1. History of Vaccination and Immunization in Developed and Developing World Seoul National University School of Public Heatlh March 8, 2010 Bill Letson MD,MS International Vaccine Institiute bletson@pdvi.org

2. History and Epidemiology of Global Smallpox Eradication

3. Why Worry About Smallpox? Allegations that Soviet BW program produced smallpox virus for use in bombs and ICBMsAllegations that Soviet BW program produced smallpox virus for use in bombs and ICBMs Concerns that smallpox virus could be obtained and used by others as terrorist weaponConcerns that smallpox virus could be obtained and used by others as terrorist weapon JAMA 1999; 281: 2127-2137

4. Smallpox Three Egyptian Mummies 1570-1085 BC Ramses the Vth Died 1157 BC

5. The Faces of Smallpox

7. Early Written Description of Smallpox India 400 AD “ Severe pain is felt in the large and small joints, with cough, shaking, listlessness and langour; the palate, lips, and tongue are dry with thirst and no appetite. The pustules are red, yellow, and white and they are accompanied by burning pain. The form soon ripens …the body has a blue color and seems studded with rice. The pustules become black and flat, are depressed in the centre, with much pain.”

8. Progression of Smallpox Source: Foege, Lane, and Millar, Am J. Epi, 1969

9. Smallpox and History In the Elephant war in Mecca 568 AD, smallpox decimated the Ethiopian soldiersIn the Elephant war in Mecca 568 AD, smallpox decimated the Ethiopian soldiers Introduction of smallpox into the new world (Carribean 1507, Mexico 1520, Peru 1524, and Brazil 1555 ) facilitated Spanish conquestIntroduction of smallpox into the new world (Carribean 1507, Mexico 1520, Peru 1524, and Brazil 1555 ) facilitated Spanish conquest Smallpox destroys Hottentots (1713)Smallpox destroys Hottentots (1713) In 1738, smallpox killed half the Cherokee Indian populationIn 1738, smallpox killed half the Cherokee Indian population Smallpox disrupted colonial army in 1776Smallpox disrupted colonial army in 1776

10. Smallpox Control Strategies Smallpox hospitals (Japan 982 AD).Smallpox hospitals (Japan 982 AD). Variolation 10 th Century.Variolation 10 th Century. Quarantine 1650s.Quarantine 1650s. Home isolation of smallpox in Virginia 1667.Home isolation of smallpox in Virginia 1667. Inoculation and isolation (Haygarth 1793).Inoculation and isolation (Haygarth 1793). Jenner and widespread practice of vaccination throughout Europe and rest of the world.Jenner and widespread practice of vaccination throughout Europe and rest of the world. Mass vaccination.Mass vaccination. Surveillance containment.Surveillance containment.

11. Variolation Inoculation with Smallpox Pus Observations:Observations: –Pocked marked persons never affected with smallpox –Persons inoculated with smallpox pustular fluid or dried scabs usually had milder disease Not ideal control strategyNot ideal control strategy –Case fatality rate still 2% –Can transmit disease to others during illness

12. The 1 st Smallpox Vaccination Jenner 1796 Cowpox lesions on the hand of Sarah Nelmes (case XVI in Jenner’s Inquiry), from which material was taken for the vaccination of James Phipps below in 1796

13. History of Smallpox Vaccination * Henderson DA, Moss M, Smallpox and Vaccinia in Vaccines, 3 rd edition, 1999 1805 Growth of virus on the flank of a calf in Italy. 1864 Publicity about vaccine production at a medical congress. After WWI Most of Europe smallpox free. After WWII Transmission interrupted in Europe and North America. 1940’s Stable freeze-dried vaccine perfected by Collier.

14. Smallpox Endemic Areas 1945 Endemic smallpox

15. History of Smallpox Eradication † Henderson DA, Moss B, Smallpox and Vaccinia in Vaccines, 3 rd edition, 1999 1950 Pan American Sanitary Organization decides to undertake eradication hemisphere-wide. 1959 World Health Assembly adopts goal to eradicate smallpox. 1966 World Health Assembly decides to intensify eradication and provide more funds.

16. Principal Indicators of Eradicability Humans essential for the life cycle.Humans essential for the life cycle. Practical diagnostic tools.Practical diagnostic tools. Effective intervention capable of interrupting transmission.Effective intervention capable of interrupting transmission. * Dowdle WR, Hopkins DR, The Eradication of Infectious Diseases, John Wiley & Sons, Chichester 1998. pp47-59

17. Smallpox Endemic Areas 1967 Endemic Importations Transmission Interrupted

18. R & D Contributions Bifurcated Needle 98%+ take Freeze-Dried Smallpox Vaccine

19. Smallpox Eradication Strategy 1.Mass vaccination campaigns in each country, using vaccine of ensured potency that would reach >80% of population. 2.Development of a system to detect and contain cases and outbreaks. † Henderson DA, Moss B, Smallpox and Vaccinia in Vaccines, 3 rd edition, 1999

20. Mass Vaccination

21. Surveillance and Containment Strategy Search for casesSearch for cases Containment of spread by vaccinating primary contacts and their contactsContainment of spread by vaccinating primary contacts and their contacts Most efficient strategyMost efficient strategy Case(s) Contacts to Case(s) Contacts to Contacts

22. Herd Immunity Sustained transmission Transmitting case SusceptibleTransmitting case Susceptible Transmitting Case (A) Immune (B) Transmission terminated Susceptible (C) (Indirectly Protected)

23. Herd Immunity Thresholds for Selected Vaccine-Preventable Diseases Immunization Levels Disease RoRoRoRo Herd Immunity 1999 19-35 Months 1997-1998Pre-School Diphtheria6-785%*83%*9% Measles12-1883-94%92%96% Mumps4-775-86%92%97% Pertussis12-1792-94%83%*97% Polio5-780-86%90%97% Rubella6-783-85%92%97% Smallpox5-780-85%____ *4 doses † Modified from Epid Rev 1993;15: 265-302, Am J Prev Med 2001; 20 (4S): 88-153, MMWR 2000; 49 (SS-9); 27-38

24. Assumptions About Smallpox Prior to Eradication Program Highly contagiousHighly contagious Vaccine-induced immunity short-livedVaccine-induced immunity short-lived High vaccination coverage needed to meet herd-immunity thresholdHigh vaccination coverage needed to meet herd-immunity threshold

25. Lessons Learned from Small Pox Experience Disease TransmissionDisease Transmission How to administer vaccine to difficult to reach populationHow to administer vaccine to difficult to reach population

26. What Was Learned about Smallpox Transmission During the Eradication Program Common transmission: Airborne by dropletsCommon transmission: Airborne by droplets –Close, face-to-face contact –Greater transmission with prolonged contact Rare transmission: Airborne over long distanceRare transmission: Airborne over long distance –More frequently seen in hospital associated outbreaks where cough was present No carrier stateNo carrier state Rare transmission: fomitesRare transmission: fomites –Bedclothes, linens, blankets. No evidence transmission by: food, water.No evidence transmission by: food, water.

27. Airborne Spread of Smallpox in the Meschede Hospital Fenner. 1988.Fig. 4.9

28. What Was Learned about Smallpox Transmission During the Eradication Program Vaccine can provide protection for several years but full protection decreases over timeVaccine can provide protection for several years but full protection decreases over time Vaccination soon after exposure can still provide some degree of protectionVaccination soon after exposure can still provide some degree of protection Transmission did not occur before onset of symptomsTransmission did not occur before onset of symptoms Surveillance and targeted vaccination could significantly decrease transmission during outbreaksSurveillance and targeted vaccination could significantly decrease transmission during outbreaks

29. Recovery of Variola Virus from the Vicinity of Smallpox Patients

30. Secondary Attack Rates by Pre-exposure Vaccination Status West Pakistan, Sheikhupura District Never vaccinated 26/2796% Vaccinated within prior 10 years 5/1154% Vaccinated >10 years previously 8/6512% †Adapted from Mack et al, Summarized in Fenner et al. Smallpox and its eradication, pg 688

31. Duration of Protection Age Group Vaccination in Infancy Case-Fatality Rate 0–4 Yes0% No45% 5-14 Yes0% No10.5% 15-29 Yes0.7% No13.9% 30-49 Yes3.7% No54.2% >50 Yes5.5% No50.0% †From Outbreak in Liverpool, England, 1902-1903 In Fenner F et al. Smallpox and its Eradication, pp53

32. Case-Fatality Rate of Smallpox After Importations into Western Countries 1950-1971 †In Fenner F et al. Smallpox and its Eradication, pp53 Successfully Vaccinated Case-Fatality Rate Never52% Only after the exposure 29% 0-10 years before exposure 1.4% 11-20 years before exposure 7% > 20 years before exposure 11%

33. Effects of Post Exposure Vaccination 2° Attack Rate (Rao 1968) Primary vaccination post exposure 29.5% Never vaccinated 47.6% (Mack 1972) 1° vaccination <10 days post exposure 75.0 Never vaccinated 96.3 (Helmer 1971)Vaccinated or revaccinated <7 days (Helmer 1971) Vaccinated or revaccinated <7 days1.9 Never Vaccinated 21.8 † Adapted from Fenner F et al. Smallpox and its Eradication, pp 591

34. Last Cases of Smallpox** Rahima Banu – 16 October 1975 Variola Major-Bangladesh Ali Maow Maalin – 26 October 1977 Variola Minor-Somalia ** Two laboratory acquired cases occurred in UK in 1978

35. 1980

36. Haemophilus influenzae type b Severe bacterial infection, particularly among infantsSevere bacterial infection, particularly among infants During late 19th century believed to cause influenzaDuring late 19th century believed to cause influenza Immunology and microbiology clarified in 1930sImmunology and microbiology clarified in 1930s

37. Haemophilus influenzae type b Clinical Features* *prevaccination era

38. Haemophilus influenzae type b Meningitis Accounted for approximately 50%-65% of cases in the prevaccine eraAccounted for approximately 50%-65% of cases in the prevaccine era Hearing impairment or neurologic sequelae in 15%-30%Hearing impairment or neurologic sequelae in 15%-30% Case-fatality rate 2%-5% despite of effective antimicrobial therapyCase-fatality rate 2%-5% despite of effective antimicrobial therapy

39. Haemophilus influenzae type b, 1986 Incidence* by Age Group *Rate per 100,000 population, prevaccine era

40. Haemophilus influenzae type b Polysaccharide Vaccine Available 1985-1988Available 1985-1988 Not effective in children younger than 18 months of ageNot effective in children younger than 18 months of age Effectiveness in older children variableEffectiveness in older children variable

41. Haemophilus influenzae type b Conjugate Vaccines 3 conjugate vaccines licensed for use in infants as young as 6 weeks of age3 conjugate vaccines licensed for use in infants as young as 6 weeks of age All utilize different carrier proteinsAll utilize different carrier proteins 2 combination vaccines available that contain Hib vaccine2 combination vaccines available that contain Hib vaccine

42. Incidence*of Invasive Hib Disease, 1990-2004 *Rate per 100,000 children <5 years of age Year

43. What about Hib in Developing World? Mostly not Used, why?Mostly not Used, why? Not as much disease as in developed world?Not as much disease as in developed world? Too expensive for broad use?Too expensive for broad use?

44. What about Hib in Developing World? Hib Incidence/100,000 in Global Regions:Hib Incidence/100,000 in Global Regions: Africa AmerM. EastEuro SE Asia W Pacif 1342 544 1417 304 1822 1142 *Watt et al. Lancet 2009;374:903-911 Vaccine is expensive

45. Approximate Vaccine Costs in Korea (non-government) Hib $55Hib $55 Pneumococcus 75Pneumococcus 75 Rotavirus 125Rotavirus 125 MMRV 55MMRV 55

46. Hepatitis B Virus Infection More than 350 million chronically infected worldwideMore than 350 million chronically infected worldwide Established cause of chronic hepatitis and cirrhosisEstablished cause of chronic hepatitis and cirrhosis Cause of up to 80% of hepatocellular carcinomasCause of up to 80% of hepatocellular carcinomas 600,000 deaths worldwide in 2002600,000 deaths worldwide in 2002

47. Risk of Chronic HBV Carriage by Age of Infection

48. Hepatitis B Perinatal Transmission* If mother positive for HBsAg and HBeAgIf mother positive for HBsAg and HBeAg –70%-90% of infants infected –90% of infected infants become chronically infected If positive for HBsAg onlyIf positive for HBsAg only –5%-20% of infants infected –90% of infected infants become chronically infected *in the absence of postexposure prophylaxis

49. 1965Discovery of Australian antigen 1973Successful HBV infection of chimpanzees 1981Licensure of plasma-derived vaccine 1986Licensure of recombinant vaccine 1991Universal infant vaccination 1996Universal adolescent vaccination Hepatitis B Vaccine

50. Why delayed Hep B introduction to Developing Countries? Expense of vaccinesExpense of vaccines No Global financing mechanism (GAVI) Global Alliance for Vaccine IntroductionNo Global financing mechanism (GAVI) Global Alliance for Vaccine Introduction Poor data on developing country vaccines and poor global infrastructure for making regional recommendationsPoor data on developing country vaccines and poor global infrastructure for making regional recommendations

51. Where are we Today with Dengue Vaccines ?

52. Aedes aegypti Mosquito

53. Dengue Epidemiology

54. Total Population at Risk of Dengue 3.61 billion people at risk3.61 billion people at risk –2007 population estimates –Limited to at risk areas within countries –54.7% of the worlds population living in countries at risk for locally acquired dengue infection

55. Undifferentiated Fever May be the most common manifestation of dengueMay be the most common manifestation of dengue Prospective study found that 87% of students infected were either asymptomatic or only mildly symptomaticProspective study found that 87% of students infected were either asymptomatic or only mildly symptomatic Other prospective studies including all age groups also demonstrate silent transmissionOther prospective studies including all age groups also demonstrate silent transmission

56. Clinical Characteristics of Classic Dengue Fever FeverFever HeadacheHeadache Muscle and joint painMuscle and joint pain RashRash LeukopeniaLeukopenia HepatomegalyHepatomegaly

57. Dengue Hemorrhagic Fever Fever, or recent history of acute feverFever, or recent history of acute fever Hemorrhagic manifestationsHemorrhagic manifestations Low platelet count (<100,000/mm 3 )Low platelet count (<100,000/mm 3 ) Evidence of “leaky capillaries:” Evidence of “leaky capillaries:” –elevated hematocrit (20% or more over baseline) –low albumin –pleural or other effusions 4 Necessary Criteria:

58. Dengue Case Fatality Rates, Western Pacific Region

59. Costs of dengue and other febrile illnesses in Kampong Cham, Cambodia Huy, et al, 2008 Case-Control study;Case-Control study; Mean total costs for dengue and non- dengue = 31.5, 27.2 US$;Mean total costs for dengue and non- dengue = 31.5, 27.2 US$; Hospitalization tripled and doubled the cost respectivelyHospitalization tripled and doubled the cost respectively 67% of households incurred debt to pay costs67% of households incurred debt to pay costs

60. 2005 2007 2006 2008 2009 2010 Expanded Phase 2 trials – children and adults Preparations for Phase 3 trials – Asia, Americas 2011 2012 2013 2014 2015 Phase 3b – Phase 4 Effectiveness / Safety studies Registration / Introduction Estimated Dengue Vaccine Timeline Phase 3 / 2b Clinical Trials

61. Dengue Vaccine Introduction Challenges Market is almost all developing worldMarket is almost all developing world Lead candidate is “Big Pharma” – will likely sell to middle class and not have enough production for world at riskLead candidate is “Big Pharma” – will likely sell to middle class and not have enough production for world at risk Need for 2 nd vaccines that can be made by developing countries mfg.Need for 2 nd vaccines that can be made by developing countries mfg. Need for WHO vaccine Introduction recommendations and financing mechanismsNeed for WHO vaccine Introduction recommendations and financing mechanisms