History:”Yellow fever”, an arboviral disease is endemic in regions of South America and Africa. It also has other nomenclatures as Yellow jack or Yellow plague. It is believed that this disease evolved in Africa from 3000 B.C.¹ Ever since then, it has rapidly spread to many countries through travel and trade. The first definitive evidence of yellow fever in the Americas was given in Malayan manuscript. It portrays the outbreak of disease in Yucatan and Guadeloupe.2 Subsequently many outbreaks were reported. Outbreaks were reported in eastern coast of United States in late 1600s, New York in 1668, Boston in 1691 and Charleston in 1699.3 In the beginning of eighteenth century, it started spreading into the European countries. In the year 1730, 2200 deaths were reported in Cadiz, Spain. Following this, outbreaks were seen in French and British seaports. Multiple epidemics were reported in tropical and sub tropical areas of Americas, West Indies, Central America and United States.3History also reveals impact of yellow fever on various wars and armies. The disease had rampant and devastating effect on the Spanish American war in 1873, wherein for every soldier who died of battle, 13 died of yellow fever.4 This led to the formation of Reed Yellow fever commission led by Walter Reed, an American army surgeon.In the later part of nineteenth century, research was focused on the methods of spread of yellow fever and mechanisms to contain the infection. Until middle of nineteenth century, yellow fever was thought to be spread by direct contact with infected individuals and contaminated objects. For the first time, suggestions were made by American physician Josiah Clark Nott in 1848 and Cuban physician Carlos Finlay that the disease might be vector borne. In the beginning of twentieth century, the Reed Yellow fever commission proved that yellow fever is transmitted by vector Aedes Aegypti Mosquito.5 This led to beginning of numerous sanitation programmes to curtail the breeding of vector mosquito. Vaccine development:In 1930s, two yellow fever vaccines, 17D strain and the French Neurotropic strain were developed. The 17D vaccine was developed by Max Theiler and Hugh Smith, Rockefeller Foundation in the year 1937.6 French Neurotropic vaccine was developed in Dakar, Senegal, (by Pasteur Institute Scientist) from a person who survived the disease. Subsequently, mass immunization campaigns were conducted in South Americas and Africa. But unfortunately, it was observed that a significant number of infants receiving the vaccines developed post vaccinal encephalitis. Following the occurrence of adverse effects, there was a reduction in the use of vaccine among infants. In 1982, French neurotropic vaccine was abandoned and 17D became the standard vaccine for use in immunization. In the second half of twentieth century, the transmission of disease was again on rise. In 1980s, there was an increase in incidence of disease in the Africa reporting 120,000 cases and 24000 deaths reported in Nigeria alone.7 Due to the profound rise in the number of cases, 17D strain of yellow fever vaccine was incorporated into routine childhood immunization of several South American and African countries in the beginning of twenty-first century. Epidemiology and transmission of Yellow fever:After more than seventy years of development of vaccine, the burden of disease is estimated to be 1,30,000 cases including 78,000 deaths in Africa in the year 2013.8 The virus causing this disease belongs to genus flavivirus, family flaviviridae, a RNA virus. The virus is maintained in nature between forest mosquito and wild primates (sylviatic cycle of transmission). 9 The disease is transmitted to human beings through infected mosquito and results in urban cycle of transmission and subsequent epidemics.9 The virus is usually brought to the urban areas by infected humans in forest area. (Fig-1)Fig-1: Sylviatic cycle of Yellow Fever transmission Another transmission cycle is observed in Africa, wherein the virus is transmitted to humans living or working in forest area.9 (Fig-2)Fig-2: Transmission cycle of Yellow Fever in Africa The disease has an incubation period of 3-6 days following which malaise, headache, dizziness, lumbosacral pain, nausea, prostration, conjunctival injection, furred tongue, bradycardia (fagets sign) develop. This period of infection continues for several days.10 This is followed by a period of remission, leading to disappearance of symptoms and fever, usually lasting for about 24 hours.10 During this period, the virus is cleared by antibodies and cellular immune response. The patients with abortive infection recover after this stage. In approximately 15-25 percent of patients the disease reappears in a more severe form. This marks the stage of intoxication period, in which patient presents with headache, epigastric pain, vomiting and jaundice.10 It starts affecting all the vital organs leading to oliguria, hypotension, shock, stupor, coma, hemorrhage and seizures. This is a highly fatal disease. Many deaths occur during this stage of disease. The patients who recover from this stage enter the period of convalescence.Diagnosis is made by Viral antigen detection or detection of virus in the pre icteric phase. Serologic diagnosis is by detection of IgM antibodies by ELISA. There is no specific treatment for yellow fever. The disease is managed symptomatically. Passive antibodies, interferon inducers or interferon gamma are effective only before or within few hours of infection.10Environment of India – Susceptibility to the disease:India is a country in tropical and subtropical region. The country has the mosquito species which can contain the yellow fever virus. Presently, the National immunisation schedule in India does not include yellow fever vaccine in routine immunisation as the disease is not endemic. This leaves the population of India non immune and highly susceptible to yellow fever. Thus, the entry of the virus to this subcontinent can lead to a huge epidemic if appropriate preparatory measures are not taken.Indian subcontinent is categorized as yellow fever receptive area. Although the disease does not exist, conditions favouring the development of virus would permit its development if virus is introduced. Factors which favor this include many. Primarily, the abundant presence of Aedes Aegypti mosquito species which are the vector for yellow fever virus leaves the country to be highly susceptible to this deadly disease. Another factor potentiating the susceptibility is the favourable climatic conditions of more than 24 degree Celsius and 60% relative humidity prevailing over large geographic area/during rainy seasons. The susceptibility of common monkey of India (Macacus rhesus and Macacus sinicus) to yellow fever virus is another risk factor.11 Initiatives taken by Government of India:Government of India is taking multiple measures to prevent this virus from entering India. A strict vaccination program is existing in the country for travelers. Receiving yellow fever vaccine is mandatory for every traveler who is travelling to the endemic countries. The person receiving vaccine is provided with a yellow card which is valid from 10 days after vaccination to 10 years. If a person reaches India before validation of card, the person is quarantined till the card is valid or for 6 days whichever is earlier. Unvaccinated individuals from endemic countries are quarantined for 6 days which is the incubation period of yellow fever. 12The demand for vaccination is increasing as people traveling to the endemic countries for job and tourism is on rise. According to India tourism statistics 2015, the number of travellers to Africa alone has increased from 3.2 lakhs approximately in the year 2007 to 4.6 lakhs approximately in the year 2014.13 This alarming rise in the number of travelers to African countries poses great threat to rise of yellow fever cases in India.Vaccination and Prevention:A single dose of 0.5 ml of 17D strain, live attenuated yellow fever vaccine is given by subcutaneous route. This one time vaccine is valid from 10 days of vaccination for next 10 years.14 It is not recommended for routine immunization in non endemic countries like India. But it is strictly recommended for travelers to endemic countries.The vaccine is currently supplied by Central research institute, Kasauli. Vaccine is imported through World Health Organization and the process takes around 8 to 9 months. Manufacturers as Bio-Manguinhos (Brazil), Institute Pasteur de Dakar (senegal), FSUE Chumakov (Russia) and Sanofi Pasteur (France) offer WHO pre-qualified vaccine.14 Due to rise in demand for vaccination, the number of vaccination centers is increasing. As of 10th March 2017, 41 centers in various parts of the country are providing yellow fever vaccination.14 A charge of rupees 300 (cost in procuring vaccine) is taken from the person who receives vaccination from these designated centres.The vaccine is stored at 2-8 degree Celsius. It is contraindicated in persons with severe allergy to egg, immunodeficiency and symptomatic HIV infection, hypersensitivity to previous dose, pregnancy and infants younger than 6 months. The vaccine has several mild side effects like fever, body aches, swelling and soreness at the site of injection. These can be managed symptomatically. The serious and rare side effects include life threatening hypersensitivity, organ failure, meningoencephalitis, Guillain barre syndrome, Acute Demyelinating Encephalomyelitis and bulbar palsy. Precaution needs to be taken while administration of vaccine to infants of six to nine months age and older people of more than 60 years age.So far the disease is not seen in India. The triad of environment, agent and host is required for the disease to start spreading. In India, the only missing link is the agent. But it can enter this country through travelers and trade if proper precautions are not taken.India’s reservations and understandings to IHR 2005:Proposed Reservation to IHR 2005:- 1. The Government of India reserves the right to consider the whole territory of a country as infected with yellow fever whenever yellow fever has been notified under Article 6 and other relevant articles in this regard of IHR (2005). The Government of India reserves the right to continue to regard an area as infected with yellow fever until there is definite evidence that yellow-fever infection has been completely eradicated from that area. 2. Yellow Fever disease will be treated as disease of Public health significance and all health measures being applied presently like disinsection of conveyance, vaccination requirements and quarantine of passengers and crew (as may be required) (as per Article 7, P.2(b), 42 and relevant annexure) will be continued as has been stipulated under Annex-II of IHR-1969.Initiatives taken by WHO against yellow fever WHO is the secretariat for the international coordinating group (ICG) for yellow fever vaccine provision. Yellow Fever initiative was launched in the year 2006 to secure global vaccine supply and boost population immunity through vaccination. As per WHO, forty seven countries in Africa (34) and Central and South America (13) are endemic for yellow fever.15 Till 2016, fourteen countries have completed preventive yellow fever vaccination campaign.15Though effective vaccine is available, the disease is still prevailing in the regions of Africa and South Americas. This is largely due to lack of immunization in the high risk regions. Recent outbreaks were seen in Angola and Democratic republic of Congo in the year 2015-16.15 The disease was noticed in 2015 December Viana, Luanda province and Angola. The outbreak caused 962 confirmed cases by November 2016. More than 7300 people were suspected of having the infection.16 With efforts of WHO, UNICEF, multiple NGOs and volunteers, mass immunization campaigns were conducted in the affected regions leading to the end of outbreak. Conclusion:Yellow fever is a fatal disease and unfortunately no treatment is available till date. Efforts by the endemic countries in providing the vaccine through routine immunization, is keeping the incidence of disease on a decreasing trend. Non- immune travelers, traveling to endemic countries are at greatest risk to contract the disease and manifest symptoms. Apart from that, the non-immune traveler can bring the virus into a naive population which can start an epidemic. India, with high number of people traveling to endemic countries is at greatest risk to contract the infection. Favourable climatic conditions and abundance o vectors in the country can pave a way for the rampant spread of the disease. Preparedness is hence needed to curb the entry of the dreadful disease and to contain the epidemic (when occurs) at the earliest. As no cases are seen in India, presently the outbreak response preparedness is poor for this particular disease. Sustainable strategies to combat the outbreak should be developed. References-1. CDC 2017. History timeline transcript. Available at https://www.cdc.gov/yellowfever/index.html. Last accessed on June 24,20172. Carter HR. Yellow fever:An epidemiological and Historical study of its place of origin.baltimore, MD: williams and Wilkins;19313. Strode GK, Bugher JC et al. Yellow fever. New York, NY: Mcgraw-Hill Book co;1951.4. Bryan CS, Moss SW, Kahn RJ. Yellow Fever in the Americas. Infect Dis Clin North Am. 2004;18(2):275-292.5. Reed W, Carroll J, Agramonte A. The etiology of yellow fever: an additional note. JAMA.1901;36:431-440.6. Norrby E. Yellow Fever And Max Theiler: the only Nobel prize For a virus vaccine. J expMed. 2007; 204(12): 2779-2784.7. Monath TP. Yellow fever: victor,Victoria?conqueror, conquest?epidemics and research in the last forty years and prospects for future. Am J Trop Med HYg. 1991;45(1):1-43.8.Garske T, Van Kerkhove M, Yactayo S et al. Yellow Fever in Africa: Estimating the Burden of Disease and Impact of Mass Vaccination from Outbreak and Serological Data. PLoS med. 2014;11(5).9. Centers for disease control and prevention. 2015. Yellow Fever. Available at http://www.cdc.gov/yellowfever/transmission/index.html. Last accessed on June 24, 2017.10. Monath TP. Yellow Fever: An Update. The Lancet Infectious Disease. 2001: 1;11-20.11. Suryakantha AH, Community Medicine With Recent Advances, 2nd ed. New Delhi: Jaypee Brothers Medical Publishers, 2010. p 423.12. Bureau of immigration. 2013. Health Regulation. Available at www.boi.gov.in/content/health-regulation. Last accessed on June25, 201713. India tourism statistics .2015. Government of India. Available at www.tourism.gov.in. Last accessed on June 26, 2017.14. Ministry of health and family welfare. 2016. Yellow Fever. Available at www.mohfw.nic.in/about-us/directorate-general-health-services/international-health/yellow-fever. Last accessed on June 24, 2017.15. WHO. 2017. Yellow Fever. Available at www.who.int/mediacentre/factsheets/fs100/en. Last accessed on July 31, 2017.16. WHO. 2017.Yellow Fever outbreak Angola, Democratic Republic of Congo and Uganda 2016-17. Available at www.who.int/emergencies/yellow fever/en. Last accessed on June 25,2017.