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Copyright 2007, The Johns Hopkins University and Kenrad Nelson. All rights reserved. Use of these materials permitted only in accordance with license rights granted. Materials provided “AS IS”; no representations or warranties provided. User assumes all responsibility for use, and all liability related thereto, and must independently review all materials for accuracy and efficacy. May contain materials owned by others. User is responsible for obtaining permissions for use from third parties as needed. 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 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 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 − , 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. , 1796, demonstrated that cowpox virus inoculated into skin could protect against smallpox

9. Vaccination with cowpox by arm-to-arm 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

No. of cases Case-fatality Age group No. of deaths (% distribution by age) 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 5 cases, 2 deaths

3. 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 : 14,168,000

17 Complications of Smallpox Vaccination—U.S.,1968

Number of reported cases (deaths in parentheses)

Vaccination Estimated Postvaccinal Progressive Eczema Generalized Accidental status and age number of Other encephalitis vaccinia vaccinatum vaccinia infection (yrs) vaccinations

Primary vaccinations <1 614,000 4 (3) – 5 43 7 10 1–4 2,733,000 6 1 31 47 91 40 5–9 1,553,000 5 (1) 1 (1) 11 20 32 8 10–19 406,000 – 1 (1) 3 5 3 1 ≥20 288,000 1 2 7 13 4 5 Unknown – – 1 3 5 2 Total 16 (4) 5,594,000 5 (2) 58 131 142 66 Revaccinations – – – – – – – <1 478,000 – – 1 – 1 1 1–4 1,643,000 – 1 (1) 4 1 3 2 5–9 2,657,000 – 1 3 – – – 10–19 3,796,000 – 4 (1) – 9 3 6 ≥20 8,574,000 – 6 (2) 8 10 7 9 Total

Unvaccinated – – 60 (1) 2 44 8 contacts

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

Notes Available 18 Complications of Vaccinia

„ Complications of vaccinia immunizations per million

vaccinations, 1968 Vaccination status

Ten-state survey CDC national survey Complications Primary 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

*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, immune- suppressive 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 >98% Logistics Practical, bifurcated needle Cost 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 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. Isolation of patient in own house 2. Front and rear house guards (with vaccine) 3. Vaccinated all household contacts and visitors 4. 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

„ 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 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 Demographic characteristics of Age (yr) smallpox vaccinees, 12/13/02 to Median (SD) 28.8 (8.3) 5/28/03 (n = 450,293). Vaccinations Median (range) 26 (17-76) continue. Current number of Sex vaccinees is larger. Data are No. (%) Female 57,460 (12.8) unless otherwise specified. 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) 39 Smallpox Vaccination: Adverse Events

Noteworthy Adverse Effects After Smallpox Vaccinations

Event Type Events DoD Rate per Million Historical Rate per (N) Vaccinees Million Vaccinees (95% CI) 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*

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 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. Smallpox 2. Polio 3. Measles 4. Guinea worm (dracunculosis) 5. Yaws and endemic syphilis 6. Onchocerciasis 7. Tuberculosis 8. 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

„ 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 Subtotal Total Epidemic 10 No OPV 10 OPV received 0 Endemic 85 Not vaccine-associated 14 OPV recipient 30 OPV contact 41 (Household) (28) (Non-household) (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 Age Immunization Onset Outcome Poliovirus Sex Clinical illness No. (yrs.) history date follow-up 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 January-July 2001

AFP with AFP with Polio Non-Polio Polio Cases AFP Adequate AFP Non-Polio Adequate Cases AFR (Wild Virus Cases Specimens† Cases AFR Rate Specimens (Wild Virus Rate* Confirmed) (%) (%) 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)

*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 % AFP with Confirmed †† Virus-Confirmed Rate ‡ Adequate (Clinical & Cases Specimens** Virological) 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 *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