1. Yellow fever: Global threat Jack Woodall, PhD Institute of Medical Biochemistry Federal University of Rio de Janeiro, Brazil (retired) (Formerly CDC & WHO Geneva) Not me! ASTMH Annual Meeting, 16 Nov.2013

2. YF endemic zones

3. Background “Fears have long been held that if yellow fever were introduced to Asia it might spread widely and rapidly with –catastrophic human mortality and – subsequent establishment of a forest reservoir in primates or other animals –because of the presence of large populations of potential vector mosquitos (Aedes aegypti, A. albopictus).”

4. Background (2) “In 1954 a meeting of experts on yellow fever at Kuala Lumpur discussed the hazard of introduction of yellow fever to south and south-east Asia. “Trials of yellow fever vaccination in Malayan volunteers were subsequently carried out with the assistance of United Kingdom Colonial Development and Welfare.” (Gordon-Smith CE, Turner LH, Armitage P. 1962)

5. 1905 New Orleans, Louisiana, 8,399 cases) & Pensacola, Florida 1911 last indigenous case http://www.gideononline.com http://www.gideononline.com Last Yellow fever epidemics USA Sailing-ship era

6. Last Yellow fever epidemics EUROPE Sailing-ship era 1861 France (St Nazaire) 44 cases, 24 deaths 1828 Gibraltar (UK) 1500 deaths

7. Yellow fever, imported cases, 1999-present Airline era Surinam Netherlands 2000

8. What has changed in the last 10 years? Yellow feverYellow fever in emerging phase

9. Yellow fever in emerging phase 2013 AFRICA WHO warning about urbanization in West Africa 2005 Sudan & 5 more African outbreaks 2012-13: one ongoing TODAY

10. WEST AFRICA URBANIZATION WHO ALERT Date: 2005 Source: WHO Global Alert and Response (GAR) http://www.who.int/csr/disease/yellowfev/urbanoutbreaks/en/ Increased risk of urban yellow fever outbreaks The risk of large and uncontrollable outbreaks in urban areas in Africa is more likely than ever. Accelerated urbanization has concentrated a non- immune population in settings where, high vector and population density, the main factors contributing to increased virus transmission are present.

11. YELLOW FEVER – SUDAN (KORDOFAN) Date: 14 Nov 2013 Source: Radio Dabanga (Hilversum)Source: Radio Dabanga http://allafrica.com/stories/201311151118.html According to the Sudanese Ministry of Health, between 3 Oct and 5 Nov [2013], a total of 22 suspected yellow fever cases, resulting in 7 deaths, occurred in West & South Kordofan, CFR 36.3%, OCHA reports in its latest Humanitarian Bulletin. 45 000 people to be vaccinated. -- Communicated by : ProMED-mail

12. Yellow fever in emerging phase 2013 SOUTH AMERICA Peru 2013 Bolivia 2013 Brazil 2012 (monkey deaths) Source: ProMED

13. Yellow fever – Brazil: CDC Alert Yellow Fever in Brazil -- Outbreak Alert 2013 Because an outbreak of yellow fever was found in areas of Brazil outside of the reported yellow fever risk areas… Travelers should follow “enhanced precautions” for that risk area [Rio Grande do Sul & SW Sao Paulo states] by receiving the yellow fever vaccine. Source: CDC

14. Yellow fever in South America increasing since 2008 ARGENTINA 2008: Ministry of Health confirmed 5 cases of jungle yellow fever in Misiones Province Source: ProMED http://promedmail.org/direct.php?id=20080401. 1206 The last outbreak of jungle yellow fever reported was in Corrientes in 1966 -- 47 years ago Source: PAHO report Misiones Corrientes Paraguay Uruguay Brazil

15. Yellow fever in South America increasing since 2008 BRAZIL Outbreaks of YF -- typically occurring in Brazil every 7 years -- have become more frequent YF has progressed to areas previously considered free –in Rio Grande do Sul (free since 1966) –& SW Sao Paulo state These 2 areas previously posed no risk for YF, but between November 2008 and April 2009 they recorded 43 infections, with 16 deaths. Source: O Estado de Sao Paulo, 21 May 2009 [in Portuguese] via ProMED http://promedmail.org/direct.php?id=204930 [in English]

16. What has changed in the last 10 years? Yellow feverYellow fever in emerging phase Dengue continues its worldwide spread

17. Map 2. * * range of Aedes aegypti Madeira (PT) 2005

18. Dengue, Madeira (PT) 2012-13 The island of Madeira, Portugal, experienced an outbreak of dengue, which began in October 2012, and saw an overall total of 2,170 cases of dengue fever through April 2013 [no deaths] DEN-1 was identified with probable Central or South American origin. (Alves MJ, et al. 2012) (Alves MJ Origin Venezuela (Annelise Wilder-Smith at ASTMH Annual Meeting, Washington DC 14 Nov 2013) 2 cases imported since from Angola (ProMED 3 June 2013 Dengue/DHF update (46): Asia, Africa)

19. Dengue, imported into Europe, 2012 Madeira 2012

20. Dengue in Europe A large number of autochthonous cases of dengue fever (2237) occurred in Europe (Italy, France, Croatia, Madeira) during the period covered by our analysis (2007-2012) (Tomasello D (Tomasello D, Schlagenhauf P. 2013)Schlagenhauf P

21. Wher e deng ue goes, YELL OW FEVE R can follow… …any - where the mosqu ito vecto rs are found ! Beavis to Butthead

22. But if USA & Europe, why not Asia? All of tropical Asia is infested with the yellow fever vector mosquito, Aedes aegypti

23. Why hasn’t YF broken out in Asia? If YF cases have occasionally been imported into the USA & Europe Cases must also have occasionally been imported into Asia But there have been no such records in medical history

24. Why hasn’t YF broken out in Asia? Cross-immunity theory Asian population protected by broad cross-immunity, because of dengue, Japanese encephalitis & other flavivirus infections

25. Why hasn’t YF broken out in Asia? BUT neither dengue nor Japanese encephalitis patients produce neutralising antibodies to YF (Makino Y et al. 1994)

26. Why hasn’t YF broken out in Asia? Ecuador: serological surveys showed “...previous exposure to dengue infection may have induced an anamnestic immune response that –did not prevent yellow fever infection but –greatly reduced the severity of the disease (Izurieta RO(Izurieta RO et al. 2009)

27. Why hasn’t YF broken out in Asia? Vector competence theory Asian strains of Aedes aegypti mosquitoes not as competent vectors of YF as in Africa & South America? BUT they can still cause urban epidemics, e.g. Nigeria 1987 (Miller BR(Miller BR, Monath TP, Tabachnick WJ, Ezike VI 1989)Monath TPTabachnick WJEzike VI

28. What has changed in the last 10 years? Yellow feverYellow fever in emerging phase (Sudan & 5 more African outbreaks 2012) Dengue continues its worldwide spread Ae. aegypti has spread to Europe

29. RUSSIA GEORGIA Aedes albopictus A. aegypti Aedes albopictus & A. aegypti, Europe, March 2013 MADEIRA (PT) ECDC 2013 2012

30. What has changed in the last 10 years? Yellow feverYellow fever in emerging phase (Sudan & 5 more African outbreaks 2012) Dengue continues its worldwide spread Ae. aegypti spread to Europe Air travel connections ever faster

31. What has changed in the last 10 years? Yellow feverYellow fever in emerging phase (Sudan & 5 more African outbreaks 2012) Dengue continues its worldwide spread Ae. aegypti spread to Europe Air travel connections ever faster

32. Yellow fever, Africa 2013 Airline connections to Europe

33. Yellow fever in capital cities with international airports SOUTH AMERICA, 2008 Asuncion, Paraguay AFRICA, 2010 Abidjan, Côte d’Ivoire

34. Travel times: Endemic zones  Asia (including connections) AFRICA Abidjan (Côte d’Ivoire)  Dubai  Pakistan Total 23hrs* SOUTH AMERICA Asuncion (Paraguay)  Dubai  Jakarta Total 35hrs* *Well within the incubation period of YF

36. What has changed in the last 10 years? Yellow feverYellow fever in emerging phase (Sudan & 5 more African outbreaks 2012) Dengue continues its worldwide spread Ae. aegypti spread to Europe Air travel connections ever faster YF vaccine production faltering

37. Vaccine situation (1) Stocks: existing world stocks (6 million doses) are insufficient to counter an epidemic in Asia Supply: production cannot be expanded fast enough to provide protection to all of Asia (viz. current worldwide shortage of single dose vials) However, see next presentation in this session on dose-sparing solutions Distribution: vaccine requires a cold chain, but in some Asian countries this is probably only adequate to handle enough vaccine for SNIDs (sub-national immunization days)

38. Vaccine situation (2) Application: a crash program of mass training and mobilization of vaccinators takes time Adverse effects: 1 or 2 deaths agttributed to the vaccine (inevitable during mass campaigns) are sufficient to shut down a vaccination program Resistance: some Asian countries may resist vaccination (as has happened recently with polio vaccination in West Africa & measles vaccination in Pakistan).

39. Fake vaccination certificates (1) Nigeria: In March 2012, 125 Nigerians on a plane to Johannesburg were denied entry and deported by the South African port health authority. The authority had concerns about the validity of the yellow fever vaccination cards Source: ProMED http://promedmail.org/direct.php?id=20120724.1213759

40. Fake vaccination certificates (2) India In March 2011, WHO organised a consultation on the yellow fever threat to India and SE Asia in which it was concluded that the threat of introduction of YF [virus] into Asia was very real in the age of faster air travel. BUT Black market: certificates were issued in India without vaccination during the 2013 vaccine shortage Source: ProMED http://www.promedmail.org/direct.php?id=20130719.1833351Source: ProMED http://www.promedmail.org/direct.php?id=20130719.1833351

41. Fake vaccination certificates (3) Tanzania: black market in certificates Source: ProMED http://promedmail.org/direct.php?id=1530747 Risk of spread by a single apparently healthy unvaccinated passenger incubating YF virus arriving in a country with the mosquito vector (e.g. Chikungunya virus: India  Italy 2007)

42. What has changed in the last 10 years? Yellow feverYellow fever in emerging phase (Sudan & 5 more African outbreaks 2012) Dengue continues its worldwide spread Ae. aegypti spread to Europe Air travel connections ever faster YF vaccine production faltering Fake YF vaccination certificates Interruption of mass vaccination in endemic zones

43. Vaccine situation Interruption of mass vaccination in many endemic countries/areas e.g. Francophone West & Central Africa: no mass vaccination since independence -- except in areas with outbreaks Nigeria: no mass vaccination since 1987 urban epidemics -- except in areas with outbreaks

44. What has changed in the last 10 years? Yellow feverYellow fever in emerging phase (Sudan & 5 more African outbreaks 2012) Dengue continues its worldwide spread Ae. aegypti spread to Europe Air travel connections ever faster YF vaccine production faltering Fake YF vaccination certificates Interruption of mass vaccination in endemic zones Failure of vector control

45. Vector control situation Existing vector control programs in Africa & Asia are failing to control dengue Reintroduction of DDT could help (India) BUT a crash program of training & deployment of spray workers will take time AND ground or aerial spraying: –householders find spray obnoxious –close up their houses when it passes –protecting the mosquitoes inside!

46. Hospital situation No specific therapy for YF Stocks of antiviral drugs will soon be exhausted In rural areas: Stocks of intravenous fluids will soon be exhausted, followed by delay in re-supply Fortunately, YF is not transmitted by fomites, because Stocks of disposable syringes/needles, will run out – & be re-used with associated risks

47. Diagnosis & Surveillance situation Nobody in Asia is expecting to see a case of YF jaundice hemorrhagic –therefore a case of high fever with jaundice and hemorrhagic symptoms will be put down to DHF, hepatitis or something else, but NOT YF –no lab test for YF will be requested Probably only the national reference lab will have reagents –preferably the rapid PCR test for YF YF is probably not a reportable disease –although it should be, even under the new IHR

48. Containment situation Populace may flee –when plague broke out in Surat, India in 1994, 400 000 people (one-fifth of population) fled the city (including doctors & nurses!) Some reached New Delhi & even Pakistan –potentially spreading the infection

49. Population at risk for YF, Asia 2010 CountryPop. x1000CountryPop. x1000 Bangladesh 151 125Nepal 26 846 Bhutan 717Pakistan 173 149 Cambodia 14 365Papua N. Guinea* 6 065 China Ϯ 406 477Philippines 93 444 Hong Kong SAR 7 050Singapore 5 079 Macau SAR 535Sri Lanka 20 759 East Timor 1 079Taiwan* 23 160 India1 205 625Thailand 66 402 Indonesia 240 676Viet Nam 89 407 Laos 6 396Yemen 22 763 Malaysia 28 276TOTAL2 641 326 Myanmar* 51 93120 countries Ϯ southern provinces under 10° isotherm UNDP Population estimates 2010 *non-UN sources 2010

50. Conclusion W hy hasn’t YF broken out in Asia yet? We don´t know -- BUT because of –Fast airline routes –and YF currently being in an expansion phase the risk is higher than it has ever been, SO if it does break out, there will be –insufficient vaccine, and –inadequate vector control With an untreated CFR of at least 20% -- HUGE NUMBERS OF DEATHS COULD OCCUR

51. YF contingency plan? We have had 10 years to worry about avian flu There are now plans in many countries to combat its spread We have had decades to think about YF invading Asia, Europe & the USA Is there even ONE contingency plan for that?

52. THE RISK OF YELLOW FEVER INTRODUCTION INTO USA, EUROPE & ASIA IS GREATER THAN AT ANY TIME IN THE LAST 150 YEARS! What are we going to do about it?

53. ?

55. MAKE CONTINGENCY PLANS? OR

56. Yellow Fever contingency plan A Regional Workshop was held by WHO/SEARO in Goa in 2011 It included developing a proposed country contingency plan for Yellow Fever (JW & DG were facilitators) Copies of the report are available from SEARO

57. Thank You! jackwoodall13@gmail.com www.promedmail.com jackwoodall13@gmail.com