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coating removal to professional users in Environmental Defense Fund. EPA–HQ– effects on children pursuant to the UK, given the requirements for OPPT–2016–0231–0912. Executive Order 13045, entitled limited access that are in place there? 6. Public Comment. DoD Comments on MeCl ‘‘Protection of Children from and NMP 19 Jan 17 Notice of Proposed Environmental Health Risks and Safety IV. Request for Comment and Rulemaking Methylene Chloride and N- Risks’’ (62 FR 19885, April 23, 1997); or Additional Information Methylpyrrolidone; Rulemaking under TSCA Section 6(a). EPA–HQ–OPPT– to consider human health or EPA is seeking comment on all 2016–0231–0519. environmental effects on minority or information outlined in this ANPRM 7. Halogenated Solvents Industry Alliance. low-income populations pursuant to and any other information, which may Responsibly Regulating Methylene Executive Order 12898, entitled not be included in this notice, but Chloride in Paint Removal Products: an ‘‘Federal Actions to Address which you believe is important for EPA Alternative Approach to Flawed Environmental Justice in Minority to consider. Proposal Published by EPA on January Populations and Low-Income EPA specifically invites public 19, 2017. Populations’’ (59 FR 7629, February 16, comment and any additional 8. EPA. How to Get Certified as a Pesticide 1994). Applicator. https://www.epa.gov/ information in response to the questions The Agency will consider such and issues identified in Unit III. pesticide-worker-safety/how-get- certified-pesticide-applicator. Accessed comments during the development of Instructions for providing written December 18, 2018. any subsequent proposed rule as it takes comments are provided under 9. REACH Restriction. Annex XVII to appropriate steps to address any ADDRESSES, including how to submit REACH—Conditions of restriction. Entry applicable requirements. any comments that contain CBI. No one 59 Dichloromethane containing Paint is obliged to respond to these questions, Strippers. https://echa.europa.eu/ List of Subjects in 40 CFR Part 751 and anyone may submit any information documents/10162/0ea58491-bb76-4a47- Environmental protection, Chemicals, and/or comments in response to this b1d2-36faa1e0f290 (Accessed December Export notification, Hazardous request, whether or not it responds to 18, 2018). substances, Import certification, every question in this notice. 10. The Reach Enforcement (Amendment) Methylene chloride, Recordkeeping. Regulations 2014 (SI 2014/2882). http:// V. References www.legislation.gov.uk/uksi/2014/2882/ Dated: March 15, 2019. made. Andrew Wheeler, The following is a listing of the 11. EPA. Economic Analysis of Final Rule Administrator. documents that are specifically TSCA Section 6 Action on Methylene [FR Doc. 2019–05865 Filed 3–26–19; 8:45 am] referenced in this document. The docket Chloride in Paint and Coating Removal includes these documents and other (EPA Docket EPA–HQ–OPPT–2016– BILLING CODE 6560–50–P information considered by EPA, 0231; RIN 2070–AK07). Office of including documents referenced within Pollution Prevention and Toxics. the documents that are included in the Washington, DC. DEPARTMENT OF HEALTH AND HUMAN SERVICES docket, even if the referenced document VI. Statutory and Executive Order is not physically located in the docket. Reviews For assistance in locating these other 42 CFR Part 100 documents, please consult the technical Under Executive Order 12866 (58 FR 51735, October 4, 1993) and Executive National Vaccine Injury Compensation person listed under FOR FURTHER Program: Statement of Reasons for INFORMATION CONTACT. Order 13563 (76 FR 3821, January 21, 2011), this action was submitted to the Not Conducting Rulemaking 1. EPA. TSCA Work Plan Chemicals. http:// Office of Management and Budget Proceedings www.epa.gov/sites/production/files/ 2014-02/documents/work_plan_ (OMB) for review. Any changes made in AGENCY: Office of the Secretary, chemicals_web_final.pdf. Retrieved response to OMB recommendations Department of Health and Human February 25, 2016. have been documented in the docket. Services (HHS). 2. EPA. TSCA Work Plan Chemical Risk Since this document does not impose ACTION: Denial of petition for Assessment Methylene Chloride: Paint or propose any requirements, and rulemaking. Stripping Use. CASRN 75–09–2. EPA instead seeks comments and suggestions Document# 740–R1–4003. August 2014. for the Agency to consider in possibly SUMMARY: In accordance with the Public Office of Chemical Safety and Pollution Prevention. Washington, DC. https:// developing a subsequent proposed rule, Health Service Act, notice is hereby www.epa.gov/sites/production/files/ the various other review requirements given concerning the reasons for not 2015-09/documents/dcm_ that apply when an agency imposes conducting rulemaking proceedings to opptworkplanra_final.pdf. requirements do not apply to this add autism, asthma, and tics as injuries 3. EPA. Summary of Stakeholder action. Nevertheless, as part of your associated with vaccines to the Vaccine Engagement, Proposed Rule Under TSCA comments on this document, you may Injury Table (Table). Also, this § 6 Methylene Chloride and NMP in include any comments or information document provides reasons for not Paint and Coating Removal. 2016. that you have regarding the various conducting rulemaking proceedings to 4. EPA. Final Report of the Small Business Advocacy Review Panel on EPA’s other review requirements. add Pediatric Infection-Triggered, Planned Proposed Rule on the Toxic In particular, EPA is interested in any Autoimmune Neuropsychiatric Disorder Substances Control Act (TSCA) Section information that could help the Agency (PITAND) and/or Pediatric Autoimmune 6(a) as amended by the Frank R. to assess the potential impact of a rule Neuropsychiatric Syndrome (PANS); Lautenberg Chemical Safety for the 21st on small entities pursuant to the Pediatric Autoimmune Century Act for Methylene Chloride and Regulatory Flexibility Act (RFA) (5 Neuropsychiatric Disorders Associated N-Methylpyrrolidone (NMP) in Paint U.S.C. 601 et seq.); to consider with Streptococcal Infections (PANDAS) Removers. Office of Chemical Safety and voluntary consensus standards pursuant as injuries associated with pertussis, Pollution Prevention. Washington, DC. 2016. to section 12(d) of the National pneumococcal conjugate and 5. Public Comment. Comments submitted by Technology Transfer and Advancement Haemophilus influenza type b vaccines; Lindsay McCormick, Chemicals and Act (NTTAA) (15 U.S.C. 272 note); to and Experimental Autoimmune Health Project Manager, on behalf of consider environmental health or safety Encephalomyelitis/Acute Demyelinating

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Encephalomyelitis as injuries associated 2114(e)(2) and (3) of the PHS Act, 42 proceed with rulemaking to amend the with pertussis vaccines to the Table. U.S.C. 300aa–14(c) and 300aa–14(e)(2) Table as requested in the petition to add DATES: Written comments are not being and (3). Finally, section 2114(c)(2) of the asthma to the Table. The Commission solicited. PHS Act, 42 U.S.C. 300aa–14(c)(2) voted 4–1 to recommend that the FOR FURTHER INFORMATION CONTACT: Dr. provides that any person, including the Secretary not proceed with rulemaking Narayan Nair, MD, Director, Division of Advisory Commission on Childhood to amend the Table as requested in the Injury Compensation Programs (DICP), Vaccines (the Commission) may petition other petitions. A petition to add food Healthcare Systems Bureau, Health the Secretary to propose regulations to allergies to the Table was discussed at Resources and Services Administration, amend the Vaccine Injury Table. Unless a previous ACCV meeting and the 5600 Fishers Lane, Room 8N146B, clearly frivolous, or initiated by the Commission recommended not to add Rockville, Maryland 20857, or by Commission, any such petition shall be this injury to the Table at that time. On telephone at 800–338–2382 or by email: referred to the Commission for its March 29, 2016, the Secretary of HHS [email protected]. recommendations. Following receipt of published a Federal Register notice any recommendation of the Commission stating reasons for not conducting SUPPLEMENTARY INFORMATION: The National Childhood Vaccine Injury Act or 180 days after the date of the referral rulemaking proceedings to add food to the Commission, whichever occurs allergies as an injury associated with of 1986 (the Vaccine Act), Title III of 1 Public Law 99–660, as amended (42 first, the Secretary shall conduct a vaccines to the Table. rulemaking proceeding on the matters U.S.C. 300aa–10 et seq.) established the Autism and Asthma proposed in the petition or publish in National Vaccine Injury Compensation the Federal Register a statement or On April 3, 2017, a private citizen Program (VICP) for persons thought to reasons for not conducting such sent an email requesting to add food be injured by vaccines. Under this proceeding. allergies, asthma and autism as injuries Federal program, petitions for During 2017, private citizens to the Table. As mentioned above, the compensation are filed with the United submitted documents to HHS and the petitioner’s request to add food allergies States Court of Federal Claims (Court). Advisory Commission on Childhood to the Table was previously addressed The Court, acting through special Vaccines (Commission) requesting that in a Federal Register notice published masters, makes findings as to eligibility certain injuries be added to the Table. on March 29, 2016 (81 FR 17423–01). for, and amount of, compensation. To These documents are considered The requests to add autism and asthma gain entitlement to compensation under petitions to the Secretary of HHS to to the Table are discussed below. the VICP for a covered vaccine, a propose regulations to amend the Table Autism petitioner must establish a vaccine- to add these injuries associated with related injury or death in one of the vaccines on the Table. Below are The National Institute of Child Health following ways (unless another cause is summaries of these petitions. and Human Development states that found): (1) By proving that the first • On April 3, 2017, a private citizen autism or autism spectrum disorder symptom of an injury or condition, as sent an email requesting to add food (ASD) refers to a group of complex defined by the Qualifications and Aids allergies, asthma and autism as injuries neurodevelopment disorders to Interpretation, occurred within the to the Table. The citizen did not specify characterized by repetitive and time period listed on the Vaccine Injury vaccines associated with these alleged characteristic patterns of behavior and Table (Table), and, therefore, is injuries in the petition. difficulties with social communication presumed to be caused by a vaccine; (2) • Letters dated March 16, 2017, and and interaction. The symptoms are by proving vaccine causation, if the May 4, 2017, sent from a second private present from early childhood and affect injury or condition is not on the Table citizen requested to add tics as an injury daily functioning.2 The exact cause of or did not occur within the time period to the Table. The citizen did not specify ASD is unknown but it is thought that specified on the Table; or (3) by proving the vaccine associated with this alleged the environment and genetics both play that the vaccine significantly aggravated injury in the petition. a role. While no specific environmental a pre-existing condition. • Two letters dated February 20, factors have been definitively identified The Vaccine Act provides for the 2017, and March 20, 2017, from a third as causes of ASD, a number of genes inclusion of additional vaccines in the private citizen, requested that the have been identified that are associated VICP when they are recommended by following be added to the Table: with ASD.3 Numerous scientific studies the Centers for Disease Control and Pediatric Infection-Triggered have found that neither vaccines nor Prevention (CDC) for routine Autoimmune Neuropsychiatric Disorder vaccine ingredients cause ASD.456 administration to children and/or (PITAND) and/or Pediatric Autoimmune To support the claim that autism is pregnant women. See section 2114(e)(2) Neuropsychiatric Syndrome (PANS), caused by vaccines, the petitioner and (3) of the PHS Act, 42 U.S.C. 300aa– and Pediatric Autoimmune 14(e)(2) and (3). Consistent with section Neuropsychiatric Disorders Associated 1 81 FR 17423 (Mar. 29, 2016); https:// 13632(a)(3) of Public Law 103–66, the with Group A Streptococcal Infections www.gpo.gov/fdsys/pkg/FR-2016-03-29/pdf/2016- 06666.pdf. regulations governing the VICP provide (PANDAS) as injuries associated with 2 National Institutes of Health, About Autism, that such vaccines will be included in pertussis, pneumococcal conjugate, and https://www.nichd.nih.gov/health/topics/autism/ the Table as of the effective date of an Haemophilus influenza type b (Hib) conditioninfo/Pages/default.aspx (accessed May 3, excise tax to provide funds for the vaccines; and Experimental 2018). 3 payment of compensation with respect Autoimmune Encephalomyelitis (EAE)/ National Institutes of Health, ‘‘Autism Spectrum Disorder Fact Sheet,’’ https://www.ninds.nih.gov/ to such vaccines, 42 CFR 100.3(c)(8). Acute Demyelinating Encephalomyelitis Disorders/Patient-Caregiver-Education/Fact-Sheets/ The statute establishing the VICP also (ADEM) as injuries associated with Autism-Spectrum-Disorder-Fact-Sheet#3082 5 authorizes the Secretary to create and pertussis vaccines. (accessed May 3, 2018). modify a list of injuries, disabilities, Pursuant to the VICP statute, these 4 https://www.cdc.gov/vaccinesafety/concerns/ illnesses, conditions, and deaths (and petitions were referred to the autism.html. 5 https://www.cdc.gov/ncbddd/autism/ their associated time frames) associated Commission on December 8, 2017. The research.html. with each category of vaccines included Commission voted unanimously to 6 https://effectivehealthcare.ahrq.gov/topics/ on the Table. See sections 2114(c) and recommend that the Secretary not vaccine-safety/research.

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references a non- peer-reviewed article autism.91011 Furthermore, a number of mediated response to common that he wrote and published online.7 professional and international allergens, is the strongest identifiable The article does not describe any organizations have reviewed the predisposing factor for developing epidemiologic evidence that vaccines evidence and also concluded that there asthma. cause autism but refers to another article is no association with vaccines and The petitioner asserts that the authored by the petitioner. This article autism. These organizations include: the injection of food allergen-contaminated proposed a theory that milk antigens in American Academy of Pediatrics, vaccines ‘‘or pathogen associated vaccines can cause autism. No clinical American Medical Association, vaccine antigens’’ causes sensitization data are provided to support this theory. American Academy of Family and subsequently asthma. The Court considered and denied Physicians, Canadian National Advisory To support the theory that vaccines claims alleging that vaccines cause Committee on Immunization, and the cause asthma, the citizen references a autism as part of the Omnibus Autism Department of Health of the United non-peer-reviewed article that he wrote Proceeding (OAP). Starting in 2001, Kingdom. In summary, current scientific and published online citing 15 parents began filing petitions for evidence does not support a causal references.12 The individual also compensation under the VICP, alleging association between vaccinations and provided four additional articles, two of that certain childhood vaccinations autism. which he wrote and published online 13 14 15 16 might be causing or contributing to Asthma without peer review. Three of autism. Specifically, they alleged that the latter references did not discuss the measles, mumps, and rubella (MMR) Asthma is a chronic inflammatory asthma. vaccines and thimerosal-containing disorder contributing to In the article, he asserts that vaccines vaccines can combine to cause autism hyperresponsive airways, decreased cause allergy-induced asthma by at least and that thimerosal-containing vaccines airflow, breathing difficulties (such as two mechanisms. First, individuals can alone can cause autism. The Court wheezing and shortness of breath), and develop IgE-mediated sensitization by created the OAP to adjudicate these disease chronicity. It is thought that injection of food proteins in vaccines. claims. asthma develops in individuals who Second, when they inhale the sensitized By 2010, over 5,600 cases had been have a combination of certain host and food particles, they can suffer asthma filed, and over 5,000 pending cases were environmental factors. There are several symptoms. The petition alleges that divided among the three presiding risk factors for developing asthma, individuals can also become sensitized special masters. In decisions released in including genetic and prenatal factors, to ‘‘pathogen associated vaccine lung size in infancy, exposure to 2009 and 2010, and affirmed without antigens’’ via IgE. Upon inhalation of environmental factors (i.e., microbial exception on appeal, the Court found these particles, such as influenza viral organisms, smoke, and pollution), viral there is no credible evidence that the particles and pertussis bacterial infections, obesity, and atopy (tendency MMR vaccines in combination with particles, they will develop asthma to produce immunoglobulin E (IgE) thimerosal-containing vaccines, or that symptoms. He cites 15 articles to antibodies). Individuals who develop thimerosal-containing vaccines alone, support his theory. However, nine of allergic-type asthma are usually cause autism. These decisions mirror these articles discuss general sensitized, or first develop IgE the current body of scientific evidence, immunology, atopic dermatitis, food (Immunoglobulin E) antibodies when including the 2001 Institute of Medicine they come into contact with an allergen 12 (IOM) report, ‘‘Immunization Safety through the respiratory route. When Arumugham, ‘‘Medical muddles that maim our Review: Thimerosal-Containing children with allergies, asthma and autism.’’ they are re-exposed to the sensitized 13 Vaccines and Neurodevelopmental Vinu Arumugham, ‘‘Strong protein sequence 8 allergen in their airways, IgE antibodies alignment between autoantigens involved in Disorders.’’ will react and bind to the specific maternal autoantibody related autism and vaccine During 2012, the Institute of Medicine antigens,’’ ResearchGate, May 2017, https:// allergen, causing an allergic reaction. _ (IOM) published a report, ‘‘Adverse Viral infections trigger up to 85 www.researchgate.net/profile/Vinu Arumugham/ Effects of Vaccines: Evidence and publication/316785758_Strong_protein_sequence_ percent of asthma exacerbations in alignment_between_autoantigens_involved_in_ Causality,’’ which reviewed the medical school-aged children and up to 50 maternal_autoantibody_related_autism_and_ and scientific evidence on vaccines and percent of exacerbations in adults and vaccine_antigens/links/59115a620f7e9bf adverse events to update the Table. The may also contribute to asthma onset. a06d43d5e/Strong-protein-sequence-alignment- IOM committee concluded, ‘‘the between-autoantigens-involved-in-maternal- This is likely mediated by IgE. Factors autoantibody-related-autism-and-vaccine-antigens. evidence favors rejection of a causal such as exercise, intense emotions, and pdf?origin=publication_list (accessed May 3, 2018). relationship between MMR vaccine and cold air, among others, can cause an 14 Vinu Arumugham, ‘‘Significant protein autism.’’ In addition, since the Court’s exacerbation through a non-allergic sequence alignment between Saccharomyces OAP decisions and the IOM’s findings, Cerevisiae Proteins (a Vaccine Contaminant) and pathway. Atopy, the genetic Systemic Lupus Erythematosus Associated several studies have also found that predisposition for developing an IgE- Epitopes,’’ ResearchGate, May 2017, https://www. vaccines are not associated with google.com/search?q=Significant+protein+ 9 Shahed Iqbal, John P. Barile, William W. sequence+alignment+between+Saccharomyces+ 7 Vinu Arumugham, ‘‘Medical muddles that maim Thompson, Frank DeStefano, ‘‘Number of antigens Cerevisiae+Proteins+%28a+Vaccin e+ our children with allergies, asthma and autism,’’ in early childhood vaccines and neuropsychological Contaminant%29+and+Systemic+Lupus+ ResearchGate, February 2017, https:// outcomes at age 7–10 years,’’ Erythematosus+Associated+Epitopes&ie=utf-8&oe= www.researchgate.net/publication/313918596_ Pharmacoepidemiology Drug Safety 22, no. 12 utf-8 (accessed May 3, 2018). Medical_muddles_that_maim_our_children_with_ (2013): 1263–70. 15 Elizabeth Fox-Edmiston and Judy Van de allergies_asthma_and_ 10 Luke E. Taylor, Amy L. Swerdfeger, Guy D. Water, ‘‘Maternal anti-fetal brain IgG autoantibodies autism?ev=publicSearchHeader&_ Eslick, ‘‘Vaccines are not associated with autism: an and autism spectrum disorders: current knowledge sg=BKfNvl584X7Rf80bZHRyAldVr- evidence-based meta-analysis of case-control and and its implications for potential therapeutics,’’ GGf85U4THDmg_ cohort studies,’’ Vaccine 32, no. 29 (2014): 3623– CNS Drugs 29, no. 9 (2015): 715–724. 7BrJ72PtrZMkhMKIXZQOWWm9cOPjEJRtLCOeqyCI 9. 16 Maryline Fresquet, Thomas A. Jowitt, Jennet (accessed May 3, 2018). 11 Frank DeStefano, Cristofer S. Price, Eric S. Gummadova, et al., ‘‘Identification of a Major 8 Institute of Medicine (IOM) Report (2001), Weintraub, ‘‘Increasing exposure to antibody- Epitope Recognized by PLA2R Autoantibodies in ‘‘Immunization Safety Review: Thimerosal- stimulating proteins and polysaccharides in Primary membranous Nephropathy,’’ Journal of the Containing Vaccines and Neurodevelopmental vaccines is not associated with risk of autism,’’ The American Society Nephrology 26, no. 2 (2015): 302– Disorders.’’ Journal of Pediatrics 163, no. 2 (2013): 561–567. 13.

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allergies, and anaphylaxis rather than asthma.27 Another study referenced in regarding asthma and vaccination. asthma.17 18 19 20 21 22 23 24 25 the citizen’s article, Smith-Morowitz et Therefore, the IOM report does not One study referenced by the citizen al. found persistence of IgE anti- support the petitioner’s position for found children had IgE anti-pertussis influenza antibody for 2 years after adding asthma to the Table for the 30 antigens after immunization, but no immunization, suggesting that rather IgE influenza vaccine. In addition to assessing the evidence generalized further increase in IgE to may be associated with protective 28 submitted in the petition, HHS assessed food or inhalant antigens to which they antibodies. The citizen also cited a study by expert reviews pertinent to asthma were already sensitive. There was no Kuno-Sakai et al. This study evaluated etiology. During 2007, the National suggestion that IgE to food or bacterial whether gelatin in the MMR vaccine Heart, Lung, and Blood Institute antigens would be a trigger for asthma caused an acute allergic reaction. MMR, (NHLBI) of the National Institutes of and the author concluded, varicella, and some influenza vaccines Health published, ‘‘Expert Panel Report ‘‘modifications of vaccine formulation continue to contain hydrolyzed gelatin, 3: Guidelines for the Diagnosis and aimed at preventing IgE production do but acute reactions are rare as is the Management of Asthma: Clinical not seem warranted.’’ 26 Another study incidence of gelatin allergy in the Practice Guidelines.’’ A panel consisting by Holt et al. found greater increases in general population, suggesting that of 18 experts commissioned by the IgE in patients immunized with vaccines are not a likely cause of National Asthma Education and acellular pertussis-containing vaccines widespread allergy to gelatin. No Prevention Program Coordinating compared to those immunized with evidence was provided that inhalation Committee and coordinated by the whole cell pertussis containing of gelatin causes asthma.29 NHLBI developed this report. It vaccines. They suggested that the IgE The 2012 IOM report reviewed discusses the causes of asthma, but antibody against those viruses could asthma exacerbation or reactive airway vaccines are not considered as a contribute to the respiratory symptoms disease episodes in children and adults potential cause.31 Additional expert during acute infection, but did not after inactivated influenza vaccine, and reviews on the etiology of asthma discuss the development of chronic asthma exacerbation/reactive airway published in the literature do not disease episodes, in both children mention vaccines as a risk factor or 17 Arthur M. Silverstein, ‘‘Clemens Freiherr von younger than 5 years of age and in potential risk factor.32 33 34 35 Pirquet: Explaining immune complex disease in persons 5 years of age or older after live In addition to considering submitted 1906,’’ Nature Immunology 1, no. 6 (2000): 453–5. evidence, HHS conducted a literature 18 H. Gideon Wells, ‘‘Studies on the Chemistry of attenuated influenza vaccine (LAIV). Anaphylaxis,’’ The Journal of Infectious Diseases 5, The IOM reached the following search of major medical databases for no. 4 (1908): 449–483. conclusions: any articles linking vaccination and the 19 H. Gideon Wells, ‘‘Studies on the Chemistry of • The evidence favors a rejection of a development of asthma, specifically, Anaphylaxis (III). Experiments with Isolated causal relationship between inactivated reviewing numerous studies published Proteins, Especially Those of the Hen’s Egg,’’ The Journal of Infectious Diseases 9, no. 2 (1911): 147– influenza vaccine and asthma during 2000 or later in peer-reviewed 71. exacerbation or reactive airway disease English language publications, which 20 H. Gideon Wells and Thomas B. Osborne, ‘‘The episodes in children and adults; directly or tangentially evaluated the biological reactions of the vegetable proteins,’’ The • The evidence is inadequate to development of asthma after Journal of Infectious Diseases 8, no. 1 (1911): 66– accept or reject a causal relationship vaccination. 124. The majority of the reviewed articles 21 Kate Grimshaw, Kirsty Logan, Sinead between LAIV and asthma exacerbation O’Donovan, et al., ‘‘Modifying the infant’s diet to or reactive airway disease episodes in found no potential causality between prevent food allergy,’’ Archives of Disease children younger than 5 years of age; vaccinations covered by the VICP and Childhood 102, no. 2 (2017): 179–186. and the development of asthma. The search 22 George Du Toit, Graham Roberts, Peter H. • The evidence is inadequate to did not identify any peer-reviewed Sayre, et al., ‘‘Randomized Trial of Peanut articles that evaluated or discussed the Consumption in Infants at Risk for Peanut Allergy,’’ accept or reject a causal relationship The New England Journal of Medicine 372, no. 9 between LAIV and asthma exacerbation possible role of food allergen (2015): 803–813. or reactive airway disease episodes in 23 Vinu Arumugham, ‘‘Evidence that Food persons 5 years of age or older. 30 Institute of Medicine (IOM), Adverse Effects of Proteins in Vaccines Cause the Development of The IOM did not evaluate evidence Vaccines: Evidence and Causality (Washington, DC: Food Allergies and its Implications for Vaccine The National Academies Press, 2012), 356. Policy,’’ Journal of Developing Drugs,’’ (October regarding a causal association between 31 National Asthma Education and Prevention 2015), https://www.researchgate.net/publication/ other vaccines and asthma. Aside from Program, Third Expert Panel on the Diagnosis and 285580954_Evidence_that_Food_Proteins_in_ influenza vaccines, the IOM does not Management of Asthma. Expert Panel Report 3: ______Vaccines Cause the Development of Food comment on the strength of the Guidelines for the Diagnosis and Management of Allergies_and_Its_Implications_for_Vaccine_ Asthma: Clinical Practice Guidelines. (Bethesda, Policy?_sg=_2GjOVUyCy epidemiologic or mechanistic evidence MD: National Heart, Lung, and Blood Institute FmiLl1OWGBk6iBA3OnpAlN-gTrpR1QpTn (NHLBI), 2007): 11–34. 0ZRXL0Vn1P6pO6f6zk9mKp0aVRVOS09R9tmY 27 Patrick G. Holt, Tom Snelling, Olivia J. White, 32 Augusto Litonjua and Scott T Weiss. ‘‘Risk (accessed May 3, 2018). et al., ‘‘Transiently increased IgE responses in Factors for Asthma,’’ UptoDate, last updated May 24 Tetsuo Nakayama, Takuji Kumagai, Naoko infants and pre-schoolers receiving only acellular 3, 2018, https://www.uptodate.com/contents/risk- Nishimura, et al., ‘‘Seasonal split influenza vaccine Diphtheria–Pertussis–Tetanus (DTaP) vaccines factors-for-asthma (accessed May 3, 2018). induced IgE sensitization against influenza compared to those initially receiving at least one 33 George Guibas, Spyridon Megremis, Peter West, vaccine,’’ Vaccine 33, no. 45 (2015): 6099–105. dose of cellular vaccine (DTwP)—Immunological and Nikolas G. Papadopoulos, et al., ‘‘Contributing 25 Ake Davidsson, Jens-Christian Eriksson, Stig curiosity or canary in the mine?’’ Vaccine 34, no. factors to the development of childhood asthma: Rudblad, Karl Albert Brokstad, ‘‘Influenza Specific 35 (2016): 4259–4261. working toward risk minimization,’’ Expert Review Serum IgE is Present in Non-Allergic Subjects,’’ 28 Tamar Smith-Norowitz, Darrin Wong, Melanie of Clinical Immunology 11, no. 6 (2015): 721–35. Scandinavian Journal of Immunology 62, no. 6 Kusonruksa, et al., ‘‘Long Term Persistence of IgE 34 George Guibas, Alexander G. Mathioudakis, (2005): 560–1. Anti-influenza Virus Antibodies In Pediatric and Marina Tsoumani, and Sophia Tsabouri, 26 E.J. Ryan, L. Nilsson, N.I.M. Kjellman, et al., Adult Serum Post Vaccination with Influenza Virus ‘‘Relationship of Allergy with Asthma: There Are ‘‘Booster immunization of children with an Vaccine,’’ International Journal of Medical Sciences More Than the Allergy ‘‘Eggs’’ in the Asthma acellular pertussis vaccine enhances Th2 cytokine 8, no. 3 (2011): 239, 241–243. ‘‘Basket’’,’’ Frontiers in Pediatrics 5 (2017): 92. production and serum IgE responses against 29 Harumi Kuno-Sakai and Mikio Kimura, 35 Padmaja Subbarao, Allan Becker, Jeffrey R. pertussis toxin but not against common allergens,’’ ‘‘Removal of gelatin from live vaccines and DTaP— Brook, et al., ‘‘Epidemiology of asthma: risk factors Clinical and Experimental Immunology 121, no. 2 an ultimate solution for vaccine-related gelatin for development,’’ Expert Review of Clinical (2000): 193–200. allergy,’’ Biologicals 31, no. 4 (2003): 245–249. Immunology 5, no. 1 (2009): 77–95.

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contaminated vaccines or ‘‘pathogen Three studies had mixed results with children with a previous reaction to associated vaccine antigens’’ in the two of them possibly having DPT vaccine were given DT suggesting development or exacerbation of asthma. confounding variables. A study by that this may be an at-risk group. In Vaccines studied in the published Laubereau showed Hib-vaccinated addition, there was a small sample size articles included diphtheria, pertussis, children had a slightly higher risk for and there was no control group.54 and tetanus (DPT), MMR, measles, oral asthma. The authors of the study stated, Another study by McDonald, et al. polio virus (OPV), Prevnar 13, Hib, and ‘‘results have to be interpreted with demonstrated an association between Hepatitis B. Fifteen studies found no caution. Biological evidence to support timing of DPT receipt and risk of association between vaccinations and a causal association is not available.’’ asthma. This study consisted of 11,531 asthma.36 37 38 39 40 41 42 43 44 45 46 47 48 Some Some of the questions the authors posed children born in Manitoba during 1995 studies found a protective effect regarding the results dealt with the who received at least four doses of DPT. suggesting that asthma risk was reduced validity of parental reports and possible The researchers looked at timing of with vaccination.49 50 51 recall bias.52 vaccine receipt and the development of A study by Benke, et al. of 3,200 22– asthma and found that delaying the first 36 H. Ross Anderson, Jan D. Poloniecki, David P. 44 year old individuals in Australia dose of DPT by greater than 2 months Strachan, et al., ‘‘Immunization and symptoms of showed no difference in the risk of decreased risk of asthma by 50 percent. atopic disease in children: results from the international study of asthma and allergies in asthma among subjects who received They identified several potential children,’’ American Journal of Public Health 91, DTP, Hepatitis B, measles, MMR, and confounding factors, including the fact no. 7 (2001): 1126–9. OPV. However, an analysis of that the reason for immunization delay 37 Kristin Wickens, Julian Crane, Trudi Kemp, et individuals who had received all three was unknown. Children without asthma al., ‘‘A case-control study of risk factors for asthma MMR, OPV and DTP vaccines showed may visit a physician less often with in New Zealand children,’’ Australian and New Zealand Journal of Public Health 25, no. 1 (2001): an increased risk of asthma. Authors fewer opportunities to be vaccinated. 44–49. state there is ‘‘relatively weak support This may lead to self-selection. Also, 38 Frank DeStefano, David Gu, Piotr Kramarz, et . . . (that) vaccinations may lead to there was not a comparison control al., ‘‘Childhood vaccinations and the risk of increased risk of asthma, but caution is (unvaccinated) group. asthma,’’ Pediatric Infectious Disease Journal 21, no. 6 (2002): 498–504. advised due to possible recall bias.’’ In summary, current scientific 39 H. P. Roost, M. Gassner, L. Grize, et al., They write that typically studies of evidence does not support a causal ‘‘Influence of MMR-vaccinations and diseases on young adults who self-report association between vaccinations and atopic sensitization and allergic symptoms in Swiss vaccination histories may be subject to asthma. There is no evidence that schoolchildren,’’ Pediatric Allergy and Immunology significant recall bias. In this study, vaccination leads to IgE antibody 15, no.5 (2004): 401–7. 40 Julie E. Maher, John P. Mullooly, Lois Drew, childhood vaccination was based against the most common causes of and Frank DeStefano, ‘‘Infant vaccinations and entirely on subject recall. In addition, as wheezing in childhood, namely childhood asthma among full-term infants,’’ noted by the authors, associations for respiratory syncytial virus, and human Pharmacoepidemiology and Drug Safety 31, no. 1 atopy and vaccinations appeared rhinovirus. There is no evidence that (2004): 1–9. consistently weak for all vaccines 41 Monique Mommers, Gerard M. H. Swaen, individuals develop IgE sensitization by Michela Weishoff-Houben, et al., ‘‘Childhood investigated. Since atopic asthma has a injection of food proteins in vaccines infections and risk of wheezing and allergic strong association with atopy, this also and that subsequent inhalation of these sensitisation at age 7–8 years,’’ European Journal of does not suggest that vaccines led to the particles causes symptoms of asthma. Epidemiology 19, no. 10 (2004): 945–51. increase in asthma.53 There is no evidence that inhalation of 42 John P. Mullooly, Roberleigh Schuler, Michael Barrett, and Julie E. Maher, ‘‘Vaccines, antibiotics, A study by Thomson, et al. vaccine antigens triggers asthma and atopy,’’ Pharmacoepidemiology and Drug demonstrated conflicting results. OPV symptoms via an IgE mechanism. Safety 16, no. 3 (2007) 275–88. and MMR vaccines decreased the risk of Although some studies show a possible 43 Ran D. Balicer, Itamar Grotto, Marc Mimouni, asthma at age 2, and OPV decreased the association with asthma, these have and Daniel Mimouni, ‘‘Is childhood vaccination risk of asthma at age 6. Also, the associated with asthma? A meta-analysis of significant lapses in methodology. The observational studies,’’ Pediatrics 120, no. 5 (2007): diphtheria and tetanus (DT) vaccine that majority of studies show no association. e1269–77. was administered in the first year of life 44 Ben D. Spycher, Michael Silverman, Matthias increased the risk of asthma at 6 years. Tics Egger, et al., ‘‘Routine vaccination against pertussis However, this study had significant On March 16, 2017, and May 4, 2017, and the risk of childhood asthma: a population- based cohort study,’’ Pediatrics 123, no. 3 (2009): limitations. Nearly 21 percent of the a private citizen submitted letters to 944–50. subjects were lost to follow-up. Only HHS requesting that tics be added to the 45 John P. Mullooly, John Pearson, Lois Drew, et Table. The petitioner claims that two al., ‘‘Wheezing lower respiratory disease and and allergy in children with and without prior CDC employees have been quoted as vaccination of full-term infants,’’ measles, mumps, and rubella vaccination,’’ believing there is evidence that vaccines Pharmacoepidemiology and Drug Safety 11, no. 1 Pediatric Allergy and Immunology 26, no. 8 (2015): (2002): 21–30. 742–749. can cause tics; neither the CDC nor the 46 Gabriele Nagel, Gudrun Weinmayr, Carsten 50 John P. Mullooly, Roberleigh Schuler, Jill Mesa, CDC employees have verified these Flohr, et al., ‘‘Association of pertussis and measles et al., ‘‘Wheezing lower respiratory disease and comments. The petitioner mentions a infections and immunizations with asthma and vaccination of premature infants,’’ Vaccine 29, no. study by Barile and Thompson in allergic sensitization in ISAAC Phase Two,’’ 44 (2011): 7611–7. Pediatric Allergy and Immunology 23, no. 8 (2012): 51 H. P. Roost, M. Gassner, L. Grize, et al., support of his request. The petitioner 737–46. ‘‘Influence of MMR-vaccinations and diseases on did not specify vaccine type or 47 Hung Fu Tseng, Lina S. Sy, In-Lu Amy Liu, et atopic sensitization and allergic symptoms in Swiss differentiate between thimerosal- al., ‘‘Postlicensure surveillance for pre-specified schoolchildren,’’ Pediatric Allergy and Immunology containing versus thimerosal-free adverse events following the 13-valent 15, no. 5 (2004): 401–7. pneumococcal conjugate vaccine in children,’’ 52 B. Laubereau, V. Grote, B. Holscher, et al., vaccines. Vaccine 24, no. 22 (2013): 2578–83. ‘‘Vaccination against Haemophilus influenzae type 48 Vittorio DeMicheli, Alessandro Rivetti, Maria b and atopy in East German schoolchildren,’’ 54 Jennifer A. Thomson, Constance Widjaja, Abbi Grazia Debalini and Carlo Di Pietrantonj, ‘‘Vaccines European Journal of Medical Research 7, no. 9 A. P. Darmaputra, et al., ‘‘Early childhood for measles, mumps and rubella in children,’’ (2002): 387, 389–391. infections and immunisation and the development Cochrane Database of Systematic Reviews 15, no. 53 G. Benke, M. Abramson, J. Raven, et al., of allergic disease in particular asthma in a high- 2 (2012): 4, 18, 21, 135–139. ‘‘Asthma and vaccination history in a young adult risk cohort: A prospective study of allergy-prone 49 Clara Amalie, Gade Timmermann, Christa cohort,’’ Australian and New Zealand Journal of children from birth to six years,’’ Pediatric Allergy Elyse Osuna, Ulrike Steuerwald, et al., ‘‘Asthma Public Health 28, no. 4 (2004): 337. and Immunology 21, no. 7: 1076, 1079–1084.

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Tics are defined as sudden, rapid, There are several significant are numerous studies and independent recurrent, non-rhythmic, stereotyped limitations of the Barile study. The only reviews supporting the safe use of motor movement or vocalization.55 training the evaluators received for tics thimerosal in They are involuntary, but can be assessment was based on a 30-minute vaccines.60 61 62 63 64 65 66 67 68 69 70 71 72 73 suppressed for varying lengths of time video on the diagnosis of Tourette An initial literature search was and are markedly diminished during syndrome from 1989 and may not have performed looking for articles on tics by sleep. The onset of tics almost always been sufficient to adequately diagnose the two CDC employees mentioned in occur in childhood with multiple tics the subjects. These raters were not the petition, Dr. Thompson and Dr. and complex vocal sounds developing required to meet any criteria for skill or over time, usually peaking in severity by reliability criteria. This could have led 60 Nick Andrews, Elizabeth Miller, Andrew Grant, to misdiagnosis of the study subjects. et al., ‘‘Thimerosal Exposure in Infants and 10–12 years of age. The precise etiology Developmental Disorders: A Retrospective Cohort of tics is not known, but it is thought to The parent’s assessment of the presence Study in the United Kingdom Does Not Support a be due to chemical abnormalities in the or absence of tics was not concordant Causal Association,’’ Pediatrics 114, no. 3 (2004): brain. The risk of developing tics and with the assessor’s reports. The study 584–591. the prognosis are influenced by does not provide the parents’ 61 Eric Fombonne, Rita Zakarian, Andrew Bennett, et al., ‘‘Pervasive Developmental Disorders temperamental, environmental, genetic, assessment of tics. However, positive in Montreal, Quebec, Canada: Prevalence and Links and physiological factors. Diagnosis of presence of tics from parent’s report and with Immunizations,’’ Pediatrics 118, no. 1 (2006): tic disorders is hierarchical and the assessor’s report of tics agreed only e139–150. complex. Therefore, specialists typically 23% of the time for motor tics and 16% 62 Anders Hviid, Michael Stellfeld, Jan Wohlfahrt, of the time for phonic tics. Thus, this et al., ‘‘Association between Thimerosal-Containing diagnose tics and tic disorders. Vaccine and Autism,’’ Journal of the American The petition mentions a study by outcome of interest, tics, was either not Medical Association 290, no. 13 (2003): 1763–1766. Barile without a citation. Presumably, noticed by, or is not consistent with, 63 Institute of Medicine, Immunization Safety this is the study published in the behaviors that would be observed by or Review: Vaccines and Autism. Institute of Medicine (Washington, DC: The National Academies Press, Journal of Pediatric Psychology in concerning to parents. The response rate was low—only 30 percent of invitees 2004): 145. 2012.56 The study’s ‘‘objective was to 64 Cristofer Price, William W. Thompson, Barbara examine associations between agreed to participate. Goodson, et al., ‘‘Prenatal and Infant Exposure to thimerosal-containing vaccines and The petition did not specify vaccine Thimerosal from Vaccines and Immunoglobulins and Risk of Autism,’’ Pediatrics 126, no. 4 (2010): immunoglobulins early in life and type or if the vaccines of concern were thimerosal-containing or not. However, 656–664. neuropsychological outcomes evaluated 65 according to the citizen, the Barile study Robert Schechter and Judith K. Grether, at children aged 7–10 years.’’ The study ‘‘Continuing Increases in Autism Reported to mentioned in the petition specifically population was 1,047 children ages 7– California’s Developmental Services System,’’ focused on thimerosal-containing Archives of General Psychiatry 65, no. 1 (2008): 19– 10, born between January 1993 and vaccines. Thimerosal is a mercury-based 24. March 1997. The evaluators measured 66 preservative that is broken down into William Thompson, Cristofer Price, Barbara seven neuropsychological outcomes Goodson, et al., ‘‘Early Thimerosal Exposure and ethyl mercury after entering the body. during a 3-hour testing period with the Neuropsychological Outcomes at 7 to 10 Years,’’ The low levels of ethyl mercury in child including the following: (1) The New England Journal of Medicine 357, no.13 vaccines are broken down by the body (2007): 12811292. Intellectual functioning, (2) speech and 67 differently and clear out of the blood Global Advisory Committee on Vaccine Safety, language, (3) verbal memory, (4) more quickly than methylmercury.58 Statement on Thiomersal (World Health executive functioning, (5) fine motor Organization, 2006): http://www.who.int/vaccine_ There is no evidence of harm caused by _ coordination, (6) tics, and (7) behavior safety/committee/topics/thiomersal/statement low doses of thimerosal in vaccines, jul2006/en/ (accessed May 3, 2018). regulation. The authors found no except for minor reactions like redness 68 Agency for Toxic Substances and Disease statistically significant associations and swelling at the injection site. Multi- Registry (ATSDR), Toxicological Profile for Mercury. (Atlanta, GA, 1999). between thimerosal exposure from dose FDA-approved seasonal influenza vaccines early in life in six of the seven 69 American Academy of Pediatrics, Vaccine vaccines contain thimerosal as a Safety: Examine the Evidence, April 2013, https:// outcomes. There was a small, preservative however, single-dose www.healthychildren.org/English/safety- statistically significant association presentations that do not contain prevention/immunizations/Pages/Vaccine-Studies- between early thimerosal exposure and thimerosal as a preservative are Examine-the-Evidence.aspx?gclid=Cj0KCQjwr the presence of tics in boys. However, LXXBRCXARIsAIttmRNIMWanl3CP-P6t8e available for use in infants, children, A1MPl07uJFNPpxF2dzPEJkshVq9-U5kRozmQQa the authors concluded that this finding adults, the elderly and pregnant women. Aki1EALw_wcB (accessed May 3, 2018). should be interpreted with caution All other vaccines routinely 70 L. Magos, ‘‘Review on the toxicity of because of limitations in the recommended for children 6 years of ethylmercury, including its presence as a measurement of tics and also the limited preservative in biological and pharmaceutical age or younger and marketed in the U.S. products,’’ Journal of Applied Toxicology 21 no. 1, biological plausibility regarding a causal do not contain thimerosal.59 MMR (2001): 1–5. relationship. The authors suggested vaccines do not and never did contain 71 Robert J. Mitkus, David B. King, Mark O. additional studies were needed to thimerosal. Varicella (chickenpox), Walderhaug, and Robert A. Forshee, ‘‘A examine these associations using more inactivated polio (IPV), and Comparative Pharmacokinetic Estimate of Mercury reliable and valid measure of tics.57 in U.S. Infants Following Yearly Exposures to pneumococcal conjugate vaccines have Inactivated Influenza Vaccines Containing also never contained thimerosal. There Thimerosal,’’ Risk Analysis 34, no. 4 (2014): 735– 55 American Psychiatric Association, Diagnostic 50. and statistical manual of mental disorders (5th ed.). 58 Centers for Disease Control and Prevention, 72 Mieszko Olczak, Michalina Duszczyk, Pawel (Arlington, VA: American Psychiatric Publishing, Understanding Thimerosal, Mercury, and Vaccine Mierzejewski, et al., ‘‘Lasting neuropathological 2013): 81. Safety, February 2013, https://www.cdc.gov/ changes in rat brain after intermittent neonatal 56 John P. Barile, Gabriel P. Kuperminc, Eric S. vaccines/hcp/patient-ed/conversations/downloads/ administration of thimerosal,’’ Folia Weintraub, et al., ‘‘Thimerosal Exposure in Early vacsafe-thimerosal-color-office.pdf (accessed May 3, Neuropathologica 48, no. 4 (2010): 258–69. Life and Neuropsychological Outcomes 7–10 Years 2018). 73 Michael E. Pichichero, Elsa Cernichiari, Joseph Later,’’ Journal of Pediatric Psychology 37, no. 1 59 One single dose presentation of seasonal Lopreiato, and John Treanor, ‘‘Mercury (2012): 115. influenza vaccine, Fluvirin’s single-dose Concentrations and Metabolism in Infants 57 John P. Barile, ‘‘Thimerosal Exposure in Early presentation, utilizes thimerosal as part of its Receiving Vaccines Containing Thiomersal: A Life and Neuropsychological Outcomes 7–10 Years manufacturing process, not as a preservative, and a Descriptive Study,’’ The Lancet 360, no. 9347 Later,’’ 115. trace remains in the final presentation. (2002): 1737–41.

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Yeargin-Allsop. There are two The dates in which individuals were hypothesized that infections with group additional studies related to tics that diagnosed do not indicate disease onset A streptococcus (GAS) and others may involved Dr. Thompson. One article dates, which may suggest a temporal trigger autoimmune responses that can examined early thimerosal exposure and association where none exists. In cause or exacerbate childhood-onset neuropsychological outcomes in addition, the control groups may not be OCD or tic disorders (including Tourette children aged 7–10 and did not find an similar enough to the disease groups. syndrome). A theory proposed is that association between tics and Furthermore, the influenza vaccine is antibodies against GAS cross-react with vaccinations containing thimerosal.74 given annually and is the most brain antigens by molecular mimicry The second article by Iqbal et al. was frequently administered vaccine. By resulting in autoantibody-mediated designed to evaluate the association chance, there may be many diagnoses neuronal cell signaling in susceptible between antibody-stimulating proteins made within a year of flu vaccination. hosts.78 Initially researchers coined the and polysaccharides from early Thus, this case-control study provides term PANDAS and later this was childhood vaccines and no more than a temporal association and modified to PANS. Neither PITAND, neuropsychological outcomes at age 7– does not give an absolute risk. PANS, nor PANDAS are officially 10 years. There were no adverse In summary, there is limited literature recognized disease entities and do not associations between antigens through on tics/tic disorders and vaccinations. have diagnostic codes in either: (a) vaccines in the first 2 years of life and Childhood vaccines do not contain International Statistical Classification of neuropsychological outcomes, including thimerosal and influenza vaccines have Diseases and Related Health Problems tics in later childhood.75 thimerosal-free formulations. Current (ICD–10, most recent revision, 2010); or HHS conducted a comprehensive scientific evidence does not support a (b) Diagnostic and Statistical Manual of literature review of the major medical causal association between thimerosal- Mental Disorders (DSM–V; most recent databases to search for articles linking containing or thimerosal-free revision, 2013). tics/tic disorders to vaccinations that do vaccinations and tics/tic disorders. The diagnostic criteria proposed for not contain thimerosal. There is a PANS include abrupt onset of PANS, PITAND, PANDAS, EAE, and paucity of literature on tics/tic disorders symptoms of OCD or food restriction ADEM as a result of vaccinations. Leslie, et al. (anorexia) plus two of the following: authored one article that discussed tics. On February 20, 2017, and March 20, • Anxiety, emotional lability and/or The objective of this study was to 2017, a private citizen submitted written depression, irritability, aggression and/ examine whether antecedent petitions requesting HHS to add PANS, or severely oppositional behaviors, vaccinations are associated with PITAND, PANDAS, EAE, and ADEM to behavioral (developmental) regression, increased incidence of obsessive the Table. The petitions assert that deterioration in school performance, compulsive disorder (OCD), anorexia certain components in pertussis sensory or motor abnormalities, somatic nervosa, anxiety disorder, chronic tic vaccines cause the development of signs and symptoms (e.g., sleep disorder, attention deficit hyperactivity PANS and/or PITAND and conjugate disturbances, enuresis, urinary disorder, major depressive disorder, and and polysaccharide pneumococcal frequency); and bipolar disorder. Using claims data, the vaccines and Hib vaccines cause or • Symptoms not better explained by a investigators compared the prior year’s enable the development of PANS and/ known neurologic or medical occurrence of vaccinations in children or PANDAS. However, not all disorder.79 and adolescents with the above pneumococcal vaccines are covered by To support the claim that PANS and/ neuropsychiatric disorders that were the VICP. There are two types of or PITAND are caused by pertussis- newly-diagnosed between January 2002 pneumococcal vaccines given in the containing vaccines, the petition and December 2002, as well as two U.S. The pneumococcal conjugate outlines a mechanism of molecular control conditions (broken bones and vaccine (PCV13), which is administered mimicry and autoantibody-mediated open wounds). The investigators found routinely to infants and children up to neuronal cell-signaling leading to children with OCD, anorexia nervosa, age 5, and the pneumococcal symptoms. To support the claim that anxiety disorder, and tic disorder were polysaccharide vaccine (PPV23), which PANS and/or PANDAS are caused or more likely to have received influenza is given to adults age 65 and older and enabled by pneumococcal and Hib vaccine during the preceding 1-year individuals of varying age with certain vaccines, the petition outlines a period. They concluded that the onset of medical conditions making them at mechanism of injury in which some neuropsychiatric disorders may be higher risk for pneumococcal infection. vaccination with pneumococcal/Hib temporally-related to prior vaccinations, Since December 18, 1999, the VICP has vaccines results in disruption of the but stated it does not prove a causal role covered only the pneumococcal blood-brain barrier in a susceptible of vaccinations in the etiology of these conjugate vaccine (PCV13). child, which then allows circulating 76 conditions. PANS, PITAND, and PANDAS GAS antibodies to enter the central This study had several limitations. It nervous system (CNS). This results in relied on administrative retrospective PANS, PITAND, and PANDAS are cross-reactivity between GAS antibodies data rather than systematically obtained proposed conditions based on a concept and CNS structures, which leads to clinical data. Therefore, diagnostic that an immune basis may underlie and symptoms of PANS/PANDAS. misclassification may have occurred. may trigger disorders associated with movement and behavioral 78 Albert J. Allen, Henrietta L. Leonard, and Susan 74 Thompson, ‘‘Early thimerosal exposure and abnormalities. A hypothesis is that E. Swedo, ‘‘Case study: a new infection-triggered, neuropsychological outcomes at 7 to 10 years,’’ ‘‘neuropsychiatric syndromes may autoimmune subtype of pediatric OCD and 1285. result from various etiologies, including Tourette’s syndrome,’’ Journal of the American 75 Iqbal, ‘‘Number of antigens in early childhood Academy of Child Adolescent Psychiatry 34, no. 3 hereditary, environmental, and (1995): 307–311. vaccines and neuropsychological outcomes at age 77 7–10 years,’’ 1263, 1266. inflammatory causes.’’ It has been 79 Susan E. Swedo, James F. Leckman, and Noel 76 Douglas L. Leslie, Robert A. Kobre, Brian J. R. Rose, ‘‘From Research Subgroup to Clinical Richmond, et al. ‘‘Temporal Association of Certain 77 Kyle A. Williams and Susan E. Swedo, ‘‘Post- Syndrome: Modifying the PANDAS Criteria to Neuropsychiatric Disorders Following Vaccination infectious autoimmune disorders: Sydenham’s Describe PANS (Pediatric Acute-onset of Children and Adolescents: A Pilot Case-Control chorea, PANDAS and beyond,’’ Brain Research Neuropsychiatric Syndrome),’’ Pediatrics & Study,’’ Frontiers in Psychiatry 8, no. 3 (2017): 6. 1617 (2015): 145. Therapeutics 2, no. 2 (2012): 3.

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The 2012 IOM report did not review pertussis, pneumococcal conjugate or the studies dealing with EAE do not any possible association between Hib vaccines. have relevance to pertussis vaccinations pertussis-containing vaccines or any and/or ADEM. These studies do not EAE and ADEM vaccine and PANS and/or PITAND, nor provide any evidence that pertussis did it review any possible association EAE is not a clinical diagnosis. EAE vaccinations cause ADEM. between pneumococcal conjugate is an animal model of autoimmune The IOM reviewed the epidemiologic vaccines and Hib vaccines or any disease of the CNS.82 As EAE does not and mechanistic evidence as to whether vaccine and PANS and/or PANDAS. occur in humans, it will not be pertussis vaccinations cause ADEM. HHS gathered data from the existing discussed separately from the human They found the evidence inadequate to medical literature in addition to the diseases (which are discussed below). accept or reject a causal relationship evidence submitted in the petition. A Pertussis toxin has been used in EAE between pertussis-containing vaccines literature search of the major medical studies due to its immunogenicity and ADEM. HHS conducted a review of databases was conducted searching for (ability to evoke an immune response). the literature published after the IOM any articles linking the development of However, acellular pertussis vaccines report regarding ADEM and vaccination. PANS, PITAND, or PANDAS to are formulated to contain inactivated A paper by Baxter et al. identified all vaccinations, including pertussis- pertussis toxin and not pertussis toxin cases of ADEM in the Vaccine Safety component, pneumococcal conjugate, that is used in animal models of EAE. Datalink (VSD). The VSD is a and Hib vaccines. Encephalopathy is currently an injury collaborative project between CDC and on the Table for vaccines containing eight health care organizations that Despite an extensive search of peer- whole cell pertussis bacteria, extracted utilizes electronic health data to reviewed English language publications, or partial cell pertussis bacteria, or monitor the safety of vaccines. The VSD HHS did not find any published specific pertussis antigen, and vaccines study analyzed 64 million vaccine doses research addressing any linkages, containing measles, mumps, and rubella and calculated the risk difference of potential causality, or enablement virus or any of its components. ADEM being diagnosed with ADEM for each between vaccinations covered by the can have encephalopathy as a symptom, vaccine. This study revealed two cases VICP, including pertussis-containing, but ADEM and encephalopathy are two of ADEM after Tdap (tetanus, pneumococcal conjugate, and Hib distinct conditions. The autoimmune diphtheria, and acellular pertussis) vaccinations, and the development of etiology is specific for ADEM and the vaccination. The study was limited with PANS, PITAND, and/or PANDAS in any onset between primary exposure and regard to assessing causality due to the population. There are no published data development of primary antibody small number of ADEM cases. It is also on PANS and PITAND regarding response is 7–10 days as opposed to 0– possible this finding could be due to possible specific infectious or non- 72 hours for the onset to meet the Table chance alone due to multiple testing. infectious triggers and autoimmune definition for encephalopathy.83 The Multiple testing refers to any instance mechanisms. Data on the more well- time period for development of ADEM that involves the simultaneous testing of studied PANDAS are conflicting.80 is outside the 0–72 hour time period of several hypotheses.95 96 Some researchers question the the Table definition for acellular autoimmune mechanism of PANDAS pertussis vaccine and encephalopathy Oxygen Species Lead to Enhanced Amyloid Beta and no specific autoimmune antibody is and encephalitis. With ADEM, there is Formation,’’ (animal study), Antioxidants and agreed upon as a pathogenic mechanism a characteristic demyelination in the Redox Signaling 16, no. 12 (2012): 1421–1433. for its symptoms.81 CNS and a strong association with 88 Dan Zhou, Rajneesh Srivastava, Stefan Nessler, et al., ‘‘Identification of a pathogenic antibody After an extensive literature search, prodromal (infectious) illness that is response to native myelin oligodendrocyte HHS has not found any published study absent in an encephalopathy as defined glycoprotein in multiple sclerosis,’’ Proceedings of that examines anti-neuronal antibodies in the Table. These differences were the National Academy of Sciences of the United significant enough that the IOM 2012 States of America (PNAS) 103, no. 50 (2006): in children suspected of PANS or 19057–19062. PITAND following pertussis infection or Report considered ADEM separate from 89 Peter M. Clifford, Shabnam Zarrabi, Gilbert Siu, following pertussis immunization. HHS encephalopathy and encephalitis. et al., ‘‘Ab peptides can enter the brain through a has not found any studies that examine Multiple articles were submitted by defective blood–brain barrier and bind selectively the petitioner in support of adding to neurons,’’ (animal study), Brain Research 1142 whether pneumococcal conjugate (2007): 223–236. ADEM/EAE to the 90 vaccines or pneumococcal infections 84 85 86 87 88 89 90 91 92 93 94 Ralf A. Linker and De-Hyung Lee, ‘‘Models of and Hib vaccines or Hib infections Table. However, autoimmune demyelination in the central nervous disrupt the filtering mechanism of the system: on the way to translational medicine,’’ 82 William J. Lindsey, ‘‘EAE: History, Clinical Experimental & Translational Stroke Medicine 1, blood-brain barrier to allow circulating Signs, and Disease Course,’’ in Experimental no. 5 (2009): 1–10. GAS antibodies to cross into the CNS in Models of Multiple Sclerosis, eds..Ehud Lavi and 91 Kevin O’Connor, Katherine A. McLaughlin, a susceptible child and, once across the Cris Constantinescu (New York: Springer Philip L. De Jager, et al., ‘‘Self-antigen tetramers barrier, to react with CNS structures to Science+Business Media, Inc., 2005): 1. discriminate between myelin autoantibodies to 83 generate neuropsychiatric symptoms. In IOM, Adverse Effects of Vaccines, 546–7. native or denatured protein,’’ Nature Medicine 13, 84 Harald H. Hofstetter, Carey L. Shive, and no. 2 (2007): 211–217. addition, HHS is not aware of any Thomas G. Forsthuber, ‘‘Pertussis Toxin Modulates 92 Fabienne Brilot, Russell C. Dale, Rebecca C. published studies concluding that the Immune Response to Neuroantigens Injected in Selter, et al., ‘‘Antibodies to native PANS, PITAND, and/or PANDAS are Incomplete Freund’s Adjuvant: Induction of Th1 myelinoligodendrocyte glycoprotein in children Cells and Experimental Autoimmune with inflammatory demyelinating central nervous caused by pertussis infection or Encephalomyelitis in the Presence of High system disease,’’ Annals of Neurology 66, no.6 Frequencies of Th2 Cells,’’ (animal model), The (2009): 833–42. 80 Sonja Orlovska, Claus H

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Another study by Chang that analyzed found a decrease in the diagnosis of scientific evidence of an association post-licensure safety for diphtheria and ADEM in individuals who received between vaccines and asthma, autism, acellular pertussis vaccines found no DTaP, IPV, and Hib vaccines.98 In tics, PITAND, PANS, PANDAS, EAE, statistically significant adverse events summary, EAE is not a disease in and/or ADEM. Therefore, HHS will not including ADEM.97 A study by humans but rather an experimental add them as injuries associated with any Pellegrino looked at the onset of ADEM model. The Table only lists conditions vaccine on the Table at this time. utilizing a post-marketing study from found in humans. In addition, the the U.S. and Europe. The investigators current literature does not support a Dated: February 22, 2019. relationship between vaccines and George Sigounas, Vaccines: A Case Centered Analysis,’’ Clinical ADEM. Administrator, Health Resources and Services Infectious Diseases 63, no. 11 (2016): 1461. Administration. 96 Joseph P. Romano, Azeem M. Shaikh, and Conclusion Michael Wolf, ‘‘Multiple Testing,’’ The New Approved: March 15, 2019. Palgrave Dictionary of Economics, Online Edition, In light of the above, HHS has eds. S.N. Durlauf and L.E. Blume (London: Palgrave determined that there is no reliable Alex M. Azar II, Macmillan, 2010), 1. http://home.uchicago.edu/ Secretary, Department of Health and Human amshaikh/webfilespalgrave.pdf. Services. 97 Soju Chang, Patrick M. O’Connor, Barbara A. 98 Paolo Pellegrino, Carla Carnovale, Valentina Slade, and Emily Jane Woo, ‘‘US post licensure Perrone, et al., ‘‘Acute Disseminated [FR Doc. 2019–05618 Filed 3–26–19; 8:45 am] safety surveillance for adolescent and adult tetanus Encephalomyelitis Onset: Evaluation Based on BILLING CODE 4150–28–P diphtheria and acelluar pertussis vaccines: 2005– Vaccine Adverse Event Reporting Systems,’’ PLoS 2007,’’ Vaccine 31, no. 10 (2013): 1447–1452. One 8, no. 10 (2013): 5.

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