus and gait instability. Approximately 80% of survivors presenting with acute encephalitis fully recover, whereas the rest may present with neurological aftereffects, such as epilepsy and personality changes. The death rate is approximately 20% during the clinical course of late-onset relapsing NiV encephalitis [172].

NiV infection has also been associated with other clinical manifestations, including myocarditis [167, 173], pancreatitis, and renal dysfunction [174] (Fig.4), which are rare but can contribute to the overall severity of the disease.

6 Diagnosis

In general, an NiV infection should be considered under the following conditions: visit in an area with endemic NiV disease; history of close contact with pigs or other infected animals; and clinical manifestations indicative of encephalitis, such as fever, headache, altered consciousness, focal neurologic symptoms, cerebrospinal fluid abnormalities, and characteristic changes observed in brain MRI scans. The diagnosis of NiV disease does not necessitate waiting for serological evidence due to only 76% of patients testing positive serologically. Moreover, considering that the average survival time from onset to death is 9 days and serum IgM positivity occurs approximately 15 days after contracting the disease while IgG positivity takes around 34 days to manifest, it is possible for some patients to rapidly deteriorate and succumb before obtaining a positive result.

The NiV disease and JE exhibit similar clinical symptoms but present some distinctions. Notably, all fatalities resulting from NiV encephalitis were observed in adult pig farm workers who had direct contact with infected pigs; many of workers had been previously vaccinated against the JE virus and had recent exposure to pigs prior to the onset of their illness. Conversely, JE predominantly affects children during the mosquito breeding season, whereas adults possess a certain level of immunity toward it. Furthermore, patients infected with the NiV display distinctive symptoms, such as neck and abdominal spasms, which serve as diagnostic markers distinguishing them from people infected with other forms of viral encephalitis.

7 Treatment

To date, no antiviral drugs have been approved for the treatment of NiV infection, and supportive care and prophylactic measures continue to be the primary strategies for managing patients, particularly those with acute encephalitis syndrome [175–177]. Anticonvulsants, maintenance of airway patency, mechanical ventilation, treatment of secondary infection, prophylaxis of venous thrombosis, and rehabilitation are major supportive measures [177].

In the previous NiV outbreak in Malaysia, ribavirin was used as an empirical treatment due to its broad-spectrum antiviral activity and its ability to penetrate the blood–brain barrier in the disease [177, 178]. In vitro studies have shown that ribavirin is effective against NiV infection [149, 179, 180]. During the initial NiV outbreak in Malaysia, an open-label trial of ribavirin was conducted, enrolling 140 cases and 54 controls; the results demonstrated a 26% reduction in mortality rate in the treatment group and reduced neurological complications in the survivors [181]. Ribavirin was also used during the NiV outbreak in Kerala, India, in 2018, but the sample size was extremely small for the evaluation of ribavirin’s efficacy against the NiV [167, 178, 182]. However, studies on animal models were not promising. Two animal studies in hamsters showed that ribavirin treatment delays but does not prevent death from NiV infection [156, 158]. A treatment combining ribavirin and chloroquine was ineffective in a hamster model [156]. Therefore, whether ribavirin improves the outcome of the NiV disease remains uncertain. Thus, an animal model that has great relevance to humans and recapitulates disease processes seen in the human cases of NiV is needed [183].

Acyclovir (zovirax) was used with ceftriaxone for the treatment of nine abattoir workers during the NiV outbreak in 1999 in Singapore; eight of them survived [35]. No other therapeutics have been used for patients with NiV infection, although some antiviral drugs have been evaluated [184]. Remdesivir led to 100% survival in a lethal challenge African green monkey model with NiV-BD after the drug was intravenously administered daily from 24 h after infection and up to 12 days [185]. Favipiravir, as a viral RNA-dependent RNA polymerase inhibitor, demonstrated effective protection against lethal NiV-MY infection in a hamster model immediately after the drug was administered daily for 14 days [157]. In addition, Poly(I)-poly (C12U), an interferon inducer, has shown some efficacy against NiV infection in vitro and in a hamster model [158]. Soluble ephrin B2, a functional receptor for the NiV G glycoprotein, inhibits viral fusion in vitro [186].

The mAb (m102.4) against the G protein of NiV was found to be effective in an animal model; this drug is currently undergoing phase I human trials [16, 187, 188]. Adverse events related to 86 treatments were reported; the placebo and treated groups showed similar rates, demonstrating that a single and repeated dose of m102.4 is safe and well tolerated [188]. Another recent therapeutic development for NiV disease is the cross-reactive humanized mAb h5B3.1 targeting the NiV F protein. The antibody provided promising protection against NiV and HeV diseases in ferrets [189]. Structural analysis of NiV F glycoprotein in complex with the mAb h5B3.1 revealed that the antibody was able to block membrane fusion activity by locking the F glycoprotein in a prefusion conformation [190]. In cell culture studies, algae derived griffithsin demonstrated antiviral activity against NiV in the nanomolar range [191] (Tab.2).

Tab.2 Summary of drugs with potential antiviral activity against NiV

Drug	Description	Experimental model	Finding	Reference
Ribavirin	Guanosine analog	In vitro	Efficacy	[149, 179–181]
		In vitro	Indefinite efficacy	[156, 158, 167, 178, 182]
Acyclovir	Guanosine analog	In vitro with small samples, or historical review	Indefinite efficacy	[35, 184]
Remdesivir	Adenosine analog	In vitro (African green monkeys)	Protection against NiV	[185]
Favipiravir	RNA polymerase inhibitor	In vitro (Syrian hamster)	Protection against NiV	[157]
Poly(I)-poly	Interferon inducer	In vitro (hamster model)	Efficacy	[158]
Ephrin B2	G glycoprotein fusion inhibitor	In vitro	Inhibit viral fusion	[186]
Human mAb m102.4	G glycoprotein fusion inhibitor	In vitro (human), or in animal models (ferrets and African green monkey)	Efficacy or being in phase I human trials	[16, 187, 188]
Human mAb h5B3.1	G glycoprotein fusion inhibitor	In vitro (ferrets)	Promising protection against NiV challenge	[188–190]
Griffithsin	Antiviral lectin	In vivo (cell culture)	Antiviral activity against NiV	[191]

Abbreviation: mAb, monoclonal antibody.

The prognostic of NiV disease is closely related to the NiV strain. In the Malaysia outbreak in 1999, the mean duration of illness from the onset of symptoms to death was 16 days, and the mortality rate was close to 40% [5, 14]. The mortality rates in Bangladesh and India were much higher, exceeding 70% [167]. Old age, severe brain-stem involvement presenting as a reduced level of consciousness, abnormal doll’s-eye reflex, abnormal pupils, vomiting, hypertension, and tachycardia during the course of the disease were considered poor prognostic factors in the outbreak in Malaysia [5]. Antiviral drugs, such as acyclovir and oseltamivir, did not alter the course of the disease in the outbreaks in Bangladesh and India [167].

8 Prevention

Vaccine is the primary measure for the prevention of an infectious disease. However, no approved vaccines for the prevention of NiV infection are currently available for humans [12]. Several vaccines have recently been studied in small-animal models, including virus-like particlebased [192], adenovirus-based [193], chimeric rabies-based [194], and epitope-based [195, 196] vaccines. Naturally occurring human mAbs, specifically those against the HeV receptor binding protein, possess the capacity to neutralize NiV as well [136]. Engineered rVSV effectively protects non-human primates from NiV infection, indicating its potential for rapid human protection against NiV infection [197, 198]. These approaches mainly induced a protection against NiV by triggering a specific response against its envelope glycoprotein G. To date, the only vaccine officially approved and registered is Equivac (Zoetis, Inc.), which was used in the prophylactic treatment of horses [173, 176, 177, 199].

mRNA-based vaccines have attracted considerable interest because of their efficacy, safety, and ease of use. The limited efficiency of HeV-sG mRNA lipid nanoparticle has been reported [200]. A phase I clinical trial to evaluate an experimental vaccine based on an mRNA-1215 NiV vaccine was launched in Maryland at the NIH Clinical Centre, Bethesda [201].

Owing to the absence of an effective vaccine, efforts should be focused on monitoring epidemiological threats and prevention of the emergence and transmission of NiV. Fruit bats belonging to the flying fox family serve as the natural reservoirs of NiV; thus, the risk of bat-to-animal and bat-to-human transmissions should be mitigated. Primary efforts should prioritize minimizing contact between bats and date juice and preventing the consumption of contaminated sap [176, 177, 202–204]. Measures include building physical barriers to prevent bats from contaminating and accessing sap, boiling freshly collected date juice before consumption, and preventing farm animals from eating fruit contaminated by bats.

Pigs serve as the primary reservoir for NiV transmission to humans. Hene, the key strategy for controlling an NiV epidemic is to effectively severe the contact among humans, infected pigs, and environmental contaminants. Appropriate protective clothing is required during work involving direct contact with farm animals, especially during slaughter and disposal procedures [176]. Thoroughly sanitizing and disinfecting pig farms with sodium hypochlorite or other suitable detergents can prevent pig infections. Regular quarantine and surveillance measures should be implemented to promptly detect any sign of an outbreak. Suspected cases must be isolated, and infected animals should be culled. Proper disposal through closely supervised burial or incineration are essential steps that minimize the risk of human transmission. Restricting or prohibiting animal transportation from affected farms to other areas can impede disease spread. Given that domestic pig outbreaks precede human cases, establishing an animal health surveillance system is crucial because it can provide early warning signals for veterinary and public health systems.

Implementing preventive measures, such as practicing meticulous hand hygiene, disinfecting surfaces with 70% ethanol, and utilizing gloves and other personal protective equipment, play a crucial role to the effective curbing NiV transmission through direct human-to-human contact [47, 205–207]. Healthcare professionals should avoid close physical contact with individuals infected by NiV; they must utilize gloves and appropriate personal protective equipment during patient care activities while adhering to meticulous hand hygiene after providing care or visiting patients. Standard infection control precautions should be followed by healthcare professionals caring for suspected or confirmed cases of NiV infection or handling specimens collected from such individuals. In addition, evaluating disinfection efficiency against NiV by chemical and physical methods is necessary. Eickmann et al. [208] effectively reduced NiV infectivity in platelet and plasma concentrates by using UV-C and MB/light.

Moreover, implementation of actions, such as local television, radio channels and printed media to raise public awareness of the risks associated with the outbreak of NiV is another factor that may help to reduce the risk of a new outbreak [202]. Conduct public campaigns and educational initiatives on NiV-related scientific advancements for individuals traveling to endemic regions. International port quarantine agencies should implement diverse measures to prevent and control the introduction of NiV, including the prompt acquisition of international epidemic information and thorough vehicle quarantine and inspection. Investments in scientific research, full utilization of rapid screening techniques, nucleic acid detection methods, viral isolation and culture procedures, gene sequencing technologies, scientifically sound responses to diseases, and other diagnostic approaches for enhancing virus detection capabilities are highly needed.

9 Conclusions

NiV has emerged as a deadly zoonotic disease. Regular NiV outbreaks have posed a substantial threat to humans and can cause a global pandemic. Bats are the natural reservoirs of the virus, and multiple intermediate hosts are effective at virus transmission. Thus, lessons learned from the COVID-19 pandemic underscore the urgency of preparedness for controlling NiV outbreaks. Current studies on NiV epidemiology, biology, and pathogenicity have paved the way for the research of vaccine and therapeutics against human NiV infections. However, improvements are needed. No licensed vaccines or antiviral drugs are available for the NiV disease, and the primary treatment is supportive. The key strategy for preventing NiV outbreak is to increase awareness of risk factors and minimize exposure to the virus. Steps should be taken to improve the surveillance of NiV emergence and transmission. Surveillance systems for NiV should be established, particularly in South and Southeast Asia. Authorities and governments should practice and follow preventive and containment measures to prevent the onset and diffusion of outbreaks. In conclusion, the “One Health approach” is required globally, in which multiple organizations coordinate and work together to achieve desired public health outcomes.

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Acknowledgements

This work was supported by the Discipline Innovation and Development Program of Tangdu Hospital (No. 2021LCYJ025).

Compliance with ethics guidelines

Conflicts of interest statements Limei Wang, Denghui Lu, Maosen Yang, Shiqi Chai, Hong Du, and Hong Jiang declare that they have no conflicts of interest.

This is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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