Introduction
Nipah virus (NiV) is a zoonotic Biological Safety Level 4 pathogen in the Paramyxoviridae family, Henipavirus genus, first identified in Malaysia in 19982. The natural reservoir is Pteropus fruit bats (flying foxes), with Pteropus giganteus serving as the primary reservoir in Bangladesh and India2. Transmission occurs through three pathways: consumption of contaminated foods (fruits and date palm sap contaminated by bat bodily fluids), direct contact with infected human or animal body fluids, and close contact with respiratory secretions (droplet-range) 2. Pigs acted as intermediate hosts in the 1998–1999 Malaysia outbreak, while horses served as intermediates in the 2014 Philippines outbreak2.
Outbreak history reflects distinct epidemiological patterns. Malaysia and Singapore (1998–1999) experienced pig-amplified outbreaks, whereas Bangladesh has documented multiple seasonal outbreaks since 2001, each representing separate spillover events linked to consumption of fresh date palm sap2. By September 2025, Bangladesh had recorded 347 cases with a case fatality rate of 71.7%28. India has reported recurrent outbreaks in West Bengal (2001, 2007, and most recently January 2026) and Kerala (2018, 2019, and recurrent spillovers through 2024)1226. The January 2026 West Bengal outbreak involved two healthcare workers aged 20–30 years, both laboratory-confirmed via RT-PCR and ELISA, with one requiring mechanical ventilation122. The incubation period ranges from 3 to 14 days (rarely up to 45 days), with clinical presentation varying by strain: the Malaysia variant showed predominantly encephalitis, whereas Indian and Bangladesh variants demonstrate respiratory involvement in approximately 70% of patients, often progressing to acute respiratory distress syndrome12. Case fatality ratios range from 40% to 75% depending on local early detection and clinical management capabilities12.
Host Immune Response: Mechanistic Insights
Innate Immunity and Viral Immune Evasion
NiV employs sophisticated innate immune evasion through its phosphoprotein (P) gene products—P, V, and W proteins—which target STAT signaling pathways central to interferon responses. The P protein sequesters STAT1 and STAT2 into viral cytosolic inclusion bodies, preventing their phosphorylation and nuclear translocation, thereby blocking interferon-stimulated gene (ISG) induction36. This sequestration transforms inclusion bodies from simple replication compartments into immune-evasion organelles that trap and inactivate key signaling molecules required for antiviral responses36.
The V protein emerges as the major determinant of lethal disease through potent antagonism of innate immunity in endothelial cells37. Ferret model studies demonstrate that recombinant NiV lacking V protein (rNiV-V ko) is susceptible to innate immunity in vitro and behaves as a replicating non-lethal virus in vivo, with animals developing neutralizing antibodies beginning at day 10 post-infection and surviving infection37. In contrast, wild-type NiV shows suppressed neutralizing antibody responses and germinal center depletion in the spleen37. The W protein modulates inflammatory pathology in endothelial cells: W-deficient NiV results in delayed clinical signs, reduced respiratory disease, but increased terminal neurological disease with enhanced CNS involvement37. In vitro analysis of primary human pulmonary microvascular endothelial cells infected with W-deficient virus shows elevated pro-inflammatory and leukocyte-attracting chemokines (ENA-78, Eotaxin, IL-8, IP-10, I-TAC, MCP-1, MCP-4, MIP-1δ) and innate cytokines (TNF-α, IL-6, IL-10) compared to wild-type virus, indicating that functional W protein suppresses endothelial inflammatory outputs37.
Comparative studies with non-pathogenic Cedar paramyxovirus confirm that efficient STAT1/STAT2 targeting is a virulence determinant: Cedar paramyxovirus phosphoprotein shows compromised ability to interact with and relocalize STAT1 or STAT2, correlating with reduced capacity to inhibit IFN-induced responses38. The matrix protein (NiV-M) provides an additional layer of innate immune antagonism by interacting with TRIM6 and reducing TRIM6 protein levels, thereby disrupting the TRIM6-IKKε axis and preventing IKKε activation through unanchored K48-linked polyubiquitin chains6. NiV-M interferes with IKKε oligomerization and autophosphorylation, limiting IRF3 phosphorylation and downstream interferon induction6.
Adaptive Immunity and Correlates of Protection
Neutralizing antibodies targeting the fusion (F) glycoprotein and the attachment glycoprotein (G) represent critical correlates of protection. Prefusion-stabilized F immunogens elicit substantially higher neutralizing titers than postfusion forms45. The humanized antibody h5B3.1 recognizes a prefusion-specific quaternary epitope on the NiV F globular head and neutralizes NiV and HeV by locking F in the prefusion conformation and preventing fusogenic rearrangements 4. The antibody m102.4 targets the G glycoprotein with binding mediated predominantly by two residues in the heavy-chain complementarity-determining region 310.
Pseudovirus-based mouse models have identified limited levels of neutralizing antibodies required for protection: F protein immunogens require 52 units in active immunization and 148 units in passive immunization; G protein immunogens require 170 units (active) and 275 units (passive)3. Escape from V-mediated innate suppression permits development of neutralizing antibodies and germinal center maintenance, establishing innate immune antagonism as a barrier to protective adaptive immunity37.
Endothelial Immunopathology in Nipah Virus Disease
Accumulating evidence indicates that endothelial cell infection is a major contributor to Nipah virus pathogenesis. NiV antigen labeling is extensive in vascular endothelium across multiple tissues, with gross histopathology revealing multifocal to coalescing hemorrhagic and necrotizing pneumonia, splenomegaly with multifocal necrosis, and brain vascular pathology37. The balance between pulmonary and CNS disease is modulated by V and W proteins through differential control of endothelial inflammatory outputs37. MRI findings in patients include multiple 2–7 mm lesions in the subcortical and deep white matter, periventricular areas, and corpus callosum without associated cerebral edema or mass effect2. Long-term neurologic sequelae include fatigue, encephalopathy, ocular motor palsies, cervical dystonia, focal weakness, and facial paralysis2.
Clinical and Translational Research: Therapeutics and Vaccines
Monoclonal Antibodies
m102.4 has completed Phase 1 clinical trials demonstrating favorable safety, tolerability, and pharmacokinetics in 40 healthy adults9. Single intravenous infusions at doses of 1, 3, 10, or 20 mg/kg showed linear dose-dependent kinetics with median half-lives of 397–663 hours; critically, anti-m102.4 antibodies were not detected at any time point, indicating no immunogenic response9. The prolonged half-life supports future dosing regimens for systemic efficacy. m102.4 has been deployed on a compassionate use basis, including during the 2018 Kerala outbreak830. CEPI is investing $43.5 million to advance m102.4 human trials29.
The humanized h5B3.1 antibody demonstrated post-infection efficacy in ferrets when administered 1 to several days after lethal NiV challenge, with all treated animals protected from disease whereas untreated controls died11. Naturally occurring human monoclonal antibodies HENV-26 and HENV-32, isolated from Hendra virus-infected individuals, protected ferrets in lethal Nipah Bangladesh models when administered 3 days post-exposure13. Crystal structures revealed diverse sites of vulnerability on the receptor-binding protein recognized by potent human antibodies that inhibit virus by multiple mechanisms13. The humanized antibody hu1F5 demonstrated effective protection against lethal Nipah virus in nonhuman primate models31.
Vaccines
The HeV-sG subunit vaccine, based on Hendra virus soluble G glycoprotein adjuvanted with Alhydrogel, is in Phase I clinical development sponsored by CEPI12. African green monkey studies demonstrated that a single 0.3 mg dose provided complete protection against lethal challenges with both Hendra and Nipah Bangladesh strains, with vaccinated animals developing robust anti-HeV-sG antibodies and serum neutralizing titers of 80–640 against both viruses at study endpoint12. A single 0.1 mg dose conferred protection as early as 7 days post-immunization12.
Structure-based vaccine design has yielded lead candidates including prefusion-stabilized F (pre-F) and chimeric pre-F/G constructs5. The pre-F/G chimera elicited neutralization titers (reciprocal IC80) exceeding 6,700 in mice, significantly higher than pre-F alone (>1,000) or trimeric G (>3,400)5. The pre-F trimer design (NiVop08) exhibits ~100% prefusion conformation and binds the prefusion F–specific antibody h5B3 with a K_d of 2.9 × 10⁻⁸ M5. Fc-based bivalent (NiV-G and HeV-G) and tetravalent (including Ghana and Mojiang virus G proteins) fusion constructs elicited broad antibody responses in mice, indicating compatibility among multiple henipavirus antigens14. No vaccine candidate has yet received regulatory approval for human use33.
Antivirals
Remdesivir has demonstrated prophylactic efficacy in preventing Nipah infection when administered to exposed nonhuman primates, and may complement immunotherapeutic treatments like m102.48. Ribavirin is recommended by the Indian National Centre for Disease Control despite conflicting efficacy reports; favipiravir showed effectiveness in hamster models2. Computational screening of piperazine-substituted favipiravir derivatives showed greater binding ability than experimentally reported favipiravir in molecular docking studies18. However, no antiviral has achieved clinical validation in human NiV infection to date in the retrieved materials.
Supportive Care and Diagnostics
Treatment remains primarily supportive with infection control practices2. Patients should be discharged only after negative RT-PCR on throat swabs and remain in isolation for 21 days following confirmation2. Rapid diagnostic platforms using recombinant human ephrin B2 as a capture ligand combined with virus-specific monoclonal antibodies enable point-of-care detection suitable for outbreak settings19. Early detection is critical given the short timeframe for therapeutic intervention and the high case fatality rate.
Clinical Development Landscape and Knowledge Gaps
WHO assesses the risk at the sub-national level as moderate, national level as low, and regional/global levels as low1. The January 2026 West Bengal outbreak was declared contained after identification and testing of over 190 contacts, all of whom tested negative125. However, Kerala continues to experience endemic circulation with over 100 acute encephalitis syndrome cases in 202426.
Despite significant progress in Nipah virus research, critical understanding of host immune responses remains limited. Direct mechanistic data on NK cell, macrophage/dendritic cell, and CD4+/CD8+ T cell responses specific to NiV V, W, and C proteins are limited in the 2015–2026 retrieved literature. While established roles of STAT1/STAT2 in dendritic cell cross-presentation, NK cell activation, and CD4+ T cell IL-10 regulation indicate that NiV STAT antagonism would broadly impair these functions3940414243, empirical validation in NiV infection models is needed. Trial design challenges include small case numbers in sporadic outbreaks, limited infrastructure in endemic regions, and ethical considerations for placebo controls given high lethality. Region-specific translational outcomes, systematic antiviral trial data, and detailed vaccine trial registries for 2024–2026 were not available in the retrieved materials. Future priorities include advancing m102.4 and combination antibody therapies to later-phase trials, completing HeV-sG and pre-F/G chimera clinical development, validating remdesivir and favipiravir in human cohorts, establishing immune correlates of protection from convalescent sera and vaccine studies, and deploying rapid diagnostics linked to early therapeutic protocols in endemic regions.