38th National Immunization ConferenceMay 14, 2004

Smallpox Vaccine Adverse Events Revisited.

What have we learned?

John Neff MD

Seattle,Washington

OutlineOutline

Nature of Adverse Events Vaccinia

pre 1940 1940-60

1960-70 2003-04

Vaccinia

• Origin unclear

• Vaccination began with Jenner Obtained from animals, presumably calves

• Initially propagated from person to person

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

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

Current Strain

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

Dryvax

Protection

• Complete protection for three to five years

• Partial protection for up to 25 years

• Perhaps long time protection against death

Adverse Events before 1940

• Bacterial infections• Transfer of syphilis• Kaposi’s Varicelliform Erruption• Generalized Vaccinia

Initial Recommendation from AAP “ Avoid Covering Vaccination Site”

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

Adverse Events 1960-70

• Diagnoses Defined

• Prevalence Rates Established

Adverse Events 1960-70Adverse Events 1960-70

1. Post Vaccinal Encephalitis2. Progressive Vaccinia3. Eczema Vaccinatum4. Accidental Infections5. Post Vaccinal Exanthems 6. Fetal Vaccinia7. Other

Post Vaccinal EncephalitisPost Vaccinal Encephalitis1960-70s1960-70s

1-2 cases per 100,000 primary vaccination

1-10% mortality or significant neurological impairment

Dermal Adverse Events1960-70

• Progressive Vaccinia

• Eczema Vaccinatum

• Inadvertent Infection

• Stevens Johnson’s Syndrome

• Post Vaccinal Rashes

Progressive VacciniaProgressive Vaccinia1960-701960-70

1-7 cases per 1,000,000 vaccinations

25-60% mortality

Susceptibility,

CD 4 T cell count < 200/mm2

Eczema VaccinatiumEczema Vaccinatium1960-701960-70

2-4 cases per 100,000 primary vaccinations

20-30% will be in contacts

Perhaps 1% mortality

Inadvertent, Auto inoculationInadvertent, Auto inoculation1960-701960-70

1-6 cases per 1,000

No mortality

May have scarring

Stevens Johnson’s Syndrome1960-70

• Infrequent

• Occurs about 1-5 per million primary vaccination

• May be very severe with prolonged hospitalization

• Should recover

Other Exanthems1960-70

• Erythema Multiforma• Hypersensitivity Reaction• May have small vesicular

component• Generally not well studied• Occurs up to 1 per 100 primary

vaccinations

Fetal VacciniaFetal Vaccinia1960-701960-70

Rare in US prior to 1970

Newborn with pox lesions

(infection late pregnancy)

Miscarriage

(infection early pregnancy)

Other Adverse Events based on Case Reports

1960-70

• Melanoma

• Osteomyelitis

• Myopericarditis

Contact or Transfer Vaccinia1960-70

• 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

2003-2004 Vaccination Program

• Excellent screening

• Education of the public

• Aggressive Surveillance

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

Adverse Reaction 2003-2004

• Common Reactions

• Successes

• New Events

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

Successes

Excellent Screening No cases of• Eczema Vaccinatum

• Progressive Vaccinia

• Nosocomial Spread

• Fetal Vaccinia

Anticipated Adverse EventsFeb 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

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

MyopericardiditisVaccine 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

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

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

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

Generalized Vaccinia

No cases of disseminated generalized vaccinia.

Reported cases most likely hypersensitivity reactions

Vaccinia Transfers to Contacts

28 Secondary Cases

2 Tertiary Cases

Significance of Vaccinia Transmission to Contacts

Vaccinees Predominantly primary, no health care workers

ContactsPredominantly unvaccinated, young adultsIntimate body contact

Transmission settingsBed partners at highest risk No nosocomial transmission

Inadvertent Vaccination of Pregnant Women

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

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

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

What have we learned?

• Nosocomial spread can be prevented by appropriate site dressing without 2nd bacterial infection

• Contact vaccinia in young intimate partners occurs. Not sure if dressings prevent this

Conclusion

Current vaccination program characterized by successful screening

Unknown if screening for risk factors will be as effective in a massive vaccination

program

Conclusion

Need to redefine generalized vaccinia

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