Nipah virus (NiV) infection causes a severe and often fatal human disease. The causative agent, NiV is an enveloped, negative-sense RNA virus belonging to the Henipa genus, family Paramyxoviridae. A close relative, Hendra virus, occurs in Australia and affects horses and humans. Both Nipah and Hendra viruses are maintained in nature by fruit bats. These viruses can spillover from bats to livestock and humans. More distant relatives belonging to the Paramyxovirus family which do not have animal reservoir hosts include measles, mumps, and respiratory syncytial virus.

Nipah was first recognized and later identified in an outbreak in 1998 in the village of Sungai Nipah in Malaysia, hence the name “Nipah.”¹Chua KB, Goh KJ, Wong KT, et al. Fatal encephalitis due to Nipah virus among pig-farmers in Malaysia. Lancet  DOI: 10.1016/S0140-6736(99)04299-3 Subsequent outbreaks have occurred in India, Malaysia, Singapore, and the Philippines and cases are reported annually from Bangladesh.²Ambat AS, Zubair SM, Prasad N, Pundir P, Rajwar E, Patil DS, Mangad P. Nipah virus: A review on epidemiological characteristics and outbreaks to inform public health decision making. J Infect Public Health. 2019 Sep – Oct;12(5):634-639.

Transmission of Nipah virus-to-humans may occur after direct contact with infected pigs, infected bats or from other NiV infected people.¹https://www.cdc.gov/vhf/nipah/transmission/index.html (accessed 27 Feb 2020). The virus enters the body through the oral and nasal routes.

In Malaysia where the first recognized Nipah outbreak occurred, humans were infected through contact with infected pigs. The NiV strain identified in this outbreak (NiV Malaysia) appeared to have been transmitted initially from bats to pigs, with subsequent spread within pig populations and then to people. Contact spread from infected pigs is enhanced in slaughterhouse situations. In Bangladesh and in India, infection of people occurs when they ingest food contaminated by NiV bat secretions, especially date palm sap which is considered a delicacy. Of special concern is transmission from person-to-person which poses a great hazard to household members, nurses and doctors caring for Nipah virus infected patients. The risk of person-to-person spread is increased by the difficulty to diagnose and isolate Nipah disease cases early, which results in further person to person spread.²Gurley ES, Hegde ST, Hossain K, et al. Convergence of Humans, Bats, Trees, and Culture in Nipah Virus Transmission, Bangladesh. Emerg Infect Dis. 2017 Sep;23(9):1446-1453. doi: 10.3201/eid2309.161922.

Persons at highest risk of exposure would benefit most from a vaccine. In an outbreak of Nipah virus disease, the vaccine would be used to protect persons in close contact with bat reservoir hosts and contaminated palm sap, contacts of Nipah virus infected patients, healthcare workers, abattoir workers, and personnel critical to maintaining food, water, transportation and social functioning. If the pattern of disease changed with increased person-to-person spread, it is possible the vaccine could be used for general use in at risk populations.

Nipah disease usually presents like many other viral illnesses with fever, headache, muscle pains, vomiting and sore throat. This can be followed in as little as 24-48 hours by infection and inflammation of the brain leading to confusion, coma and oftentimes death. About half of the patients develop respiratory symptoms marked by pneumonia which can progress to severe respiratory failure.¹Hossain MJ, Gurley ES, Montgomery JM, et al. Clinical presentation of Nipah virus infection in Bangladesh. Clin Infect Dis. 2008 Apr 1;46(7):977-84. At this stage, patients shed virus and pose a risk of transmiting it to contacts. A prominent pathological feature is infection and inflammation of blood vessels (vasculitis). Death rates range between 40 and 70%; survivors often have disabling long-term neurological health problems.²Ng BY, Lim CC, Yeoh A, Lee WL. Neuropsychiatric sequelae of Nipah virus encephalitis. J Neuropsychiatry Clin Neurosci. 2004 Fall;16(4):500-4.

Most long-term survivors of Nipah virus disease suffer from persistent fatigue and functional impairment. Survivors who experienced acute brain inflammation (encephalitis) may have persistent weakness, cranial nerve abnormalities, brain atrophy, learning disabilities and behavioral problems.¹Sejvar JJ, Hossain J, Saha SK, Gurley ES, Banu S, Hamadani JD, Faiz MA, Siddiqui FM, Mohammad QD, Mollah AH, Uddin R, Alam R, Rahman R, Tan CT, Bellini W, Rota P, Breiman RF, Luby SP. Long-term neurological and functional outcome in Nipah virus infection. Ann Neurol. 2007 Sep;62(3):235-42

Nipah virus disease is treated with supportive care and management of acute encephalitis and respiratory disease. There are no licensed treatments. A report by the Centers for Disease Control and Prevention in Atlanta, GA, USA, describes the complete protection of African green monkeys infected with a lethal inoculum of NiV who were treated with Remdesivir, an experimental drug available on a compassionate use basis from Gilead Sciences (Foster City, CA).¹Lo MK, Feldmann F, Gary JM et al. Remdesivir (GS-5734) protects African green monkeys from Nipah virus challenge. Sci Transl Med. 2019 May 29;11(494). A second therapeutic, an experimental human monoclonal antibody (mAb102.4) has shown promise in treating monkeys infected with Nipah virus,²Geisbert TW, Mire CE, Geisbert JB, Chan YP, Agans KN, Feldmann F, Fenton KA, Zhu Z, Dimitrov DS, Scott DP, Bossart KN, Feldmann H, Broder CC. Therapeutic treatment of Nipah virus infection in nonhuman primates with a neutralizing human monoclonal antibody. Sci Transl Med. 2014 Jun 25;6(242):242ra82. and has completed a Phase 1 clinical trial in Australia.³Playford EG, Munro T, Mahler SM, et al. Safety, tolerability, pharmacokinetics, and immunogenicity of a human monoclonal antibody targeting the G glycoprotein of henipaviruses in healthy adults: a first-in-human, randomised, controlled, phase 1 study. Lancet Infect Dis. 2020 Feb 3. pii: S1473-3099(19)30634-6. Nipah virus proteins present multiple opportunities as targets for small molecule antivirals, and it is expected that new candidate treatments will be developed.  Recently, the WHO has published a draft “Nipah Research and Development Roadmap” which is currently in revision that describes the experimental use of unlicensed products.⁴https://www.who.int/docs/default-source/blue-print/nipah-draft-r-d-roadmap.pdf?sfvrsn=d59dfd26_4 (accessed 21 February 2020).

Current estimates indicate that 2 billion people live in areas of the world where Pteropus bats, the carrier of Nipah virus, are found. There is also a risk that Nipah could spread to areas where fruit bats do not live due to person-to-person transmission. A vaccine would be an important tool to slow and then stop any outbreak of Nipah virus infection.

This Nipah vaccine is currently being developed by PHV’s manufacturing partner, a Contract Manufacturing Organization (CMO), in the USA. In the future, other manufacturers with similar capabilities could manufacture the vaccine.

The Coalition for Epidemic Preparedness and Innovation (CEPI) is funding this program. CEPI is a global partnership committed to develop vaccines to stop future epidemics of emerging infectious diseases. The Coalition includes public, private, philanthropic and civil society organizations. CEPI funds not only the development of the vaccine but plans to enable equitable access to all who need it during outbreaks.¹https://cepi.net/about/whyweexist/ (accessed 21 February 2020).

CEPI is funding Nipah vaccine development efforts with a stated goal of developing a stockpile of vaccine for emergency use within 5 years.¹https://CEPI.net In December 2019, CEPI informally announced plans to raise additional funds to support efforts to further develop selected candidate vaccines towards licensure.

Safety is an inherent goal of the NiV Vaccine program. During development of the vaccine, extensive tests are performed to demonstrate safety and lack of toxicity in nonclinical models with the oversight of FDA and other regulatory agencies to ensure adequate testing before initiation of human clinical trials. All clinical trials will be conducted under an FDA Investigational New Drug (IND) Application and with approval by host nation ethical review committees. During the clinical trials, study physicians will assess study participants for any adverse events. In addition, a Data Safety Monitoring Board (DSMB) composed of experts in clinical trials of vaccines will monitor safety data from all trials involving the vaccine.

Vaccine development efforts will be conducted in close consultation with the FDA to demonstrate the vaccine is both safe and effective in protecting people against Nipah disease. Before a vaccine can be approved by the FDA, the sponsor (vaccine developer) must prove safety and efficacy, i.e., that the product is safe for widespread use and has benefit for protection against disease. Since Nipah is an episodic disease, it is not possible to plan a human efficacy study during an outbreak. Therefore, the plan is to seek FDA approval based on well-controlled nonclinical studies and use the results of those studies to establish that the vaccine is reasonably likely to protect against disease during an outbreak. This will be done by establishing a marker of vaccine protection in animals such as a quantitative antibody level that is associated with protection, and then demonstrate the vaccine elicits the same antibody level in people. Alternatively, under regulatory provisions established by the FDA (the “Animal Rule”), the vaccine will be tested in animals and shown to be effective.

The vaccine is expected to be safe and well-tolerated based on the experience with the closely related licensed vaccine used to protect against Ebola virus disease. In some vaccinees, side effects reported in the first few days after vaccination include mild to moderate fever, headache, myalgia, and arthralgia of short duration. In a minority of subjects (typically less than 5%), a self-limited oligo-arthritis or rash may appear.

PHV designed its Nipah vaccine based on characteristics of other successful VSV-vector vaccines. After reviewing all published, peer-reviewed scientific reports describing a wide range of experimental NiV vaccines, initial studies in animal models of the vaccine candidate demonstrated that it was safe and effective for protection against NiV disease.¹DeBuysscher BL, Scott D, Marzi A, Prescott J, Feldmann H. Single-dose live-attenuated Nipah virus vaccines confer complete protection by eliciting antibodies directed against surface glycoproteins. Vaccine. 2014 May 7;32(22):2637-44.²Prescott J, DeBuysscher BL, Feldmann F, Gardner DJ, Haddock E, Martellaro C, Scott D, Feldmann H. Single-dose Live-attenuated Vesicular Stomatitis Virus-based Vaccine Protects African Green Monkeys from Nipah Virus Disease. 2015 Jun 4; 33(24): 2823–2829. DOI: 10.1016/j.vaccine.2015.03.089

The PHV Nipah vaccine, rVSV-Nipah, is designed to protect against the two main strains of the Nipah virus, Nipah Malaysia and Nipah Bangladesh. As an essential step in development, the ability of the VSV-Nipah vaccine to protect against both these different strains will be confirmed in rigorous nonclinical studies.