Choose your own : responding to requests for ‘alternative’ schedules Kristen A. Feemster, MD MPH MSHP Assistant Professor of Pediatrics, Division of Infectious Diseases Research Director, Vaccine Education Center The Children’s Hospital of Philadelphia University of Pennsylvania Perelman School of Medicine

IMMUNIZE NEVADA- April 29, 2014 Disclosures

I have no financial disclosures or conflicts of interest to report. Objectives

 Explore factors that contribute to

 Review evidence related to the safety of the currently recommended vaccine schedule

 Review common questions and misperceptions among parents that contribute to requests for ‘alternative’ vaccine schedules

 Explore strategies for addressing vaccine concerns

2014 Vaccine Schedule Vaccine Pipeline

 CMV  New HPV and  Dengue pneumococcal  HIV vaccines   Malaria Meningitis B   S. aureus Group B Strep and RSV vaccines for  Cell-based influenza pregnant women Impact of Vaccines

MMWR / October 7, 2011 / Vol. 60 A consequence of success

 Slow adoption of new vaccines or new Concerns about vaccine vaccine recommendations safety  Increasing frequency of requests for delayed vaccine schedules  Growing number of exemption requests Concerns from school mandates regarding risk of disease Number and Percentage of Cases, Centers for Disease Control and Prevention

Rates of Nonmedical Exemptions from School , According to Type of Exemption and Ease of Obtaining One, 2006–2011. Omer SB, etal. NEJM 2012; 367

Child in Arizona declining, Arizona Department of Health Services fears outbreak- abc15.com, 1/4/2013 How frequently do parents refuse or delay vaccines?

• Majority of physicians report >1 vaccine refusal / month

• 13% children under-vaccinated due to parental choice

Glanz JM JAMA Pediatr. 2013;167(3):274-281; Gowda, etal. Hum Vac Imm, 2013. Who chooses an alternative schedule?

 More likely to agree that delaying : ◦ Is safer ◦ Is associated with fewer side effects ◦ Allows parents to avoid unnecessary vaccines ◦ Allows parents to be in charge of child’s care

Dempsey A, etal. Pediatrics 2011;128;848 Which vaccines are delayed?

Dempsey A, etal. Pediatrics 2011;128;848 Pediatricians’ Response to Requests for Alternative Vaccine Schedule

 In one study of pediatricians from Washington State, 61% report being comfortable using an alternative schedule if requested

Wightman A, etal. Pediatrics, 2011. The spectrum of vaccine hesitancy

Go along to Health Immunization Worried Fence Sitter get along advocate Advocate (2.6%) (13%) (26%) (25%) (33%)

Late / Selective Cautious Unquestioning The hesitant Refuser (<2%) Vaccinator (2- Acceptor (25- Acceptor (30- (20-30%) 27%) 35%) 40%)

Each group requires a different approach. Gust DA, etal. Am J Health Behavior, 2005,29; Leask J, etal. BMC Pediatrics. 2012, 12. What influences vaccine acceptance?

Vaccine Policies

Personal Characteristics Attitudes towards vaccination Communication Vaccine

regarding vaccine / Acceptance vaccine-preventable Intention to be disese vaccinated

Previous experience w/ vaccine and / or disease Perceived norms Too many shots Too many preservatives Isn’t natural immunity better?

I want to decide what WHY PARENTS REFUSE OR is best for my child DELAY VACCINES FOR THEIR CHILDREN: ADDRESSING COMMON MISPERCEPTIONS We never see this disease Pharmaceutical companies are just anymore pushing vaccines to make money

A Close Examination of Dr. Bob’s Message

 Recommended schedule  Natural comes exposes infants to too at risk of disease that much aluminum could be severe  Herd immunity has  Vaccine preventable eroded due to delay and diseases are not that refusal serious  Misrepresents risk  It is okay to hide in the  Confuses coincidence herd with causality  Natural infection is better  Clear evidence that than vaccination recommended vaccines  Suggests vaccines cause are NOT associated with chronic diseases such as chronic diseases diabetes, eczema, or MS  Vaccine safety testing is insufficient Offit P, Moser C. Pediatrics 2009

Are alternative vaccine schedules safer?

 Alternative schedules have NOT been evaluated for safety and efficacy  IOM report supports safety of currently recommended schedule

Delaying Vaccination Has Consequences  Increases time a child is at risk for a preventable disease  Delayed administration of MMR associated with increased risk of seizures

Incidence Rate (per 1000 Person-years) of Fever (A) and Seizures (B) by Age During the Risk Interval (Days 7-10) and Control Interval (Days 0-6 and 11-42) Following Immunization With a Measles-Containing Vaccine

Rowhani-Rahbar, etal. JAMA Pediatr. 2013;167(12):1111-1117. doi:10.1001/jamapediatrics.2013.2745 Are all of these vaccines too much for the immune system, especially in babies?

The schedule has changed…

Year Vaccines # shots by 2 # shots at years of age one time 1900 Smallpox 1 1

1980 DTwP, (OPV) 5 2 MMR

2011 DTaP, Polio (IPV) 26 5 MMR, Varicella Hib, Pneumococcal conj. Hepatitis A and B Influenza, Rotavirus

Fewer immunologic components are in vaccines today than 100 years ago

Number of antigens in vaccines

Year Vaccines # shots # shots at # antigens by age 2 one time yrs 1900 Smallpox 1 1 200

1980 Diptheria 5 2 1 Tetanus 1 Pertussis (wc ) 3,000 Polio (OPV) 15 Measles 10 9 5 ~3,041 Number of antigens in vaccines

Year Vaccines # shots by # shots at # antigens age 2 yrs one time 2012 Diptheria 26 5 1 Tetanus 1 Pertussis (ac) 2-5 Polio (IPV) 15 MMR 24 Varicella 69 Hib 2 Pneumococcal conj. 8 Hepatitis A and B 5 Influenza 8 Rotavirus 15 ~150-153 That still seems like a lot - can infants handle 150 antigens?

 From birth, infants are challenged by bacteria in the environment (colonizing bacteria on intestines, skin, and throat; bacteria inhaled on dust).  Vigorous sIgA responses within the first week of life keeps colonizing bacteria from invading.

Are infants too young to be vaccinated?

 Excellent immune responses to HBV vaccines given at birth.

 About 95% of infants will develop protective immune responses to HBV, Hib, DTaP, polio, and pneumococcal vaccines by 6 months of age.

 Need to be fully immunized against certain (Hib, pertussis, pneumococcus) by 6 months of age.

Vaccine Immunology 101 Goal: induce protective immunity in a high enough proportion of the population to stop transmission

Vaccine types and infant immune response

 Live attenuated viral (MMR,  (diptheria and tetanus) Varicella, Rotavirus) ◦ Made from disease-causing ◦ Mimics natural infection toxins made by bacteria ◦ Higher antibody response but ◦ Antibodies against toxin  infants do not generate a long prevent disease lasting response due to  Polysaccharide (pneumo- and circulating maternal antibodies meningococcus)

◦ Induce antibody production but  Inactivated or killed viral do not induce immune memory (influenza, hepatitis A, IPV)  Protein (pertussis, Hep B) and ◦ Activate T and B cells and Conjugate (new induce memory pneumococcus, new ◦ Good immune response but meningococcus, Hib) need more than one dose ◦ Induce helper T-cells and memory Conjugate vaccines

 Goebel and Avery (1929) show improved immunogenicity of carbohydrate antigens if coupled to an immunogenic carrier protein Primary and Secondary Immune Response

Todar’s Online Textbook of Bacteriology, ©2005 Kenneth Todar, PhD What does this mean for childhood vaccines?  An infant’s immune system is immature but very robust and effectively responds to an onslaught of pathogens from birth onward

 Do not make as much antibody ◦ Inhibition from maternal antibody  Antibodies to proteins do not persist as long  May have shorter memory

 Goal- induce strong primary response to offer early protection  Prime immune system for secondary response as immune system matures This just seems like too many shots at one time- why can’t I spread them out?

Spreading put shots does not reduce stress for infant  Study showing that two shots are not more likely to induce cortisol (as a marker for stress) than one shot.

 Antigen load from vaccine is MUCH smaller than what an infant confronts every day in the environment

Ramsay DS, Lewis M. Developmental changes in infant cortisol and behavioral response to . Child Development 1994;65;1491-1502.

What about all of the additives in vaccines? Aluminum? Thimerosal?

“The alternative schedule suggests only one aluminum containing vaccine at a time in infant years. By spreading out the shots, you spread out the exposure so infants can process the aluminum without it reaching toxic levels.”

Robert Sears, The Vaccine Book, p. 239

Aluminum and Thimerosal  Aluminum is the third most abundant element on the earth’s surface and the most abundant metal ◦ Occurs naturally in teas, herbs, and spices ◦ Added to foods such as leavening agents, anti-caking agents, emulsifiers, and coloring agents

 Thimerosal contains mercury (ethylmercury) which is also everywhere including food and water sources

Aluminum and mercury in food  Aluminum and mercury are found in breast milk and infant formulas.  By 6 months of age infants ingest: ◦ 10mg aluminum from breast milk and 30mg from infant formula compared to 4mg from vaccines ◦ 400µg mercury from breast milk compared to <200µg from vaccines  Ethylmercury is readily excreted from body- breastmilk, fish and other food sources contain methylmercury which is more likely to accumulate

“The dose makes the poison”  Aluminum can cause encephalopathy, osteomalacia and anemia in severely premature infants and patients on chronic dialysis.  Circulating levels of aluminum in those with symptoms between 100-1,000 ng/ml. ◦ Typically, children and adults have between 1-5 ng/ml of aluminum in blood.  Injected vaccines do not raise that level.

“The dose makes the poison”

 Thimerosal removed from vaccines in 2001 ◦ Now only in multidose preparations of inactivated influenza vaccines  No evidence of mercury toxicity among children who received thimerosal-containing vaccines in multiple studies ◦ Infants <6 months old who received thimerosal doses 8x greater than levels in vaccines showed no toxicity  Everyone has small quantities heavy metals in body

Can you really be sure that vaccines don’t cause autism?  Sparked by 1998 publication in The Lancet by Wakefield, etal linking autism and MMR ◦ Vaccine causes bowel inflammation letting brain- damaging proteins circulate  Study retracted and findings refuted by multiple studies that have shown no evidence of this link1

 Concern has shifted to thimerosal and mercury  No link found in multiple studies AND even after thimerosal removed from vaccines, autism rates have increased Dales, etal. JAMA 2001; D’Souza etal. Pediatrics 2006; Farrington, etal. Vaccine 2001; Madsen etal, NEJM 2002, Taylor, etal. BMJ 2002; Taylor, etal. Lancet 1999. Has evidence removed concern? HOW DO I ANSWER QUESTIONS ABOUT VACCINES? General Principles

 Majority of individuals look to their health care provider for reliable information and recommendations regarding vaccines

 Health care providers may also have questions and concerns about vaccines

 Parents want to make the best decision to keep their child safe and healthy  Health care providers also want to keep children safe and healthy

Role of the Provider

 Provider recommendation a key predictor of vaccine acceptance, but…

Media and Vaccines Provider Recommendation Matters  Make it strong ◦ Help parents understand risk for diseases prevented by childhood vaccines

 Make it personal ◦ Let parents know that you vaccinate your children

 Know the diseases and the vaccines (or have readily available resources) so you can provide information to address questions and concerns An approach  Listen and acknowledge  Find a common ground  Use numbers to communicate risk and provide perspective ◦ 1 in 100 infants <2 months old infected with pertussis will die, 1 in 10,000 who receive DTaP will have moderate adverse event  Talk about risk associated with other daily activities to provide context  Use personal stories

Healy CM, etal Pediatrics 2011;127 Suppl 1:S127-33; Offit PA, Coffin SE. Vaccine 2003;22:1-6; Turnbull AE. Health Commun 2011;26:775-6.; Macdonald NE, etal.. Biologicals 2011.; Daley MF, etal. Sci Am 2011;305:32, 4. What matters: providing information or making a recommendation?

Different types of information had little influence on beliefs about vaccine side effects

• Likelihood of parental refusal of vaccination 17 times higher (aOR 17.5) in the participatory group • 47% of parents with initial resistance accepted vaccination when providers pursued their initial recommendation

Nyhan B, etal. Pediatrics 2014; Opel DJ, etal. Pediatrics 2013 Targeted Messaging

 Address specific concerns  Consider hesitancy type

Leask et al. BMC Pediatrics 2012, 12:154. Resources and Tools

Easy to read and interactive vaccine schedule tools

• When questions arise, listen and acknowledge • Parents and clinicians have same goal to keep child safe and healthy • Personalize discussion • Have some go-to resources for information about vaccines and vaccine preventable diseases Resources

 Offit PA, Moser, CA. Vaccines and Your Child: What Every Parent Should Know. New York, NY: Columbia University Press; 2011

 Vaccine Education Center at The Children’s Hospital of Philadelphia (http://www.chop.edu/service/vaccine-education-center/home.html) ◦ www.prevent-HPV.org

 National Network for Immunization Information (www.immunizationinfo.org)

 National Cancer Institute (http://www.cancer.gov/cancertopics/factsheet/prevention/HPV-vaccine)

Project (www.cdc.gov/od/science/iso/vsd)

 Centers for Disease Control and Prevention: http://www.cdc.gov/vaccines/vpd- vac/hpv/default.htm#clinical

 Immunization Action Coalition: http://www.immunize.org

 Every Child By Two: http://www.ecbt.org

Questions? References Aluminum: Thimerosal; Baylor, NW et al. Aluminum salts in vaccines— Andrews N, etal. Thimerosal exposure in US perspective. Vaccine 2002;20:S18-S23 infants and developmental disorders: A Bishop NJ et al. Aluminum neurotoxicity in retrospective cohort study in the preterm infants receiving intravenous United Kingdom does not support a feeding solutions. N Engl J Med causal association. Pediatrics 114 (2004): 1997;336:1557-1561 584-591. Committee on Nutrition. Aluminum toxicity in Hviid A, etal. Association between infants and children. Pediatrics 1996;97:413- thimerosal containing vaccine and 416 autism. JAMA. 290 (2003): 1763-66. Keith LS, et al. Aluminum toxicokinetics Institute of Medicine. Immunization Safety regarding infant diet and vaccinations. Review: Vaccines and Autism. Washington, Vaccine 2002;20:S13-S17 D.C. National Academies Press, 2004. Pennington JA. Aluminum content in food and Thompson W, etal. Early thimerosal diets. Food Additives and Contaminants exposure and neuropsychological 1987;5:164-232 outcomes at 7 to 10 years. NEJM 357 (2007): 1281-92.