NiV is an emerging zoonotic pathogen with significant epidemic potential. NiV infection is associated with severe disease and high mortality, with case-fatality rates ranging from 40% to 75% across reported outbreaks, depending on local capabilities, early detection, and clinical management. Currently, no licensed vaccines or specific antiviral therapies are available for the prevention or treatment of NiV infection [1].

In response to the public health threat posed by NiV and related henipaviruses, the WHO identified NiV as a priority pathogen under its R&D Blueprint and released an advanced draft research and development roadmap in 2019. This roadmap, updated with strategic goals for 2024–2029, aims to accelerate the development of diagnostics, therapeutics, and vaccines to enable rapid and effective outbreak response [1,2].

NiV is an enveloped, negative-sense, single-stranded RNA virus that belongs to the family Paramyxoviridae and the genus Henipavirus. The viral genome encodes six major structural proteins: nucleocapsid (N), phosphoprotein (P), matrix (M), fusion (F), attachment glycoprotein (G), and large polymerase (L) protein. The G and F glycoproteins are critical for viral attachment and membrane fusion, mediating entry into host cells [3].

The attachment glycoprotein G binds with high affinity to the cellular ephrin ligands Ephrin-B2 and Ephrin-B3, which serve as the principal functional receptors for NiV in both human and bat hosts [4]. Ephrin-B2 and ephrin-B3 are transmembrane ligands involved in bidirectional signaling with Eph receptor tyrosine kinases and play critical roles in vascular development and neuronal guidance. Structural and biochemical studies have demonstrated that the NiV G glycoprotein adopts a six-bladed β-propeller architecture that engages the G–H loop of ephrin-B2/B3 with high specificity. This interaction mimics the natural binding interface between ephrins and Eph receptors, enabling the virus to exploit a conserved cellular signaling pathway for host cell attachment [5].

Upon receptor engagement, conformational changes in the G glycoprotein are transmitted to the metastable pre-fusion form of the F glycoprotein. The F protein, which is synthesized as an inactive precursor (F0), undergoes proteolytic cleavage by host endosomal proteases, such as Cathepsin L, to generate the fusion-competent subunits F1 and F2. Following receptor-induced triggering, the F protein undergoes a dramatic structural rearrangement from a pre-fusion to a post-fusion conformation, exposing the hydrophobic fusion peptide that inserts into the host cell membrane. This process results in the formation of a six-helix bundle structure that brings the viral envelope and cellular membrane into close proximity, ultimately facilitating membrane merger and the delivery of the viral ribonucleoprotein complex into the host cytoplasm [6].

The distribution of ephrin-B2 and ephrin-B3 in host tissues provides a mechanistic explanation for NiV tissue tropism and pathogenesis. Ephrin-B2 is highly expressed in arterial endothelial cells, smooth muscle cells, and various epithelial tissues, whereas Ephrin-B3 is predominantly expressed in neurons within the central nervous system. Consequently, NiV infection is characterized by widespread endothelial involvement, vasculitis, and severe encephalitis. Importantly, these receptors are highly conserved among mammals, including fruit bats of the genus Pteropus, which serve as natural reservoir hosts [7]. The strong structural conservation of ephrin-B2/B3 across species enables efficient cross-species receptor recognition, facilitating zoonotic spillover events. Genetic analyses have identified at least two major NiV lineages: the Malaysia lineage (NiV-M) and the Bangladesh lineage (NiV-B). These lineages differ in geographic distribution, transmission dynamics, and clinical outcomes, with NiV-B being more frequently associated with human-to-human transmission and higher case-fatality rates [8,9]. The phylogenetic relationships are illustrated in Figure 1, and a comparative analysis of both lineages is presented in Table 1.

Genetic diversity among circulating strains has important implications for diagnostic sensitivity, therapeutic efficacy, and vaccine design [4,5,10].

Fruit bats of the genus Pteropus, commonly referred to as flying foxes, are the natural reservoirs of NiV. Viral maintenance in bat populations enables periodic spillovers into humans and domestic animals. Human infection occurs through direct contact with infected animals, consumption of food contaminated with bat saliva, urine, or excreta, or close contact with infected individuals [10,11].

Human-to-human transmission has been well documented, particularly in healthcare settings and among household contacts. The incubation period typically ranges from 3 to 14 days, although incubation periods of up to 45 days have been reported in rare cases [12].

Following infection, NiV exhibits systemic dissemination with a strong tropism for endothelial and neuronal tissues, leading to widespread vasculitis, encephalitis, and respiratory complications. These pathogenic mechanisms contribute to the rapid clinical deterioration in severe cases [13].

NiV infection presents a wide clinical spectrum, ranging from asymptomatic infection to severe, rapidly progressive disease. Early symptoms are nonspecific and include fever, headache, myalgia, vomiting, and sore throat. As the disease progresses, neurological manifestations such as dizziness, somnolence, altered mental status, and focal or generalized neurological deficits may develop, consistent with acute encephalitis [14].

Severe disease is frequently characterized by seizures and rapid progression to coma within 24–48 h of onset. Respiratory involvement, including atypical pneumonia and acute respiratory distress syndrome (ARDS), has been reported and is more commonly associated with increased transmissibility and poor outcomes [15,16].

NiV was first recognized during outbreaks of respiratory illness in swine and encephalitis in humans in Malaysia between 1998 and 1999, followed by cases in Singapore in 1999 linked to pig exposure [17,18]. Since then, recurrent outbreaks and sporadic cases have been reported in South and Southeast Asia, particularly in Bangladesh and India.

A recent (NiV) infection in India resulted in the death of a 25-year-old nurse in West Bengal in early 2026 due to post-infectious complications. As of January 26, 2026, two laboratory-confirmed NiV cases from West Bengal State were reported to the World Health Organization [4,5]. This episode constitutes the third documented NiV outbreak in West Bengal, following prior outbreaks in (2001) and (2007) [5,10,11]. NiV is a highly pathogenic zoonotic paramyxovirus associated with a case-fatality rate ranging from 40% to 75%, depending on the outbreak context and healthcare capacity. The recurrence of outbreaks in this region underscores the persistent risk of NiV re-emergence and highlights the critical need for sustained epidemiological surveillance, rapid diagnostic capacity, and strengthened outbreak preparedness and response systems.

Outbreaks involving sustained human-to-human transmission often demonstrate higher fatality rates, highlighting the importance of rapid case identification and isolation [19,20].

Currently, no licensed vaccines or specific antiviral therapies are available for NiV infection. Clinical management is limited to supportive care, including management of respiratory failure, seizures, and cerebral edema, alongside strict infection prevention and control practices [11].

Multiple vaccine and therapeutic candidates are in various stages of preclinical and clinical development worldwide. These efforts are guided by the WHO R&D roadmap, which prioritizes interventions with the potential for rapid deployment during outbreaks [1].

Laboratory confirmation of NiV infection can be achieved during both acute and convalescent phases using a combination of diagnostic assays [7], a summary of laboratory diagnostic approaches at both phases is shown in Table 2. Molecular detection of viral RNA by reverse transcription polymerase chain reaction (RT-PCR) remains the gold standard during the acute phase, providing high sensitivity and specificity. RT-PCR typically targets conserved viral genomic regions, such as the nucleocapsid (N), phosphoprotein (P), and fusion (F) genes. Serological assays, including enzyme-linked immunosorbent assays (ELISA) for NiV-specific IgM and IgG antibodies, are essential for retrospective diagnosis and sero-epidemiological studies [21]. The kinetics of antibody responses are clinically informative: IgM antibodies typically appear within 3–10 days post-infection, serving as markers of recent or ongoing infection, whereas IgG antibodies emerge later and persist, indicating past exposure and potential immunity. Rapid diagnostic tests (RDTs) and syndromic multiplex panels are increasingly recognized as critical tools for point-of-care testing, especially in outbreak scenarios and low-resource settings [21]. The incorporation of both molecular and serological testing enhances diagnostic accuracy and informs clinical and public health decision-making.

The validation of diagnostic assays for NiV has been constrained by the limited availability of well-characterized human clinical specimens. Consequently, animal-derived samples are frequently used for assay evaluations. For example, serum or tissue samples from experimentally infected Syrian hamsters (Mesocricetus auratus) are widely used because this model closely reproduces the pathological and virological features of human NiV infection, including respiratory disease and encephalitis. Viral replication patterns and antigen expression in hamsters are comparable to those observed in human infection, making these samples suitable for preliminary diagnostic assay validation [21,22].

Persistent gaps include limited routine external quality assessments, incomplete characterization of viral and antibody kinetics, outdated proficiency testing panels, and insufficient surveillance data, as highlighted in successive WHO assessments [23].

In response to these challenges, a consensus group of 15 subject matter experts has outlined strategic priorities for 2024–2029 to strengthen global preparedness for NiV and related henipavirus outbreaks. Key recommendations include: (1) Development and deployment of affordable, easy-to-use point-of-care diagnostic tests capable of detecting all known NiV lineages. (2) Expansion of access to well-characterized clinical specimens to support diagnostic validation and regulatory approvals. (3) Updating target product profiles to align with current epidemiology and leverage advances in multiplex diagnostic technologies. (4) Strengthening local laboratory capacity and integrating diagnostics into One Health surveillance frameworks. (5) Accelerating the development of effective therapeutics and vaccines with clear pathways for emergency use during outbreaks [1].

Despite advances in diagnostics, a critical knowledge gap in NiV research lies in defining the host molecular pathways modulated during infection. Understanding the host–pathogen biology of NiV and potently suppressing innate immunity, particularly interferon signaling, through phosphoprotein-mediated inhibition of antiviral signaling, yet the broader network of dysregulated pathways, including NF-κB signaling, endothelial injury, and neuroinflammation, remains poorly defined. Integrative multi-omics profiling of infected tissues and survivor cohorts could identify biomarkers of disease severity and uncover host pathways exploitable for therapeutic intervention. Targeting conserved host responses rather than viral proteins may offer more durable antiviral strategies [23]. Addressing these questions will require coordinated global research efforts, particularly strengthened research capacity, and longitudinal studies in outbreak-prone low- and middle-income regions.

NiV continues to represent a substantial global public health threat due to its high case-fatality rate, potential for epidemic spread, and the absence of licensed vaccines or targeted antiviral therapies. Despite advances in understanding its virology, transmission dynamics, and clinical spectrum, significant gaps remain in diagnostic preparedness, surveillance coverage, and access to well-validated diagnostic tools, particularly in low- and middle-income countries. Strengthening diagnostic capacity through the development and deployment of sensitive, lineage-inclusive, and field-deployable assays, alongside improved quality assurance and surveillance systems, is essential for timely outbreak detection and response. Coordinated international efforts aligned with WHO research and development priorities are critical for accelerating the availability of effective diagnostics and medical countermeasures and enhancing global readiness for future NiV outbreaks.