Development of Nipah Virus Vaccine

Nipah virus (NiV) is a highly pathogenic zoonotic paramyxovirus of the genus Henipavirus. First identified during a 1998-1999 outbreak among pig farmers in Malaysia and Singapore—with 265 cases and 105 deaths (CFR ~40%)—NiV has since caused recurrent outbreaks across South and Southeast Asia. The natural reservoir is the Pteropus fruit bat (flying fox), with spillover to humans occurring through intermediate hosts such as pigs or via consumption of bat-contaminated raw date palm sap.

Clinical disease ranges from mild respiratory illness to rapidly progressive severe disease characterized by acute respiratory distress syndrome and fatal encephalitis. Reported CFRs vary from ~40% in Malaysia to 70-100% in Bangladesh and India outbreaks. Person-to-person transmission through close contact with infectious body fluids has been documented, particularly in nosocomial settings. NiV is classified as a WHO priority pathogen with epidemic potential and requires BSL-4 containment.

Despite over two decades of research, no licensed human vaccine exists. In 2025, eight confirmed cases were reported across Bangladesh (four, all fatal) and India's Kerala state (four, two deaths), with sporadic cases continuing into early 2026. The combination of high mortality, broad host range, and recurrent spillover underscores the urgent need for an effective NiV vaccine.

Life Cycle and Transmission

The replication cycle proceeds through attachment (G binding ephrin-B2/B3), fusion (F-mediated membrane merger), cytoplasmic transcription and replication by the L-P polymerase, assembly at the plasma membrane driven by M, and budding of progeny virions.

Fig. 2 Nipah virus transmission cycle

Pteropus bats are distributed across South and Southeast Asia, northern Australia, and parts of East Africa, shedding virus in saliva, urine, and feces without clinical disease. Two principal spillover pathways predominate: foodborne transmission via raw date palm sap or partially eaten fruit (the main route in Bangladesh and eastern India), and contact with infected pigs (the route in the 1998-1999 Malaysian outbreak). While person-to-person transmission is generally limited, it has occurred in family clusters and healthcare settings, raising concerns about adaptive mutations that could enhance transmissibility.

Vaccine Development Strategies

Virtually all NiV vaccine candidates target the F and/or G glycoproteins. Multiple active immunization platforms are in development.

Viral Vector Vaccines

rVSV-NiV/G: A replication-competent recombinant vesicular stomatitis virus vector encoding NiV G demonstrated complete protection in African green monkeys one month after a single dose, and even when administered one day before exposure. The rVSV platform has a proven track record via the licensed Ebola vaccine Ervebo.

ChAdOx1 Nipah B: A replication-deficient chimpanzee adenovirus vector encoding the NiV-B G protein, developed by the University of Oxford. Following a successful first-in-human Phase 1 trial, the world's first Phase II NiV vaccine trial launched in Bangladesh in December 2025, enrolling 306 participants aged 18-55 in an endemic region with CEPI funding.

AAV vectors: Adeno-associated virus vectors expressing NiV G elicited strong antibody responses in mice and protected hamsters, offering an alternative for populations with pre-existing adenovirus immunity.

Subunit Vaccines

The most extensively studied approach uses soluble recombinant G glycoprotein (NiVsG) or the cross-reactive Hendra virus soluble G (HeVsG). Adjuvanted soluble G induced high cross-neutralizing titers and protected ferrets and African green monkeys from lethal challenge. A HeV G subunit vaccine (Equivac® HeV) is already licensed for horses in Australia. More recently, ferritin-based nanoparticle vaccines displaying NiV G showed enhanced immunogenicity and complete protection in Syrian hamsters at low doses.

Virus-Like Particles (VLPs)

NiV virus-like particles composed of the G, F, and M proteins produced in mammalian cells faithfully mimic the native virion structure without containing viral genetic material. NiV-VLPs have been validated as immunogens in BALB/c mice and Syrian hamsters, eliciting both neutralizing antibody and cellular immune responses. The particulate nature of VLPs promotes efficient uptake by antigen-presenting cells and activation of innate immune pathways, making them an attractive platform for NiV vaccine development.

mRNA Vaccines

mRNA-1215 (Moderna/NIAID): An LNP-encapsulated mRNA vaccine encoding a chimeric prefusion-stabilized F protein linked to a G monomer (Pre-F/G) from NiV-M. A Phase 1 dose-escalation trial (NCT05398796) in 40 healthy adults was completed in October 2025; results published in Nature Medicine in March 2026 demonstrated safety, tolerability, and robust neutralizing antibody responses—the first clinical data for any NiV vaccine.

Self-amplifying mRNA (saRNA): In March 2025, CEPI awarded up to US$13.38 million to India's Gennova Biopharmaceuticals to develop an AI-enhanced saRNA NiV vaccine with Houston Methodist Research Institute, offering potential for lower doses and more durable immunity.

DNA Vaccines

DNA vaccines encoding NiV F or G glycoproteins have been evaluated in preclinical models, eliciting both humoral and cellular immune responses. While early DNA platforms suffered from poor immunogenicity in humans, modern formulations incorporating electroporation delivery and molecular adjuvants have improved performance. DNA vaccines remain a viable platform due to their stability, ease of manufacturing, and lack of anti-vector immunity.

Conclusion

Nipah virus remains one of the deadliest known zoonotic pathogens with no licensed human vaccine. However, the landscape has transformed rapidly: the first-in-human mRNA-1215 Phase 1 trial has yielded positive safety and immunogenicity data, the first Phase II trial is underway in an endemic region, and multiple next-generation platforms are advancing. Future success will depend on demonstrating cross-protection against both NiV-M and NiV-B, establishing validated immune correlates for Animal Rule licensure, and developing thermostable formulations for resource-limited settings. The convergence of structural biology, mRNA technology, and coordinated global funding through CEPI provides unprecedented momentum toward a licensed NiV vaccine.

Resources

Rapid Response to Nipah Virus Outbreak: Essential Research Reagents Now Available