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Copyright 2007, The Johns Hopkins University and Neal Halsey. 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. This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike License . Your use of this material constitutes acceptance of that license and the conditions of use of materials on this site.

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Page 1: Eid Lec6 Halsey

Copyright 2007, The Johns Hopkins University and Neal Halsey. 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.

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike License. Your use of this material constitutes acceptance of that license and the conditions of use of materials on this site.

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Vaccines—Impact, Questions, and Challenges

Neal A. Halsey, MD Johns Hopkins University

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Neal Halsey

Professor, Johns Hopkins BloombergSchool of Public HealthInfectious disease prevention with the safest vaccines possibleEpidemiological studies of vaccine-preventable diseases and phase I, II, and III vaccine trials of hepatitis A and B, inactivated polio virus, pertussis, Haemophilus influenzae type B, tetanus, Lyme disease, rotavirus, Argentina hemorrhagic fever, and influenzae vaccine virusesControl of measles has been a particular focus of interest

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Section A

Background and History

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5Source: CDC. (2006, Januar). 9th Edition Pink Book.

The Most Effective Tool

Vaccines are the most effective tool we have to control infectious diseases

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First elimination goal announced

Second eliminationgoal announced

Vaccine Licensed

Third eliminationgoal announced

Reported Measles in the United States

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Reported Measles in the United States

0

5

10

15

20

25

30

85 87 89 91 93 95 97 99 01 03 05Year

First elimination goal announced

Second eliminationgoal announced

Vaccine Licensed

Third eliminationgoal announced

Second dose recommended

One dose is ~95% effective.

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Initial 9 months to 14 years SIA

Follow-up9 months to 4 years SIA

Supplemental campaigns

Measles Cases and Weighted Average of Coverage

Measles cases and weighted average of routine measles vaccination coverage, Southern African countries

Adapted from Otten M, et al. Public-health impact of accelerated measles control in the WHO African Region 2000–03. Lancet 2005;366:832-839.

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9Source: CDC. (2006). Morb Mortal Wkly Rep, 55 (Dispatch), 1–5.

Jan Feb Mar Apr

Mumps Cases Linked to Multi-State Outbreak

Number of reported mumps cases linked to multi-state outbreak, January 1 to May 2, 2006

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N = 2,597

† 3 cases related to the outbreak

§ 12 cases related to the outbreak

Mumps Cases Linked to Multi-State Outbreak

Number of reported mumps cases linked to multi-state outbreak, January 1 to May 2, 2006

Source: CDC. (2006). Morb Mortal Wkly Rep, 55 (Dispatch), 1–5.

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11Source: CDC. (2006). Morb Mortal Wkly Rep, 55 (Dispatch), 1–5.

Number of Reported Mumps Cases, U.S., 1980–2006

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12

Questions

1. How did scientists figure out how to make vaccines?2. Why aren’t some vaccines more effective?3. Why can’t we eradicate more disease?4. What new vaccines might be approved in the future?5. What diseases other than infections might be prevented

with vaccines?6. Why do we have so many misunderstandings about

vaccine safety?

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Louis Pasteur

1879 Laboratory Attenuation

1. Chicken cholera culture exposed to air over a holiday2. Infected chickens3. Chickens protected from challenge4. “Induced immunity”

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195424 passages human kidney tissue

28 passages primary human amnion tissue

6 passages chick embryos

Chick embryo cellsEdmonston B

Vaccine1963

Wild type virus

Edmonston B Measles Vaccine

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1890s: Killed Typhoid Vaccines

Richard Pfeiffer, Wilhelm Kolle (Germany)Almoth Wright (England)1899 Boer War—mass immunization in military−

Great opposition, dumped vaccine overboard

58,000 cases, 9,000 deaths in military

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How Are Vaccines Made?

Insert DNA into

vector

Vectored

Inactivated Killed

Attenuate (live)Serial passage Attenuated

Inactivated Disrupt Purify Subunit

Extract DNA

Insert inyeast orbacteria

Expressantigen Purify Recombinant

vaccine

Naked DNA

Reassortant

Cold adapted “parent”

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U.S.

Routine Vaccines in U.S. and Developing Country EPI Programs

1. Diphtheria2. Tetanus3. Pertussis4. Polio (IPV)5. Hepatitis B6. H. influenzae type b7. S. pneumoniae8. N. meningitidis9. Measles 10. Mumps 11. Rubella12. Varicella13. Rotavirus14. Influenza15. HPV

1. BCG2. Diphtheria3. Tetanus4. Pertussis5. Polio (OPV)6. Measles 7. (Yellow Fever)8. Hepatitis B9. (H. influenzae type b)10. (Rubella)

Vaccines for Routine Use in U.S. and in Developing Country Expanded Programme on Immunization (EPI) Programs

EPI

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Vaccines for Selective Populations

SmallpoxAnthraxArgentine hemorrhagic feverTyphoid feverRabiesJapanese encephalitisPlagueClostridium perfringens “pig bell”

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Section B

Modern Vaccine Issues

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Needed Vaccines

Viruses

– Herpes simplex – Dengue – HIV – RSV – Hepatitis C – Cytomegalovirus – EBV – West Nile – Parainfluenza

Parasites

– Malaria – Helminths – Schistosomes

Bacteria

– Syphilis – Gonorrhea – E. coli – Lyme disease – C. trachomatis – Group A streptococci – Oral streptococci

– Under development

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1.7 Million Childhood Deaths

1.7 million childhood deaths due to vaccine-preventable diseases in 2000 (not including influenza, pneumococcal, and meningococcal diseases)

Adapted from Henao-Restrepo et al. J Infect Dis. 2003:187(Suppl. 1):S20.

Pertussis, 17% Neonatal Tetanus, 12%

Diptheria, 0%

Haemophilus influenzae, 23%

Yellow Fever, 2%

Polio, 0%

Measles, 46%

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Why Do We Still Have So Much Preventable Disease?

1. Failure of delivery systems2. Incomplete protection from some vaccines3. Financing

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Why Aren’t Some Vaccines More Effective?

Influenza: rapid evolution of new strainsHuman variability: genetic differences−

Hepatitis B, measles (1 dose): ~95–98%

Incomplete immunity−

Pertussis: 70–90% (June 2005—booster at 11–12 years for U.S.)

Varicella (1 dose): 70–90% (2 doses 2006)Errors in storage or administrationEvasion of the immune system−

HCV, HIV, parasites

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Vaccine Shortages

San Francisco Chronicle

Baltimore Sun

L.A. Times

Photo courtesy of Lance McCord. Some rights reserved.

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Why Can’t We Eradicate More Diseases?

Tetanus: animal reservoirsPneumococcal disease: too many typesVaricella and hepatitis B: viral persistent infections and transmissions

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26Rafael Harpaz

Varicella Zoster Virus Persists in Dorsal Root Ganglia

Varicella zoster virus persists in dorsal root ganglia of sensory nerves

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Incidence Ratio0.75 (0.632-0.89)

-100200300400500600700800900

1,00016

-19

20-2

4

25-2

9

30-3

4

35-3

9

40-4

4

45-4

9

50-5

4

55-5

9

60-6

4

65+

Age Group

Zost

er in

cide

nce

rate

(per

100

,000

per

son-

year

s)

No Children

Children < 16 years

Herpes Zoster and Presence of Children in HouseholdRate of herpes zoster by presence of children in household

Adapted from Brisson et al. Exposure to varicella boosts immunity to herpes-zoster: implications for mass vaccination against chickenpox Vaccine. 2002;20:2500-2507

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Postherpetic neuralgia

Herpes zoster

p<0.001

p<0.001

66.5% efficacy 61.1% efficacy

Postherpetic Neuralgia, Herpes Zoster after Zoster VaccineIncidence of Postherpetic Neuralgia and Herpes Zoster following Zoster Vaccine (5-6 X Potency of VaricellaVaccine)

Copyright © 2005 Massachusetts Medical Society. All rights reserved.Adapted with permission 2006.

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Cervical Cancer

Age-standardized incidence rate per 100,000

OBOCAN 2002, http://www-dep.iarc.fr/globocan/GLOBOframe.htm.

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Burden of Cervical Cancer

400,000–500,000 cases and 230,000 deaths from cervical cancer each yearSecond leading cause of cancer-related deaths among women worldwide

Lauri Markowitz

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31Lauri Markowitz

Papillomaviruses

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16184531335258Others

Clifford. (2003). Br J Cancer.

Types

Lauri Markowitz

HPV Types and Cervical Cancer Worldwide

HPV types in cases of cervical cancer from different regions of the world

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33Winer. (2003). Am J Epidemiol, 157.

Cumulative Incidence of HPV Infection

Cumulative incidence of HPV infection from time of first sexual intercourse, female college students, U.S.

Lauri Markowitz

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GARDASIL™ (Merck) 6, 11, 16, 18

Cervarix (GSK) 16, 18

HPV types

Vaccines That Prevent Cervical Cancer

Types 16 and 18 cause ~70% of cancerTypes 6 and 11 cause 90% of genital warts

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Infectious Causes of Cancer

1. Hepatitis B Liver cancer

2. HPV Cervical, penile, anal

3. EBV Lymphoma

4. HTLV-I Lymphoma

5. HHV-8 Kaposi’s sarcoma

6. H. pylori Gastric carcinoma

?

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All Vaccines Cause Adverse Events

1. Pain2. Local reactions3. Fever4. Allergic reactions5. Unchecked replication (immune deficient)6. Adverse immune responses

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Vaccine-Associated Paralytic Poliomyelitis

Oral polio vaccine can cause vaccine-associated paralytic poliomyelitis1. Similar to wild type paralysis2. Risk ~ 1 per 760,000 children vaccinated

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Measles Mumps Congenital rubella

SmallpoxDiphtheria Tetanus

Diseases Once Common in the U.S.

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Current Vaccine Dilemmas

1. How do we maintain high acceptance in absence of disease?

2. Causal assessment: science vs. legal?3. Vaccines to treat chronic infections (hep B)4. Criteria to stop vaccinating (polio)?5. Who should receive vaccines for bioterrorism agents?6. How do we get new expensive vaccines introduced and

sustained in developing countries?