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Chasing Nipah

July 16, 2019

Monsoon season was just around the corner. A 26-year-old man living on the outskirts of a dense South Indian tropical forest became sick with flu-like symptoms. It was early May 2018 in the state of Kerala and the man’s symptoms quickly progressed to respiratory distress, mental confusion, disorientation, and ultimately death. A religious ritual burial followed where they bathed, shrouded him and prayed as they put him to rest. Two weeks later his brother died. A week after, his father. The aunt that visited him in the hospital died the following week.

Twelve people at the hospital to which the man, known as patient zero, came in chance contact with all died, except for two individuals of no relation. 

Immediately, the Kerala state government and the Indian Consulate of Medical Research (the high authority in India similar to the U.S. Centers for Disease Control) became involved and contained the infection. 

The cause: Nipah virus, a deadly disease. 

Nipah is an RNA virus like Ebola, Zika, chikungunya (CHIKV), severe acute respiratory syndrome (SARS), measles, West Nile virus (WNV), and the common cold. RNA viruses tend to change and evolve faster than DNA viruses because their genetic material is prone to more mutations to adapt to new hosts. This allows the virus to jump from species to species, like how avian flu and swine flu jumped from birds and pigs to humans. 

An Unknown Disease

Nipah was named after a town in Malaysia where it was first identified in 1998. There, an outbreak on a pig farm resulted in 257 people afflicted and 105 deaths. A zoonotic disease, the outbreak was caused by fruit bats and the overlap between bat habitats and pig farms. Fruit orchards in close proximity to pig farms created a point of contact between pig and bat habitats. From pigs it was spread to humans and infected pigs were transferred to other farms unknowingly. The virus was isolated in 1999 and one million pigs were culled. 

Nipah is known to kill as quickly as it infects. Symptoms come on fast, appearing five to 14 days after exposure, and can progress within 24-48 hours into coma. Symptoms include fever, headache, aches, vomiting, drowsiness, shortness of breath, mental confusion, and disorientation. Complications include seizures and encephalitis (brain inflammation). 

Luckily, to date, Nipah outbreaks have been small and contained. The virus appears each year in Bangladesh and has hit India three times, with previous outbreaks occurring in West Bengal in 2001 and 2007. 

The 2018 outbreak in the Kerala State caught the attention of Kar Muthumani, Ph.D., director of the Laboratory of Emerging Infectious Diseases and assistant professor of the Vaccine & Immunotherapy Center, at The Wistar Institute. His hometown is near Kerala, and he specializes in the design and creation of synthetic enhanced DNA vaccines and antibody therapies against emerging infectious diseases that tend to land on the watch list of the World Health Organization (WHO).

Inspired by Curiosity

Muthumani is part of a global community of scientists, epidemiologists and health workers in government agencies, academia and the private sector, who monitor disease outbreaks and engineer vaccines for future pandemics. His lab — like others in Wistar’s Vaccine & Immunotherapy Center — is creating synthetic DNA vaccines and therapeutics against Nipah, Zika, Mayaro, CHIKV, Middle East respiratory syndrome coronavirus (MERS-CoV), human immunodeficiency virus (HIV), respiratory syncytial virus (RSV), Dengue (DV), Powassan (POWV), and others.

In May 2018, Muthumani was following international news related to his home-country and read an article about a Nipah virus outbreak in Kerala.

“Nipah is deadly, it’s transmitted easily and there is no effective treatment,” said Muthumani. “But there were some survivors. They were family members who cared for the infected and never had signs of the disease and people who contracted Nipah and lived.”

Muthumani needed to understand more and wanted to figure out what protective immune mechanisms allowed those family members who lived with infected patients to survive and how certain people were infected but their immune systems ultimately protected them from succumbing to the disease.

“Understanding what kind of protective immune mechanism is in place and what is different about the survivors will inform us on how to make better vaccines and therapeutics,” said Muthumani. 

Four months after the Kerala outbreak, Muthumani personally visited the house where it all started. He needed to understand the timeline of events and how, from a single person, infection spread to two separate towns 50-60 miles apart, infecting 19 people and killing 17. 

“Four people exposed to the virus did not die from Nipah: two contracted Nipah and survived and two had direct contact with a Nipah-exposed person and never caught it,” said Muthumani.

Patient zero became sick on May 3, 2018 and died just two days later. It was thought he had contracted the deadly disease from a traditional fermented drink consisting of raw date palm sap collected in open containers. As bats are endemic to the region, it is believed the open collection buckets high atop palm trees are the zoonotic link whereby infected bat urine and feces inadvertently become collected.

“The mother of patient zero lived,” said Muthumani. “She took care of all three sick family members and was never virus-positive. I still don’t know the details of her immunological response and need to understand more.”

Muthumani met the son whose mother contracted Nipah from patient zero and died. He took his mother and cousin (patient zero) to hospital and never contracted the disease. His pregnant sister was also not positive for Nipah. Muthumani wondered what was special about their immune system? 

Connected by Events; a Continuing Investigation

He then learned a series of events that happened at the hospital and may be able to explain the spread of disease in another town, 50 miles away. 

Another man, unrelated to the patient zero’s family took his friend to the hospital and was waiting for his friend’s x-ray in the same space where patient zero had also received an x-ray. The man became infected and went to his parents’ house to recover from what he thought was the flu. His parents took care of him for more than two weeks before he died. Before his death, he exhibited strange neurological behaviors including sleeplessness and hyper and manic behaviors. None of his family members contracted Nipah even though several resided in the house together.

Through working with local research scientists, Muthumani has puzzled together the Kerala outbreak story to understand how the virus spread. Government disease control teams have scoured the original outbreak area and the surrounding forest for bat samples and confirmed bats are, in fact, the source of the Nipah outbreak. 

Muthumani is still driven by curiosity:  why did certain people die yet others didn’t — even though they came in contact with same people. What protected them?

Now, as Muthumani works to better understand immune protection with his collaborators, these data will prove invaluable in fine-tuning a synthetic DNA Nipah vaccine and therapeutics he has been developing at Wistar.

“Our vaccine generated strong T-cell and antibody responses in mice and proves synthetic DNA can drive T and B cell activation, which are important for clearance of a viral infection,” said Muthumani. “Now we’re ready to conduct challenge studies and take the next testing steps, which will continue to test the response efficacy of our Nipah vaccine.”

Muthumani is working with labs in India to better understand these immunological puzzles. 

“This is a valuable resource of national and international interest — every country will benefit from analysis of these samples,” said Muthumani. “Our studies will support an immune therapy approach for Nipah and ultimately lead to the application of our pioneering synthetic DNA monoclonal antibody therapy approach against Nipah and other emerging infectious diseases.”

Time will tell. 

And time, conviction, curiosity, and scientific expertise are all on Muthumani’s side.

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