Yellow fever. Development of vaccine - Research Paper Example

Yellow Fever Introduction Yellow fever has been a cause of life threatening epidemics throughout the last few hundreds of years of human civilization. It is believed to have originated in Africa and transported to the western hemisphere through the slave trade with the first reported outbreak being in Yucatan in 1648. 1 The ensuing years reported a number of outbreaks in the Americas and Europe. 2 The disease remained an enigma though Cuban Carlos Finlay suggested the mosquito Culex cubensis which is now called Aedes aegypti to be responsible for the spread of the disease. 3 His multiple attempts however could not prove the theory and it was not until the end of the 19th century that the mystery surrounding the enigmatic disease was unlocked by Surgeon Walter Reed of the United States Army. The work done by Reed and his colleagues found that the mosquito Aedes aegypti was critical in the dissemination of the disease and a filterable agent found in the patients' blood was the cause of the disease. 4 A rapid eradication campaign against the mosquito vector followed the discovery and in 1918 a Yellow Fever Commission funded by the Rockfeller foundation was established for the purpose. The eradication drive though effective in curbing the disease in most part could not eradicate the disease completely the possible explanation for which did not come until the 1930s when new techniques were used to study the yellow fever virus. It then became known that the disease was a zoonosis with the natural reservoir of the virus being non-human primates and jungle dwelling sylvatic mosquito species. The disease transmission follows a pattern where a range of vectors transmit the virus from infected monkeys to humans resulting in sporadic cases of the disease. These cases when comes in contact with larger human populations in urban dwellings where it is transmitted by A. aegypti from man to man results in the possibility of an epidemic. 2 Yellow fever is an infectious disease which causes damage of many organs due to severe bleeding. One of the clinical symptoms that give the disease its name is jaundice. The acute phase symptoms that develop following the incubation of the virus in the body for three to six days include fever, nausea, muscle pain with headache, backache, loss of appetite and shivers. Following initial remission some patients enter a severe toxic phase with the return of high fever. Various organs including the kidney and liver are affected. Bleeding occur from nose, mouth, eyes and stomach which also appears in vomit and faeces. 5 There is no treatment specified for yellow fever except for supportive care for fever and dehydration and antibiotics for associated bacterial infections. Vaccines Development of vaccine An important breakthrough that identified Reed's filterable agent to be a virus came from the work done by Adrain Stokes and his collaborators in 1927 which showed monkeys could be infected with materials from yellow fever patients. The isolated virus was called the Asibi strain after the patient who provided the blood sample. 6 Yellow fever virus was identified to be a relatively small virus which readily lost infectivity but stabilized with proteins. 7 Yellow fever in the present classification is grouped under flavivirus (flavus in Latin meaning yellow) group along with more than 80 viruses seen in arthropod vectors. 8 Max Theiler in 1930 discovered a more convenient way of propagating the virus in mouse brain and developed a test for measuring protective antibodies in them. This led to the development of an important tool for epidemiological and diagnostic studies. 9 Theiler and his collaborators discovered the 17D variant when passaging the Asibi strain of the virus in cell cultures. 10 This would eventually become the basis for the first ever yellow fever vaccine responsible for saving innumerable lives and Nobel Prize for Theiler in 1951. Another live attenuated vaccine called the French Neurotropic Vaccine was developed from a different strain of virus isolated in 1927 in Dakar which resulted in a virtual disappearance of the disease in francophone Africa following its use through the 1960s 11. However concerns regarding post vaccinal encephalitis following the use the vaccine in children led to its abandonment in 1982. 17 D on the other hand proved to be extremely durable showing immunity following a single dose making it one of the most effective vaccines. The 1990s saw the successful harnessing of 17D as a live vector for other flavivirus genes resulting in a slate of vaccines to prevent Japanese encephalitis, dengue and West Nile disease in an advanced clinical development. 12 The World Health Organization (WHO) recommends yellow fever vaccination through routine immunization programs for children in areas at risk. Travelers to regions endemic for the disease are also advised to be vaccinated. The risk associated with the vaccine is far less than that associated with the virus and few categories of people exempted from the vaccination include children less than 9 months of age in normal case and less than 6 months during epidemic, pregnant women except in the case of a disease outbreak, severely immunodeficient people due to symptomatic HIV/AIDS or thymus disorder and also people with severe egg protein allergy. 5 The earlier discoveries contributed much to the advancement of etiology, epidemiology, diagnostics and prevention of yellow fever. More sylvatic mosquitoes capable of transmitting yellow fever were identified through ecologic assessments. Long term persistence of the virus was explained through vertical transmission in mosquitoes confirming reports that came in 1905. 13 Diagnosis and detection were made easier by complement fixation and hemagglutination-inhibition tests in the 60s 14 and Enzyme Linked Immunosorbent Assay and reverse transcription Polymerase Chain Reaction. 15 Charles Rice and co workers made advances in the molecular basis of virulence by sequencing the vaccine virus and its parent Asibi strain. 16 World Health Organization and Pan American Health Organization have been working together to promote yellow fever vaccine in routine immunization programs in children. This however proved risky to the current at risk population not being vaccinated at the short term over long term susceptible persons who were vaccinated. Global Alliance for Vaccines and Immunization has provided funding support to WHO to address the issue by performing preventive campaigns in twelve West African countries most at risk for yellow fever. 17 Though vaccine coverage is high in South America and urban vector eradication measures have resulted in A. aegypti elimination from the coastal area, a different kind of threat emerge with expansion of cities along the coastal region. With the mosquito control measures stopped the cities are at risk of the jungle yellow fever to urban transmission cycle repeating. Ease of international travel also puts other countries of Europe, Australia, Asia and North America at risk. 18 Current Research Researchers working on yellow fever currently focus on interactions between the virus, cellular factors that control replication and the immune system. Sporadic cases of viscerotropic adverse events to 17 D vaccine that resemble the wild type disease occur the reason for which remain elusive even after intensive investigation. Much research needs to be done to understand this and also to improve the safety of the vaccine. 19 Computer simulation of the disease has opened up new doors for research since 2007. The World Community Grid set up a project to test potential anti viral properties of a number of molecules against the computer simulated disease. Another area of research is on ribavirin which is believed to be useful in the early treatment of yellow fever due to the positive results shown in treating diseases related to the liver. Conclusion The last 50-100 years have significantly advanced our knowledge of the deadly yellow fever disease, a number of questions still remain unanswered. In a scenario where the threat of urban outbreaks and introduction to non-endemic regions through travel is increasing much research need to be done about the upswings in enzootic transmission. Pathogenesis of the fatal adverse events that have been reported lately of the generally safe 17D vaccine need to be understood to improve vaccine safety. Research in the field has not yet come up with specific drugs to treat the disease or even adverse reaction to the vaccines. All these remain challenges to be taken upon in the future of yellow fever research. Bibliography 1. Carter HR. Yellow Fever: An Epidemiological and Historical Study of Its Place of Origin. Baltimore, MD: Williams & Wilkins; 1931. 2. Strode GK, Bugher JC, et al, eds. Yellow Fever. New York, NY: McGraw-Hill Book Co; 1951. 3. Bryan CS, Moss SW, Kahn RJ. Yellow fever in the Americas. Infect Dis Clin North Am. 2004;18(2):275-292. 4. Reed W, Carroll J, Agramonte A. The etiology of yellow fever: an additional note. JAMA. 1901;36:431-440. 5. World Health Organization. Yellow Fever factsheet. http://www.who.int/mediacentre/factsheets/fs100/en/. December 2009. Accessed on March 10, 2010 6. Stokes A, Bauer JH, Hudson NP. Transmission of yellow fever to Macacas rhesus, preliminary note. JAMA. 1928.90:253-254. 7. Bauer JH, Mahaffy AF. Studies of the filtrability of yellow fever virus. Am. J. Hyg. 1930. 12:175-195. 8. Fauquet CM, Mayo MA, Maniloff J, Desselberger U, Ball LA. editors. Virus Taxonomy: VIIIth Report of the International Committee on Taxonomy of Viruses. Elsevier Academic Press, New York.1162 pp. 2005. 9. Theiler M. A yellow fever protection test in mice by intracerebral injection. Am.Trop. Med. Parasit. 1933. 25:57-77. 10. Theiler M, Smith HH. The effect of prolonged cultivation in vitro upon the pathogenicity of yellow fever virus. J. Exp.Med. 1937.65:767-786. 11. Monath TP. Yellow fever: Victor, Victoria conqueror, conquest epidemics and research in the last forty years and prospects for the future. Am J Trop Med Hyg. 1991;45(1):1-43. 12. Lai CJ, Monath TP. Chimeric flaviviruses: novel vaccines against dengue fever, tick-borne encephalitis, and Japanese encephalitis. Adv Virus Res. 2003; 469:509. 13. Germain M, Cornet M, Herve JP, et al. Recent advances in research regarding sylvatic yellow fever in West and Central Africa. Bull Inst Pasteur. 1982;80: 315-325. 14. Theiler M, Downs WG. The Arthropod-Borne Viruses of Vertebrates: An Account of the Rockefeller Foundation Virus Program, 1951-1970. London, UK: Yale Press, Ltd; 1973. 15. Monath TP, Cetron MS, Teuwen DE. Yellow fever. In: Plotkin S, Orenstein WA, Offit P, eds. Vaccines. 5th ed. Philadelphia, PA: Saunders Elsevier; 2008: 959-1056. 16. Rice CM, Lenches EM, Eddy SR, et al. Nucleotide sequence of yellow fever virus: implications for flavivirus gene expression and evolution. Science. 1985; 229(4715):726-730. 17. World Health Organization. Assessment of yellow fever epidemic risk - a decisionmaking tool for preventive immunization campaigns. Wkly Epidemiol Rec. 2007; 82(18):153-160. 18. Gubler DJ. The changing epidemiology of yellow fever and dengue, 1900 to 2003: full circle Comp Immunol Microbiol Infect Dis. 2004;27(5):319-330. 19. Staples JE, Monath TP. Yellow fever: 100 years of discovery. JAMA. 2008;300(8):960-962 Read More