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Disease Eradication
Kenrad Nelson, MD
Johns Hopkins University
Objectives
„
Review issues related to the eradication of an infectious
disease
− Smallpox
− Polio
3
Section A
Smallpox
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
X Note the elements of geography, time, and implied
surveillance
X This 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
5
Advantages of an Eradication Strategy
„
Advantages of a strategy of eradication of an infectious
disease
1. 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
6
Disadvantages of an Eradication Strategy
„
Disadvantages of a strategy of eradication of an infectious
disease
1. 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
7
Criteria to Determine Whether a Disease Is Eradicable
„
„
„
Biological and technical feasibility
Consensus on positive costs and benefits
Broad societal and political support
8
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 support
Smallpox
− Vaccination, surveillance, containment strategy
− 1958–1980
− Successful
9
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 traders
4. 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 century
5. 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
10
History of Smallpox
7. Use of pustular scabs from smallpox cases introduced into skin or by
nasal insufflation began in India around 10th century
8. Edward Jenner, 1796, demonstrated that cowpox virus inoculated
into skin could protect against smallpox
9. Vaccination with cowpox by arm-to-arm inoculation practiced during
19th century
10. Growth of cowpox in flank of calf publicized and used, 1864
11. 1940s—freeze-dried vaccine for production of vaccine
12. 1950—PAHO began program to eliminate smallpox from
the western hemisphere
− By 1967 smallpox still present only in Brazil
11
History of Smallpox
13. 1958—the U.S.S.R. proposed that WHO undertake a global
program to eradicate smallpox
14. 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, Somalia
16. 1980—smallpox vaccination discontinued
− Except for special lab workers
17. June, 1995—the last remaining smallpox cultures to be destroyed
12
Natural History of Smallpox
13
Smallpox
Photo Source: CDC PHIL
14
Smallpox
Photo Source: CDC PHIL
15
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
16
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
17
Complications of Smallpox Vaccination—U.S.,1968
Number of reported cases (deaths in parentheses)
Vaccination
status and age
(yrs)
Estimated
number of
vaccinations
Postvaccinal
encephalitis
Progressive
vaccinia
Eczema
vaccinatum
Generalized
vaccinia
Accidental
infection
Other
–
1
1 (1)
1 (1)
2
–
5 (2)
5
31
11
3
7
1
58
43
47
20
5
13
3
131
7
91
32
3
4
5
142
10
40
8
1
5
2
66
Primary
vaccinations
<1
1–4
5–9
10–19
≥20
Unknown
Total
614,000
2,733,000
1,553,000
406,000
288,000
5,594,000
4 (3)
6
5 (1)
–
1
–
16 (4)
Revaccinations
<1
1–4
5–9
10–19
≥20
Total
–
478,000
1,643,000
2,657,000
3,796,000
8,574,000
–
–
–
–
–
–
–
–
1 (1)
1
4 (1)
6 (2)
–
1
4
3
–
8
–
–
1
–
9
10
–
1
3
–
3
7
–
1
2
–
6
9
–
–
60 (1)
2
44
8
16 (4)
11 (4)
126 (1)
143
193
83
Unvaccinated
contacts
Total
14,168,000
Notes Available
18
Complications of Vaccinia Immunizations
„
Complications of vaccinia immunizations per million
vaccinations, 1968
Vaccination status
Complications
Ten-state survey
Primary
Revaccination
CDC national survey
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
*Immunocompromised hosts are at greatest risk
Notes Available
19
Progressive Vaccinia
Photo Source: CDC PHIL
20
Progressive Vaccinia
Photo Source: CDC PHIL
21
Eczema Vaccinatum
Photo Source: CDC PHIL
22
Accidental Inoculation
Photo Source: CDC
23
Contraindications of Smallpox Vaccination
1. Immune disorders
− Agammaglobulinemia, neoplasms, immunesuppressive drugs, etc.
2. Eczema
− Including eczema in a household contact
3. Pregnancy
4. Disorders of the central nervous system
24
Factors Favoring Successful Smallpox Eradication
1. A very effective vaccine that produced long lasting
immunity
2. A high proportion of the population already vaccinated
3. Single genetically stable virus
4. No animal or environmental reservoir
5. Disease only moderately contagious (contagious after
onset of rash)
25
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
Vaccine
Efficacy
Logistics
Cost
>98%
Practical, bifurcated needle
Minimal
Seasonality
Striking
26
Essential Principles in WHO Eradication Program
„
Essential principles in WHO smallpox eradication program
1. 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
X Program relied on active surveillance
X When cases were identified, their contacts were
immediately vaccinated to abort further
transmission
27
Bifurcated Needle
Photo Source: CDC
28
Smallpox Eradication Program: Bangladesh
„
Surveillance
1. 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 outbreaks
4. Epidemiologic investigation of every smallpox
outbreak to detect source, travel of case, and travel of
contacts
5. Monthly municipal area house-to-house search
6. In later stages, national house-to-house search
29
Smallpox Eradication Program: Bangladesh
1.
2.
3.
4.
Isolation of patient in own house
Front and rear house guards (with vaccine)
Vaccinated all household contacts and visitors
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
30
Smallpox Incidence in Ethiopia
31
Countries with Endemic Smallpox
Notes Available
32
Number of Countries with Endemic Smallpox
33
Effects of Discontinuation of Smallpox Vaccine
„
„
Monkeypox
− Less contagious than smallpox
X Secondary household attack rate = 5% (for smallpox, 40–50%)
− Cases
X 1970–1975: 55 cases
X 1980–1986: 349 cases
− Fatality rate = 11%
− 72% primary (contact with monkey)
X 1987–1992: 13 cases
X 1993–1996: 0 cases
X 1996–1997: 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
34
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 locations
1. CDC, Atlanta
2. Novosibirsk, Russia
There is some suspicion, but no good evidence, that
smallpox supplies may have been disseminated
35
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?
36
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 bioterrorism
1. Level of disease risk and threat
2. Expected severe adverse reactions to vaccination
3. Vaccine and vaccinia immune globulin supply
4. State and local vaccination capacity
37
ACIP Recommendation on Smallpox Vaccine, 2002
38
Demographics of Vaccinees
Characteristics
Age (yr)
Median (SD)
28.8 (8.3)
Median (range)
26 (17-76)
Sex
Female
57,460 (12.8)
Male
392,833 (87.2)
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.
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)
39
Smallpox Vaccination: Adverse Events
Noteworthy Adverse Effects After Smallpox Vaccinations
Event Type
Events
(N)
DoD Rate per Million
Vaccinees
(95% CI)
Historical Rate per
Million Vaccinees
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*
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*
Mild or temporary
Moderate or serious
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.
40
Myopericarditis following Smallpox Vaccination
„
Myopericarditis following smallpox vaccination among
vaccinia-naïve U.S. military personnel
1. 18 cases of myopericarditis in 230,734 primary
smallpox vaccines in U.S. military; incidence
7.8/100,000/30 days
X None in men with prior vaccination
2. 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
41
Section B
Polio
Infectious Diseases: Possible Candidates for Eradication
1.
2.
3.
4.
5.
6.
7.
8.
Smallpox
Polio
Measles
Guinea worm (dracunculosis)
Yaws and endemic syphilis
Onchocerciasis
Tuberculosis
Leprosy
43
Current Efforts at Disease Eradication
1. Poliomyelitis
2. Guinea worm
3. Measles
44
Paralytic Polio in the U.S.
45
Paralytic Polio in Chicago
46
Polio Incidence and Immunization
47
WHO Strategy for Polio Eradication
1. Immunization with OPV
a. 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
48
Advantages of Oral Polio Vaccine
„
Advantages of oral polio vaccine for polio eradication
1. Ease of administration (professional health care
workers not needed)
2. Cheap
3. Infectious to contacts
4. Provides intestinal immunity (will prevent carrier state)
5. Safety
49
Epidemiological Classification of Reported Cases
„
Epidemiological classification of reported cases of
poliomyelitis, U.S., 1975–1984
Category
Epidemic
No OPV
OPV received
Endemic
Not vaccine-associated
OPV recipient
OPV contact
(Household)
(Non-household)
Subtotal
Total
10
10
0
85
14
30
41
(28)
(13)
Imported
12
12
Immune deficient
11
11
Total
118
50
Period between Vaccination and Onset
51
Polio in Finland
52
Polio in Scandinavia, U.K., and U.S.A.
53
Polio in Finland, 1984–1985
Case
No.
Age
(yrs.)
Sex
Immunization
history
Onset
date
Clinical illness
Outcome
follow-up
Poliovirus
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
54
Incidence of Poliomyelitis in Cuba, 1932–1982
55
Polio Cases by Four-Week Period, Brazil, 1975–1992
56
Status of Poliomyelitis Eradication in 1999
57
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
58
AFP, WHO African Region, January 2000–July 2001
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
2000
Angola
DR
Congo‡
Ethiopia
Nigeria
Total
January-July 2001
AFP
Cases
Non-Polio
AFR
Rate*
AFP with
Adequate
Specimens†
(%)
Polio Cases
(Wild Virus
Confirmed)
AFP
Cases
217
1.6
54
119 (55)
1078
2.3
35
345
0.7
978
0.7
2618
Non-Polio
AFR Rate
AFP with
Adequate
Specimens
(%)
Polio
Cases
(Wild Virus
Confirmed)
63
1.2
52
20 (0)
513 (28)
1312
9.0
72
0 (-)
45
144 (3)
170
0.6
53
69 (1)
37
637 (28)
1090
3.8
64
10 (10)
1413 (114)
2635
99 (11)
*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.
59
Confirmed Poliomyelitis in Polio-Endemic Countries, 2001
60
Performance Indicators for AFP Surveillance
Performance Indicators for acute flaccid paralysis (AFP) surveillance – WHO regions, 2001-2001*
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
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
30,562
33,510
1.6
1.6
75
84
2971
537
719
473
Southeast Asia
Total
*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.
61
Polio in Nigeria
62
Distribution of Isolates from AFP Cases, Nigeria, 2001
63
Polio in Nigeria
64
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 safe
As 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
65
Current Issues
„
„
„
„
Use of mOPV to control outbreaks
Improve surveillance and response to outbreaks
Control of Nigeria outbreak
Chronic excretion of OPV in immunosuppressed children
66
Current Issues
„
„
„
„
„
Use of mOPV to control outbreaks
Improve surveillance and response to outbreaks
Control of Nigeria outbreak
Chronic excretion of OPV in immunosuppressed children
When can OPV and IPV be stopped??
67