National Vaccine Injury Compensation Program: Statement of Reasons for Not Conducting Rulemaking Proceedings

AGENCY:

Office of the Secretary, Department of Health and Human Services (HHS).

ACTION:

Denial of petition for rulemaking.

SUMMARY:

In accordance with the Public Health Service Act, notice is hereby given concerning the reasons for not conducting rulemaking proceedings to add autism, asthma, and tics as injuries associated with vaccines to the Vaccine Injury Table (Table). Also, this document provides reasons for not conducting rulemaking proceedings to add Pediatric Infection-Triggered, Autoimmune Neuropsychiatric Disorder (PITAND) and/or Pediatric Autoimmune Neuropsychiatric Syndrome (PANS); Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) as injuries associated with pertussis, pneumococcal conjugate and Haemophilus influenza type b vaccines; and Experimental Autoimmune Encephalomyelitis/Acute Demyelinating Encephalomyelitis as injuries associated with pertussis vaccines to the Table.

DATES:

Written comments are not being solicited.

FOR FURTHER INFORMATION CONTACT:

Dr. Narayan Nair, MD, Director, Division of Injury Compensation Programs (DICP), Healthcare Systems Bureau, Health Resources and Services Administration, 5600 Fishers Lane, Room 8N146B, Rockville, Maryland 20857, or by telephone at 800-338-2382 or by email: VaccineCompensation@hrsa.gov.

SUPPLEMENTARY INFORMATION:

The National Childhood Vaccine Injury Act of 1986 (the Vaccine Act), Title III of Public Law 99-660, as amended (42 U.S.C. 300aa-10 et seq.) established the National Vaccine Injury Compensation Program (VICP) for persons thought to be injured by vaccines. Under this Federal program, petitions for compensation are filed with the United States Court of Federal Claims (Court). The Court, acting through special masters, makes findings as to eligibility for, and amount of, compensation. To gain entitlement to compensation under the VICP for a covered vaccine, a petitioner must establish a vaccine-related injury or death in one of the following ways (unless another cause is found): (1) By proving that the first symptom of an injury or condition, as defined by the Qualifications and Aids to Interpretation, occurred within the time period listed on the Vaccine Injury Table (Table), and, therefore, is presumed to be caused by a vaccine; (2) by proving vaccine causation, if the injury or condition is not on the Table or did not occur within the time period specified on the Table; or (3) by proving that the vaccine significantly aggravated a pre-existing condition.

The Vaccine Act provides for the inclusion of additional vaccines in the VICP when they are recommended by the Centers for Disease Control and Prevention (CDC) for routine administration to children and/or pregnant women. See section 2114(e)(2) and (3) of the PHS Act, 42 U.S.C. 300aa-14(e)(2) and (3). Consistent with section 13632(a)(3) of Public Law 103-66, the regulations governing the VICP provide that such vaccines will be included in the Table as of the effective date of an excise tax to provide funds for the payment of compensation with respect to such vaccines, 42 CFR 100.3(c)(8). The statute establishing the VICP also authorizes the Secretary to create and modify a list of injuries, disabilities, illnesses, conditions, and deaths (and their associated time frames) associated with each category of vaccines included on the Table. See sections 2114(c) and 2114(e)(2) and (3) of the PHS Act, 42 U.S.C. 300aa-14(c) and 300aa-14(e)(2) and (3). Finally, section 2114(c)(2) of the PHS Act, 42 U.S.C. 300aa-14(c)(2) provides that any person, including the Advisory Commission on Childhood Vaccines (the Commission) may petition the Secretary to propose regulations to amend the Vaccine Injury Table. Unless clearly frivolous, or initiated by the Commission, any such petition shall be referred to the Commission for its recommendations. Following receipt of any recommendation of the Commission or 180 days after the date of the referral to the Commission, whichever occurs first, the Secretary shall conduct a rulemaking proceeding on the matters proposed in the petition or publish in the Federal Register a statement or reasons for not conducting such proceeding.

During 2017, private citizens submitted documents to HHS and the Advisory Commission on Childhood Vaccines (Commission) requesting that certain injuries be added to the Table. These documents are considered petitions to the Secretary of HHS to propose regulations to amend the Table to add these injuries associated with vaccines on the Table. Below are summaries of these petitions.

• On April 3, 2017, a private citizen sent an email requesting to add food allergies, asthma and autism as injuries to the Table. The citizen did not specify vaccines associated with these alleged injuries in the petition.
• Letters dated March 16, 2017, and May 4, 2017, sent from a second private citizen requested to add tics as an injury to the Table. The citizen did not specify the vaccine associated with this alleged injury in the petition.
• Two letters dated February 20, 2017, and March 20, 2017, from a third private citizen, requested that the following be added to the Table: Pediatric Infection-Triggered Autoimmune Neuropsychiatric Disorder (PITAND) and/or Pediatric Autoimmune Neuropsychiatric Syndrome (PANS), and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Group A Streptococcal Infections (PANDAS) as injuries associated with pertussis, pneumococcal conjugate, and Haemophilus influenza type b (Hib) vaccines; and Experimental Autoimmune Encephalomyelitis (EAE)/Acute Demyelinating Encephalomyelitis (ADEM) as injuries associated with pertussis vaccines.

Pursuant to the VICP statute, these petitions were referred to the Commission on December 8, 2017. The Commission voted unanimously to recommend that the Secretary not proceed with rulemaking to amend the Table as requested in the petition to add asthma to the Table. The Commission voted 4-1 to recommend that the Secretary not proceed with rulemaking to amend the Table as requested in the other petitions. A petition to add food allergies to the Table was discussed at a previous ACCV meeting and the Commission recommended not to add this injury to the Table at that time. On March 29, 2016, the Secretary of HHS published a Federal Register notice stating reasons for not conducting rulemaking proceedings to add food allergies as an injury associated with vaccines to the Table.

Autism and Asthma

On April 3, 2017, a private citizen sent an email requesting to add food allergies, asthma and autism as injuries to the Table. As mentioned above, the petitioner's request to add food allergies to the Table was previously addressed in a Federal Register notice published on March 29, 2016 (81 FR 17423-01). The requests to add autism and asthma to the Table are discussed below.

Autism

The National Institute of Child Health and Human Development states that autism or autism spectrum disorder (ASD) refers to a group of complex neurodevelopment disorders characterized by repetitive and characteristic patterns of behavior and difficulties with social communication and interaction. The symptoms are present from early childhood and affect daily functioning. The exact cause of ASD is unknown but it is thought that the environment and genetics both play a role. While no specific environmental factors have been definitively identified as causes of ASD, a number of genes have been identified that are associated with ASD. Numerous scientific studies have found that neither vaccines nor vaccine ingredients cause ASD.

To support the claim that autism is caused by vaccines, the petitioner references a non- peer-reviewed article that he wrote and published online. The article does not describe any epidemiologic evidence that vaccines cause autism but refers to another article authored by the petitioner. This article proposed a theory that milk antigens in vaccines can cause autism. No clinical data are provided to support this theory.

The Court considered and denied claims alleging that vaccines cause autism as part of the Omnibus Autism Proceeding (OAP). Starting in 2001, parents began filing petitions for compensation under the VICP, alleging that certain childhood vaccinations might be causing or contributing to autism. Specifically, they alleged that the measles, mumps, and rubella (MMR) vaccines and thimerosal-containing vaccines can combine to cause autism and that thimerosal-containing vaccines alone can cause autism. The Court created the OAP to adjudicate these claims.

By 2010, over 5,600 cases had been filed, and over 5,000 pending cases were divided among the three presiding special masters. In decisions released in 2009 and 2010, and affirmed without exception on appeal, the Court found there is no credible evidence that the MMR vaccines in combination with thimerosal-containing vaccines, or that thimerosal-containing vaccines alone, cause autism. These decisions mirror the current body of scientific evidence, including the 2001 Institute of Medicine (IOM) report, “Immunization Safety Review: Thimerosal-Containing Vaccines and Neurodevelopmental Disorders.”

During 2012, the Institute of Medicine (IOM) published a report, “Adverse Effects of Vaccines: Evidence and Causality,” which reviewed the medical and scientific evidence on vaccines and adverse events to update the Table. The IOM committee concluded, “the evidence favors rejection of a causal relationship between MMR vaccine and autism.” In addition, since the Court's OAP decisions and the IOM's findings, several studies have also found that vaccines are not associated with autism. Furthermore, a number of professional and international organizations have reviewed the evidence and also concluded that there is no association with vaccines and autism. These organizations include: the American Academy of Pediatrics, American Medical Association, American Academy of Family Physicians, Canadian National Advisory Committee on Immunization, and the Department of Health of the United Kingdom. In summary, current scientific evidence does not support a causal association between vaccinations and autism.

Asthma

Asthma is a chronic inflammatory disorder contributing to hyperresponsive airways, decreased airflow, breathing difficulties (such as wheezing and shortness of breath), and disease chronicity. It is thought that asthma develops in individuals who have a combination of certain host and environmental factors. There are several risk factors for developing asthma, including genetic and prenatal factors, lung size in infancy, exposure to environmental factors (i.e., microbial organisms, smoke, and pollution), viral infections, obesity, and atopy (tendency to produce immunoglobulin E (IgE) antibodies). Individuals who develop allergic-type asthma are usually sensitized, or first develop IgE (Immunoglobulin E) antibodies when they come into contact with an allergen through the respiratory route. When they are re-exposed to the sensitized allergen in their airways, IgE antibodies will react and bind to the specific allergen, causing an allergic reaction.

Viral infections trigger up to 85 percent of asthma exacerbations in school-aged children and up to 50 percent of exacerbations in adults and may also contribute to asthma onset. This is likely mediated by IgE. Factors such as exercise, intense emotions, and cold air, among others, can cause an exacerbation through a non-allergic pathway. Atopy, the genetic predisposition for developing an IgE-mediated response to common allergens, is the strongest identifiable predisposing factor for developing asthma.

The petitioner asserts that the injection of food allergen-contaminated vaccines “or pathogen associated vaccine antigens” causes sensitization and subsequently asthma.

To support the theory that vaccines cause asthma, the citizen references a non-peer-reviewed article that he wrote and published online citing 15 references. The individual also provided four additional articles, two of which he wrote and published online without peer review. Three of the latter references did not discuss asthma.

In the article, he asserts that vaccines cause allergy-induced asthma by at least two mechanisms. First, individuals can develop IgE-mediated sensitization by injection of food proteins in vaccines. Second, when they inhale the sensitized food particles, they can suffer asthma symptoms. The petition alleges that individuals can also become sensitized to “pathogen associated vaccine antigens” via IgE. Upon inhalation of these particles, such as influenza viral particles and pertussis bacterial particles, they will develop asthma symptoms. He cites 15 articles to support his theory. However, nine of these articles discuss general immunology, atopic dermatitis, food allergies, and anaphylaxis rather than asthma.

One study referenced by the citizen found children had IgE anti-pertussis antigens after immunization, but no generalized further increase in IgE to food or inhalant antigens to which they were already sensitive. There was no suggestion that IgE to food or bacterial antigens would be a trigger for asthma and the author concluded, “modifications of vaccine formulation aimed at preventing IgE production do not seem warranted.” Another study by Holt et al. found greater increases in IgE in patients immunized with acellular pertussis-containing vaccines compared to those immunized with whole cell pertussis containing vaccines. They suggested that the IgE antibody against those viruses could contribute to the respiratory symptoms during acute infection, but did not discuss the development of chronic asthma. Another study referenced in the citizen's article, Smith-Morowitz et al. found persistence of IgE anti-influenza antibody for 2 years after immunization, suggesting that rather IgE may be associated with protective antibodies.

The citizen also cited a study by Kuno-Sakai et al. This study evaluated whether gelatin in the MMR vaccine caused an acute allergic reaction. MMR, varicella, and some influenza vaccines continue to contain hydrolyzed gelatin, but acute reactions are rare as is the incidence of gelatin allergy in the general population, suggesting that vaccines are not a likely cause of widespread allergy to gelatin. No evidence was provided that inhalation of gelatin causes asthma.

The 2012 IOM report reviewed asthma exacerbation or reactive airway disease episodes in children and adults after inactivated influenza vaccine, and asthma exacerbation/reactive airway disease episodes, in both children younger than 5 years of age and in persons 5 years of age or older after live attenuated influenza vaccine (LAIV). The IOM reached the following conclusions:

• The evidence favors a rejection of a causal relationship between inactivated influenza vaccine and asthma exacerbation or reactive airway disease episodes in children and adults;
• The evidence is inadequate to accept or reject a causal relationship between LAIV and asthma exacerbation or reactive airway disease episodes in children younger than 5 years of age; and
• The evidence is inadequate to accept or reject a causal relationship between LAIV and asthma exacerbation or reactive airway disease episodes in persons 5 years of age or older.

The IOM did not evaluate evidence regarding a causal association between other vaccines and asthma. Aside from influenza vaccines, the IOM does not comment on the strength of the epidemiologic or mechanistic evidence regarding asthma and vaccination. Therefore, the IOM report does not support the petitioner's position for adding asthma to the Table for the influenza vaccine.

In addition to assessing the evidence submitted in the petition, HHS assessed expert reviews pertinent to asthma etiology. During 2007, the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health published, “Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma: Clinical Practice Guidelines.” A panel consisting of 18 experts commissioned by the National Asthma Education and Prevention Program Coordinating Committee and coordinated by the NHLBI developed this report. It discusses the causes of asthma, but vaccines are not considered as a potential cause. Additional expert reviews on the etiology of asthma published in the literature do not mention vaccines as a risk factor or potential risk factor.

In addition to considering submitted evidence, HHS conducted a literature search of major medical databases for any articles linking vaccination and the development of asthma, specifically, reviewing numerous studies published during 2000 or later in peer-reviewed English language publications, which directly or tangentially evaluated the development of asthma after vaccination.

The majority of the reviewed articles found no potential causality between vaccinations covered by the VICP and the development of asthma. The search did not identify any peer-reviewed articles that evaluated or discussed the possible role of food allergen contaminated vaccines or “pathogen associated vaccine antigens” in the development or exacerbation of asthma. Vaccines studied in the published articles included diphtheria, pertussis, and tetanus (DPT), MMR, measles, oral polio virus (OPV), Prevnar 13, Hib, and Hepatitis B. Fifteen studies found no association between vaccinations and asthma. Some studies found a protective effect suggesting that asthma risk was reduced with vaccination.

Three studies had mixed results with two of them possibly having confounding variables. A study by Laubereau showed Hib-vaccinated children had a slightly higher risk for asthma. The authors of the study stated, “results have to be interpreted with caution. Biological evidence to support a causal association is not available.” Some of the questions the authors posed regarding the results dealt with the validity of parental reports and possible recall bias.

A study by Benke, et al. of 3,200 22-44 year old individuals in Australia showed no difference in the risk of asthma among subjects who received DTP, Hepatitis B, measles, MMR, and OPV. However, an analysis of individuals who had received all three MMR, OPV and DTP vaccines showed an increased risk of asthma. Authors state there is “relatively weak support . . . (that) vaccinations may lead to increased risk of asthma, but caution is advised due to possible recall bias.” They write that typically studies of young adults who self-report vaccination histories may be subject to significant recall bias. In this study, childhood vaccination was based entirely on subject recall. In addition, as noted by the authors, associations for atopy and vaccinations appeared consistently weak for all vaccines investigated. Since atopic asthma has a strong association with atopy, this also does not suggest that vaccines led to the increase in asthma.

A study by Thomson, et al. demonstrated conflicting results. OPV and MMR vaccines decreased the risk of asthma at age 2, and OPV decreased the risk of asthma at age 6. Also, the diphtheria and tetanus (DT) vaccine that was administered in the first year of life increased the risk of asthma at 6 years. However, this study had significant limitations. Nearly 21 percent of the subjects were lost to follow-up. Only children with a previous reaction to DPT vaccine were given DT suggesting that this may be an at-risk group. In addition, there was a small sample size and there was no control group.

Another study by McDonald, et al. demonstrated an association between timing of DPT receipt and risk of asthma. This study consisted of 11,531 children born in Manitoba during 1995 who received at least four doses of DPT. The researchers looked at timing of vaccine receipt and the development of asthma and found that delaying the first dose of DPT by greater than 2 months decreased risk of asthma by 50 percent. They identified several potential confounding factors, including the fact that the reason for immunization delay was unknown. Children without asthma may visit a physician less often with fewer opportunities to be vaccinated. This may lead to self-selection. Also, there was not a comparison control (unvaccinated) group.

In summary, current scientific evidence does not support a causal association between vaccinations and asthma. There is no evidence that vaccination leads to IgE antibody against the most common causes of wheezing in childhood, namely respiratory syncytial virus, and human rhinovirus. There is no evidence that individuals develop IgE sensitization by injection of food proteins in vaccines and that subsequent inhalation of these particles causes symptoms of asthma. There is no evidence that inhalation of vaccine antigens triggers asthma symptoms via an IgE mechanism. Although some studies show a possible association with asthma, these have significant lapses in methodology. The majority of studies show no association.

Tics

On March 16, 2017, and May 4, 2017, a private citizen submitted letters to HHS requesting that tics be added to the Table. The petitioner claims that two CDC employees have been quoted as believing there is evidence that vaccines can cause tics; neither the CDC nor the CDC employees have verified these comments. The petitioner mentions a study by Barile and Thompson in support of his request. The petitioner did not specify vaccine type or differentiate between thimerosal-containing versus thimerosal-free vaccines.

Tics are defined as sudden, rapid, recurrent, non-rhythmic, stereotyped motor movement or vocalization. They are involuntary, but can be suppressed for varying lengths of time and are markedly diminished during sleep. The onset of tics almost always occur in childhood with multiple tics and complex vocal sounds developing over time, usually peaking in severity by 10-12 years of age. The precise etiology of tics is not known, but it is thought to be due to chemical abnormalities in the brain. The risk of developing tics and the prognosis are influenced by temperamental, environmental, genetic, and physiological factors. Diagnosis of tic disorders is hierarchical and complex. Therefore, specialists typically diagnose tics and tic disorders.

The petition mentions a study by Barile without a citation. Presumably, this is the study published in the Journal of Pediatric Psychology in 2012. The study's “objective was to examine associations between thimerosal-containing vaccines and immunoglobulins early in life and neuropsychological outcomes evaluated at children aged 7-10 years.” The study population was 1,047 children ages 7-10, born between January 1993 and March 1997. The evaluators measured seven neuropsychological outcomes during a 3-hour testing period with the child including the following: (1) Intellectual functioning, (2) speech and language, (3) verbal memory, (4) executive functioning, (5) fine motor coordination, (6) tics, and (7) behavior regulation. The authors found no statistically significant associations between thimerosal exposure from vaccines early in life in six of the seven outcomes. There was a small, statistically significant association between early thimerosal exposure and the presence of tics in boys. However, the authors concluded that this finding should be interpreted with caution because of limitations in the measurement of tics and also the limited biological plausibility regarding a causal relationship. The authors suggested additional studies were needed to examine these associations using more reliable and valid measure of tics.

There are several significant limitations of the Barile study. The only training the evaluators received for tics assessment was based on a 30-minute video on the diagnosis of Tourette syndrome from 1989 and may not have been sufficient to adequately diagnose the subjects. These raters were not required to meet any criteria for skill or reliability criteria. This could have led to misdiagnosis of the study subjects. The parent's assessment of the presence or absence of tics was not concordant with the assessor's reports. The study does not provide the parents' assessment of tics. However, positive presence of tics from parent's report and the assessor's report of tics agreed only 23% of the time for motor tics and 16% of the time for phonic tics. Thus, this outcome of interest, tics, was either not noticed by, or is not consistent with, behaviors that would be observed by or concerning to parents. The response rate was low—only 30 percent of invitees agreed to participate.

The petition did not specify vaccine type or if the vaccines of concern were thimerosal-containing or not. However, according to the citizen, the Barile study mentioned in the petition specifically focused on thimerosal-containing vaccines. Thimerosal is a mercury-based preservative that is broken down into ethyl mercury after entering the body. The low levels of ethyl mercury in vaccines are broken down by the body differently and clear out of the blood more quickly than methylmercury. There is no evidence of harm caused by low doses of thimerosal in vaccines, except for minor reactions like redness and swelling at the injection site. Multi-dose FDA-approved seasonal influenza vaccines contain thimerosal as a preservative however, single-dose presentations that do not contain thimerosal as a preservative are available for use in infants, children, adults, the elderly and pregnant women. All other vaccines routinely recommended for children 6 years of age or younger and marketed in the U.S. do not contain thimerosal. MMR vaccines do not and never did contain thimerosal. Varicella (chickenpox), inactivated polio (IPV), and pneumococcal conjugate vaccines have also never contained thimerosal. There are numerous studies and independent reviews supporting the safe use of thimerosal in vaccines.

An initial literature search was performed looking for articles on tics by the two CDC employees mentioned in the petition, Dr. Thompson and Dr. Yeargin-Allsop. There are two additional studies related to tics that involved Dr. Thompson. One article examined early thimerosal exposure and neuropsychological outcomes in children aged 7-10 and did not find an association between tics and vaccinations containing thimerosal. The second article by Iqbal et al. was designed to evaluate the association between antibody-stimulating proteins and polysaccharides from early childhood vaccines and neuropsychological outcomes at age 7-10 years. There were no adverse associations between antigens through vaccines in the first 2 years of life and neuropsychological outcomes, including tics in later childhood.

HHS conducted a comprehensive literature review of the major medical databases to search for articles linking tics/tic disorders to vaccinations that do not contain thimerosal. There is a paucity of literature on tics/tic disorders as a result of vaccinations. Leslie, et al. authored one article that discussed tics. The objective of this study was to examine whether antecedent vaccinations are associated with increased incidence of obsessive compulsive disorder (OCD), anorexia nervosa, anxiety disorder, chronic tic disorder, attention deficit hyperactivity disorder, major depressive disorder, and bipolar disorder. Using claims data, the investigators compared the prior year's occurrence of vaccinations in children and adolescents with the above neuropsychiatric disorders that were newly-diagnosed between January 2002 and December 2002, as well as two control conditions (broken bones and open wounds). The investigators found children with OCD, anorexia nervosa, anxiety disorder, and tic disorder were more likely to have received influenza vaccine during the preceding 1-year period. They concluded that the onset of some neuropsychiatric disorders may be temporally-related to prior vaccinations, but stated it does not prove a causal role of vaccinations in the etiology of these conditions.

This study had several limitations. It relied on administrative retrospective data rather than systematically obtained clinical data. Therefore, diagnostic misclassification may have occurred. The dates in which individuals were diagnosed do not indicate disease onset dates, which may suggest a temporal association where none exists. In addition, the control groups may not be similar enough to the disease groups. Furthermore, the influenza vaccine is given annually and is the most frequently administered vaccine. By chance, there may be many diagnoses made within a year of flu vaccination. Thus, this case-control study provides no more than a temporal association and does not give an absolute risk.

In summary, there is limited literature on tics/tic disorders and vaccinations. Childhood vaccines do not contain thimerosal and influenza vaccines have thimerosal-free formulations. Current scientific evidence does not support a causal association between thimerosal-containing or thimerosal-free vaccinations and tics/tic disorders.

PANS, PITAND, PANDAS, EAE, and ADEM

On February 20, 2017, and March 20, 2017, a private citizen submitted written petitions requesting HHS to add PANS, PITAND, PANDAS, EAE, and ADEM to the Table. The petitions assert that certain components in pertussis vaccines cause the development of PANS and/or PITAND and conjugate and polysaccharide pneumococcal vaccines and Hib vaccines cause or enable the development of PANS and/or PANDAS. However, not all pneumococcal vaccines are covered by the VICP. There are two types of pneumococcal vaccines given in the U.S. The pneumococcal conjugate vaccine (PCV13), which is administered routinely to infants and children up to age 5, and the pneumococcal polysaccharide vaccine (PPV23), which is given to adults age 65 and older and individuals of varying age with certain medical conditions making them at higher risk for pneumococcal infection. Since December 18, 1999, the VICP has covered only the pneumococcal conjugate vaccine (PCV13).

PANS, PITAND, and PANDAS

PANS, PITAND, and PANDAS are proposed conditions based on a concept that an immune basis may underlie and may trigger disorders associated with movement and behavioral abnormalities. A hypothesis is that “neuropsychiatric syndromes may result from various etiologies, including hereditary, environmental, and inflammatory causes.” It has been hypothesized that infections with group A streptococcus (GAS) and others may trigger autoimmune responses that can cause or exacerbate childhood-onset OCD or tic disorders (including Tourette syndrome). A theory proposed is that antibodies against GAS cross-react with brain antigens by molecular mimicry resulting in autoantibody-mediated neuronal cell signaling in susceptible hosts. Initially researchers coined the term PANDAS and later this was modified to PANS. Neither PITAND, PANS, nor PANDAS are officially recognized disease entities and do not have diagnostic codes in either: (a) International Statistical Classification of Diseases and Related Health Problems (ICD-10, most recent revision, 2010); or (b) Diagnostic and Statistical Manual of Mental Disorders (DSM-V; most recent revision, 2013).

The diagnostic criteria proposed for PANS include abrupt onset of symptoms of OCD or food restriction (anorexia) plus two of the following:

• Anxiety, emotional lability and/or depression, irritability, aggression and/or severely oppositional behaviors, behavioral (developmental) regression, deterioration in school performance, sensory or motor abnormalities, somatic signs and symptoms (e.g., sleep disturbances, enuresis, urinary frequency); and
• Symptoms not better explained by a known neurologic or medical disorder.

To support the claim that PANS and/or PITAND are caused by pertussis-containing vaccines, the petition outlines a mechanism of molecular mimicry and autoantibody-mediated neuronal cell-signaling leading to symptoms. To support the claim that PANS and/or PANDAS are caused or enabled by pneumococcal and Hib vaccines, the petition outlines a mechanism of injury in which vaccination with pneumococcal/Hib vaccines results in disruption of the blood-brain barrier in a susceptible child, which then allows circulating GAS antibodies to enter the central nervous system (CNS). This results in cross-reactivity between GAS antibodies and CNS structures, which leads to symptoms of PANS/PANDAS.

The 2012 IOM report did not review any possible association between pertussis-containing vaccines or any vaccine and PANS and/or PITAND, nor did it review any possible association between pneumococcal conjugate vaccines and Hib vaccines or any vaccine and PANS and/or PANDAS. HHS gathered data from the existing medical literature in addition to the evidence submitted in the petition. A literature search of the major medical databases was conducted searching for any articles linking the development of PANS, PITAND, or PANDAS to vaccinations, including pertussis-component, pneumococcal conjugate, and Hib vaccines.

Despite an extensive search of peer-reviewed English language publications, HHS did not find any published research addressing any linkages, potential causality, or enablement between vaccinations covered by the VICP, including pertussis-containing, pneumococcal conjugate, and Hib vaccinations, and the development of PANS, PITAND, and/or PANDAS in any population. There are no published data on PANS and PITAND regarding possible specific infectious or non-infectious triggers and autoimmune mechanisms. Data on the more well-studied PANDAS are conflicting. Some researchers question the autoimmune mechanism of PANDAS and no specific autoimmune antibody is agreed upon as a pathogenic mechanism for its symptoms.

After an extensive literature search, HHS has not found any published study that examines anti-neuronal antibodies in children suspected of PANS or PITAND following pertussis infection or following pertussis immunization. HHS has not found any studies that examine whether pneumococcal conjugate vaccines or pneumococcal infections and Hib vaccines or Hib infections disrupt the filtering mechanism of the blood-brain barrier to allow circulating GAS antibodies to cross into the CNS in a susceptible child and, once across the barrier, to react with CNS structures to generate neuropsychiatric symptoms. In addition, HHS is not aware of any published studies concluding that PANS, PITAND, and/or PANDAS are caused by pertussis infection or pertussis, pneumococcal conjugate or Hib vaccines.

EAE and ADEM

EAE is not a clinical diagnosis. EAE is an animal model of autoimmune disease of the CNS. As EAE does not occur in humans, it will not be discussed separately from the human diseases (which are discussed below). Pertussis toxin has been used in EAE studies due to its immunogenicity (ability to evoke an immune response). However, acellular pertussis vaccines are formulated to contain inactivated pertussis toxin and not pertussis toxin that is used in animal models of EAE.

Encephalopathy is currently an injury on the Table for vaccines containing whole cell pertussis bacteria, extracted or partial cell pertussis bacteria, or specific pertussis antigen, and vaccines containing measles, mumps, and rubella virus or any of its components. ADEM can have encephalopathy as a symptom, but ADEM and encephalopathy are two distinct conditions. The autoimmune etiology is specific for ADEM and the onset between primary exposure and development of primary antibody response is 7-10 days as opposed to 0-72 hours for the onset to meet the Table definition for encephalopathy. The time period for development of ADEM is outside the 0-72 hour time period of the Table definition for acellular pertussis vaccine and encephalopathy and encephalitis. With ADEM, there is a characteristic demyelination in the CNS and a strong association with prodromal (infectious) illness that is absent in an encephalopathy as defined in the Table. These differences were significant enough that the IOM 2012 Report considered ADEM separate from encephalopathy and encephalitis.

Multiple articles were submitted by the petitioner in support of adding ADEM/EAE to the Table. However, the studies dealing with EAE do not have relevance to pertussis vaccinations and/or ADEM. These studies do not provide any evidence that pertussis vaccinations cause ADEM.

The IOM reviewed the epidemiologic and mechanistic evidence as to whether pertussis vaccinations cause ADEM. They found the evidence inadequate to accept or reject a causal relationship between pertussis-containing vaccines and ADEM. HHS conducted a review of the literature published after the IOM report regarding ADEM and vaccination. A paper by Baxter et al. identified all cases of ADEM in the Vaccine Safety Datalink (VSD). The VSD is a collaborative project between CDC and eight health care organizations that utilizes electronic health data to monitor the safety of vaccines. The VSD study analyzed 64 million vaccine doses and calculated the risk difference of being diagnosed with ADEM for each vaccine. This study revealed two cases of ADEM after Tdap (tetanus, diphtheria, and acellular pertussis) vaccination. The study was limited with regard to assessing causality due to the small number of ADEM cases. It is also possible this finding could be due to chance alone due to multiple testing. Multiple testing refers to any instance that involves the simultaneous testing of several hypotheses.

Another study by Chang that analyzed post-licensure safety for diphtheria and acellular pertussis vaccines found no statistically significant adverse events including ADEM. A study by Pellegrino looked at the onset of ADEM utilizing a post-marketing study from the U.S. and Europe. The investigators found a decrease in the diagnosis of ADEM in individuals who received DTaP, IPV, and Hib vaccines. In summary, EAE is not a disease in humans but rather an experimental model. The Table only lists conditions found in humans. In addition, the current literature does not support a relationship between vaccines and ADEM.

Conclusion

In light of the above, HHS has determined that there is no reliable scientific evidence of an association between vaccines and asthma, autism, tics, PITAND, PANS, PANDAS, EAE, and/or ADEM. Therefore, HHS will not add them as injuries associated with any vaccine on the Table at this time.