1. Addressing and Overcoming Vaccine Hesitancy
William Atkinson, MD, MPH*
Boise Immunization Summit
September 30, 2013
*Representing the Immunization Action
Coalition, Saint Paul, MN

2. Disclosures
The speaker has no financial interest or conflict with the manufacturer of any product named in this presentation
The speaker will not discuss the off-label use of any vaccine
The speaker will not discuss vaccines not currently licensed by the Food and Drug Administration

4. Comparison of Pre-Vaccine and Current Reported Morbidity of Vaccine-Preventable Diseases and Vaccine Adverse Events, United States
Diphtheria ,
Measles ,
Mumps ,
Pertussis , ,
Polio (paralytic) ,
Rubella ,
Congenital Rubella Syn
Tetanus ,
H. influenzae type b ,
and unknown (<5 yrs)
Disease Pre-vaccine Era* ** % decrease
Today, vaccine-preventable diseases are at or near record lows. By virtue of their absence, these diseases are no longer a reminder of the benefits of vaccination. At the same time, approximately 10,000 cases of adverse events following vaccination are reported in the U.S. each year (these include both true adverse reactions and events that coincidentally occur after vaccination). This number exceeds the current reported incidence of vaccine-preventable childhood diseases. As a result, parents and providers in the U.S. are more likely to know someone who has experienced an adverse event following immunization than they are to know someone who has experienced a reportable vaccine-preventable disease.
Total ,064, ,
Vaccine Adverse Events N/A ~30,
* Baseline 20th century annual morbidity
+ Estimated because no national reporting existed in the pre-vaccine era
** Source: MMWR 2013;62(33)

5. Vaccine-Preventable Diseases Eliminated from the United States
Disease Last Case*
Smallpox
Polio
Measles
Rubella
*Indigenous case. Importations may occur except for smallpox, which was eradicated from the planet in 1977

7. Vaccination Coverage National Immunization Survey 2012
U.S.
Idaho
DTaP3+
94.3
92.9
DTaP4+
82.5
76.6
IPV3+
92.8
92.6
Hib3+
93.3
92.7
MMR1
90.8
HepB3
89.7
87.7
Var1
90.2
90.3

8. Causes of Parent/Guardian Vaccine Hesitancy
Risk versus Benefit
risk: side effects, against personal, religious, or political beliefs
benefit: protection from vaccine- preventable diseases
Most only see risk
No threat from disease

9. Causes of Parent/Guardian Vaccine Hesitancy
“Lifestyle” issues
Political issues
Fear of side effects

13. Homeopathy Conceived by a German physician in the late 1700s
Originally involved the “law of similars“
symptoms of disease can be cured by extremely small amounts of substances that produce similar symptoms in healthy people when administered in large amounts
Products are extremely diluted and generally contain no active ingredient

14. Causes of Parent/Guardian Vaccine Hesitancy
“Lifestyle” issues
Political issues
Fear of side effects

15. Causes of Parent/Guardian Vaccine Hesitancy
“Lifestyle” issues
Political issues
Fear of side effects
real or imagined

16. Importance of Vaccine Safety
Decreases in disease risks and increased attention on vaccine risks
Public confidence in vaccine safety is critical
higher standard of safety is expected of vaccines
vaccinees generally healthy (vs. ill for drugs)
lower risk tolerance results in the need to search for rare reactions
While the majority of parents believe in the benefits of immunization and have their children vaccinated, some have concerns about the safety of vaccines. Close monitoring and timely assessment of suspected vaccine adverse events can distinguish true vaccine reactions from coincidental unrelated events and help to maintain public confidence in immunizations.
A higher standard of safety is generally expected of vaccines than of other medical interventions because, in contrast to most pharmaceutical products which are administered to ill persons for curative purposes, vaccines are generally given to healthy persons to prevent disease. Public tolerance of adverse reactions related to products given to healthy persons, especially healthy infants and children, is substantially lower than for products administered to persons who are already sick.
This lower risk tolerance for vaccines translates into a need to investigate the possible causes of very rare adverse events following vaccinations; a frequency of side effects that would be acceptable for other pharmaceutical products.

17. Importance of Vaccine Safety
Vaccinations universally recommended or mandated
Ongoing safety monitoring needed for the development of sound policies and recommendations
Vaccines must also meet the highest safety standards because almost all U.S. children are immunized, either because of parental choice or school entry mandates. Therefore, safety problems with vaccines have the potential to impact a large number of people.
Vaccine safety monitoring is necessary to accurately weigh the risks of vaccine side effects against the benefits of preventing diseases in a context in which the chances of contracting these diseases are now low. By assessing this risk/benefit balance, vaccine safety monitoring can help us develop sound recommendations and adjust policy as necessary.

18. Pre-Licensure Vaccine Safety Studies
Laboratory
Animals
Humans
Like other pharmaceutical products, vaccines undergo extensive safety and efficacy evaluations in the laboratory, in animals, and in sequentially-phased human clinical trials prior to licensure.

19. Prelicensure Human Studies
Phases I, II, III trials
Phase III trials usually include a control group who receive a placebo
Common reactions are identified
Most Phase III trials include 2,000 to 5,000 participants
Largest recent Phase III trial was REST – more than 68,000 children
Phase I human clinical trials usually involve anywhere from 20 to 100 volunteers and focus on detecting serious side effects.
Phase II trials generally enroll hundreds of volunteers and may last a few months to a few years. Safety is still an important focus, but now tests are also looking at how the human immune system responds to the vaccine. These trials determine the most effective use of the vaccine, the best dose for effectiveness and safety, and the right number of doses.
Phase III trials involve a few hundred to several thousand volunteers and may last several years. Phase III trials usually include a control group who receive either a placebo or another already-licensed vaccine, allowing researchers to compare one vaccine to another (or to a placebo) for adverse health effects (also to calculate efficacy).
The largest Phase III trial in the last few years was the Rotavirus Efficacy and Safety Trial (REST), which included more than 68,000 children. More than 34,000 children received the vaccine and 34,000 received a placebo. The trial needed to be this large in order to assess for a relatively uncommon POSSIBLE adverse event – intussusception. The trial determined that intussusception was no more common in vaccine recipients than among placebo recipients.
If the vaccine is shown to be safe and effective in Phase III, the manufacturer applies for a license from the Food and Drug Administration. During the application, the FDA reviews everything – the clinical trial results, product labeling, the plant itself, and the manufacturing protocols.
However, while rates of common vaccine reactions, such as injection site reactions and fever, can be estimated before licensure, the comparatively small number of patients enrolled in these trials generally limits detection of rare side effects, side effects that may occur many months after the vaccine is given, and side effects that may occur in certain subpopulations (such as different age groups).
Therefore, it is essential to monitor reports of vaccine-associated adverse events once the vaccine has been licensed and released for public use. This is part of post-licensure surveillance. 19

20. Postlicensure Surveillance
Identify rare reactions
Monitor increases in known reactions
Identify risk factors for reactions
Identify vaccine lots with increased rates of reactions
Identify “signals” – reports of adverse events more numerous than would be expected
The objectives of post-licensure surveillance are to:
Identify rare reactions not detected during pre-licensure studies;
Monitor increases in known reactions;
Identify risk factors or pre-existing conditions that may promote reactions;
Identify whether there are particular vaccine lots with unusually high rates or types of events; and
Identify signals of possible adverse reactions which may warrant further study or affect current immunization recommendations.
The largest post-licensure surveillance tool we have is VAERS, which stands for Vaccine Adverse Event Reporting System. It is the cornerstone of post-licensure surveillance efforts.

21. Vaccine Adverse Event Reporting System (VAERS)
Jointly administered by CDC and FDA
National reporting system
Passive - depends on healthcare providers and others to report
Receives ~30,000 reports per year
VAERS was created 1990 and is jointly administered by the CDC and FDA. It is a national passive reporting system to collect all reports of clinically significant adverse events reported by manufacturers, healthcare workers, and the general public. VAERS receives about 10,000 reports per year (>130,000 reports to date). Though this seems like a large number, it is relatively small compared to the approximately 100 million doses of childhood vaccines distributed during the past decade, as well as millions of additional doses given to adults.

22. Vaccine Adverse Event Reporting System (VAERS)
Detects:
new or rare events
increases in rates of known events
patient risk factors
VAERS cannot establish causality
additional studies required to confirm VAERS signals and causality
Not all reports of adverse events are causally related to vaccine
VAERS seeks to capture all clinically significant medical events occurring post-vaccination, even if the reporter is not certain that the incident is vaccine-related.
Despite some limitations, VAERS has been able to fulfill its primary purpose of detecting new and/or rare vaccine adverse events, increases in rates of known side effects, and patient risk factors for particular types of adverse events.
For example, VAERS tracked and raised the concern about intussusception after rotavirus vaccine and anaphlyactic reaction to MMR vaccine cause by gelatin allergy.
Additional studies are always required to confirm “signals” detected by VAERS because not all reported events are causally related to vaccine. Simply because a health problem occurred after vaccination does not mean that vaccination caused the health problem.
In addition to VAERS, we now have 3 other methods for post-licensure evaluation at our disposal.

23. Post hoc ergo propter hoc “After this therefore because of this” Temporal association does not prove causation Just because one event follows another does not mean that the first caused the second

24. Elements Needed To Assess Causation of Vaccine Adverse Events
Disease No disease
Vaccine a b
No vaccine c d
Rate in “vaccine” group = a /a + b
Rate in “no vaccine” group c/ c + d
To assess causation 4 pieces of information are needed. Among persons who received the vaccine you must know how many cases of the event of interest occurred, AND how many vaccinated persons did NOT develop the event. You also need to know the background rate of the event of interest. You determine this be identifying an unvaccinated group, and determining the number of persons who did and did not have the event of interest. These four pieces of data allow you to calculate the RATE of the event among the vaccinated group, and the “background” rate of the event in the unvaccinated population. If the rate in the vaccinated group is higher than the rate in the unvaccinated group, and other factors have been properly controlled (such as age and other underlying conditions) then the vaccine may be contributing to the higher rate in the vaccinated group.
Unfortunately, the VAERS system provides only ONE of these four important pieces of information- the number of events that occur in a population of vaccinated persons. This is why VAERS data cannot be used to assess whether or not a vaccine CAUSES an event. Many events reported among vaccinated persons is a “signal” and additional studies are needed- which include all 4 cells- to evaluate causation.
If the rate in “vaccine” group is higher than the rate in the “no vaccine” group then vaccines may be the cause

25. ASD No ASD Vaccine 345 440,310 No vaccine 77 96,571
Risk of Autism Spectrum Disorder (ASD) Among Children in Denmark,
ASD No ASD Vaccine ,310 No vaccine 77 96,571
Risk in “vaccine” group 7.83/10,000
Risk in “no vaccine” group 7.96/10,000
This is an example of such a study. These are the actual data published in the 2002 New England Journal of Medicine paper that looked at ASD among vaccinated and unvaccinated children.
Relative Risk = 0.98
Madsen et al. N Eng J Med 2002;347:

26. Postlicensure Vaccine Safety Activities
Phase IV Trials
~10,000 participants
better but still limited
Large Linked Databases
Clinical Evaluation Network
Today, Phase IV trials, large-linked databases (LLDBs), and a clinical evaluation network have been added to improve our capabilities to study rare risks associated specific vaccines.
Beginning with phase IV studies, these studies can include tens of thousands of volunteers and may be used to address questions of long-term effectiveness and safety, or examine unanswered questions identified in Phase III studies.

27. Vaccine Safety Datalink
Large linked database
Links vaccination and health records
Population under “active surveillance”
9 HMOs
>2.5% (8 million) of U.S. population
Powerful tool for monitoring vaccine safety
Next, large-linked databases connect computerized pharmacy prescriptions and immunization records with computerized medical records. These LLDBs are derived from defined populations such as members of HMOs, single-provider healthcare systems, and Medicaid programs. Data are usually generated in the routine administration of these programs and these databases do not require the completion of a vaccine adverse event reporting forms, thereby reducing the problems of under-reporting or recall bias. The populations are under “active surveillance” rather than passive surveillance and therefore allow for the establishment of causal relationships and timely analysis. LLDBs are a rapid means of conducting post licensure studies and provide a powerful tool for monitoring vaccine safety.
CDC’s Vaccine Safety Datalink (VSD) Project is one example of such a system. It links the immunization and medical records from members of 8 HMOs, totaling >2.5% of the U.S. population.

28. Improve understanding of vaccine safety issues at individual level
Evaluate individuals who experience adverse health events
Gain better understanding of events
Develop protocols for health care providers
Finally, the Clinical Immunization Safety Assessment (CISA) Network was established in 2001 as a network of 7 centers with vaccine safety experience in partnership with the CDC. The network is designed to improve the understanding of vaccine safety issues at the individual level. This network of coordinated facilities investigates and manages vaccine side effects on an individual basis for the purposes of providing patient care. It also systematically collects and evaluates data on these experiences in order to gain a better understanding of how such events might occur and to develop protocols or guidelines for healthcare providers to help them manage similar situations.
So that’s a summary of the systems in place to try to ensure vaccine safety and to monitor for adverse events. But we know that in spite of these efforts, some rare adverse events occur. What happens then?

29. Vaccine Injury Compensation Program
Established by National Childhood Vaccine Injury Act (1986)
“No fault” program
Covers all routinely recommended childhood vaccines
Vaccine Injury Table
Reportable Events Table
Well, that’s where the Vaccine Injury Compensation Program comes in.
Backing up a bit, during the mid-1970s, lawsuits concerning vaccine adverse events were being filed, resulting in legal decisions and damages awarded despite lack of scientific evidence to support the claims. As a result of the liability, vaccine prices soared and several manufactures stopped vaccine production. A vaccine shortage resulted and there was concern about the return of epidemic disease. This situation led to the National Childhood Vaccine Injury Act of 1986, which in turn established the Vaccine Injury Compensation Program.
This program is intended to compensate individuals who experience certain health events following vaccination on a “no fault” basis, meaning that they aren’t required to prove negligence to receive compensation. The program covers all routinely recommended childhood vaccines (and I believe the process is underway to included TIV on this list). Settlements are based on a Vaccine Injury Table, which summarizes the adverse events associated with vaccines.
So, we’ve now talked about the processes to ensure vaccine safety and the process to compensate for rare cases of injury. With that I’d like to end our brief discussion of vaccine safety but there is more information on this subject in Chapter 4 of the Pink Book.
In the interests of time, however, I need to move on to our next topic…

30. Parental Vaccine Safety Concerns in 2009
>1 in 5 believe vaccines cause autism
1 in 8 parents has refused at least 1 vaccine recommended by the clinician
90% believe vaccines are good way to protect against diseases
88% will do what the clinician recommends
2010 Study by Freed et al published in j of peds - , almost 1 in every 8 parents has refused at least 1 vaccine recommended by their provider, >50% of parents worry about side effects, > 1 in 5 parents believe vaccines can cause autism, but 90% still believe vaccines are a good way to protect their children and 88% will do what the doctor recommends
Freed et al,, J of Peds, March 2010

31. Personal Belief Exemptions
Permitting personal belief exemptions and easily granting exemptions are associated with higher and increasing nonmedical U.S. exemption rates
State policies granting personal belief exemptions and states that easily grant exemptions are associated with increased pertussis incidence
JAMA. 2006;296:

32. Children With Personal Belief Exemption
9-fold higher risk of varicella (Colorado, )
23-fold higher risk of pertussis (Colorado, )
Introduce vaccine-preventable diseases (particularly measles) into school settings
Expose children with medical exemptions to infection

33. Reducing Vaccine Hesitancy and Personal Belief Exemptions
Engage the parent and answer their questions if possible
Be sure the parent understands that unvaccinated students will be excluded from school in the event of an outbreak
Provide the parent with information
Suggest reliable websites for further information (some are listed on IAC “What If” fact sheet)

36. Recent (and ongoing) Vaccine Safety Concerns by the Public
MMR and autism
Additives (particularly thimerosal) in vaccines
“Immune ovreload”
Too many shots

40. Autism and Vaccines
Multiple population-based studies have examined the rate of autism among vaccinated and unvaccinated children
Available evidence does not indicate that autism is more common among children who receive MMR or thimerosal- containing vaccines than among children who do not receive vaccines

41. Studies of Autism and Vaccines*
Taylor, B, et al. Autism and measles, mumps, and rubella vaccine: no epidemiologic evidence for a causal association. Lancet 351: , 1999.
Kaye JA, et al. Measles, mumps, and rubella vaccine and incidence of autism recorded by general practitioners: a time-trend analysis. Brit Med J 322: , 2001.
Madsen KM, et al. A population-based study of measles, mumps, and rubella vaccination and autism. N Engl J Med. 2002;347:
Frambonne E, et al. Pervasive developmental disorders in Montreal, Quebec, Canada: prevalence and links with immunizations. Pediatrics 118:e139-50, 2006.
Thompson WW, et al. Early thimerosal exposure and neuro-psychological outcomes at 7 to 10 years. N Engl J Med 2007; 357(13):
Schechter R, Grether JK. Continuing increases in autism reported to California's developmental services system: mercury in retrograde. Arch Gen Psychiatry 2008;65(1):19-24.
*partial listing of representative studies

43. “... given what the scientific literature tells us today, there is no evidence that thimerosal or the MMR vaccine cause autism. Evidence does not support the theory that vaccines are causing an autism epidemic.“
- Dr. Geri Dawson, July 30, 2009

44. Benefit and Risk Communication
Opportunities for questions should be provided before each vaccination
Vaccine Information Statements (VISs)
must be provided before each dose of vaccine
public and private providers
available in multiple languages

45. Your Source for VISs www.immunize.org

46. Providers Can Change Minds
NIS interviews suggested:
1. 28% of parents doubtful about benefits & safety of certain vaccines
2. Doubtful parents delayed or refused their child's vaccination
Most parents who changed their minds about delaying or refusing vaccination cited information from their physician as the main reason for the change
This is an article recently published in Pediatrics. Interviews that were conducted with parents as part of the National Immunization Survey suggest that 28% of parents are doubtful about the benefits and safety of certain vaccines, which led to them delaying their child’s vaccinations or even refusing vaccinations.
Most of the parents who changed their minds and decided to vaccinate their children cited information from their physician as the main reason for the change.
So what you say does matter.
Oct 2008, J. of Pediatrics

47. How to Have a Successful Dialogue with Parents
Take time to listen
Solicit and welcome questions
Keep the conversation going
Balance science with anecdotal information
Acknowledge benefits and risks

48. How to Have a Successful Dialogue with Parents
Respect parents’ authority
Reduce the stress of shots
Document parents’ questions and concerns
Follow up
Don’t give up

56. Thank You