INTRODUCTION:

Back in 1999, Kaw Bing Chau a graduate student at the University of Malaya in Kuala Lumpur Malaysia, busy with a microscope came across a bright green stained virus. Right there, was a virus the world never has seen before. A mysterious disease was devasting a farming town called Sungari Nipah near Chua’s laboratory, spreading lighting fast. People became comatose and paralyzed. On mistaking for Japanese encephalitis, the Malaysian government was busy fighting mosquitoes to control disease spread¹. Chau wrapped the samples to centers for Disease Control and Prevention Lab in Fort Collins, Colo for further analysis. The image revealed signs of a frightening group of viruses: paramyxo.

These viruses grouped under zoonosis come from livestock, not mosquitoes. Chau's persistence on the virus stopped it from further spreading by the culling of 1.1 million of cattle and pigs. The virus was later named after the village as Nipah virus^2,3.

Zoonosis is an infectious disease that may be transmitted from animals (wild and domestic) to humans. The word zoonosis is derived from the Greek word zoon (animal) and nosos (disease)⁴. Of all 1415 microbial diseases affecting humans, 61% are zoonotic and 75% of emerging infectious diseases are zoonotic⁵. Nearly 65% of zoonotic pathogens are originated from wildlife. Bats have been the primary reservoirs of zoonoticviruses like Ebola, Marburg, SARS, and Melaka viruses and are also the source of the respiratory syndrome in the Middle East and Europe, emerging as a threat to the human beings providing lethal effects. Case mortality was estimated to be 40% to 75% in both humans and animals based on various geographical location^6,7.

Chronological Nipah Outbreaks:

NiV has a strong and varied pattern of outbreaks in various geographical locations especially in the southern parts of Asia likely Bangladesh and India^8,9,10.

The first outbreak of NiV in the south-east part of the Asia region was observed in the MeherpurDistrict of Bangladesh in 2001 since then almost every year selected districts of Bangladesh are affected with NiV outbreaks¹¹. During 2001, a febrile illness with neurological symptoms was observed in Siliguri of West Bengal state in India¹². Outbreaks of NiV encephalitis was observed in India during 2001with a death toll of 45 out of 66 cases¹³. The chronological data of Nipah virus outbreaks around the world is depicted. Intensive agriculture practices implicated in the transmission of NiV between the 70s and 90s. Bats used to feed on fruit trees planted near the pig enclosures, bat bitten fruits led to infection in livestock and from there to farm labourers. Permanent risk of outbreaks is being expected due to the wide distribution of genes Pteropus (flying fox) in Australia, Southeast Asia, India, and Africa which is a reservoir of Henipavirus¹⁴.

Natural Host:

Fruit bats (Microchiroptera) of family pteropodidae and genus Pteropus are a natural host for NiV¹⁵mainly in India, Australia, Indonesia, Madagascar, and islands in Indian and Pacific oceans. Bats with their evolved antiviral defense strategy produce antibodies against the virus so finally acting as reservoirswith no apparent disease in them^16,17, which is evident from anti-Nipah antibody in fruit bats in Cambodia, 2002¹⁸. Pteropusgiganteus (Indian flying fox) and Cynopterus sphinx (short-nosed Indian Fruitbat) are the main natural reservoir with widespread and common species in South Asia¹⁹.

Rousettusaegyptiacus, Taphozous longimanus, Taphozous melanopogon, Rhinolophus luctus, Chaerophon plicatus, and Macroglossus minimus that is not currently identified as NiV reservoirs, have high likelihood in future based on trait similarity with known NiV reservoirs²⁰. Under experimental conditions, the clinical aspects and characteristics can be observed in ferrets (Murteloputoriousfuro), guinea pig (Caviaporcellus), squirrel monkey (Saimirisciureus), African green monkey (Chlorocebusaethiops), hamster (Cricetinae) and mouse (Musmusculus), the animals which are susceptible to NIV are Humans, pigs, dogs, cats, goats, and horses^21,2².

STRUCTURE AND GENOME:

NiV is a close relative to Hendra virus (HeV) and Cedar virus, recognized species of genus Henipavirus of paramyxoviridae family characterized by a wider host range with larger genome capacity²³.

NiV genome includes six structural proteins i.e. Glycoprotein (G), Fusion protein (F), Matrix protein (M), Nucleoprotein (N), RNA-directed RNA polymerase (L), Phosphoprotein (P) and three non-structural proteins (W, C, V). The host cell infection is initiated by attachment of glycoprotein (G) to host cell ephrin receptor²⁴and the fusion (F) protein which drives virus-host cell membrane fusion.²⁵ the p protein binds N protein to increase specificity towards viral RNA, thereby forming nucleocapsid²⁶. This acts as a template for viral polymerase L to replicate²⁷. On replication, M protein homodimerizes and forms array at the plasma membrane that induces curvature in the membrane for budding and release of new viral proteins^28,29. W, V, C helps to escape the host immune response by acting against interferon signaling.

Paramyxovirusis inactive at 60°C/60min, use of soaps, and disinfectants, lipid solvents like alcohol, ether, and sodium hypochlorite can decrease the chance of being infected. It is stable at 4.0 to 10.0 pH and can survive for days in fruit bat urine and fruit juices³⁰.

TRANSMISSION:

Transmission of NiV occurs in contact with excreta, saliva, semen, urine of infected bats, or on the consumption of bat bitten fruits or by infected pigs and other infected livestock. No person to person transmission was reported in Malaysia, Singapore outbreaks but observed in South East Asia mostly Bangladesh and India in case of NiV patient’s caregivers.³¹ 75% of cases occurred among hospital staff or visitors from 2001 to date half of the cases of Bangladesh are through human-human contact.³²

Vertical transmission is suggested by the detection of the Nipah virus in placental and fetal tissues. In the hamster infection model, the Nipah virus-associated with leukocytes acted as a vehicle to transfer infection within the organism to permissive tissues without any prior sign and symptoms^33,34.

SIGNS AND SYMPTOMS:

Blood vessels are targets of earlier infection stage with the central nervous system are the most severely affected, although lung, kidney, and other organs are also infected. Vacuities induced thrombosis in brain, pneumonia, and respiratory distress is also reported in some. The other symptoms associated with NiV are Myalgia (Muscle aches), sore throat, vomiting, dizziness, and atypical pneumonia. Nipah encephalitis often relapses sometime later in their life. Respiratory involvement in Singapore strain was only 18% and about 29% for Malaysian strain while in the case of Bangladeshi and Indian strain half to two-third cases developed acute respiratory distress syndrome. Fatality cases reported in Bangladesh are way higher than Malaysia, which can be accounted forthe difference in viral traits.³⁵

DIAGNOSIS:

Precaution should be taken in the sample collection, submission, and processing of the tests since NiV is biosafety level 4 (BSL4) agents and precaution guidelines state that tests should be carried in physical contaminant 4 (PC4) facilities to reduce the risk of gamma irradiation and heat inactivation. Symptoms of Nipah virus often overlap with influenza i.e., fever and muscle pain giving a chance of mistreatment and transmission which implicates the need for better diagnostic methods.Developed bio-analytical methods paved a way for early, efficient detection of the Nipah virus. Viral isolation, reverse transcriptase-polymerase chain reaction RT-PCR, detection of circulating antibodies against NiV by serological assays are employed to confirm the reservoir bat species in various geographical locations and virus detection in throat swabs, blood, urine, respiratory secretion and cerebrospinal fluid of infected. PCR techniques can be employed without propagating the live infection virus.³⁶ Immunohistochemistry helps to identify antigens on formalin-fixed tissues or formalin fix cells of endothelium from the brain, lung, lymph, spleen, kidney, uterus, placenta, and fetus¹. MRI of the brain can differentiate NiV encephalitis from normal encephalitis³⁷

ELISA can be applied for diagnosis of NiV infection but due to the false-positive specificity of ELISA, positive reactions must be further confirmed by Serum neutralization test. The serum neutralization test is designated as the reference standard for anti-henipavirus antibody detection. Antibodies like anti-NiV IgM can be detected in the blood of the patient after week whereas anti-Nipah virus IgG antibody is seen after 17-18 days delaying diagnosis.

THERAPEUTIC STRATEGIES:

Despite the high mortality rate of Nipah outbreaks, there is no approved drug or vaccine for its treatment. Even though the overall fatalities of each outbreak were less than 105, the disease could become pandemic which causes a devastating effect. Vaccine and antiviral therapy are necessary not only for public health and NiV patients but also for researchers, care providers, and health care workers who serve infected.

Animal models like a golden hamster and African green monkey are developed for NiV experimental study in antiviral drug and vaccine research^37,38. Guinea pigs are best antiviral animal models as they show similar histological lesions, where a cat has been used as a model for successful G protein subunit vaccine development, furthermore, ferrets have been used for successful post-exposure of passive antibody therapy in which Nipah virus protein was targeted by a human monoclonal antibody and non-human primates models have been developed. Equirac^©HeV, a vaccine licensed in Australia by Pfizer animal health for prevention of Hendra virus in the horse, produces cross-protective antibodies agent HeV & NiV this offers great potential for human protection from henipavirus as well but still, there is a need for a specific vaccine.³⁹

All the 9 Nipah virus proteins discussedearlier are potential targets for rational drug and vaccine design and researches are trying to predict the epitopes of these viral proteins. Guillemin et al. proposed that Nipah virus glycoproteins (G and F) when expressed as vaccine virus recombinants induced an immune response in hamsters showing a prophylactic response. However, hyper immunization is expressed in animal models. Prescott et. al., attempted to develop single-dose live-attenuated vesicular stomatitis virus (VSV)-based vaccine. VSV is an animal virus that primarily affects cattle and was successfully used as a vaccine platform against several viruses, it encodes Nipah virus glycoprotein as antigen and highly efficacious in the hamster model. On testing, in African green monkeys the vaccinated animals showed rapid and strong Nipah specific immune response that inhibited virus shredding and replication⁴⁰. Kamthania M, et al., predicted and modeled T cell epitope with high binding to MHC II alleles by binding simulation studies. The docked peptide allele complex structure was optimized through molecular dynamics simulation⁴¹.

Structure-based design of therapeutics helps to fight against the disease. As Nipah virus entry and cell-cell fusion require the concerted efforts of the attachment of glycoprotein G and fusion protein F, Mohammed et al., used an immune informatics approach and population coverage analytical tools to predict effective epitope-based vaccine against glycoprotein G of Nipah. This study proposed peptide with a strong affinity towards MHC I and MHC II alleles⁴². Despite heterogeneity and mutations in NiV B and M strains identified in Bangladesh and Malaysia respectively, scientists believed in the conservation of epitopes on the transmembrane glycoprotein G, which could bind to m102.4. m102.4 is a humanized monoclonal antibody with strong cross-reactivity and neutralizing activity towards Nipah and Hendra viruses. It prevents viral entry to host cells by binding to G glycoprotein and blocking receptor engagement⁴³. Through promising results in preliminary trials of NiV on ferret⁴⁴ and non-human primate models⁴⁵, m102.4 entered phase I clinical trials to establish its safety in human beings. No deaths and serious events occurred during the study. Single repeated dosing of m102.4 showed linear pharmacokinetics with no evidence of an immunogenic response⁴⁶. Effectiveness of m102.4 in clinical trials could pave the path for a new era of henipaviruses prevention and treatment.

While one part of the world is searching for new therapies, other half is concentrating on using available therapies to fight new targets. Sayantan Banerjee et al. shared their experiences during the 2018 outbreak in Kerala in a letter to the editor about post-exposure prophylaxis by ribavirin. In the Kerala outbreak, due to the unavailability and inexperience of any other alternatives ribavirin, PEP (rPEP) was the only option left over. From the evidence of safety and efficacy of short-course high-dose rPEP used for Lassa fever, all contacts started using rPEP within 72 hours. 1000mg thrice daily dose was taken for 14 days, experiencing minor side effects of fatigue, headache, nausea, dry mouth, and palpitations. Ribavirin efficiently shielded most of the exposed healthcare workers but with only 2 survivors of 23 infected persons. Drop-in hemoglobin between 17 and 21 days after starting rPEP therapy along with increased bilirubin was observed, hemoglobin rose back within one week after stopping rPEP. Banerjee suggested a pre-planned trial for rPEP in case of any other outbreak⁴⁷. Even during the 98-99 Malaysian outbreak, a 36% reduction in mortality is reported compared to control⁴⁸ but in vivo efficacy of ribavirin is still unclear in NiV cases.

Favipiravir (T-705), approved antiviral in japan for emerging influence strains was still in phase 2 and phase 3 in the United States and Europe. Its broad spectrum against RNA viruses aroused a thought of evaluating its efficacy against NiV in the hamster model with the first dose of 600mg/kg/day followed by a dose of 300mg/ kg/ day on days 1-13. Though no clinical signs of the disease reported in study⁴⁹, the emergence of resistance towards Favipiravir among the influenza family could be a limitation to its applicability⁵⁰.

Researchers of the Indian Institute of Science Education and Research Pune took a step towards the identification of drug targets in different strains of the Nipah virus. A three-dimensional model of 9 Nipah virus proteins is made to design inhibitory molecules that can block the protein activity. The molecules are assessed against 15 different strains of the virus- 3 Bangladeshi, 7 Malaysian, and 5 Indian strains. 4 peptide inhibitors and 146 small molecule inhibitors are identified against Nipah virus proteins. Based on binding strength, stability, and effectiveness against multiple strains, 13 peptide inhibitors are short listed⁵¹. This can portray the effect of sequential variation among strains on the efficacy of proposed drugs.

Although the vaccine is a potent technology that could restrict the disease spread in the root stage, drug companies might be hesitant to invest a lot in relatively rare tropical diseases like Nipah requiring support for equitable access of vaccine to all people. Coalition of Epidemic Preparedness and Innovations (CEPI) is such support that works to accelerate vaccine development against emerging infectious diseases. CEPI granted $25m to develop the Nipah vaccine in a global partnership with Auro Vaccines and PATH. G glycoprotein portion of Hendra virus is employed to develop this recombinant subunit Nipah vaccine, HeV-sG-V. CEPI announced the news on the entry of vaccine to Phase 1 clinical trial on 13^th March 2020 to investigate the safety, tolerability, and immunogenicity of three ascending doses 10mcg, 30mcg, and 100mcg. CEPI has four early-stage Nipah vaccine candidates and this was the first to reach phase 1 giving hope of future vaccination to prevent NiV⁵².

Preventive Measures:

Lack of specific treatment leads to the adoption of few precautions like barrier nursing and isolation of suspected to avoid the spread of infection from person to person. As NiV can be prevented by avoiding exposure to sick pigs and bats in endemic areas and not consuming raw date palm sap, the ban on commercial piggeries having mango and other fruit trees that attract Pteropus bat was believed in Malaysia. Horse vaccination is now also considered as an alternative in Australia. Preventing the contamination of date palm sap through bat exclusion methods believed in Bangladesh⁵³.

Additional efforts on surveillance and awareness will help prevent future outbreaks by studying the ecology of bats and Nipah virus, seasonality of disease within reproductive cycles of bats along with laboratory assays in early detections of disease in communities and livestock. Improved medical facilities and education are of utmost importance and necessary throughout the regions where the Nipah virus exists, for example, Bangladesh and India, where transmission is from human to human.

Economic and Social Impacts of The Outbreak:

The devastating impact on pig and their associated industry in the Malaysian outbreak, lead to major economic loss. The government paid US$35 million in compensation for 1million pigs and an estimated cost of US$136 million was spent on control programs in veterinary services. Tax revenues estimated US$105 Millions, 618 homes, and 111shops were lost from the pig industry, Further 50 farms were culled, under the national testing and surveillance programmes. Loss of export price US$120Million to Hong Kong and Singapore in addition to that local pork consumption has been down by 80% and a huge loss to the farmers who supply pork to the market estimated to be around US$124Million, pig farming in Malaysia is now allowed only in identified pig farming areas with farmers in other areas encouraged to undertake other agricultural and livestock activities. However, the high fatality rate surpasses the other social impacts of the outbreak⁵⁴.

Recent (Word With Meaning of Last) Outbreaks – India:

On 19 May 2018, an outbreak of NiV in Kozhikode district of Kerala state was observed in India, three deaths were observed in a family cluster^55,56,57,58. On the field investigation, the team found bats living in an abandoned water well on the premises of a new house where the family had plans to move after the renovation. One bat from the well was caught and sent to the National Institute of Virology, Pune for laboratory testing, and ended up finding seropositive, carrying Nipah virus⁵⁶. 15 suspects from Kozhikode and Malappuram districts of Kerala were confirmed seropositive on 28 May 2018. Two are hospitalized and the remaining thirteen were dead including the health care worker who was involved in the treatment of the deceased among these 13 deaths, two are from mallapuram and the remaining 10 are from Kozhikode district⁵⁷.

There are 16 suspected cases identified through contact testing and at least 753 additional people including health care workers kept under observation then. Laboratory testing is conducted by the ManipalInstitute of virus research and the National Institute of Virology, Pune with good capacity to conduct RT-PCR. Respiratory distress syndrome and encephalitis have been observed. Since the last of the Nipah outbreak in 2001, this is the first outbreak in Kerala state and the overall third outbreak in India⁵⁸.

The outbreak was brought under control by the immediate and efficient response from the government, health organization, and WHO. A multi-disciplinary central team from the National Centre for disease control was sent to investigate and respond to the case in Kerala. Hospital and community surveillance have strengthened in identifying the case of acute fever and acute encephalitis syndrome (AES) across the state. The government coordinated with relevant sectors including zoonosis, wildlife animal husbandry, human health, clinicians, pulmonologists, and neurologists. Guidelines drafted by the National Centre for disease control are shared with states and stakeholders through The Ministry of Health and Women's welfare of India⁵⁸. WHO which is the governing body expressed its support by sharing the materials, especially risk communication materials on the Nipah virus, including those used in Bangladesh upon the request of The Ministry of Health and Family Welfare (MoHFW)⁵⁸.

WHO, Ministry of Health and prevention of United Arab Emirates, etc., released a travel alert and ban on the export of fruit and vegetables from Kerala. A list of countries that should remain alert for a potential influx of infected travelers was released. The UK is 10^th on the list remained alert even after declaring control. Kerala declared that the outbreak has been contained; the success is owed to hundreds of medical professionals. A poignant note written by nurse Lini who succumbed whilst looking after patients has touched hearts of thousand remained as a shining example of unassuming dedication and courage. From the unexpected outbreak of NiV Kerala strengthened its health facilities and strategies to tackle viral attacks for early identification and isolation of infected⁵⁹.

DISCUSSION:

NiV emerged as a menacing virus twenty years back with severe morbidity and mortality in humans and animals and a hugely destructive effect on society. It almost turned endemic in some regions like Bangladesh with outbreaks being recorded every year. Future risk of Nipah outbreak in new regions is evident from widespread reservoir host, Pteropus bat. The outbreak of NiV on 19 May 2018 in Kozhikode district of Kerala state in India ended with 17 deaths (including a health care worker) but started a threat throughout the world. WHO highlighted the need for intense research and development on the Nipah virus by including it in the WHO R&D Blueprint list of priority diseases in 2018.

From two decades our researchers, ecologists, health organizations, and government are fighting against the same old enemy, NiV to which still there is no specific treatment or vaccine. Modern analytical methods and biotechnological advancements are lighting a hope for a remedy that could prevent and destroy the virus. WHO along with other international organizations are working on collaborations to search for new insights and fasten the drug/vaccine development? HeV-sG-V developed through the support of CEPI and other vaccine strategies being studied by researches may halt these twenty years of NiV outbreaks. Knowledge sharing between Nipah virus experts, industry, and key public-health stakeholders is important to this fight against Nipah Virus. Unavailability of vaccine or specific drug made supportive care and prevention the best approach against Nipah virus outbreaks. This could be made possible only by the development of awareness among people of most susceptible areas.

STATEMENT OF CONFLICT:

The authors report no conflicts of interest.

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Received on 22.07.2020 Modified on 17.05.2021

Research J. Pharm. and Tech 2022; 15(9):4048-4054.

DOI: 10.52711/0974-360X.2022.00679