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Disease Eradication

Kenrad Nelson, MDJohns Hopkins University

3

Objectives

Review issues related to the eradication of an infectious disease−

Smallpox

−

Polio

Section A

Smallpox

5

Disease Eradication: Definitions

Cockburn (1961)−

…the complete extinction of the pathogen that causes infectious disease…

so long as a single member of the species survives, the eradication has not been accomplished

Andrews and Langmuir (1963)−

The purposeful reduction of specific disease prevalence to the point of a continued absence of transmission within a specific area

Note the elements of geography, time, and implied surveillanceThis is probably the “best” simple definition

WHO (1980) for smallpox−

…the eradication of clinical infection by variola virus…

since there is no carrier state, no subclinical infection, and no animal reservoir…

the absence of clinical disease implies the absence of disease transmission

6

Advantages of an Eradication Strategy

Advantages of a strategy of eradication of an infectious disease1.

Once disease is truly eradicated, further control efforts can be abandoned, with savings of cost, adverse vaccine reactions, etc.

2.

Cost savings continue indefinitely when disease is eradicated

3.

Expenditures for eradication are temporary

7

Disadvantages of an Eradication Strategy

Disadvantages of a strategy of eradication of an infectious disease1.

Rigorous surveillance and control efforts need to be continued even when disease incidence is very low

2.

Competition with more important diseases for the health care resources that are needed to support successful eradication

3.

Some diseases have biological characteristics inimical to eradication, for example those with environmental or animal reservoir

8

Criteria to Determine Whether a Disease Is Eradicable

Biological and technical feasibilityConsensus on positive costs and benefitsBroad societal and political support

9

Past Efforts at Disease Eradication

Yellow fever−

Aedes aegypti vector elimination 1915–1977; program failed because of sylvatic YF cycle

Yaws−

Disease affected only remote and rural population

−

Program 1954–1967; failed because applied to remote and rural population and political, social, economic support faltered

Malaria−

Insecticide spraying 1955–1969

−

Failed due to insecticide resistance and lack of supportSmallpox−

Vaccination, surveillance, containment strategy

−

1958–1980−

Successful

10

History of Smallpox

1.

The disease smallpox (variola major) probably emerged from the first agricultural human settlements about 12,000 years ago

2.

Evidence of smallpox in Egyptian mummies (1580–

1350 BC) and Ramses V (1157 BC)3.

Probably carried to India by Egyptian traders4.

Variola (“spotted”) applied to the disease by Bishop Marius of Switzerland during the 6th century; later called “smallpox”

to distinguish variola from “greatpox,”

i.e., syphilis, in 15th century5.

16th century—imported into the Americas with widespread epidemics among Native American populations

6.

16th–18th centuries—major epidemics in Europe; 400,000 deaths per year from smallpox at end of 18th century

11

History of Smallpox

7.

Use of pustular scabs from smallpox cases introduced into skin or by

nasal insufflation began in India around 10th century8.

Edward Jenner, 1796, demonstrated that cowpox virus inoculated

into skin could protect against smallpox9.

Vaccination with cowpox by arm-to-arm inoculation practiced during

19th century10. Growth of cowpox in flank of calf publicized and used, 186411. 1940s—freeze-dried vaccine for production of vaccine12. 1950—PAHO began program to eliminate smallpox from

the western hemisphere−

By 1967 smallpox still present only in Brazil

12

History of Smallpox

13.

1958—the U.S.S.R. proposed that WHO undertake a global

program to eradicate smallpox14.

The WHO global smallpox eradication program began in 1967−

At that time smallpox was endemic in 31 countries. An estimated 10 to 15 million cases per year probably occurred in these endemic countries (131,789 cases reported).

15.

October 16, 1977—the last naturally occurring case of smallpox

diagnosed in Merka, Somalia16.

1980—smallpox vaccination discontinued−

Except for special lab workers

17.

June, 1995—the last remaining smallpox cultures to be destroyed

13

Natural History of Smallpox

14

Smallpox

Photo Source: CDC PHIL

15

Smallpox

Photo Source: CDC PHIL

16

India: Cases of Smallpox

Deaths and case-fatality rates, by age group, 1974–1975

Age group No. of cases

(% distribution by age) No. of deaths Case-fatality

rate

Younger than 1 yr. 1,373 (6) 597 43.5

1–4 5,867 (25) 1,436 24.5

5–9 5,875 (25) 783 13.3

10–19 5,542 (23) 432 7.8

20+ 4,889 (21) 855 17.5

Total 23,546 (100) 4,103 17.4

Notes Available

17

Complications of Smallpox Vaccination—U.S.,1968

1. Postvaccinal

encephalitis 16 cases, 4 deaths

2. Progressive vaccinia 5 cases, 2 deaths

3. Eczema vaccinatum 126 cases, 1 death

4. Generalized vaccinia 143 cases

5. Accidental infection 193 cases

6. Other complications 83 cases

Total complications 566 cases, 7 deaths

Total estimated number of vaccinations: 14,168,000

18

Complications of Smallpox Vaccination—U.S.,1968

Vaccination status and age

(yrs)

Estimated number of

vaccinations

Postvaccinal

encephalitisProgressive

vacciniaEczema

vaccinatumGeneralized

vacciniaAccidental infection Other

Primary vaccinations

<11–45–9

10–19≥20

UnknownTotal

614,0002,733,0001,553,000

406,000288,000

5,594,000

4 (3)6

5 (1)–1

–16 (4)

–1

1 (1)1 (1)

2–

5 (2)

5311137158

4347205133

131

79132345

142

10408152

66

Revaccinations<11–45–9

10–19≥20

Total

–478,000

1,643,0002,657,0003,796,0008,574,000

––––––

––

1 (1)1

4 (1)6 (2)

–143–8

––1–910

–13–37

–12–69

Unvaccinated contacts – – 60 (1) 2 44 8

Total 14,168,000 16 (4) 11 (4) 126 (1) 143 193 83

Notes Available

Number of reported cases (deaths in parentheses)

19

Complications of Vaccinia Immunizations

Complications of vaccinia immunizations per million vaccinations, 1968

ComplicationsPrimary Revaccination Primary Revaccination

Accidental infection 529 42 25 0.8

Generalized vaccinia 242 9 23 1.2

Erythema

multiforme 165 10 – –

Eczema vaccinatum 39 3 10 0.9

Encephalitis 12 2 3 0

Progressive vaccinia* 1.5 3 0.9 0.7

Other 266 39 12 1.0

Ten-state survey CDC national survey

Vaccination status

*Immunocompromised

hosts are at greatest risk

Notes Available

20

Progressive Vaccinia

Photo Source: CDC PHIL

21

Progressive Vaccinia

Photo Source: CDC PHIL

22

Eczema Vaccinatum

Photo Source: CDC PHIL

23

Accidental Inoculation

Photo Source: CDC

24

Contraindications of Smallpox Vaccination

1.

Immune disorders−

Agammaglobulinemia, neoplasms, immune-

suppressive drugs, etc.2.

Eczema−

Including eczema in a household contact

3.

Pregnancy4.

Disorders of the central nervous system

25

Factors Favoring Successful Smallpox Eradication

1.

A very effective vaccine that produced long lasting immunity

2.

A high proportion of the population already vaccinated3.

Single genetically stable virus

4.

No animal or environmental reservoir5.

Disease only moderately contagious (contagious after onset of rash)

26

Epidemiologic Features That Favor Eradication

Epidemiologic features of smallpox that favor eradication

Reservoir and host Man

Transmissibility Relatively low

Subclinical cases Never or rare

Incubation Long—12 days

Public concern Very great

VaccineEfficacyLogisticsCost

>98%Practical, bifurcated needleMinimal

Seasonality Striking

27

Essential Principles in WHO Eradication Program

Essential principles in WHO smallpox eradication program1.

Development and use of uniformly potent smallpox vaccines tested at several international laboratories

2.

Provision of widespread vaccination of populations in target countries where smallpox was endemic

3.

Principle outcome measure was the absence of cases of smallpox

Program relied on active surveillanceWhen cases were identified, their contacts were immediately vaccinated to abort further transmission

28

Bifurcated Needle

Photo Source: CDC

29

Smallpox Eradication Program: Bangladesh

Surveillance1.

Mobile surveillance teams visit bazaars, schools, train and bus stations, beggar colonies, bustees

2.

Rewards for notification of smallpox cases—at train and bus stations, rickshaw announcers, school children, soccer games

3.

Intensive search around areas of outbreaks4.

Epidemiologic investigation of every smallpox outbreak to detect source, travel of case, and travel of contacts

5.

Monthly municipal area house-to-house search6.

In later stages, national house-to-house search

30

Smallpox Eradication Program: Bangladesh

1.

Isolation of patient in own house2.

Front and rear house guards (with vaccine)

3.

Vaccinated all household contacts and visitors4.

Line listing of all residents within half-mile of infected house, vaccinated all

5.

Searched for cases within five-mile radius; repeated search at 5, 15, 25, and 40 days

31

Smallpox Incidence in Ethiopia

32

Countries with Endemic Smallpox

Notes Available

33

Number of Countries with Endemic Smallpox

34

Effects of Discontinuation of Smallpox Vaccine

Monkeypox−

Less contagious than smallpox

Secondary household attack rate = 5% (for smallpox, 40–50%)−

Cases

1970–1975: 55 cases1980–1986: 349 cases−

Fatality rate = 11%

−

72% primary (contact with monkey)1987–1992: 13 cases1993–1996: 0 cases1996–1997: 511 cases, many were varicella

−

Modeling supports that monkey pox is not sufficiently contagious

to maintain itself in humans

Biological terrorism−

Felt to be a real threat

−

Organisms easily grown in vitro−

Easily aerosolized and highly fatal

−

Population not vaccinated since 1976, limited supplies of vaccine

35

Level of Uncertainty about Smallpox Risk

After the breakup of the Soviet Union in 1991, several reports that widespread production of smallpox, anthrax, plague, and other biological warfare agents had been under way for the past 20 years (Kent Alibek, Biohazard)All smallpox supplies were supposed to be kept in two maximum containment locations1.

CDC, Atlanta

2.

Novosibirsk, RussiaThere is some suspicion, but no good evidence, that smallpox supplies may have been disseminated

36

Current Public Health Questions

A.

What steps should the U.S. government take to counteract the threat of biological warfare using smallpox?1.

Mass vaccination of entire U.S. population

2.

Vaccination of selected populations of “early responders”

a.

Which populations?b.

How many people?

3.

Wait for an event and then identify cases and vaccinate their contacts

B.

What information would you need in order to arrive at a decision?

37

Use of Smallpox Vaccine for Bioterrorism Prevention

Critical considerations of Advisory Committee on Immunization Practices (ACIP) in deciding on use of smallpox vaccine to prevent bioterrorism1.

Level of disease risk and threat

2.

Expected severe adverse reactions to vaccination3.

Vaccine and vaccinia immune globulin supply

4.

State and local vaccination capacity

38

ACIP Recommendation on Smallpox Vaccine, 2002

39

Demographics of VaccineesCharacteristics

Age (yr)

Median (SD) 28.8 (8.3)

Median (range) 26 (17-76)

Sex

Female 57,460 (12.8)

Male 392,833 (87.2)

Ethnicity

Non-Hispanic 394,587 (87.7)

Hispanic 39,461 (8.8)

Unspecified 15,975 (3.5)

Race

White 328,612 (73.0)

African American 80,796 (17.9)

Asian/Pacific Islander 10,459 (2.3)

Native American 3,927 (0.9)

Other 26,499 (5.9)

Vaccination status

Primary vaccines 317,637 (70.5)

Revaccinees 132,656 (29.5)

Demographic characteristics of smallpox vaccinees, 12/13/02 to 5/28/03 (n = 450,293). Vaccinations continue. Current number of vaccinees

is larger. Data are No. (%) unless otherwise specified.

40

Smallpox Vaccination: Adverse Events

Event Type Events(N)

DoD Rate per MillionVaccinees(95% CI)

Historical Rate perMillion Vaccinees

Mild or temporary Generalized vaccinia, mild 36 80 (63-100) 45-212*

Erythema

multiforme 1 NA NA

Inadvertent inoculation, self 48† 107 (88-129) 606*

Vaccinia

transfer to contact 21 47 (35-63) 8-27*

Moderate or serious

Encephalitis 1 2.2 (0.6-7.2) 2.6-8.7*

Acute myopericarditis 37 82 (65-102) 100‡

Eczema vaccinatum 0 0 (0-3.7) 2-35*

Progressive vaccinia 0 0 (0-3.7) 1-7*

Death 0 0 (0-3.7) 1-2*

Noteworthy Adverse Effects After Smallpox Vaccinations

DoD, US Dept of Defense; NA, not available. *Based on adolescent and adult smallpox vaccinations from 1968 studies (both primary and revaccination); †Includes 38 inadvertent inoculations of the skin and 10 of the eye; ‡Based on case series in Finnish military recruits given the Finnish strain of smallpox vaccine.

41

Myopericarditis following Smallpox Vaccination

Myopericarditis following smallpox vaccination among vaccinia-naïve U.S. military personnel1.

18 cases of myopericarditis in 230,734 primary smallpox vaccines in U.S. military; incidence 7.8/100,000/30 days

None in men with prior vaccination2.

All were in men 21–33 years of age

3.

MP occurred 7–19 days (u = 10.5 days) after vaccination

4.

Rate is 3.6-fold higher (3.33–4.11) above expected rate in this population

5.

Incidence is 1 per 12,819 primary vaccinations

Notes Available

Section B

Polio

43

Infectious Diseases: Possible Candidates for Eradication

1.

Smallpox2.

Polio

3.

Measles4.

Guinea worm (dracunculosis)

5.

Yaws and endemic syphilis6.

Onchocerciasis

7.

Tuberculosis8.

Leprosy

44

Current Efforts at Disease Eradication

1.

Poliomyelitis2.

Guinea worm

3.

Measles

45

Paralytic Polio in the U.S.

46

Paralytic Polio in Chicago

47

Polio Incidence and Immunization

48

WHO Strategy for Polio Eradication

1.

Immunization with OPVa.

Routine (with other EPI vaccines)

b.

National immunization days (mass immunization of all children 0–5 years of age, twice yearly, separated by 30 days

2.

Outbreak response−

Investigation of cases and immunization of contacts with OPV

3.

Surveillance−

Epidemiological and virological

investigation of all

cases of acute flaccid paralysis (AFP)−

Immunization of contacts of AFP cases

−

Environmental monitoring (sewage) for wild polio viruses

49

Advantages of Oral Polio Vaccine

Advantages of oral polio vaccine for polio eradication1.

Ease of administration (professional health care workers not needed)

2.

Cheap3.

Infectious to contacts

4.

Provides intestinal immunity (will prevent carrier state)5.

Safety

50

Epidemiological Classification of Reported Cases

Epidemiological classification of reported cases of poliomyelitis, U.S., 1975–1984

Category Subtotal Total

EpidemicNo OPVOPV received

100

10

EndemicNot vaccine-associatedOPV recipientOPV contact

(Household)(Non-household)

143041

(28)(13)

85

Imported 12 12

Immune deficient 11 11

Total 118

51

Period between Vaccination and Onset

52

Polio in Finland

53

Polio in Scandinavia, U.K., and U.S.A.

54

Polio in Finland, 1984–1985

Case No.

Age (yrs.) Sex Immunization

historyOnset date Clinical illness Outcome

follow-upPoliovirus

isolate

1 48 M None 8/84 Paralysis Residual* None

2 28 F 5 IPV 9/84 Paralysis Residual* None

3 6 M 3 IPV 10/84 Aseptic meningitis Healthy P3

4 17 M 5 IPV 10/84 Quadriplegia Died P3

5 14 M 3 IPV 10/84 Paralysis Weakness† P3

6 31 F None 11/84 Paralysis Residual* P3

7 12 M 5 IPV 11/84 Paralysis Residual* P3

8 26 M 5 IPV 11/84 Paralysis Weakness† P3

9 33 M 1 IPV 12/84 Paralysis Residual* P3

10 28 F 5 IPV 1/85 Paralysis Residual* None

*Residual refers to persistent residual paralysis 60 days after onset

†Patients had only weakness of the affected limbs 60 days after onset

55

Incidence of Poliomyelitis in Cuba, 1932–1982

56

Polio Cases by Four-Week Period, Brazil, 1975–1992

57

Status of Poliomyelitis Eradication in 1999

58

Polio Eradication Program Targeted Surveillance Goals

1.

Active acute flaccid paralysis−

(AFP) surveillance

−

Goal: one or more non-polio AFP cases per 100,000 population—under age 15 years

2.

Two stool specimens for poliovirus isolation from ≥80% of AFP cases−

Taken 24 hours apart

−

Within 14 days of onset of AFP

59

AFP, WHO African Region, January 2000–July 2001

2000 January-July 2001

AFP Cases

Non-Polio AFR Rate*

AFP with Adequate

Specimens†

(%)

Polio Cases (Wild Virus Confirmed)

AFP Cases

Non-Polio AFR Rate

AFP with Adequate

Specimens(%)

Polio Cases

(Wild Virus Confirmed)

Angola 217 1.6 54 119 (55) 63 1.2 52 20 (0)

DR Congo‡ 1078 2.3 35 513 (28) 1312 9.0 72 0 (-)

Ethiopia 345 0.7 45 144 (3) 170 0.6 53 69 (1)

Nigeria 978 0.7 37 637 (28) 1090 3.8 64 10 (10)

Total 2618 1413 (114) 2635 99 (11)

Number of reported cases of acute flaccid paralysis (AFP), nonpoliomyelitis

AFP rates, and confirmed polio cases in priority countries –

African Region, World Health Organization, January 2000-July 2001

*Per 100,000 children aged <15 yr; †2 stool specimens collected at an interval of at least 24 hours within 14 days of onset of paralysis and adequately shipped to the laboratory; ‡Democratic Republic of Congo.

60

Confirmed Poliomyelitis in Polio-Endemic Countries, 2001

61

Performance Indicators for AFP Surveillance

AFP Cases Non-Polio AFP Rate ‡

% AFP with Adequate

Specimens**

Confirmed †† (Clinical &

Virological)

Virus-Confirmed Cases

Region/Country† 2000 2001 2000 2001 2000 2001 2000 2001 2000 2001

Africa 5936 8444 1.5 3.0 50 71 1863 113 160 63

Nigeria 979 1931 0.7 3.8 36 67 638 51 28 51

Niger 93 229 1.2 4.4 37 80 33 6 2 6

Angola 213 149 1.3 2.4 55 66 115 1 55 1

Ethiopia 345 552 0.7 1.9 45 47 152 1 3 1

Eastern Mediterranean 3253 3852 1.4 1.9 70 83 505 140 287 140

Pakistan 1152 1562 1.5 2.3 71 84 199 116 199 116

Afghanistan 252 213 1.1 1.7 50 74 120 11 27 11

Egypt 275 257 1.3 1.2 90 91 4 5 4 5

Sudan 269 303 1.4 2.2 49 74 79 1 4 1

Somalia 161 129 2.2 4.1 50 59 96 7 46 7

Southeast Asia 10,758 10,658 1.8 1.8 78 83 591 268 272 268

India 8103 7510 2.0 1.9 82 83 265 268 265 268

American 2076 2186 1.2 1.1 80 89 12 10 ‡‡ 0 0

European 1645 1818 1.1 1.2 80 81 0 3 0 2

Pacific 6894 6552 1.5 1.4 90 88 0 3 ‡‡ 0 0

Total 30,562 33,510 1.6 1.6 75 84 2971 537 719 473

Performance Indicators for acute flaccid paralysis (AFP) surveillance –

WHO regions, 2001-2001*

*Data as of 3/10/02; †Data from countries with indigenous polio during 2001 & do not add to regional and global totals; ‡Per 100K children aged <15 yr; **2 stool specimens collected at an interval of at least 24 hrs within 14 d of paralysis onset and adequately shipped to the laboratory; ††Decrease in total confirmed cases during 200-2001 through switch from clinical to virological

case classification criteria in most countries; ‡‡Vaccine-derived poliovirus.

62

Polio in Nigeria

63

Distribution of Isolates from AFP Cases, Nigeria, 2001

64

Polio in Nigeria

65

Setback in the Polio: Eradication Program (2003–2004)

Rumors of “contaminated” polio vaccine led to suspension of polio vaccine use in northern Nigeria, mid 2003 (no vaccine from January to September 2004)Commission established to investigate safety of polio vaccine; concluded by July 2004 that vaccine was safeAs a consequence of suspension of polio vaccine in northern Nigeria, wild polio was spread to 12 other previously polio-free countries in sub-Saharan Africa

66

Current Issues

Use of mOPV to control outbreaksImprove surveillance and response to outbreaksControl of Nigeria outbreakChronic excretion of OPV in immunosuppressed children

67

Current Issues

Use of mOPV to control outbreaksImprove surveillance and response to outbreaksControl of Nigeria outbreakChronic excretion of OPV in immunosuppressed childrenWhen can OPV and IPV be stopped??