1. 38 th National Immunization Conference May 14, 2004 Smallpox Vaccine Adverse Events Revisited. What have we learned? John Neff MD Seattle,Washington

2. Outline Outline Nature of Adverse Events Vaccinia pre 1940 1940-60 1960-70 2003-04

3. Vaccinia Origin unclear Vaccination began with Jenner Obtained from animals, presumably calves Initially propagated from person to person

4. Vaccinia Around 1850 vaccinia propegated from calf innoculation Around 1900 Glycerin added to decrease bacterial contamination. Later antibiotics added Many strains used throughout the world

5. Vaccinia In 1970s WHO recommended three strains: Lister, Moscow, New York Board of Health United States uses NYBOH strain propagated from calves, treated with glycerin and antibiotics, neomycin, streptomycin and polymyxin

6. Current Strain Current strain used in United States is a freeze dry preparation from NY Board of Health Strain Dryvax

7. Protection Complete protection for three to five years Partial protection for up to 25 years Perhaps long time protection against death

8. Adverse Events before 1940 Bacterial infections Transfer of syphilis Kaposi’s Varicelliform Erruption Generalized Vaccinia Initial Recommendation from AAP “ Avoid Covering Vaccination Site”

9. Adverse Events 1940 to 1960 Post Vaccinal Encephalitis- Wide Range of Prevalence Rates Eczema Vaccinatum- Improved Definition Progressive Vaccinia – Described for the first time. Contact Vaccinia - Recognized

10. Adverse Events 1960-70 Diagnoses Defined Prevalence Rates Established

11. Adverse Events 1960-70 1.Post Vaccinal Encephalitis 2.Progressive Vaccinia 3.Eczema Vaccinatum 4.Accidental Infections 5.Post Vaccinal Exanthems 6.Fetal Vaccinia 7.Other

12. Post Vaccinal Encephalitis 1960-70s 1-2 cases per 100,000 primary vaccination 1-10% mortality or significant neurological impairment

13. Dermal Adverse Events 1960-70 Progressive Vaccinia Eczema Vaccinatum Inadvertent Infection Stevens Johnson’s Syndrome Post Vaccinal Rashes

14. Progressive Vaccinia 1960-70 1-7 cases per 1,000,000 vaccinations 25-60% mortality Susceptibility, CD 4 T cell count < 200/mm 2

15. Eczema Vaccinatium 1960-70 2-4 cases per 100,000 primary vaccinations 20-30% will be in contacts Perhaps 1% mortality

16. Inadvertent, Auto inoculation 1960-70 1-6 cases per 1,000 No mortality May have scarring

17. Stevens Johnson’s Syndrome 1960-70 Infrequent Occurs about 1-5 per million primary vaccination May be very severe with prolonged hospitalization Should recover

18. Other Exanthems 1960-70 Erythema Multiforma Hypersensitivity Reaction May have small vesicular component Generally not well studied Occurs up to 1 per 100 primary vaccinations

19. Fetal Vaccinia 1960-70 Rare in US prior to 1970 Newborn with pox lesions (infection late pregnancy) Miscarriage (infection early pregnancy )

20. Other Adverse Events based on Case Reports 1960-70 Melanoma Osteomyelitis Myopericarditis

21. Contact or Transfer Vaccinia 1960-70 Transfer of vaccinia to close contact Most common in atopic or normal host Generally requires close body contact 4 to 6 cases per 100,000 Most severe cases of Eczema Vaccinatum were in contacts No nosocomial spread

22. 2003-2004 Vaccination Program Excellent screening Education of the public Aggressive Surveillance

23. Smallpox Vaccination Program Feb 04 DoD DSSH Vaccinated: 581,183 40,449 Primary: 71% 36% Revaccination: 29% 64% Male: 88% 36% Female: 12% 64% Age: Median: 27 y 49y

24. Adverse Reaction 2003-2004 Common Reactions Successes New Events

25. Common Reactions to Vaccinations 1 % unable to work for about one day 30% have systemic symptoms – such as muscle aches, headaches, chest pain, fever 1% have mild rashes

26. Successes Excellent Screening No cases of Eczema Vaccinatum Progressive Vaccinia Nosocomial Spread Fetal Vaccinia

27. Anticipated Adverse Events Feb 2004 DoD Vacc - 581,183 Contact - 28 sec 2 tert Auto non Oc - 52 Auto Oc - 11 Gen Vacc - 28 susp 8 prob Post Vac Enc - 1 atyp DHHS Vacc 40,449 Auto non Oc - 20 Auto Oc - 3 Gen Vacc - 2 susp - 1 con Post Vac Enc - 1 atyp

28. Unanticipated Cardiac Events Myo/pericarditis DoD Vacc - 581,183 DHHS Vacc –40,449 Total 72 Total 21 Suspected 0 Suspected 16 Probable 68 Probable 5 Confirmed 4 Confirmed 0

29. Myopericardiditis Vaccine Trial Tissue Culture Vaccine ACAM 2000 and Dryvax Suspect 3 cases of myo/pericarditis in 1,132 primary vaccinations including both ACAM 2000 and Dryvax

30. Dilated Cardiomyopathy DoD vacc 581,183 DHHS vacc 40,449 4 cases * 3 case Ages 34*, 37, 42, 44 Ages 53, 55, 56 Onset Recognized Onset Recognized 1, 4.5, 5.3, 6.5*, mo 2, 2.6, 3.3 mo * one case under review

31. Myocardial Infarction Occurs at same level of frequency as expected in US population adjusted for age Cases cluster around 7-12 days after vaccination suggesting a possible association Includes four deaths

32. Fatal Events Possibly Related 4 cases of ischemic heart disease 1 case of systemic lupus Not Related 1 case of pulmonary emboli 1 case of illicit drug overdose

33. Generalized Vaccinia No cases of disseminated generalized vaccinia. Reported cases most likely hypersensitivity reactions

34. Vaccinia Transfers to Contacts 28 Secondary Cases 2 Tertiary Cases

35. Significance of Vaccinia Transmission to Contacts Vaccinees Predominantly primary, no health care workers Contacts Predominantly unvaccinated, young adults Intimate body contact Transmission settings Bed partners at highest risk No nosocomial transmission

36. Inadvertent Vaccination of Pregnant Women

37. Pregnancy Registry Status Report 190 of >94,218 women vaccinated by DoD + DHHS About 70% vaccinated pre-conception or post- conception before pregnancy identifiable by testing Outcomes in Spring 2004 –Rates of spontaneous abortions & ectopic pregnancies do not appear to be higher than anticipated for age, risk history

38. What have we learned Can prevent “preventable” adverse events with extensive screening. Cardiac events are unexpected adverse events and may be related directly to the vaccinia virus. These may occur as frequently as 1 per 300 vaccinations

39. What have we learned? Post Vaccinal Encephalitis may be rare and occur less frequently than expected with lower mortality Generalized Vaccinia may be non- existent in absence of immunological risk factors

40. What have we learned? Nosocomial spread can be prevented by appropriate site dressing without 2 nd bacterial infection Contact vaccinia in young intimate partners occurs. Not sure if dressings prevent this

41. Conclusion Current vaccination program characterized by successful screening Unknown if screening for risk factors will be as effective in a massive vaccination program

42. Conclusion Need to redefine generalized vaccinia

43. Conclusion Vaccinia virus may cause cardiac inflamation The significance of these cardiac events is not clear Should continue to avoid vaccination of those with cardiac risk factors Raises questions about advisability of current vaccination program