A transboundary biological threat

A transboundary biological threat

Nipah virus (NiV), which is classified as a highly pathogenic biosafety level-4 agent, is a bat-borne paramyxovirus belonging to the henipavirus family.

First reported in the 1990s, the henipavirus caused serious disease outbreaks in humans and livestock, spilling over from their natural bat hosts. Several species of fruit bats from the pteropodid megabats family are found to harbour NiV. The virus is not known to cause disease in bats.

NiV first appeared in Malaysia. Following the Malaysian outbreak in 1998, outbreaks of NiV infection have been reported almost every year, primarily in Bangladesh but also India, especially since 2001.

Compared to the original Malaysian outbreak which infected over 300 people, these NiV virus spillovers have been smaller in case numbers. But the overall fatality rates in people have been significantly higher, ranging from 75–100%.

More importantly, direct transmission of NiV from bats to humans and significant human-to-human transmission have also been documented during outbreaks in India and Bangladesh.

NiV possess an exceptional capacity to cause fatal disease in horses, pigs, cats, dogs, ferrets, hamsters, guinea pigs, monkeys and humans — spanning 6 mammalian orders.

The virus causes a systemic infection that is characterised as wide-spread vasculitis and endothelial cell tropism with an incubation period of 4–21 days in disease-susceptible animal hosts and people.

The infection, which majorly involves the lung and the brain, often manifests as a severe respiratory syndrome, encephalitis or a combination of both. In addition to the acute symptomatic infection, people can also have longer-term consequences because NiV infection can take a protracted course following recovery from an initial infection.

Ribavirin: Unproven benefits

There are no approved or licensed therapeutics for treating NiV infection or disease in people. Ribavirin, an approved treatment for several viral infections that exhibits antiviral activity against a wide variety of RNA and some DNA viruses, has been found effective against NiV in in-vitro studies.

An open label ribavirin treatment trial carried out during the outbreak of NiV in Malaysia in 1998 was reported to reduce mortality by 36% in treated patients.

Also, the anti-malarial drug chloroquine was shown to inhibit NiV infection in cell culture.

However, more recent animal studies have revealed no therapeutic benefit of either drug. Two animal studies revealed that ribavirin treatment only delayed but did not prevent death after NiV infection.

A monoclonal promise?

Recent experimental studies have demonstrated that a human monoclonal antibody targeting the viral G glycoprotein can be effective as post-exposure treatment against NiV infection.

The virus attaches to host cell-surface displayed ephrin-B2 or -B3 proteins and infect host cells by the coordinated activity of their attachment (G) and fusion (F) glycoproteins.

In addition, the henipavirus G and F envelope glycoprotein spikes are major targets of virus-neutralising antibodies.

Known as m102.4, which was isolated from a recombinant naïve human phage-displayed Fab library, the mAb demonstrated exceptionally potent neutralising activity against both Nipah and Hendra viruses and its epitope maps to the ephrin receptor binding site in animal studies. It was found to effectively neutralise several isolates of the virus, including NiV-Malaysia and NiV-Bangladesh.

A 10- hour post-exposure dose of m102.4 could protect against a 10-fold lethal oronasal NiV challenge in ferrets. Similarly, post-exposure use of the mAb at 24, 72, or 120 hour was found to effectively protect against a 10-fold lethal intratracheal virus challenge in African green monkeys.

In 2010, Queensland health authorities were allowed to manufacture m102.4 antibodies for its potential use on a compassionate basis in future cases of high-risk human exposure to Hendra virus despite the absence of clinical or safety data from human trials.

Apart from Australia, the United States is also developing the m102.4 antibody for human use as a Nipah and Hendra virus countermeasure.

Following the 2018 outbreak in Kerala, the Indian Council of Medical Research initiated talks with the Australian health authorities, exploring the possibility of testing m102.4 antibodies on a compassionate basis on Indian patients with high-risk NiV exposure. But the status of the clinical  studies could not be confirmed by ICMR.

No vaccine yet

A subunit vaccine based on the G glycoprotein of Hendra virus (HeV) offers protection against Hendra and NiV. The HeV-sG subunit vaccine is a secreted version of G glycoprotein with the ability to bind ephrin receptors and elicit potent cross-reactive (Hendra and Nipah virus) neutralizing antibody responses.

The vaccine, called Equivac HeV, was approved for use in horses in Australia. It is the first vaccine licensed and marketed against a BSL-4 agent and is currently the only licensed prophylactic treatment for henipaviruses.

Efforts are currently underway to develop HeV-sG for human use as well as for use in pigs. Several vaccine candidates that target an immune response, besides the neutralising antibody approach, are reportedly in development.

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