Statement of  Roger Bernier, Ph.D., M.P.H.

Associate Director for Science,

National Immunization Program

Centers for Disease Control and Prevention,

U.S. Department of Health and Human Services

 

Good afternoon Mr. Chairman, Congressman Waxman, and members of the Committee.  I am Dr. Roger Bernier, of the National Immunization Program at the Centers for Disease Control and Prevention (CDC).  Thank you for the opportunity to testify today on CDC’s activities on vaccine safety research.  

 I am accompanied today by Dr. William Egan, Deputy Director, Office of Vaccines Research and Review, Center for Biologics Evaluation and Review, Food and Drug Administration, and Dr. Stephen Foote, Director, Division of Neuroscience and Basic Behavioral Science, National Institute of Mental Health, National Institutes of Health.  At your request, Dr. Robert Chen of CDC’s National Immunization Program and Dr. Frank DeStefano of CDC’s National Center on Birth Defects and Developmental Disabilities are here to respond to questions.

 AUTISM AND VACCINES

Autism spectrum disorders (ASD) are a group of life-long developmental disabilities caused by an abnormality of the brain.  The most recent data suggests that between 2 and 6 children per 1,000 have ASD.  The impact on families of children diagnosed with autism spectrum disorders is tremendous.  We recognize that there is considerable public interest and concern on this issue and we are committed to addressing concerns of parents and families.  The Department of Health and Human Services (HHS) is dedicated to finding the answer to what causes autism and how it can be prevented.  There is a great deal of ongoing research throughout the various public health agencies.  While my focus today is on vaccine safety related issues, it should be noted that HHS has implemented an Interagency Autism Coordinating Committee (IACC).  The IACC is composed of representatives from MIH (top which the Department has delegated a leadership role in organizing and supporting the committee), CDC, FDA, the Health Resources and Services Administration (HRSA), the Agency for Toxic Substances and Disease Registry (ATSDR), the Substance Abuse and Mental Health Services Administration (SAMHSA), the Department of Education, and four public members appointed by the Secretary of HHS.  The IACC takes as its mandate enhanced coordination of the autism-related activities of these federal agencies, from biomedical research to services delivery.  At the most recent IACC meeting, topics included the progress being made on implementation of autism research centers programs by NIH and CDC; efforts to comprehensively map the autism research field in order to analyze its strengths and weaknesses; information about each of the individual grants that collectively constitute the majority of the NIH autism research portfolio; strategies to improve the coordination of gene and tissue banking, data sharing, and federal interactions with voluntary organizations; and, strategic planning for the development of treatments and interventions for autism.  The activities of this committee highlight the large-scale, coordinated response that has been launched by HHS in order to understand, prevent and treat autism. 

Some parents, researchers and others have expressed concerns about a potential link between autism and vaccines currently being used in the United States, focusing primarily on thimerosal, a preservative in some vaccines, and secondly, on measles, mumps, and rubella (MMR) vaccine.

In mid-1999, the United States Public Health Service agencies, including NIH, FDA, HRSA, and CDC took action, working collaboratively with the American Academy of Pediatrics, the American Academy of Family Physicians and the vaccine manufacturers, to begin removing thimerosal preservative from the vaccine supply.  While the risk of harm was only theoretical, the decision was made as a precautionary measure in order to reduce overall mercury exposure of infants.  As a result of this action, all manufacturers are now producing only vaccines that are free of thimerosal as a preservative for routine infant immunization. 

The suggestion that MMR vaccine, which has never contained thimerosal, triggers autism was initially based on some reports of cases of autism in which parents noted the onset of autistic behaviors shortly after MMR vaccination.  Over the last few years, a number of studies have been performed in countries around the world to address this issue.  Systematic scientific reviews by some of the most prestigious medical bodies around the world including the Medical Research Council in the United Kingdom, the American Academy of Pediatrics, and the Institute of Medicine of the National Academy of Sciences have unanimously concluded that evidence does not support a relationship between MMR and autism.  The most recent review was conducted in the United Kingdom and commissioned by the British Medical Association.  British experts reviewed five decades of research on the MMR vaccine and concluded that there is no link to autism or bowel disease.   However, despite these findings and because of continued public concerns, CDC is committed to further scientific research on this issue as detailed in this testimony. 

CDC’S COMMITMENT TO VACCINE SAFETY

CDC is actively involved in detecting and investigating vaccine safety concerns and supporting a wide range of vaccine safety research to address safety questions. 

In order to enhance the understanding of rare adverse effects of vaccines, CDC developed the Vaccine Safety Datalink (VSD) project in 1990.  This project is a collaborative effort, which utilizes the databases of eight large health maintenance organizations (HMOs).  The database contains comprehensive medical and immunization histories of approximately 7.5 million children and adults.  The VSD enables vaccine safety research studies comparing incidence of health problems between unvaccinated and vaccinated people.  Over the past decade, the VSD has been used to answer many vaccine-related questions, and has been used to support policy changes that have reduced adverse effects from vaccines.

CDC recognizes the importance of data sharing when questions are raised regarding a particular study’s design and methodology.  Therefore, CDC has been actively engaged with the participating HMOs to determine how their clients’ personal medical records can be maintained confidentially and the proprietary interests of the HMOs protected, while still allowing for external researchers to reanalyze the data from studies which have been conducted through the Vaccine Safety Datalink.  As a result, CDC has developed a data sharing process designed to allow an independent researcher to replicate or conduct a modified analysis of a previous VSD study, while maintaining the confidential nature of the data.

Another critical part of our vaccine safety effort is the objective, scientific evaluation of safety concerns by independent experts. In collaboration with NIH and other U. S. Public Health Service agencies, CDC requested the Institute of Medicine (IOM) to conduct independent reviews by independent scientific experts to determine: 1) whether the available scientific information favors, or does not favor, vaccines playing a role in causation, 2) the level of public health priority the concern should receive, and 3) recommendations for research.  The IOM Immunization Safety Review Committee has released reports on MMR Vaccine and Autism, Thimerosal and Neurodevelopmental Disorders, Hepatitis B and Neurological Disorders and the Multiple Immunizations and Immune Dysfunction.  The IOM was asked to review the available scientific information on these issues.  CDC has initiated a broad range of studies to address recommendations made by the IOM Immunization Safety Review Committee.

MMR and Autism Studies

In its report regarding the association between the MMR vaccine and autism spectrum disorder (ASD) in April 2001, the IOM concluded “the evidence favors rejection of a causal relationship at the population level between MMR vaccine and autism spectrum disorder.”  The IOM made several recommendations regarding future research including the following epidemiological studies:

1.                  Explore whether exposure to MMR vaccine is a risk factor for ASD in a small number of children;

 

2.                  Develop targeted investigations of whether or not measles vaccine-strain virus is present in the intestines of some children with ASD;

 

3.                  Study the possible effects of different MMR immunization exposures; and

 

4.                  Conduct further clinical and epidemiological studies of sufficient rigor to identify risk factors and biological markers of ASD in order to better understand genetic or environmental causes.

CDC takes this issue very seriously and therefore, is currently funding five research studies that address the above four recommendations from the IOM:

The first study, the Metropolitan Atlanta Developmental Disabilities Surveillance Program (MADDSP) MMR/Autism Study, is a large case-control study. The autism cases for the study were identified through MADDSP. The control subjects were selected from the same or similar schools in the Atlanta area and matched to cases based on age and gender. The study is assessing the relationship between the timing of receipt of the first MMR vaccine and risk for developing autism. The analyses for this study and a manuscript should be completed by early fall 2002.

The second study, the MMR/Regression Autism Study funded by CDC and the National Institutes of Child Health and Human Development (NICHD) is also a large case-control study that is using a sample of autism cases identified as part of the NICHD and the National Institute on Deafness and other Communication Disorders (NIDCD) 10 Collaborative Programs of Excellence in Autism (CPEA). This study is specifically designed to examine the association between regression autism and the timing of first receipt of the MMR vaccine. The study is being carried out over a three-year period and results from this study are expected in the spring of 2004.

The third study, the Denmark MMR/Autism Study, is a recent study that was carried out in Denmark in collaboration with CDC. The study was designed to follow-up on approximately 537,000 children born in Denmark during the period from January 1, 1991 to December 31, 1998.  Of these, 82% received MMR vaccine.  The cohort was generated based on data obtained from the Danish Civil Registration System and subsequently linked with other national registries.  This manuscript has been submitted for publication this year.

The fourth study is a large epidemiological study to identify risk factors and biological markers of ASD to better understand genetic or environmental causes.  The study is being planned in the four Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE), which are being supported by CDC.

Additionally, CDC is in the early stages of planning a study to investigate whether or not measles vaccine-strain virus is present in the intestines of some children with ASD.

There have been a limited number of laboratory reports of the finding of measles virus sequences in intestinal tissue and white blood cells of children with ASD; therefore, there has been speculation that MMR vaccine either precipitates or aggravates ASD.  However, other epidemiologic and laboratory studies do not support this observation.  To resolve differences in results from previous studies that may have occurred due to differences in study design, sampling biases, and differences in laboratory asstesting procedures and their sensitivity, an independent, multicenter study is being designed.  The study plan is to determine the prevalence of measles virus vaccine strain gene sequences in bowel biopsy tissue from children with gastrointestinal tract complaints with and without ASD.  The study will be designed to ensure use of standardized clinical and laboratory protocols, appropriate enrollment of controls, blinding of specimens, use of standardized laboratory reagents and assays, and appropriate statistical evaluation.  

Thimerosal and Neurodevelopmental Delay Studies

In October 2001, the IOM Immunization Safety Review Committee published a report on the possible association between thimerosal-containing vaccines and neurodevelopmental disorders.  In this report, the IOM concluded “that the evidence is inadequate to accept or reject a causal relationship between exposure to thimerosal from childhood vaccines and the neurodevelopmental disorders of autism, ADHD (attention deficit hyperactivitity disorder), and speech or language delay.”  The IOM made several recommendations regarding future research studies including several epidemiological studies.  They recommended:

1.                  Case-control studies examining the potential link between neurodevelopmental disorders and thimerosal-containing vaccines

2.                  Further analysis of neurodevelopmental outcomes in several cohorts of children outside the U.S. who participated in a clinical trial of DTaP vaccine; and,       

3.                  Conducting epidemiological studies that compare the incidence and prevalence of neurodevelopmental disorders before and after the removal of thimerosal from vaccines.

While there have been no vaccines being produced for routine childhood immunization for over a year that contain thimerosal as a preservative, CDC takes this issue very seriously and therefore, has undertaken several studies that address the above IOM recommendations: 

The first study, the Thimerosal Screening Analysis in the Vaccine Safety Datalink (VSD) project, was started in the fall of 1999.  The VSD, described earlier, was used to screen for possible associations between exposure to thimerosal-containing vaccines and a variety of renal, neurologic and developmental problems. In the first phase of this study, the CDC used data from the 2 VSD HMOs with automated outpatient data (where more subtle effects of mercury toxicity might be seen). The CDC and VSD researchers found statistically significant associations between thimerosal and neurodevelopmental disorders, such as language and speech delays, ADHD, stuttering, and tics.  No association was shown with autism.  However, the associations were weak and were not consistent between the two HMOs.  In the second phase of the investigation, CDC investigators examined data from a third HMO with similar available automated vaccination and outpatient databases to see if these findings could be replicated. Analyses of these data using the same methods as the first study did not confirm results seen in the first phase.  A statistically significant relationship between autism and thimerosal was not found in either the preliminary study or the later, larger analysis.  Due to the methodological limitations of the screening analysis using automated data and the difference between the preliminary study and the later analyses, the results required further examination.  

 

CDC and VSD researchers are committed to clarifying the results encountered during the VSD Screening Analysis; therefore, a Thimerosal Follow-Up Study will be conducted.  This second study will be designed to assess whether preliminary results from automated data used in the Thimerosal Screening Analysis can be confirmed using objective neuropsychological testing.  The study will focus on the conditions found in the first screening analyses, including language and speech delays and ADHD.  The design of the new study will address the main drawback of the Thimerosal Screening Analysis, which was that children were not objectively assessed on the neurodevelopmental disorders of interest. The various VSD HMOs categorize neurodevelopmental disabilities in different ways, provide different services for these disorders, and often refer children out of the health care network when they are identified with these particular disorders.

The Thimerosal Follow-Up Study is planned to examine approximately 1200 children between the ages of 7 and 9 years of age randomly selected from four VSD HMOs based on thimerosal exposure during the first 3 months of life. All 1200 children will be brought into their respective HMOs and will be assessed using a standardized set of neuropsychological test batteries. The preliminary proposal for this study was presented to a panel of external consultants including a consumer representative in March of 2001. In September of 2001, CDC awarded a contract to Abt Associates Inc. to carry out the planning phase of the study. The panel of external consultants continues to provide individual input into the study design and the planning phase should be completed by June 2002. Data collection is expected to begin in the latter half of 2002. Abt Associates Inc. is expected to present the results of the study by the end of 2003.

Several additional studies are being planned to address additional issues raised by the IOM.  These include:

The Thimerosal/Autism Study will be a case-control study to be conducted simultaneously with the Thimerosal Follow-up Study.  Autism cases identified through review of automated medical records will be assessed objectively by using a standardized autism assessment tool.  Controls will be selected from the Thimerosal Follow-up Study and matched to cases by age and sex.  

CDC has developed a proposal for a pilot study to conduct further analyses of a group of Italian children who had participated in a prior DTaP trial in which thimerosal exposure was randomly allocated.  CDC is pursuing this to determine the feasibility of recruiting these participates for a follow-up study of neurodevelopmental outcomes.

Two other studies being planned will examine changes over time in the diagnosis of neurodevelopmental delays including autism.  These studies will use inpatient and outpatient discharge diagnoses to compare rates of these conditions over time with changes in levels of thimerosal in recommended childhood vaccines.  Because recommendations for the removal of thimerosal from vaccines did not occur until 1999, several years of data following the removal of thimerosal will be necessary before these comparisons can be made.  Thus, results will not be available until 2005 or later. 

BENEFITS OF VACCINES

We remain vigilant to assure the safety of vaccines.   We must also remember that vaccines benefit the public by protecting persons from the consequences of infectious diseases. 

Continued high U.S. vaccination rates are crucial to prevent the spread of diseases such as measles, pertussis (whooping cough) and rubella among U.S. children.   Current measles coverage is approximately 91% in children 19-35 months old and about 97% at school entry, and only about 100 cases of measles have been reported per year; many of the cases are imported; and ongoing indigenous transmission of measles no longer occurs.  From 1989-91, a measles epidemic in the United States led to more than 55,000 cases of measles and more than 11,000 hospitalizations, with 123 deaths in three years.  Before this epidemic, vaccination coverage was estimated at 61-66% nationally and at 51-79% in 15 major cities.  These outbreaks stopped only when vaccination coverage increased.  Thus, if pre-school coverage dropped by 25-30% below the current level, large measles outbreaks are likely to occur once again.  Additionally, pertussis has continued to be a public health threat.  For example, in 1999, there were 7297 cases of pertussis in the United States, with 15 reported deaths.

 Vaccines are cited as one of the greatest achievements of biomedical science and public health in the 20th century.  We can point to the remarkable success we have had in controlling numerous infectious diseases which used to be widely prevalent in the United States, including polio, measles, and pertussis.  In fact, several of these vaccine-preventable infectious diseases are known to cause developmental disabilities, including Haemophilus influenzae type b (Hib) and congenital rubella syndrome (CRS), one of the few known causes of autism.  Rubella vaccine, by preventing CRS, thus prevents some cases of autism.  Prior to routine immunization with Hib vaccine, of young children who developed Hib meningitis, 5 percent died and another 15 to 30 percent were left with residual brain damage leading to language disorders and mental retardation.

While we have made great progress to reduce the number of cases of vaccine-preventable diseases, the threats posed by vaccine-preventable diseases are known and real.  The viruses and bacteria that cause vaccine-preventable diseases still circulate in the U.S. and around the world.  Maintaining vaccination coverage and high levels of immunity are crucial to protect the U.S. population and to continue progress toward elimination of diseases that, at one time, caused millions of infections in the U.S. each year and that globally remain the leading causes of death and of preventable birth defects.

CONCLUSION

CDC remains committed to collecting accurate data on prevalence of autism and conducting studies on vaccine safety.  Research is already underway, and more is planned, to look at the relationship between the MMR vaccine and autism.  We want each child to be born healthy and to grow and develop normally, so that they are able to lead productive lives.  Vaccines are one of our most valuable weapons against disease and have afforded us one of our proudest achievements in public health. 

Thank you, Mr. Chairman and members of the Committee, for the opportunity to testify before you today.  I would be happy to answer any questions that you may have.