Disclosures. A Sampling of Anti-Vaccine Groups. From Fear of Disease to Fear of Adverse Events. Immunization Truths. Who Are the Vaccine Protestors?

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1 Addressing Parents Concerns About Vaccines Disclosures GlaxoSmithKline, Merck, Novartis, sanofi pasteur Ad hoc consultant Principal investigator Gary S. Marshall, M.D. Professor of Pediatrics Chief, Division of Pediatric Infectious Diseases Director, Pediatric Clinical Trials Unit University of Louisville School of Medicine Louisville, Kentucky From Fear of Disease to Fear of Adverse Events A Sampling of Anti-Vaccine Groups National Vaccine Information Center The Alliance for Informed Choice in Vaccination Pennsylvania Parents for Vaccine Awareness Concerned Parents For Vaccine Safety Citizens for Healthcare dom Vaccine Information Resource Center Coalition For Informed Choice PAVE: People Advocating Vaccine Education Future Generations VOICE: Vaccinations- Offering Individuals Choice & Education Vaccination Alternatives Natural Immunity Information Network Ohio Parents for Vaccine Safety Healthy Alternatives Salk. Pediatr Infect Dis J 1987;6:889; Infectious Disease News; November, 1998 Who Are the Vaccine Protestors? Black Undervaccinated Young, unmarried mother without college degree White Unvaccinated Married mother with college degree Near poverty level Annual income >$75, Live in central city Live in states with philosophical exemptions Claim doctors have little influence over vaccination decisions Immunization Truths 1. Vaccines are good 2. Public concern about vaccines is pervasive 3. Fear of vaccines can lead to public harm 4. Vaccines are not 1% safe 5. Parents are human 6. People don t understand vaccinology 7. It s all about risk perception 8. There are vaccine anti-champions 9. Questions remain 1.Parents have to make a choice Smith PJ. Pediatrics 24;114:187 Marshall. Infect Dis Child (Suppl): Jan, 23

2 Vaccine Programs Initiated Before 198 Historical Peak Cases Deaths Cases Deaths Diphtheria 3,58 3,65 Measles 763, Mumps 212, ,584 Pertussis 265,269 7,518 15, Poliomyelitis (acute) 42,33 2,72 Poliomyelitis (paralytic) 21,269 3,145 Rubella 488, Congenital rubella synd 2, 2,16 1 Smallpox 11,672 2,51 Tetanus Vaccine Programs Initiated After 198 Historical Peak Cases Deaths Cases Deaths Hepatitis A 254, , Hepatitis B 74, , Hib (invasive) >2, >1, <5 <5 Pneumo (invasive) 64,4 7,3 41,55 4,85 Varicella 5,358, , Estimates Roush. JAMA 27;298:2155 Roush. JAMA 27;298:2155 Immunization Truth 1 Immunization Truth 1 Childhood immunizations Cervical cancer Colorectal cancer Breast cancer Adolescent tobacco Physical activity Newborn screening Alcohol and drugs Diet Folic acid Childhood safety Infant feeding QALYs Saved x 1 Coffield. Am J Prev Med 21;21:1 Childhood immunizations Infant feeding Alcohol and drugs Newborn Screening Adolescent tobacco Childhood safety Colorectal cancer Folic acid Cervical cancer Breast cancer Physical activity Diet Dollars per QALYs Saved x 1 Coffield. Am J Prev Med 21;21:1 Immunization Truth 1 21 Birth Cohort (N=3,83,295) Cases Deaths Total Costs Without 14,33,376 33,564 $46,557 mil With 78, $482 mil DTaP, Hib, IPV, MMR, HepB, varicella (not included: rotavirus, HepA, PCV-7, influenza, MCV-4, HPV) Parental Concerns About Vaccines Vaccines are a good way to protect children 9% Generally follow doctor s recommendations 88% Concerned about adverse effects 54% Vaccines cause autism 25% Personally know someone harmed by MMR 4% Refused at least one recommended vaccine 12% $1 spent = $5 in direct medical costs $11 in societal costs Zhou F et al. Arch Pediatr Adolesc Med 25;159: d. Pediatrics 21;125:654

3 Incidence of Pertussis: England and Wales 5 81% 31% 93% Vaccine uptake Exemptions and Pertussis Incidence Type of exemption Adjusted Incidence Rate Ratio (95% CI) Only religious 32 Reference Personal belief ( ) Exemption ease Difficult 19 Reference Medium ( ) Easy ( ) Gangarosa. Lancet 1998;351:356 Omer SB. JAMA 26;296:1757 Case-Control Studies MMR and Autism: United Kingdom Disease Risk Attributable Risk Among Refusers Attributable Risk in Population Pertussis 23-times higher 99.5% 11% Varicella 9-times higher 99.4% 5% Glanz. Pediatrics 29;123:1446; Glanz. Arch Pediatr Adol Med 21;164:66 (Kaiser Permanente, CO) Cases per 1, Boys Yrs Kaye JA. BMJ 21;322:46 Autism MMR Annual Birth Cohort Annual Birth Cohort Vaccine Prevalence (%) MMR and Autism: California PDD in Montreal, Canada Cases Autism MMR by 24 Months Birth Cohort Vaccine Prevalence (%) Prevalence/1, (1987) 1 (1988) 9 (1989) Prevalence of PDD 8 (199) 7 (1991) 6 (1992) 5 (1993) 4 (1994) 3 (1995) Grade (Year of Birth) MMR Coverage 2 (1996) 1 (1997) K (1998) Coverage (%) Dales L. JAMA 21;285:1183 Fombonne. Pediatrics 26;118:e139

4 Retrospective Cohort Study Design Danish Cohort Study The Past The Present The Past The Present Risk factor present Disease No Disease MMR 1,647,54 person-yr Autism: 263 ASD: 345 Population Sample Relative risk: rate of outcome in exposed individuals rate of outcome in unexposed individuals Children born between 1/1/91 and 12/31/98 Population of Denmark Relative risk: Autism:.92 ( ) ASD:.83 ( ) Madsen. N Engl J Med 22;347:1477 Measles Vaccine and Autism with Enteropathy Blinded search for measles RNA using RT-PCR 3 separate laboratories 25 children with autism and GI disturbances 13 children with GI disturbances alone Study Group Sex Age at Biopsy Time Since MMR Where Sequences Found Autism Male 4.7 yr 41 mo Ileum RLF Control Male 4. yr 27 mo Ileum RLF RLF= reactive lymphoid follicles Pathology 2 21 Hornig. PLOS 28;3:e314 Godlee. BMJ 211;342:64 Consequences of Public Fear Measles United States, January-July Measles eliminated 28 Measles endemic (again) 131 cases 17 directly imported 99 linked to imported cases 15 link not established 11% hospitalized 123 cases among US residents 8% <2 years of age 91% unvaccinated or vaccination status unknown 66% of eligible individuals not vaccinated because of religious or philosophical beliefs Jansen. Science 23;31:84; viewarticle.aspx?articleid=18919 CDC. MMWR 28;57:893

5 Invasive Hib Disease Minnesota, 28 Public Confidence: Vaccine Safety Patient Age Syndrome Outcome Hib Doses 1 15 mo Meningitis Survived 2 mo, 5 mo 2 3 yr Pneumonia Survived 3 7 mo Meningitis Died Pre-Clinical Licensure and Recommendation Post-Marketing 4 5 mo Meningitis Survived 2 mo, 4 mo 5 2 mo Epiglottitis Survived Subsequently diagnosed with hypogammaglobulinemia Parents or guardians refused vaccination Highest number of reported cases since 1992 Center for Biologics Evaluation and Research Good Manufacturing, Laboratory and Clinical Practices Phased clinical trials FDA ACIP AAP AAFP Phase 4 studies Pharmacovigilance Vaccine Adverse Event Reporting System Vaccine Safety Datalink CISA Network Brighton Collaboration Ad-hoc committees CDC. MMWR 29;58(ER);Jan 23 Marshall. The Vaccine Handbook. PCI Books, Inc.:28 Subjects Needed to Test for Increased Risk of Adverse Event Relative to Background Rates The Power of Box a Background rate in general population Rate in vaccinated population 2-fold higher 1-fold higher 1-fold higher 1 in 1, 141, 5,5 5 1 in 1, 1,238, 53,5 2,5 1 in 1,, 12,951,5 532,5 23,5 Assumes 5% risk of Type I error and power of 9% Exposure Outcome Yes No Yes a b No c d Evans. J Infect Dis 29;2:321 Heuristic Thinking Folk Numeracy Do no harm: a bad outcome is more tolerable if it occurs from inaction rather than action Ambiguity: a known risk is more acceptable than an unknown risk Availability and representativeness: the probability that something will occur correlates with the ease with which we remember it or with similarity of circumstances Compression: rare risks are overestimated and common risks are underestimated Intuitive sense of numbers that upholds small, anecdotal experiences and makes it difficult to see the big picture 1 million women given a shot: 86 will develop optic neuritis within 6 weeks 1 million pregnant women given a shot: 16,684 will have a spontaneous abortion within 6 weeks Evans. Risk Comm and Vac. Natl Acad Press, 1997; Ball. Pediatrics 1998;11:453 Shermer M. Sci Amer 28;Sep;4; Black S. Lancet 29;374:2115

6 Antigen Burden Alternative Vaccine Schedule Vaccine Smallpox 2 Diphtheria Tetanus Pertussis Polio MMR Hib 2 2 Varicella PCV7/PCV HepB 1 1 HepA 4 HPV4 4 Rotavirus 2 MCV4 5 Influenza 12 Total HepB Rota DTaP Hib PCV7 IPV Flu Measles Varicella HepA Offit. Pediatrics 22;19:124 and Marshall. The Vaccine Handbook. PCI Books: 21 Sears. The Vaccine Book. Little Brown & Co. 27 Consequences of Intentional Delay Coverage at 24 mo (%) General Intellectual Functioning Measure Untimely (N=556) Timely (N=491) Verbal IQ Performance IQ Full-scale IQ Intentional delay (N=546) No intentional delay (N=2,365) Smith PJ. Pub Health Rep 21;125:534 Smith MJ. Pediatrics 21;125:1134 (Wechsler Abbreviated Scale of Intelligence, primary analysis; P<.5 for each measure) Alternative Vaccine Schedule Parameter Alternative ACIP Total visits to completion 15 visits 4 or 5 Age at completion 42 months 15 or 18 months Alternative Vaccine Schedule Argument Parents can educate themselves to know more than doctors. Government and pharmaceutical companies conspire to misrepresent data. Natural immunity is better than vaccineinduced immunity. Vaccines are not adequately tested for safety. Vaccines are recommended for protection of the public, not individuals. There is a middle ground between causality and coincidence. Science fails because it cannot prove that vaccines don t cause adverse events. The Truth Advisory committees are composed of experts who review the primary data. There is no evidence of conspiracy. The cost of natural immunity is the risk of serious disease or death. Vaccines are among the most thoroughly tested pharmaceuticals in the world. Individuals benefit from vaccines through both individual and herd immunity. Either vaccines do or don t cause certain adverse events. Science can only reject or fail to reject the null hypothesis. Marshall. The Vaccine Quarterly 29;3[1]:17 Offit. Pediatrics 29;123:e164

7 Risk Perception Projected Mortality: U.S., 211 What We re Afraid Of What The Real Risk Is Shark attacks (28) Dog bites (4.5 million) Murder (14,18) Suicide (33,289) Death by peanut allergy (5) Death by poisoning (27,531) Death by plane crash (321) Death by car crash (34,17) Deaths 4, 3, 2, 36, 1, 1 Influenza Varicella Anthrax Smallpox BLALOCK.ssrn.com/abstract=677549; Gigerenzer. Psych Sci 24;15:286. The New McCarthyism Cohort Studies of Thimerosal Exposure I have a family history of genetic vulnerability that my kid can t detox vaccines. They say the mercury (thimerosal ) is gone, but it s still in there! no wheat, no dairy, because his system can t break them down it turns them into an opiate making them stoned or drunk detoxing and occasionally antifungal medicines. It s the pediatrician s fault! Not my fault! I m on an airplane and the pilot comes out to talk to me because his kid is autistic. Geier 23 Geier 23 Geier 23 Andrews 24 Heron 24 Hviid 23 Verstraeten 23 Inclusion/ Diagnoses Outcome Appropriate Control Calculation Precisely Measures Exclusion for of Defined Validated Location Database Criteria Thimerosal Bias Exposure USA VAERS No No No No No USA VAERS No No No No No DOE USA VAERS No No No No No DOE UK National Yes Yes Yes Yes Yes Statistics UK Avon Long Yes No No Yes Yes Study Denmark National Yes Yes No Yes Yes Registries USA HMOs Yes Yes Yes Yes No US Weekly. Oct 27, 28 Parker. Pediatrics 24;114:793 Vaccine Adverse Event Reporting System VAERS Only Contains Box a Post-marketing surveillance system Mandatory reporting by health care providers Events listed as contraindications Events listed in the Reportable Events Table Voluntary reporting of any event by any one Hypothesis generation not hypothesis testing Exposure Outcome Yes No Yes a b No c d Offit, in Marshall. The Vaccine Handbook. Lippincott Williams & Wilkins, 24

8 Danish Population-Based Study Swedish Population-Based Study Autism Incidence per 1, Age! Thimerosal-containing vaccines removed Year In-Patient Autism Cases per 1, Person- Years Diagnosed in Year Cumulative Ethylmercury Dose from Vaccines by Age 2 Madsen. Pediatrics 23;112:64 Stehr-Green. Am J Prev Med 23;25:11 PDD in Montreal, Canada Autism in California Prevalence of PDD 12 Prevalence/1, No thimerosal exposure K (1987) (1988) (1989) (199) (1991) (1992) (1993) (1994) (1995) (1996) (1997) (1998) Grade (Year of Birth) Fombonne. Pediatrics 26;118:e139 Schechter. Arch Gen Psych 28;65:19 Danish Cohort Study Retrospective Case Control Study Design The Past The Present The Past The Present Thimerosal 1,66,159 person-yr Autism: 14 ASD: 321 Risk factor present Risk factor absent Cases Children born between 1/1/9 and 12/31/96 Population of Denmark Relative risk: Autism:.85 (.6-1.2) ASD: 1.12 ( ) Odds ratio: odds of risk factor in cases odds of risk factor in controls Hviid. JAMA 23;29:1763

9 Vaccine Safety Datalink Study Strengths The Past Risk factor present Risk factor absent The Present ASD (N=256) Looked at multiple outcomes Looked at prenatal exposures Included stakeholders in study design Conducted careful individual assessments Well-documented exposures Surveyed for undiagnosed autism Risk factor: Increase of 1 mcg/kg ethylmercury from birth through 7 mo Odds ratio:.967 For every 1 mcg/kg increase in exposure, the odds of autism go up.967 Price. Pediatrics 21;29126:656 Thimerosal Status of Current Vaccines Vaccine Trade Name Manufacturer Status Diphtheria, tetanus, Infanrix GlaxoSmithKline pertussis DAPTACEL Aventis Pasteur Tripedia Aventis Pasteur <.3 mcg/.5ml Mercury Exposure PCV-7 Prevnar Wyeth Polio IPOL Aventis Pasteur Hepatitis B RECOMBIVAX HB Engerix-B Merck GlaxoSmithKline Hib conjugate ActHIB Aventis Pasteur PedvaxHIB Hiberix Merck GlaxoSmithKline Hib/Hepatitis B COMVAX Merck MMR M-M-R II Merck Varicella VARIVAX Merck DTaP/Hep-B/IPV Pediarix GlaxoSmithKline Influenza Fluzone T-free sanofi pasteur Fluvirin P-free Chiron/Evans <1. mcg/.5 ml Flumist MedImmune Hepatitis A VAQTA Merck Havrix GlaxoSmithKline 5.6 oz 3 mcg Tripedia <.3 mcg/dose UCM96228#t1 (accessed 9/1/9) Yess. J AOAC Intl 1993;76:36 Aluminum Exposure VICP Petitions 1 L.225 mg ActHIB.225 mg/dose Number of Petitions Filed 3 Autism Non-autism Year (accessed 1/2/9)

10 Omnibus Autism Proceedings Magnitude of The Vaccine Court Hearings Theories of general causation MMR and thimerosal-containing vaccines combine to cause autism Thimerosal-containing vaccines cause autism MMR causes autism (dropped) Three test cases per theory Typical vaccine case 1 medical articles 2-6 experts Omnibus Autism Proceedings (Theory 1) 5, pages of transcript >7 pages of post-hearing briefs 939 medical articles 5 expert reports Testimony of 28 experts US Court of Federal Claims. (accessed 2/18/9) OAP Theory 1 MMR plus Thimerosal February 12, 29 OAP Theory 2 Thimerosal March 12, 21 Questions Which challenges deserve scientific investigation? What about perceived conflict of interest? How do families differ in medical orientation? How should families who refuse to vaccinate be handled? Bruesewitz v. Wyeth VICP covers design defects February 22, 211 Parents Have to Choose Don t vaccinate Discredited scientists Advocacy groups Celebrities Robust science Vaccinate Authoritative bodies You Vulnerability to disease Protection with minimal risk It s not about belief. It s about science.

11 WEBINAR SIGN-IN SHEET Project: Date: 3/9/211 Topic: Addressing Parents Concerns Regional Office: Name Title Program (lxb##) Please fax or mail this sign in sheet to Kathleen Cummings at , or Continuing Education, School of Public Health, One University Place, Renssleaer, NY 12144

12 WEBINAR SIGN-IN SHEET Project: Date: 3/9/211 Topic: Addressing Parents Concerns Regional Office: Name Title Program (lxb##) Please fax or mail this sign in sheet to Kathleen Cummings at , or Continuing Education, School of Public Health, One University Place, Renssleaer, NY 12144