Autism and Vaccination—The Current Evidence jspn_194 166..

172

Lisa Miller, MD, MSPH and Joni Reynolds, RN, MSN

PURPOSE. The purpose of this article is to Lisa Miller, MD, MSPH, is the Disease Control and
Environmental Epidemiology Division Director, and Joni
review relevant background literature Reynolds, RN, MSN, is the Immunization Program
Director, Colorado Department of Public Health and
regarding the evidence linking Environment, Denver, Colorado, USA.

thimerosal-containing vaccine and the

measles, mumps, and rubella vaccine to A utism Spectrum Disorders (ASD) are a group of
developmental disabilities characterized by impairments in
social interaction and communication and repetitive behav-
autism. iors. The prevalence of these conditions has increased over
the past several decades, but it is unclear whether this is due
CONCLUSIONS. Rigorous scientific studies to a true increase, increasing awareness, or differences in the
methods used to assess prevalence. By definition, the onset of
have not identified links between autism and ASD occurs prior to age 3 (Volkmar & Pauls, 2003).
No clear etiology has been identified for ASD, although
either thimerosal-containing vaccine or the many possible associations have been investigated (News-
chaffer et al., 2007). Given the increase in prevalence, there
measles, mumps, and rubella vaccine. has been interest in “environmental” exposures that may
have also increased over the past several decades. One of
PRACTICE IMPLICATIONS. Nurses are often in these exposures, vaccinations, has received widespread
interest and attention. An increasing number of vaccinations
the position of providing advice regarding have become available over the past several decades to
protect children against infectious diseases, and many
vaccines in their formal practice areas as are given at a time period during early childhood that coin-
cides with the onset of developmental concerns related to
well as in their daily lives. Families need autism.
This article will explore vaccination history, vaccine safety
monitoring systems in the United States, and the two most
current and credible evidence to make publicized theoretical vaccine-related exposures that have
been associated with autism—the vaccine preservative thime-
decisions for their children. Excellent rosal and the measles, mumps, and rubella (MMR) vaccine.
Understanding both the history and recent research will
vaccine information resources are available assist nurses in providing accurate patient information and in
interpreting new findings in an area that continues to gener-
online. ate controversy and research interest.
The art and science of vaccinology is complex and
Search terms: ASD, autism, immunization, requires significant rigor in educating providers about vac-
cines and their administration. Vaccines are a cornerstone
MMR, measles, thimerosal, vaccine in public health practice, as “Vaccines are one of the greatest
achievements of biomedical science and public health”
(Centers for Disease Control and Prevention [CDC], 1999a, p.
247). Yet, the success of vaccines and drastically reduced rates
First Received November 14, 2008; Revision received February 25, of disease have resulted in parents not experiencing firsthand
2009; Accepted for publication March 16, 2009. the significant effects of these diseases. Some parents are

166 © (2009), The Authors

Journal Compilation © (2009), Wiley Periodicals, Inc.
now more concerned about the risks, real and theoretical, of papillomavirus, rotavirus, invasive meningococcal infections,
recommended childhood vaccines. and polio. In addition, there are vaccines that can protect
high-risk individuals from other diseases, including small-
History of Vaccines pox, yellow fever, rabies, anthrax, Japanese encephalitis,
herpes zoster (shingles), and typhoid fever.
The earliest medical vaccine is considered to be the small- The Advisory Committee on Immunization Practices
pox vaccination, developed by Dr. Edward Jenner in the eigh- (ACIP) provides recommendations for vaccinations to the
teenth century. Impressively, Jenner’s work preceded the CDC. Annually, the CDC, the American Academy of Pediat-
work of Louis Pasteur, who introduced the concept of viruses rics, and the American Academy of Family Physicians jointly
to the scientific world. publish a schedule of recommended immunizations.
In 1796, Edward Jenner vaccinated James Phipps using Children today are routinely vaccinated against 14 diseases
material from a cowpox lesion on the hand of a milkmaid, during their infancy and preschool years.
theorizing that vaccination with cowpox would lead to immu- Childhood vaccinations are administered as early as pos-
nity against the dreaded smallpox. A later attempt to give sible to assure that infants are protected against diseases that
Phipps smallpox demonstrated his immunity, and the vacci- occur in early childhood. Some have questioned the need to
nation era began. Although Jenner lacked our understanding administer vaccines according to the recommended ACIP
of viruses, the immune system, or vaccinology, his clinical schedule, essentially indicating it is too many vaccines too
observations convinced him that milkmaids were protected early for children (Ball et al., 2001). The timing of vaccines is
from smallpox because of their previous exposure to cowpox, essential to assure that, if possible, protection precedes the
and he acted to see if nature could be replicated (Foege, 2006). disease exposure. It’s key to remember that literally from
Of the many illnesses circulating in the twentieth century, birth, infants are exposed to environmental organisms that
none was as widely feared as polio, which caused crippling can cause infections. Delaying vaccines can be risky because
illness, particularly in children. There were many pools and it extends the time that infants are susceptible to real diseases
beaches closed in the summertime due to concerns of polio that can have serious complications, particularly for the
epidemic. Parents feared polio and anxiously supported the youngest children.
development of a polio vaccine. The goal of the immune system is to identify “non-self”
Dr. Salk introduced the first killed polio vaccine in the and destroy it. The basic components of the immune system
United States in 1955 through massive clinical trials. There include antigens (non-self foreign bodies) and antibodies (our
were concerns with the vaccine, however, as several hundred defense against the antigens). Immune systems are exposed to
cases of paralytic polio were induced by the vaccine. Dr. Sabin hundreds or thousands of antigens daily. Infant immune
researched and developed a different polio vaccine that was systems are capable of responding to these routine exposures,
introduced in the early 1960s. This vaccine proved to be safer which present themselves from the moment of birth. Infants
than and as effective as the prior polio vaccine. An improved and children build effective antibodies to vaccine antigens
Salk Inactivated Polio vaccine is still used routinely for U.S. and are then able to develop internal defenses against a
children today, while the Sabin Oral Polio vaccine is used in variety of infectious diseases, many of which took a tremen-
some international efforts to eradicate polio worldwide. dous toll in the past.
These early vaccine pioneers were fortunate to have
success. Historically, it was a common trait among scientists
to take personal risks for the benefit of science. Jenner, Salk,
Infants and children build effective antibodies
and Sabin risked their reputations for these early break-
throughs, setting the stage for future vaccine development. to vaccine antigens and are then able to
Today, the risks and benefits of vaccines are closely calculated develop internal defenses against a variety of
and monitored. The early vaccines were developed using a infectious diseases, many of which took a
crude approach compared to the laboratory-based vaccine tremendous toll in the past.
development processes of today.

Vaccines Today
Information Regarding Systems for Vaccine
Today there are routine vaccines that can protect individu- Safety Monitoring
als from measles, mumps, rubella, chickenpox, pertussis,
diphtheria, tetanus, invasive Haemophilus influenzae type b Parents, nurses, other medical providers, vaccine manu-
(Hib) infections, viral hepatitis A, viral hepatitis B, invasive facturers, and the government all play critical roles in moni-
Streptococcus pneunomoniae infections, influenza, human toring the safety of vaccines. As parents know their children

JSPN Vol. 14, No. 3, July 2009 167

Autism and Vaccination—The Current Evidence

best, it is important to encourage them to trust their instincts vaccine results in an asymptomatic or mild infection that
related to their children’s health. Parents should report any cannot be transmitted to others. Measles vaccination has
concerns after their children’s vaccinations to their primary resulted in a decrease in reported measles cases from about
healthcare provider. Nurses and other healthcare providers 500,000 cases and 500 deaths per year to a few dozen cases
are required to record key information (e.g., lot number, each year in the United States (CDC, 2007). In 2008, however,
product, administration site, and method) for each vaccine more than 100 cases were reported, due to importations from
administered, which can be used when reporting a possible other countries. Most of these cases have occurred among
vaccine adverse event. Vaccine lot numbers can be used to unvaccinated persons (CDC, 2008b). The ACIP recommends
track unusual patterns within a specific vaccine lot. In addi- that MMR be administered between the ages of 12 and 15
tion, if necessary, a provider can identify which patients months, with a second dose administered between 4 and 6
received a dose of recalled vaccine. years of age (Kroger, Atkinson, Marcuse, & Pickering, 2006).
The National Childhood Vaccine Injury Act was passed in A decade ago, a British researcher and 12 coauthors pub-
1986. The Act created the National Vaccine Injury Compen- lished a paper describing abnormal gastrointestinal features
sation Program, which provides compensation for those among 12 children who had been referred to their university
found to be harmed by specific vaccines. This Act also pediatric gastroenterology clinic. All children had some type
requires healthcare providers to report any serious adverse of developmental disorder, and in 9 of the children, a diag-
events that occur within 30 days after vaccination with any nosis of autism had been made. In 6 of these 9 children, either
vaccine. The reports must be submitted to the Vaccine the parent or a physician had linked the onset of develop-
Adverse Event Reporting System (VAERS), which was set up mental regression with the receipt of the MMR vaccine
in 1990 and is managed by the CDC and the Food and Drug (Wakefield et al., 1998). In 2000, a second paper was pub-
Administration (FDA). Reports can be submitted online at lished, in which white blood cells in the same 9 autistic
http://vaers.hhs.gov/. This is a passive surveillance system children (with what was now referred to as “autistic entero-
that accepts all submitted reports without validation. The colitis”) were examined for the presence of measles virus.
VAERS can identify reporting trends that need further inves- Using polymerase chain reaction, the measles virus RNA
tigation. In 1999, the suspicion of a link between the rotavirus fragments were found in 3 out of the 9 children but in none
vaccine and intussusception was identified through the of the 22 controls (Kawashima et al., 2000). In 2004, 10 of the
VAERS (Department of Health and Human Services, n.d.). 11 coauthors of Wakefield’s original paper asked to “formally
Vaccine manufacturers are required to complete preli- retract the interpretation placed upon these findings . . .”
censing vaccine testing through clinical trials for each (Murch et al., 2004).
vaccine. In addition, vaccine manufacturers are required by However, these initial reports of a possible relationship
the National Childhood Vaccine Injury Act to report adverse between the MMR vaccine and the onset of autism received
events to the Department of Health and Human Services significant attention, and in England, MMR immunization
(CDC, n.d.). Vaccine manufacturers have a vested interest in rates dropped from greater than 90% prior to 1998 (National
assuring vaccines are safe, reinforcing public confidence in Statistics, T.I.C., 2005) to a low of 80% in 2003–2004 (National
vaccines. Statistics, T.I.C., 2008).
The Vaccine Safety Datalink includes data from several In response to this concern in the United States, the CDC
health maintenance organizations. This database is used to and the National Institutes of Health convened a panel of
monitor for any possible adverse event from vaccines. Large, experts in the fall of 2000 to examine three vaccine safety
ongoing studies are conducted using these data (CDC, n.d.). issues, the first of which was the hypothesis of a link between
The FDA monitors adverse events reporting rates, using the MMR vaccine and autism (Immunization Safety Review
both the VAERS data and manufacturer’s data. Among the Committee, Board on Health Promotion and Disease Preven-
things the FDA looks for are large numbers of adverse event tion, & Institute of Medicine, 2001). The committee, after
reports early in the circulation of a lot, clusters of similar cases, performing an in-depth review of the relevant scientific and
syndromes (groups of symptoms), or other patterns; addi- medical literature, rejected a causal relationship between the
tional information from other sources with knowledge of a MMR vaccine and ASD based on the following: (i) a lack of
particular case; patterns of reported adverse events linked to epidemiologic evidence linking autism and MMR vaccine,
final lots filled from the same bulk vaccine; and documenta- (ii) case reports of children with autism and bowel disorders
tion that lots in question have passed all the required tests. that did not address causality, and (iii) a lack of biologic
models linking ASD and MMR vaccine. Similarly, the Ameri-
Measles, Mumps, and Rubella (MMR) Vaccine can Academy of Pediatrics and the Medical Research
Counsel both published similar conclusions (Halsey &
The MMR vaccine was licensed in the United States in Hyman, 2001; Medical Research Council, 2001) in 2001,
1971 and includes a live, attenuated measles strain. The based on the research available at that time.

168 JSPN Vol. 14, No. 3, July 2009

 Shortly thereafter, several studies were published refut- among those without PDD-NOS. The study concluded that
ing the association between MMR vaccine and autism. One of those with PDD-NOS were no more likely to have been vacci-
the first examined the California Department of Develop- nated than those without PDD-NOS (Smeeth et al., 2004).
mental Services data and the state’s MMR immunization rate In 2005, researchers reported on the incidence of autism in
data. They hypothesized that if there were a link, the pattern an area of Japan where MMR vaccination was withdrawn in
of change in the immunization rate should be similar to the 1993. They found that the incidence of autism continued to
pattern of change in the autism rate. Instead, they found that increase, even after the withdrawal (Honda, Shimizu, &
the autism rate had increased by 373% between 1980 and Rutter, 2005). Fombonne, Zakarian, Bennett, Meng, and
1994 but the immunization rate had been fairly constant McLean-Heywood (2006) also examined the relationship of
during that period, increasing by only 14% (Dales, Hammer, MMR vaccination rates with autism rates in Canada, noting
& Smith, 2001). that among children born from 1987 to 1998, PDD-NOS
In that same year, another pair of British researchers set increased in a linear fashion, while MMR immunization rates
out to test several theories suggested by the hypothesis of a just slightly increased. In addition, a second MMR was added
link between a regressive form of autism and the MMR for children at 18 months beginning with those born in 1996.
vaccine. The researchers compared a group of children with This additional MMR dose did not affect the rate at which
autism who had been diagnosed prior to the introduction of PDD-NOS increased (Fombonne et al.).
the MMR vaccine with two groups of children with Perva- In addition to the epidemiologic reports examining the
sive Developmental Disorder Not Otherwise Specified relationship between MMR vaccine and autism, others have
(PDD-NOS; a condition in which children have some of the tried to replicate the findings of measles virus RNA in chil-
features of autism) or autism diagnosed after the introduc- dren with autism. Three studies (Afzal et al., 2006; D’Souza,
tion of MMR vaccine. Among the theories tested was that 2006; Baird et al., 2008) have found no difference in the preva-
the mean age of parental concern should be younger, or lence of measles virus in peripheral blood mononuclear cells
closer to the age at vaccination in the vaccinated group. between children with autism and controls, or failed to find
Instead, there was no difference between groups. If MMR any virus in either group. Martin et al. (2002) did find
vaccine were associated with a regressive form of autism, measles virus RNA more commonly in the bowel tissue of
the authors also theorized that the rate of regression would children with autism and regression compared to a group of
be higher in the groups of children who had received the controls, using a variety of polymerase chain reaction
vaccine. Such an association was not seen (Fombonne & methods. More recently, Hornig et al. (2008) have reported
Chakrabarti, 2001). Later, a group of U.S. researchers tested negative findings among 25 children with autism and 13
similar theories with a large group of well-studied children control children, all with clinically significant gastrointestinal
with autism. They also found no support for the hypoth- symptoms. No significant difference in the prevalence of
esis, though they did find a higher rate of gastrointestinal measles virus RNA in bowel tissue was found between the
symptoms in children with autism and regression com- cases (4%) and controls (8%).
pared to children with autism but no regression. However,
they also documented that for many of the children with
regression, communication skills prior to the onset of
As the preponderance of evidence from around
regression was atypical (Richler et al., 2006).
Kaye, Mar Melero-Montes, and Jick (2001) examined the the world has accumulated showing no
temporal trends by comparing rates of autism in England relationship between MMR vaccine and
between boys born in 1988, when MMR vaccine was intro- autism, MMR immunization rates in England
duced, and those born in 1993. They found that while the have begun to increase.
rate of autism diagnoses increased almost fourfold, the rate
of MMR immunization was fairly constant over that time
period. The authors also compared the mean age at vaccina-
tion among those with an autism diagnosis to the mean age As the preponderance of evidence from around the world
at vaccination among the general population and found no has accumulated showing no relationship between MMR
difference. vaccine and autism, MMR immunization rates in England
Madsen et al., in 2002, published findings from a cohort of have begun to increase. In 2007–2008, rates were 85%, up from
more than half a million children in Denmark that found no their low of 80% (National Statistics, T.I.C., 2008). However,
difference in the risk of autism between MMR-vaccinated and measles cases have increased dramatically in England, from
unvaccinated children. Further evidence was provided in 2004 only 56 cases in 1998 to 1,370 cases in 2008 (Health Protection
from a case control study in which the rate of MMR vaccina- Agency, 2008). Interestingly, in the United States, national
tion among children with PDD-NOS was compared to the rate immunization rates for MMR vaccine have not dipped below

JSPN Vol. 14, No. 3, July 2009 169

Autism and Vaccination—The Current Evidence

90% since 1995, and they have showed no significant reduc- Many studies have been undertaken to examine the risks
tion during the controversy (CDC, 2001, 2004, 2008a). associated with thimerosal in vaccines. In 2003, Stehr-Green
et al. assessed autism incidence and the use of thimerosal-
Thimerosal containing vaccines: “Data did not support an association
between thimerosal-containing vaccines and autism in
Vaccine manufacturers who produce multidose vaccine Denmark and Sweden where exposure to thimerosal was
vials use thimerosal as a preservative. Thimerosal is approxi- eliminated in 1992 and where autism rates continued to
mately 50% mercury by weight, and it has been one of the increase” (Stehr-Green et al., 2003, p. 106).
most widely used preservatives in vaccines. It is metabolized Another study in 2003 utilized the Vaccine Safety Datalink
or degraded to ethylmercury and thiosalicylate. Ethylmer- (VSD) to screen for possible associations between exposure
cury is an organomercurial that should be distinguished to thimerosal-containing vaccines and a variety of renal, neu-
from methylmercury, a related substance that has been the rologic, and developmental problems: “No consistent signifi-
focus of considerable study (Thimerosal in Vaccines, n.d.). cant associations were found between thimerosal-containing
Methylmercury is bioavailable and can accumulate in the vaccines and neurodevelopmental outcomes” (Verstraeten
brain and cause neurologic damage. The ethylmercury found et al., 2003, p. 1,042).
in thimerosal is not bioavailable. In studies, ethylmercury The CDC conducted a follow-up study to the Verstraeten
does not accumulate in the body or the brain and is metabo- et al. VSD study. This was a large study that also utilized the
lized and cleared by the body (Burbacher, Shen, Liberato, VSD data to investigate a possible link between thimerosal in
Grant, & Cernichiari, 2005). vaccines and childhood developmental concerns. An excerpt
Thimerosal has antimicrobial qualities that keep vaccines from the study finding reads:
safe from inadvertent contamination through routine
multiple punctures in a vial. Thimerosal had been used by . . . some people believe increased exposure to thimerosal
vaccine manufacturers for years but came under scrutiny in (from the addition of important new vaccines recom-
1999, as discussed earlier in this article. At that time, the mended for children) explains the higher prevalence in
FDA and the CDC published statements that indicated recent years. However, evidence from several studies
manufacturers should reduce or eliminate the amount of examining trends in vaccine use and changes in autism
thimerosal used in vaccines. The CDC further recom- frequency does not support such an association. Further-
mended the birth dose of hepatitis B vaccine be suspended more, a scientific review by the Institute of Medicine
for infants until thimerosal-free vaccine was available (CDC, (IOM) concluded that “the evidence favors rejection of a
1999b). causal relationship between thimerosal-containing vac-
The CDC stated: cines and autism.” (CDC, 2007, p. 144.)

. . . given the widely acknowledged value of reducing Thompson et al. (2007) further examined the hypotheses
exposure to mercury, vaccine manufacturers, the FDA, that “increasing exposure to thimerosal is associated with
and other Public Health Service (PHS) agencies are col- neurodevelopmental disorders. Findings did not support a
laborating to reduce the thimerosal content of vaccines or causal association between early exposure to mercury from
to replace them with formulations that do not contain thimerosal-containing vaccines and immune globulins and
thimerosal as a preservative as soon as possible without deficits in neuropsychological functioning at the age of 7 to
causing unnecessary disruptions in the vaccination 10 years” (Thompson et al., p. 1,290).
system. The FDA will expedite review of supplements to
manufacturers’ product license applications that present Recent Events
formulations for eliminating or reducing the mercury
content of vaccines. (CDC, 1999, p. 997) As a result of public concern about autism and vaccines,
thousands of claims have been submitted to the National
Vaccine manufacturers then worked to assure removal of Vaccine Injury Compensation Program. On February 12,
thimerosal from vaccines. By 2001, all vaccines routinely rec- 2009, the U.S. Court of Federal Claims published decisions
ommended for children 6 years of age and under in the about these claims, which were considered as a group under
United States were produced without thimerosal as a preser- the Omnibus Autism Proceeding. The Court found, after
vative, with the exception of some doses of inactivated influ- reviewing 5,000 pages of transcripts, 939 medical articles, 50
enza vaccine. Today, all vaccines are available without expert reports, and hearing testimony from 28 experts, that
thimerosal, including several influenza vaccine presentations the MMR and thimerosal-containing vaccines, independently
(e.g., single-dose prefilled syringes and the intranasal or together, were not causal factors in the development of
vaccine). autism or ASD (U.S. Court of Federal Claims, n.d.).

170 JSPN Vol. 14, No. 3, July 2009

 Burbacher, T., Shen, D., Liberato, N., Grant, K., & Cernichiari, T.
How Do I Apply This Evidence to (2005). Comparison of blood and brain mercury levels in infant
Nursing Practice? monkeys exposed to methylmercury or vaccines containing
thimerosal. Environmental Health Perspectives, 113, 1015–1021.
Centers for Disease Control and Prevention. (1999a). Ten great
Studies about vaccination and autism are often complex public health achievements. Morbidity and Mortality Weekly
and difficult for consumers to access and review. Yet it is Report, 48, 241–264.
critical that the findings are shared widely to assure all Centers for Disease Control and Prevention. (1999b). Recommenda-
healthcare professionals have this information in order to tions regarding the use of vaccines that contain thimerosal as a
perservative. Morbidity and Mortality Weekly Report, 48, 996–
provide evidence-based information to parents. Providers 998.
can guide parents in their review of available vaccine infor- Centers for Disease Control and Prevention. (2001). National, state,
mation. A systematic framework can be utilized by parents and urban area vaccination coverage levels among children aged
to assure the available information is reliable. An excel- 19–35 months–United States, 2000. Morbidity and Mortality Weekly
lent tool for reviewing information is available on the Report, 50, 637–641.
Centers for Disease Control and Prevention. (2004). National, state,
American Academy of Pediatrics Web site: http://www. and urban area vaccination coverage among children aged 19–35
cispimmunize.org/fam/facts/FAQ-Internet.pdf. Rigorous months–United States, 2003. Morbidity and Mortality Weekly
scientific studies have not identified concerns with thimero- Report, 53, 658–661.
sal in vaccines or the measles, mumps, and rubella vaccine. Centers for Disease Control and Prevention. (2007). Measles. In
Atkinson, W., Hamborsky, J., McIntyre, L., & Wolfe, S. (Eds.),
Vaccines continue to be a vital tool in the prevention of
Epidemiology and prevention of vaccine-preventable diseases
vaccine-preventable disease. (10th eds., pp. 129–147). Washington, DC: Public Health
Nurses are often in the unique position of providing Foundation.
advice regarding vaccines in their formal practice areas as Centers for Disease Control and Prevention. (2008a). National, state,
well as in their daily lives. Many consider nurses to be and local area vaccination coverage among children aged 19–35
months–United States, 2007. Morbidity and Mortality Weekly
experts in all areas of health care, leading neighbors, patients, Report, 57, 961–966.
and others to ask for and value their opinions. Nurses par- Centers for Disease Control and Prevention. (2008b). Update:
ticipate in this crucial aspect of the prevention of diseases, measles–United States, January-July 2008. Morbidity and Mortality
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Vaccine safety datalink (VSD) project. Retrieved October 18, 2008,
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