Nipah virus

What is Nipah virus (NiV)?

Nipah virus (NiV) is a single-stranded negative-strand RNA virus belonging to the family Paramyxoviridae, a rare but extremely deadly pathogen that has been the focus of public health attention since it was first identified in Malaysia in 1998 due to its high lethality rate. As a specific zoonotic virus, Nipah virus can invade the lungs and brains of humans and animals, causing a range of serious health problems, including fever, headache, drowsiness, coma, and confusion. Of particular note is the high fatality rate of this viral infection, with a mortality rate of about 60% in animals and up to 75% in humans.

There are two main genetic lineages of NiV: the NiV Malaysian strain (NiV-MY) and the NiV Bangladeshi strain (NiV-BD). NiV is quite unstable in vitro and has weak resistance to heat and disinfectants, and is destroyed in 30 minutes when heated to 56℃ which can be easily inactivated by detergents such as soap and general disinfectants.

Nipah virus structure

The genome of the virus consists of approximately 18.2 kb long unsegmented single-strand negative-strand RNA encoding six proteins: nucleocapsid (N), phosphoprotein (P), matrix protein (M), fusion protein (F), glycoprotein (G), and RNA polymerase (L). N, P, and L, as well as viral RNA, form a ribonucleoprotein complex, an indispensable complex that regulates transcription and viral RNA synthesis. Glycoprotein G recognizes and binds to Ephrin-B2 and B3 receptors on the surface of host cells, and fusion protein F induces fusion of the virus with the host cell membrane, thereby facilitating viral invasion.

Fig.1 The structure of the Nipah virus. (Faus-Cotino Javier, et al., 2024)

Nipah virus transmission

Infection

Animals, people, or contaminated food and water sources that carry the virus, etc. Fruit bats are the natural host of the virus, and pigs are the main hosts.

Susceptible animals and populations

Animals are generally susceptible, and the incidence in the population is significantly occupational, with the majority of those engaged in pig farming and slaughtering.

Mode of transmission

1. Direct contact with infected animals, such as bats or pigs, or their bodily fluids (such as blood, urine, or saliva).

2. Eating food contaminated with body fluids of infected animals (e.g., palm juice or fruit contaminated with infected bats).

3. Close contact with a person infected with NiV or their bodily fluids, including nasal or respiratory droplets, urine, or blood.

Nipah virus treatment

Nipah virus vaccines

Vaccine development for Nipah virus (NiV) has focused on its F and G proteins. Passive immunization strategies utilize humanized monoclonal antibodies (mAbs) such as m102.4 and h5B3.1 to provide strong neutralization against the fusion site of the F protein, effectively protecting animals from infection. Active immunization strategies include multiple vaccine platforms, such as vaccinia virus, parainfluenza virus, adeno-associated virus, adenovirus, measles virus, and rabies virus vectors, as well as virus-like particles (VLPs) and subunit vaccines, all encoding F or G proteins as immunogens to induce the production of neutralizing antibodies and other immune responses. Among them, the HeV-sG subunit vaccine has shown good results in equine vaccines and has demonstrated the potential for future human vaccine development. In addition, mRNA-based vaccine technologies also show potential, but further optimization is needed to improve protection.

Antiviral inhibitors of NIV

Testing of antiviral drugs targeting different stages of the Nipah virus (NiV) life cycle is underway (Fig.2).

Fig.2 Diagram of antiviral compounds inhibiting virus entry and replication. (Mishra Gayatree, et al., 2024)

Ribavirin: As a broad-spectrum nucleoside analogue, ribavirin was used to treat infected patients in early outbreaks of NiV and showed some therapeutic efficacy. In the first NiV outbreak in Malaysia in 1998-1999, one study found that ribavirin treatment was associated with a 36% reduction in mortality and a reduction in neurological deficits. However, the efficacy of ribavirin in the 2018 NiV outbreak in India is unclear, suggesting that further studies are needed to determine its antiviral mechanism and range of action.

Favipiravir: Favipiravir was shown complete protection as a synthetic prodrug that inhibits RNA-dependent RNA polymerase (RdRp) activity in the study of lethal NiV infection in an African green monkey (AGM) model. Studies of the drug in a golden hamster model in Syria showed that administration for 14 consecutive days immediately after infection could effectively inhibit the fatal infection of the virus with a survival rate of 100%.

Griffithsin/GRFT: Griffithsin is a protein isolated from red algae and their synthesized trimer tandem (3mG). At low concentrations (nM), GRFT exhibits significant antiviral activity against NiV by interfering with viral entry and fusion processes, particularly syncytial formation. Its mechanism of action is to prevent the fusion of the viral envelope and the host cell membrane, and inhibit the replication and spread of the virus.

KIN1408: As an agonist of the RIG-1-like receptor (RLR) pathway, KIN1408 has broad-spectrum antiviral activity. It exhibits inhibitory effects against infection with a variety of viruses, including Ebola, Nipah, and Lassa viruses, by activating the host's immune response mechanisms. This mechanism gives KIN1408 the potential for a wide range of applications in antiviral research.

R1479: R1479 is a cytidine analogue that has a broad-spectrum antiviral effect against viruses of the Flaviviridae family. Studies have shown that it can inhibit the replication of NiV and exhibit strong antiviral activity at low micromolar concentrations. The mechanism of action of R1479 may be related to its interference with the RNA synthesis process of the virus.

GS-5734 (Remdesivir): As a broad-spectrum antiviral prodrug, GS-5734 has shown potent anti-RNA synthesis activity in experiments against NiV infection. It interferes with the RNA polymerase activity of the virus by mimicking the structure of the native nucleotides, preventing the replication and synthesis of viral RNA.

ALS-8112: ALS-8112 is a novel nucleoside analogue that shows potent antiviral activity against NiV at low concentrations (0.89-3.08 μM). The mechanism of action of ALS-8112 is similar to that of other nucleoside analogues, blocking the viral replication cycle by inhibiting the synthesis of viral RNA. In addition, peptide fusion inhibitors have been developed to prevent viruses from entering host cells for the fusion process between the viral envelope and the host cell membrane.

Chloroquine: In vitro experiments, chloroquine has been shown to be effective in inhibiting NiV infection. Its mechanism of action may be related to blocking the activity of NiV F protein, thereby preventing the cell fusion and entry process of the virus.

However, these drugs have shown potential efficacy in animal models, but their antiviral effects in their natural hosts still need to be further studied and evaluated to determine their clinical value.

References

• Mishra, Gayatree, et al., Advancements in Nipah virus treatment: Analysis of current progress in vaccines, antivirals, and therapeutics. Immunology 171.2 (2024): 155-169.
• Faus-Cotino, Javier, et al., Nipah Virus: A Multidimensional Update. Viruses 16.2 (2024): 179.

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