Vaccine Hesitancy: An Emerging Epidemic Dean A. Blumberg, MD, FAAP Disclosure clinical research grants: Novartis speakers bureau: sanofi pasteur Discussion vaccines not approved by FDA “off label” use of FDA approved vaccines

Vaccine Hesitancy: An Emerging Epidemic Vaccines and public health Recent vaccine safety concerns in the news HPV4 publicity Other allegations overwhelm the immune system thimerosal aluminum autism Addressing vaccine hesitancy

Vaccine-Preventable Diseases: Baseline 20th Century & Current Morbidity *provisional MMWR 1999;48:245, 2011;59:1700

HPV4: Adverse Experiences package insert

Post-Licensure Vaccine Safety Monitoring CDC/FDA Vaccine Adverse Events Reporting System (VAERS) Vaccine Safety Datalink (VSD) Manufacturer Post marketing studies There are a variety of different post-licensure hpv vaccine Safety monitoring activities—these include: CDC/FDA Vaccine Adverse Events Reporting System (VAERS) Vaccine Safety Datalink (VSD) Clinical Immunization Safety Assessment (CISA) Manufacturer Post marketing study in managed care Pregnancy registry Nordic Cancer Registry 5 5

Vaccine Adverse Events Reporting System (VAERS) National post-licensure safety surveillance system jointly operated by CDC and FDA Spontaneous reporting system in existence since 1990 reports submitted by clinicians, manufacturers, patients/parents and others Subject to well-described limitations of passive surveillance VAERS is one of the adverse events reporting systems. This is a National post-licensure safety surveillance system jointly operated by CDC and FDA Spontaneous reporting system in existence since 1990; reports submitted by clinicians, manufacturers, patients/parents and others Subject to well-described limitations of passive surveillance 6 6

VAERS Advantages Limitations covers US population permits monitoring for known adverse events detects signals for previously unrecognized /rare adverse events generates hypothesis Limitations risk of underreporting or overreporting incomplete data lack of availability of denominator data Advantages Covers US population Permits monitoring for known AEs Detects signals for previously unrecognized /rare AEs Generates hypothesis Limitations Risk of underreporting or overreporting of unfavorable events due to media/other Incomplete data (no routine collection methods) Lack of availability of denominator data (not population based) 7

VAERS HPV Data: Venous Thromboembolism Total reports: 65; US reports: 41 Pending evaluation: 6; Unable to follow-up or “no case”: 17 Confirmed cases: 18 Hormonal contraception current use (n=14) 12 cases – Oral Contraceptive Pills 2 cases on Nuvaring (increase risk of clots) Some have additional risk factors No hormonal contraception use (n=4) 1 case of pregnancy 1 case obesity, smoking, truck driver 1 case long bus ride preceded to the VTE onset 1 case had no reported risk factors This is an example of an evaluation of a specific outcome in vaers. The reports on venous thromboembolism. Total reports: 65 US reports: 41 Pending evaluation: 6 Unable to follow-up or “no case”: 17 Confirmed cases: 18 Hormonal contraception current use (n=14) 12 cases – Oral Contraceptive Pills 2 cases on Nuvaring (increase risk of clots) Some have additional risk factors No hormonal contraception use (n=4) 1 case of pregnancy 1 case obesity, smoking, truck driver 1 case long bus ride preceded to the VTE onset 1 case had no reported risk factors 8

Exposure window (days) Rapid Cycle Analysis, VSD Outcome Exposure window (days) Medical Setting Signal? Guillain Barré Syndrome (GBS) 1 to 42 All NO Seizures 0 to 42 Inpatient, ED Syncope Appendicitis Stroke Venous Thromboembolism (VTE) Anaphylaxis 0 to 2 Other Allergic rxns 0 to 2* This is an example of an analysis in the VSD—a rapid cycle analysis. Various outcomes, with specific exposure windows, are evaluated. For each of these outcomes, a signol is generated if the number Of cases meets a threshold compared to a control group. As you can see, to date, none of these have produced A signal. 9

Vaccine Hesitancy: Oregon Survey Robison et al NIC 2008

Parental Vaccine Safety Concerns Freed et al, Pediatr 2010;125:654

Vaccine Adverse Event Myths No credible scientific evidence that vaccines cause: autism multiple sclerosis diabetes asthma inflammatory bowel disease SIDS overwhelm immune system

Dr. Bob’s Alternative Vaccine Schedule Vaccines not recommended polio, HBV, diphtheria, tetanus uncommon in children measles, mumps, rubella, HAV, rare and not serious for infants and toddlers varicella not serious Vaccines included 2 mo DTaP, PCV7 4 mo DTaP, Hib 6 mo Hib, PCV7 9 mo DTaP, PCV7 12 mo Hib 15 mo Hib, PCV7 5 years Tetanus booster

Overwhelm Immune System? Infant immune system naïve can respond to thousands of antigens simultaneously Challenges other than vaccines natural environmental exposures strep throat: >50 antigens otitis media: >2,000 antigens

Number of Immunogens in Vaccines 1900 1960 1980 2011 Vaccine Immunogens Smallpox ~200 Diphtheria 1 Tetanus Pert-WC ~3000 Pert-AC 2-5 Polio 15 Measles 10 Mumps 9 Rubella 5 Hib 2 Varicella 69 PCV 14 Hepatitis B Hepatitis A MCV RV HPV Influenza* 4 2-7 6-114 Total ~3217 ~3041 142-258 Offit et al, Pediatrics 2002;109:124 *Influenza yearly, new strains every year

Thimerosal Concerns: Neurotoxin? preservative ethylmercury Toxicity data methylmercury 7 well done studies methods both retrospective & prospective ecological & cohort several 100,000 children results: no association

Thimerosal Content: US Vaccines Trade name Manufacturer Thimerosal Concentration DTaP Tripedia® Sanofi Pasteur ≤0.00012% Infanrix® GlaxoSmithKline Daptacel® DTaP-HepB-IPV Pediarix® Tdap Adacel® Boostrix® Haemophilus influenzae type b conjugate (Hib) ActHIB® PedvaxHIB® Merck & Co, Inc Hib/Hepatitis B combo Comvax® Hepatitis B Engerix B® Recombivax HB® Hepatitis A/Hepatitis B Twinrix® <0.0002% Influenza* Various Varies

Aluminum Concerns Aluminum in vaccines Aluminum exposure adjuvant maximum amount 0.85 mg/dose Aluminum exposure deodorant food adults average 7-9 mg/day 200 mg in antacids breast milk 0.04 mg/L formula 0.225 mg/L

Aluminum Exposure: 1st 6 Months of Life Robison et al NIC 2008

MMR & Autism 1998: Wakefield Lancet publication case series 12 children Biological plausibility: no 10 well done studies methods both retrospective & prospective ecological & case control millions of children results: no association

Permanent Medical Exemptions & Personal Beliefs Exemptions, Kindergarten Students, California 1977: Requirements for DTP, polio, measles passed, effective Jan 1, 1978; Started annual assessments 1979: Requirements for mumps and rubella added, effective Jan 1, 1980 1995: Requirement for hepatitis B added, effective Aug 1, 1997 1999: Requirement for varicella added, effective Jul 1, 2001 Lee et al NVIC 2010 21

Refused pertussis vaccination 22.8 times increased risk of pertussis

Refused varicella vaccination 8.6 times increased risk of varicella

Why Parents Who Planned To Delay/Refuse Vaccine Changed Their Minds Gust et al Pediatr 2009;122:718

Parental Immunization Refusal Listen carefully to concerns encourage questions Discuss known risks and benefits risks to unimmunized child Concerns about specific vaccines discuss administer other vaccines Multiple injection concerns modify schedule Revisit discussion in future visits Document

Vaccine Safety Discussion Strategies Empathize: acknowledge that there are many conflicting messages in the media Assess level of scientific evidence desired Maximize benefits to their child not a public health discussion vaccines provide protection risk of disease for omitted vaccines Provide appropriate resources e.g., CDC, AAP, NNII, CHOP

Continued Vaccine Refusal Challenges time commitment for discussions frustration “Fire” patient from practice/clinic? acknowledge differences “it sounds like you and I have different philosophies” offer referral to a different practice/clinic “you might be more comfortable with this group”

Vaccine Hesitancy: An Emerging Epidemic Immunization challenges education of health care providers education of patients and parents discussion