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PHP 2013: Controlling the Disease of the Future

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Dengue is the World's most important arbovirus with 2.5 billion people at risk globally and estimates of 100 million infections annually,[1] 2 million of which develop into dengue hemorrhagic fever, a more severe form of the disease, resulting in 21,000 deaths[2]. The disease is caused by four serotypes,meaning re-infection is possible, making control harder. A vaccine preventing infection from all serotypes is needed[3].

Epidemiology

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The dengue virus is mainly vectored by the mosquito, Aedes aegypti and due to increasing urbanization and populations, dengue epidemiology is fast evolving: expanding and increasing outbreak frequency. Unsatisfactory sanitisation and water storage, within urban areas allow for proliferation of the Aedes mosquito and thus increased spread of the virus. The maximum burden of dengue is borne by the Asia-Pacific Region, approximately 1.8 billion (over 70%) of the 2.5 billion individuals at risk globally, reside there[1]. Dengue also has the potential to re-establish in areas such as the United States[4].

Infection with any of the four serotypes (DEN 1–4) leads to dengue fever. While recovery from an infection of one serotype provides life-long immunity against that serotype, it does not protect against the others. During the infection, presence of maternally acquired heterologous antibodies or those from a previous infection, increase the risk of severe disease (dengue haemorrhagic fever and dengue shock syndrome). Therefore, recovery from an infection with one serotype, means a secondary case is likely to be worse[5].

Recently a vaccine admixture (TV003) has been developed and undergone trials, entering further clinical development and evaluation. TV003 induced a trivalent or greater neutralizing antibody response in 90% of flavivirus-naive adult vaccinees. With such positive results the vaccine has been licensed for in-country production and use by manufacturers in multiple countries[2].

Global burden of disease

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Dengue is one of the World Health Organisation's 17 neglected tropical diseases. Its incidence has increased 30-fold in the past 50 years. Annual estimates suggest up to 50-100 million infections occur in over 100 endemic countries, therefore nearly half of the world's population is at risk[6]. Dengue is also spreading and has been found in: the Middle East and the states of Texas and Hawaii. This spread increases the need for an effective control programme[7].

Current funding situation

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As one of the 17 neglected tropical diseases, funding for dengue is very limited[6]. Internationally the funding for dengue prevention and control is very limited and the increasing funding gap between dengue and other dieases affects outbreak preparedness and response[8]. The baseline disease burden of dengue in South-East Asia is approximately 0.42 DALYs (Disability-Adjusted life year) per 1000 population, of which 52% is due to premature mortality and 48% to acute morbidity. The baseline cost of treatment is US$99 per 1000 population per year[7].

Controlling the Disease of the Future

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As funding is so poor for dengue, £1 billion would greatly benefit the development and distribution of a vaccine[5], which can provide lifelong immunity and reduce dengue's significant impact [9].

Background

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Vector control appears incapable of giving long term protection against dengue, let alone eradicating it. Therefore Controlling the Disease of the Future aims to tackle dengue using a large-scale vaccination programme. With vaccine candidates in later trials and having shown positive early results (trivalent or greater antibody response in 90% of candidates)[2] this programme appears possible. Due to the large scale spread of the disease the project aims to target the Pacific South-East, namely Cambodia, Indonesia, Philippines and Vietnam due to feasibility, endemicity, large populations and where financial constraints limit large-scale programmes[5].

Justification

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Despite prolonged efforts for effective vector control in dengue and other diseases, such as Malaria, evidence suggests that community-based control programmes, alone and in combination, only very weakly control dengue[10], particularly as mosquitoes become insecticide resistant[11]. On the other hand vaccines are showing promising results and have been licensed for production and in-country use in Brazil, Vietnam and India[2].

Proposal

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The project aims to control the spread of the disease through a multi-year immunising programme of all 15 month old infants through existing immunization schedules. In total this would lead to 10,760,000 vaccination per year,[12] (10% adjusted to account for error) if 100% coverage is achieved. While achieving 100% coverage is practically impossible and vaccines are not 100% effective, aiming for it gives a higher feasibility to achieving the 70% coverage necessary for herd immunity[2].

By working with current programmes the cost and logistics of a new initiative are greatly reduced, 15 months was chosen as this is the age of measles vaccination. Furthermore, the severe cases of dengue (shock syndrome and haemorrhagic fever) are more common in the under-fifteens and most individuals are immune to a majority of the serotypes by age fifty[2]. The vaccine has been costed at 22p (needle, syringe and drug, in a multidose vial),[2] and through further examination non-vaccination costs have been estimated at £9.38[7]. [13]. This is likely to be an overestimate, due to saving through utilising pre-established programmes. A budget of £1 Billion will fund this programme for ten years, by which time it will be possible to analyse results and implement further steps.

Due to the vaccine still being in trial stages there will be a time lag of 1-2 years[14] before large-scale vaccination could be implemented. However this gives time to coordinate with the governments and set up the logistics, including ensuring manufacturing capabilities are present. If further problems were encountered it is hopeful that another vaccine could be implemented, as multiple candidate vaccines now exist,[15].

Goals

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The overall aims of the project are to see a yearly reduction in the number of dengue cases in the four target countries, within the vaccinated group. Over a ten year period it is is hoped that the majority of the most vulnerable group will become immune and therefore cases should drop significantly, particularly the most severe ones. At the end of the period, it is hoped that further funding will be secured to continue the programme and roll it out across other countries.

References

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  1. ^ a b World Health Organisation. "The Dengue Strategic Plan for the Asia Pacific Region 2008 - 2015" (PDF). http://www.wpro.who.int. WHO. Retrieved 30 May 2013. {{cite web}}: External link in |work= (help)
  2. ^ a b c d e f g Durbin, Anna P.; Kirkpatrick, Beth D.; Pierce, Kristen K.; Elwood, Daniel; Larsson, Catherine J.; Lindow, Janet C.; Tibery, Cecilia; Sabundayo, Beulah P.; Shaffer, Donna; Talaat, Kawsar R.; Hynes, Noreen A.; Wanionek, Kimberli; Carmolli, Marya P.; Luke, Catherine J.; Murphy, Brian R.; Subbarao, Kanta; Whitehead, Stephen S. (17 January 2013). "A Single Dose of Any of Four Different Live Attenuated Tetravalent Dengue Vaccines Is Safe and Immunogenic in Flavivirus-naive Adults: A Randomized, Double-blind Clinical Trial". Journal of Infectious Diseases. 207 (6): 957–965. doi:10.1093/infdis/jis936. PMC 3571448. PMID 23329850.
  3. ^ Murphy, Brian R.; Whitehead, Stephen S. (23 April 2011). "Immune Response to Dengue Virus and Prospects for a Vaccine". Annual Review of Immunology. 29 (1): 587–619. doi:10.1146/annurev-immunol-031210-101315. PMID 21219187.
  4. ^ Sun, W.; Eckels, K. H.; Putnak, J. R.; Lyons, A. G.; Thomas, S. J.; Vaughn, D. W.; Gibbons, R. V.; Fernandez, S.; Gunther, V. J.; Mammen, M. P.; Statler, J. D.; Innis, B. L. (5 December 2012). "Experimental Dengue Virus Challenge of Human Subjects Previously Vaccinated With Live Attenuated Tetravalent Dengue Vaccines". Journal of Infectious Diseases. 207 (5): 700–708. doi:10.1093/infdis/jis744. PMID 23225894.
  5. ^ a b c Deroeck, Denise; Deen, Jacqueline; Clemens, John D. (1 December 2003). "Policymakers' views on dengue fever/dengue haemorrhagic fever and the need for dengue vaccines in four southeast Asian countries". Vaccine. 22 (1): 121–129. doi:10.1016/S0264-410X(03)00533-4. PMID 14604579.
  6. ^ a b World Health Organisation. "Dengue Control". http://www.who.int. WHO. Retrieved 30 May 2013. {{cite web}}: External link in |work= (help)
  7. ^ a b c Shepard, Donald S.; Suaya, Jose A.; Halstead, Scott B.; Nathan, Michael B.; Gubler, Duane J.; Mahoney, Richard T.; Wang, Daniel N.C.; Meltzer, Martin I. (1 March 2004). "Cost-effectiveness of a pediatric dengue vaccine". Vaccine. 22 (9–10): 1275–1280. doi:10.1016/j.vaccine.2003.09.019. PMID 15003657.
  8. ^ World Health Organisation. "Report of a WHO technical working group meeting on dengue prevention and control" (PDF). http://www.who.int. WHO. Retrieved 30 May 2013. {{cite web}}: External link in |work= (help)
  9. ^ Mahoney, R.T.; Francis, D.P.; Frazatti-Gallina, N.M.; Precioso, A.R.; Raw, I.; Watler, P.; Whitehead, P.; Whitehead, S.S. (30 June 2012). "Cost of production of live attenuated dengue vaccines: A case study of the Instituto Butantan, Sao Paulo, Brazil". Vaccine. 30 (32): 4892–4896. doi:10.1016/j.vaccine.2012.02.064. PMID 22406455.
  10. ^ Heintze, C.; Velasco Garrido, M.; Kroeger, A. (2007 Apr). "What do community-based dengue control programmes achieve? A systematic review of published evaluations". Transactions of the Royal Society of Tropical Medicine and Hygiene. 101 (4): 317–25. doi:10.1016/j.trstmh.2006.08.007. PMID 17084427. {{cite journal}}: Check date values in: |date= (help)
  11. ^ Bisset, J. A.; Marín, R.; Rodríguez, M. M.; Severson, D. W.; Ricardo, Y.; French, L.; Díaz, M.; Pérez, O. (1 March 2013). "Insecticide Resistance in Two Aedes aegypti (Diptera: Culicidae) Strains From Costa Rica". Journal of Medical Entomology. 50 (2): 352–361. doi:10.1603/ME12064. PMID 23540124.
  12. ^ United Nations. "World Population Prospects". http://esa.un.org. UN. Retrieved 30 May 2013. {{cite web}}: External link in |work= (help)
  13. ^ World Health Organisation. "Historical Analysis of the Comprehensive Multi-Year Plans in GAVI-Eligible countries (2004 - 2015)" (PDF). http://www.who.int. Retrieved 30 May 2013. {{cite web}}: External link in |work= (help)
  14. ^ Chao, Dennis L.; Halstead, Scott B.; Halloran, M. Elizabeth; Longini, Ira M. (25 October 2012). "Controlling Dengue with Vaccines in Thailand". PLOS Neglected Tropical Diseases. 6 (10): e1876. doi:10.1371/journal.pntd.0001876. PMC 3493390. PMID 23145197.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  15. ^ Webster, D. P.; Farrar, J.; Rowland-Jones, S. (2009 Nov). "Progress towards a dengue vaccine". The Lancet Infectious Diseases. 9 (11): 678–87. doi:10.1016/S1473-3099(09)70254-3. PMID 19850226. {{cite journal}}: Check date values in: |date= (help)
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