[Federal Register Volume 84, Number 59 (Wednesday, March 27, 2019)]
[Proposed Rules]
[Pages 11473-11481]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-05618]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

42 CFR Part 100


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.

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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

[[Page 11474]]

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: [email protected].

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.\1\
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    \1\ 81 FR 17423 (Mar. 29, 2016); https://www.gpo.gov/fdsys/pkg/FR-2016-03-29/pdf/2016-06666.pdf.
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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.\2\ 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.\3\ Numerous scientific studies have found 
that neither vaccines nor vaccine ingredients cause 
ASD.4 5 6
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    \2\ National Institutes of Health, About Autism, https://www.nichd.nih.gov/health/topics/autism/conditioninfo/Pages/default.aspx (accessed May 3, 2018).
    \3\ National Institutes of Health, ``Autism Spectrum Disorder 
Fact Sheet,'' https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Autism-Spectrum-Disorder-Fact-Sheet#3082 5 
(accessed May 3, 2018).
    \4\ https://www.cdc.gov/vaccinesafety/concerns/autism.html.
    \5\ https://www.cdc.gov/ncbddd/autism/research.html.
    \6\ https://effectivehealthcare.ahrq.gov/topics/vaccine-safety/research.
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    To support the claim that autism is caused by vaccines, the 
petitioner

[[Page 11475]]

references a non- peer-reviewed article that he wrote and published 
online.\7\ 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.
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    \7\ Vinu Arumugham, ``Medical muddles that maim our children 
with allergies, asthma and autism,'' ResearchGate, February 2017, 
https://www.researchgate.net/publication/313918596_Medical_muddles_that_maim_our_children_with_allergies_asthma_and_autism?ev=publicSearchHeader&_sg=BKfNvl584X7Rf80bZHRyAldVr-GGf85U4THDmg_7BrJ72PtrZMkhMKIXZQOWWm9cOPjEJRtLCOeqyCI (accessed May 
3, 2018).
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    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.'' \8\
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    \8\ Institute of Medicine (IOM) Report (2001), ``Immunization 
Safety Review: Thimerosal-Containing Vaccines and Neurodevelopmental 
Disorders.''
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    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.9 10 11 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.
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    \9\ Shahed Iqbal, John P. Barile, William W. Thompson, Frank 
DeStefano, ``Number of antigens in early childhood vaccines and 
neuropsychological outcomes at age 7-10[thinsp]years,'' 
Pharmacoepidemiology Drug Safety 22, no. 12 (2013): 1263-70.
    \10\ Luke E. Taylor, Amy L. Swerdfeger, Guy D. Eslick, 
``Vaccines are not associated with autism: an evidence-based meta-
analysis of case-control and cohort studies,'' Vaccine 32, no. 29 
(2014): 3623-9.
    \11\ Frank DeStefano, Cristofer S. Price, Eric S. Weintraub, 
``Increasing exposure to antibody-stimulating proteins and 
polysaccharides in vaccines is not associated with risk of autism,'' 
The Journal of Pediatrics 163, no. 2 (2013): 561-567.
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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.\12\ The individual also provided four 
additional articles, two of which he wrote and published online without 
peer review. 13 14 15 16 Three of the latter references did 
not discuss asthma.
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    \12\ Arumugham, ``Medical muddles that maim our children with 
allergies, asthma and autism.''
    \13\ Vinu Arumugham, ``Strong protein sequence alignment between 
autoantigens involved in maternal autoantibody related autism and 
vaccine antigens,'' ResearchGate, May 2017, https://www.researchgate.net/profile/Vinu_Arumugham/publication/316785758_Strong_protein_sequence_alignment_between_autoantigens_involved_in_maternal_autoantibody_related_autism_and_vaccine_antigens/links/59115a620f7e9bfa06d43d5e/Strong-protein-sequence-alignment-between-autoantigens-involved-in-maternal-autoantibody-related-autism-and-vaccine-antigens.pdf?origin=publication_list (accessed 
May 3, 2018).
    \14\ Vinu Arumugham, ``Significant protein sequence alignment 
between Saccharomyces Cerevisiae Proteins (a Vaccine Contaminant) 
and Systemic Lupus Erythematosus Associated Epitopes,'' 
ResearchGate, May 2017, https://www.google.com/search?q=Significant+protein+sequence+alignment+between+Saccharomyces+Cerevisiae+Proteins+%28a+Vaccin 
e+Contaminant%29+and+Systemic+Lupus+Erythematosus+Associated+Epitopes
&ie=utf-8&oe=utf-8 (accessed May 3, 2018).
    \15\ Elizabeth Fox-Edmiston and Judy Van de Water, ``Maternal 
anti-fetal brain IgG autoantibodies and autism spectrum disorders: 
current knowledge and its implications for potential therapeutics,'' 
CNS Drugs 29, no. 9 (2015): 715-724.
    \16\ Maryline Fresquet, Thomas A. Jowitt, Jennet Gummadova, et 
al., ``Identification of a Major Epitope Recognized by PLA2R 
Autoantibodies in Primary membranous Nephropathy,'' Journal of the 
American Society Nephrology 26, no. 2 (2015): 302-13.
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    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

[[Page 11476]]

allergies, and anaphylaxis rather than 
asthma.17 18 19 20 21 22 23 24 25
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    \17\ Arthur M. Silverstein, ``Clemens Freiherr von Pirquet: 
Explaining immune complex disease in 1906,'' Nature Immunology 1, 
no. 6 (2000): 453-5.
    \18\ H. Gideon Wells, ``Studies on the Chemistry of 
Anaphylaxis,'' The Journal of Infectious Diseases 5, no. 4 (1908): 
449-483.
    \19\ H. Gideon Wells, ``Studies on the Chemistry of Anaphylaxis 
(III). Experiments with Isolated Proteins, Especially Those of the 
Hen's Egg,'' The Journal of Infectious Diseases 9, no. 2 (1911): 
147-71.
    \20\ H. Gideon Wells and Thomas B. Osborne, ``The biological 
reactions of the vegetable proteins,'' The Journal of Infectious 
Diseases 8, no. 1 (1911): 66-124.
    \21\ Kate Grimshaw, Kirsty Logan, Sinead O'Donovan, et al., 
``Modifying the infant's diet to prevent food allergy,'' Archives of 
Disease Childhood 102, no. 2 (2017): 179-186.
    \22\ George Du Toit, Graham Roberts, Peter H. Sayre, et al., 
``Randomized Trial of Peanut Consumption in Infants at Risk for 
Peanut Allergy,'' The New England Journal of Medicine 372, no. 9 
(2015): 803-813.
    \23\ Vinu Arumugham, ``Evidence that Food Proteins in Vaccines 
Cause the Development of Food Allergies and its Implications for 
Vaccine Policy,'' Journal of Developing Drugs,'' (October 2015), 
https://www.researchgate.net/publication/285580954_Evidence_that_Food_Proteins_in_Vaccines_Cause_the_Development_of_Food_Allergies_and_Its_Implications_for_Vaccine_Policy?_sg=_2GjOVUyCyFmiLl1OWGBk6iBA3OnpAlN-gTrpR1QpTn0ZRXL0Vn1P6pO6f6zk9mKp0aVRVOS09R9tmY (accessed May 3, 
2018).
    \24\ Tetsuo Nakayama, Takuji Kumagai, Naoko Nishimura, et al., 
``Seasonal split influenza vaccine induced IgE sensitization against 
influenza vaccine,'' Vaccine 33, no. 45 (2015): 6099-105.
    \25\ Ake Davidsson, Jens-Christian Eriksson, Stig Rudblad, Karl 
Albert Brokstad, ``Influenza Specific Serum IgE is Present in Non-
Allergic Subjects,'' Scandinavian Journal of Immunology 62, no. 6 
(2005): 560-1.
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    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.'' \26\ 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.\27\ 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.\28\
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    \26\ E.J. Ryan, L. Nilsson, N.I.M. Kjellman, et al., ``Booster 
immunization of children with an acellular pertussis vaccine 
enhances Th2 cytokine production and serum IgE responses against 
pertussis toxin but not against common allergens,'' Clinical and 
Experimental Immunology 121, no. 2 (2000): 193-200.
    \27\ Patrick G. Holt, Tom Snelling, Olivia J. White, et al., 
``Transiently increased IgE responses in infants and pre-schoolers 
receiving only acellular Diphtheria-Pertussis-Tetanus (DTaP) 
vaccines compared to those initially receiving at least one dose of 
cellular vaccine (DTwP)--Immunological curiosity or canary in the 
mine?'' Vaccine 34, no. 35 (2016): 4259-4261.
    \28\ Tamar Smith-Norowitz, Darrin Wong, Melanie Kusonruksa, et 
al., ``Long Term Persistence of IgE Anti-influenza Virus Antibodies 
In Pediatric and Adult Serum Post Vaccination with Influenza Virus 
Vaccine,'' International Journal of Medical Sciences 8, no. 3 
(2011): 239, 241-243.
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    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.\29\
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    \29\ Harumi Kuno-Sakai and Mikio Kimura, ``Removal of gelatin 
from live vaccines and DTaP--an ultimate solution for vaccine-
related gelatin allergy,'' Biologicals 31, no. 4 (2003): 245-249.
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    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.\30\
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    \30\ Institute of Medicine (IOM), Adverse Effects of Vaccines: 
Evidence and Causality (Washington, DC: The National Academies 
Press, 2012), 356.
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    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.\31\ Additional 
expert reviews on the etiology of asthma published in the literature do 
not mention vaccines as a risk factor or potential risk 
factor.32 33 34 35
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    \31\ National Asthma Education and Prevention Program, Third 
Expert Panel on the Diagnosis and Management of Asthma. Expert Panel 
Report 3: Guidelines for the Diagnosis and Management of Asthma: 
Clinical Practice Guidelines. (Bethesda, MD: National Heart, Lung, 
and Blood Institute (NHLBI), 2007): 11-34.
    \32\ Augusto Litonjua and Scott T Weiss. ``Risk Factors for 
Asthma,'' UptoDate, last updated May 3, 2018, https://www.uptodate.com/contents/risk-factors-for-asthma (accessed May 3, 
2018).
    \33\ George Guibas, Spyridon Megremis, Peter West, and Nikolas 
G. Papadopoulos, et al., ``Contributing factors to the development 
of childhood asthma: working toward risk minimization,'' Expert 
Review of Clinical Immunology 11, no. 6 (2015): 721-35.
    \34\ George Guibas, Alexander G. Mathioudakis, Marina Tsoumani, 
and Sophia Tsabouri, ``Relationship of Allergy with Asthma: There 
Are More Than the Allergy ``Eggs'' in the Asthma ``Basket'','' 
Frontiers in Pediatrics 5 (2017): 92.
    \35\ Padmaja Subbarao, Allan Becker, Jeffrey R. Brook, et al., 
``Epidemiology of asthma: risk factors for development,'' Expert 
Review of Clinical Immunology 5, no. 1 (2009): 77-95.
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    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

[[Page 11477]]

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.36 37 38 39 40 41 42 43 44 45 46 47 48 Some studies 
found a protective effect suggesting that asthma risk was reduced with 
vaccination.49 50 51
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    \36\ H. Ross Anderson, Jan D. Poloniecki, David P. Strachan, et 
al., ``Immunization and symptoms of atopic disease in children: 
results from the international study of asthma and allergies in 
children,'' American Journal of Public Health 91, no. 7 (2001): 
1126-9.
    \37\ Kristin Wickens, Julian Crane, Trudi Kemp, et al., ``A 
case-control study of risk factors for asthma in New Zealand 
children,'' Australian and New Zealand Journal of Public Health 25, 
no. 1 (2001): 44-49.
    \38\ Frank DeStefano, David Gu, Piotr Kramarz, et al., 
``Childhood vaccinations and the risk of asthma,'' Pediatric 
Infectious Disease Journal 21, no. 6 (2002): 498-504.
    \39\ H. P. Roost, M. Gassner, L. Grize, et al., ``Influence of 
MMR-vaccinations and diseases on atopic sensitization and allergic 
symptoms in Swiss schoolchildren,'' Pediatric Allergy and Immunology 
15, no.5 (2004): 401-7.
    \40\ Julie E. Maher, John P. Mullooly, Lois Drew, and Frank 
DeStefano, ``Infant vaccinations and childhood asthma among full-
term infants,'' Pharmacoepidemiology and Drug Safety 31, no. 1 
(2004): 1-9.
    \41\ Monique Mommers, Gerard M. H. Swaen, Michela Weishoff-
Houben, et al., ``Childhood infections and risk of wheezing and 
allergic sensitisation at age 7-8 years,'' European Journal of 
Epidemiology 19, no. 10 (2004): 945-51.
    \42\ John P. Mullooly, Roberleigh Schuler, Michael Barrett, and 
Julie E. Maher, ``Vaccines, antibiotics, and atopy,'' 
Pharmacoepidemiology and Drug Safety 16, no. 3 (2007) 275-88.
    \43\ Ran D. Balicer, Itamar Grotto, Marc Mimouni, and Daniel 
Mimouni, ``Is childhood vaccination associated with asthma? A meta-
analysis of observational studies,'' Pediatrics 120, no. 5 (2007): 
e1269-77.
    \44\ Ben D. Spycher, Michael Silverman, Matthias Egger, et al., 
``Routine vaccination against pertussis and the risk of childhood 
asthma: a population-based cohort study,'' Pediatrics 123, no. 3 
(2009): 944-50.
    \45\ John P. Mullooly, John Pearson, Lois Drew, et al., 
``Wheezing lower respiratory disease and vaccination of full-term 
infants,'' Pharmacoepidemiology and Drug Safety 11, no. 1 (2002): 
21-30.
    \46\ Gabriele Nagel, Gudrun Weinmayr, Carsten Flohr, et al., 
``Association of pertussis and measles infections and immunizations 
with asthma and allergic sensitization in ISAAC Phase Two,'' 
Pediatric Allergy and Immunology 23, no. 8 (2012): 737-46.
    \47\ Hung Fu Tseng, Lina S. Sy, In-Lu Amy Liu, et al., 
``Postlicensure surveillance for pre-specified adverse events 
following the 13-valent pneumococcal conjugate vaccine in 
children,'' Vaccine 24, no. 22 (2013): 2578-83.
    \48\ Vittorio DeMicheli, Alessandro Rivetti, Maria Grazia 
Debalini and Carlo Di Pietrantonj, ``Vaccines for measles, mumps and 
rubella in children,'' Cochrane Database of Systematic Reviews 15, 
no. 2 (2012): 4, 18, 21, 135-139.
    \49\ Clara Amalie, Gade Timmermann, Christa Elyse Osuna, Ulrike 
Steuerwald, et al., ``Asthma and allergy in children with and 
without prior measles, mumps, and rubella vaccination,'' Pediatric 
Allergy and Immunology 26, no. 8 (2015): 742-749.
    \50\ John P. Mullooly, Roberleigh Schuler, Jill Mesa, et al., 
``Wheezing lower respiratory disease and vaccination of premature 
infants,'' Vaccine 29, no. 44 (2011): 7611-7.
    \51\ H. P. Roost, M. Gassner, L. Grize, et al., ``Influence of 
MMR-vaccinations and diseases on atopic sensitization and allergic 
symptoms in Swiss schoolchildren,'' Pediatric Allergy and Immunology 
15, no. 5 (2004): 401-7.
---------------------------------------------------------------------------

    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.\52\
---------------------------------------------------------------------------

    \52\ B. Laubereau, V. Grote, B. Holscher, et al., ``Vaccination 
against Haemophilus influenzae type b and atopy in East German 
schoolchildren,'' European Journal of Medical Research 7, no. 9 
(2002): 387, 389-391.
---------------------------------------------------------------------------

    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.\53\
---------------------------------------------------------------------------

    \53\ G. Benke, M. Abramson, J. Raven, et al., ``Asthma and 
vaccination history in a young adult cohort,'' Australian and New 
Zealand Journal of Public Health 28, no. 4 (2004): 337.
---------------------------------------------------------------------------

    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.\54\
---------------------------------------------------------------------------

    \54\ Jennifer A. Thomson, Constance Widjaja, Abbi A. P. 
Darmaputra, et al., ``Early childhood infections and immunisation 
and the development of allergic disease in particular asthma in a 
high-risk cohort: A prospective study of allergy-prone children from 
birth to six years,'' Pediatric Allergy and Immunology 21, no. 7: 
1076, 1079-1084.
---------------------------------------------------------------------------

    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.

[[Page 11478]]

    Tics are defined as sudden, rapid, recurrent, non-rhythmic, 
stereotyped motor movement or vocalization.\55\ 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.
---------------------------------------------------------------------------

    \55\ American Psychiatric Association, Diagnostic and 
statistical manual of mental disorders (5th ed.). (Arlington, VA: 
American Psychiatric Publishing, 2013): 81.
---------------------------------------------------------------------------

    The petition mentions a study by Barile without a citation. 
Presumably, this is the study published in the Journal of Pediatric 
Psychology in 2012.\56\ 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.\57\
---------------------------------------------------------------------------

    \56\ John P. Barile, Gabriel P. Kuperminc, Eric S. Weintraub, et 
al., ``Thimerosal Exposure in Early Life and Neuropsychological 
Outcomes 7-10 Years Later,'' Journal of Pediatric Psychology 37, no. 
1 (2012): 115.
    \57\ John P. Barile, ``Thimerosal Exposure in Early Life and 
Neuropsychological Outcomes 7-10 Years Later,'' 115.
---------------------------------------------------------------------------

    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.\58\ 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.\59\ 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.60 61 62 63 64 65 66 67 68 69 70 71 72 73
---------------------------------------------------------------------------

    \58\ Centers for Disease Control and Prevention, Understanding 
Thimerosal, Mercury, and Vaccine Safety, February 2013, https://www.cdc.gov/vaccines/hcp/patient-ed/conversations/downloads/vacsafe-thimerosal-color-office.pdf (accessed May 3, 2018).
    \59\ One single dose presentation of seasonal influenza vaccine, 
Fluvirin's single-dose presentation, utilizes thimerosal as part of 
its manufacturing process, not as a preservative, and a trace 
remains in the final presentation.
    \60\ Nick Andrews, Elizabeth Miller, Andrew Grant, et al., 
``Thimerosal Exposure in Infants and Developmental Disorders: A 
Retrospective Cohort Study in the United Kingdom Does Not Support a 
Causal Association,'' Pediatrics 114, no. 3 (2004): 584-591.
    \61\ Eric Fombonne, Rita Zakarian, Andrew Bennett, et al., 
``Pervasive Developmental Disorders in Montreal, Quebec, Canada: 
Prevalence and Links with Immunizations,'' Pediatrics 118, no. 1 
(2006): e139-150.
    \62\ Anders Hviid, Michael Stellfeld, Jan Wohlfahrt, et al., 
``Association between Thimerosal-Containing Vaccine and Autism,'' 
Journal of the American Medical Association 290, no. 13 (2003): 
1763-1766.
    \63\ Institute of Medicine, Immunization Safety Review: Vaccines 
and Autism. Institute of Medicine (Washington, DC: The National 
Academies Press, 2004): 145.
    \64\ Cristofer Price, William W. Thompson, Barbara Goodson, et 
al., ``Prenatal and Infant Exposure to Thimerosal from Vaccines and 
Immunoglobulins and Risk of Autism,'' Pediatrics 126, no. 4 (2010): 
656-664.
    \65\ Robert Schechter and Judith K. Grether, ``Continuing 
Increases in Autism Reported to California's Developmental Services 
System,'' Archives of General Psychiatry 65, no. 1 (2008): 19-24.
    \66\ William Thompson, Cristofer Price, Barbara Goodson, et al., 
``Early Thimerosal Exposure and Neuropsychological Outcomes at 7 to 
10 Years,'' The New England Journal of Medicine 357, no.13 (2007): 
12811292.
    \67\ Global Advisory Committee on Vaccine Safety, Statement on 
Thiomersal (World Health Organization, 2006): http://www.who.int/vaccine_safety/committee/topics/thiomersal/statement_jul2006/en/ 
(accessed May 3, 2018).
    \68\ Agency for Toxic Substances and Disease Registry (ATSDR), 
Toxicological Profile for Mercury. (Atlanta, GA, 1999).
    \69\ American Academy of Pediatrics, Vaccine Safety: Examine the 
Evidence, April 2013, https://www.healthychildren.org/English/safety-prevention/immunizations/Pages/Vaccine-Studies-Examine-the-Evidence.aspx?gclid=Cj0KCQjwrLXXBRCXARIsAIttmRNIMWanl3CP-P6t8eA1MPl07uJFNPpxF2dzPEJkshVq9-U5kRozmQQaAki1EALw_wcB (accessed 
May 3, 2018).
    \70\ L. Magos, ``Review on the toxicity of ethylmercury, 
including its presence as a preservative in biological and 
pharmaceutical products,'' Journal of Applied Toxicology 21 no. 1, 
(2001): 1-5.
    \71\ Robert J. Mitkus, David B. King, Mark O. Walderhaug, and 
Robert A. Forshee, ``A Comparative Pharmacokinetic Estimate of 
Mercury in U.S. Infants Following Yearly Exposures to Inactivated 
Influenza Vaccines Containing Thimerosal,'' Risk Analysis 34, no. 4 
(2014): 735-50.
    \72\ Mieszko Olczak, Michalina Duszczyk, Pawel Mierzejewski, et 
al., ``Lasting neuropathological changes in rat brain after 
intermittent neonatal administration of thimerosal,'' Folia 
Neuropathologica 48, no. 4 (2010): 258-69.
    \73\ Michael E. Pichichero, Elsa Cernichiari, Joseph Lopreiato, 
and John Treanor, ``Mercury Concentrations and Metabolism in Infants 
Receiving Vaccines Containing Thiomersal: A Descriptive Study,'' The 
Lancet 360, no. 9347 (2002): 1737-41.
---------------------------------------------------------------------------

    An initial literature search was performed looking for articles on 
tics by the two CDC employees mentioned in the petition, Dr. Thompson 
and Dr.

[[Page 11479]]

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.\74\ 
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.\75\
---------------------------------------------------------------------------

    \74\ Thompson, ``Early thimerosal exposure and 
neuropsychological outcomes at 7 to 10 years,'' 1285.
    \75\ Iqbal, ``Number of antigens in early childhood vaccines and 
neuropsychological outcomes at age 7-10 years,'' 1263, 1266.
---------------------------------------------------------------------------

    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.\76\
---------------------------------------------------------------------------

    \76\ Douglas L. Leslie, Robert A. Kobre, Brian J. Richmond, et 
al. ``Temporal Association of Certain Neuropsychiatric Disorders 
Following Vaccination of Children and Adolescents: A Pilot Case-
Control Study,'' Frontiers in Psychiatry 8, no. 3 (2017): 6.
---------------------------------------------------------------------------

    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.'' \77\ 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.\78\ 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).
---------------------------------------------------------------------------

    \77\ Kyle A. Williams and Susan E. Swedo, ``Post-infectious 
autoimmune disorders: Sydenham's chorea, PANDAS and beyond,'' Brain 
Research 1617 (2015): 145.
    \78\ Albert J. Allen, Henrietta L. Leonard, and Susan E. Swedo, 
``Case study: a new infection-triggered, autoimmune subtype of 
pediatric OCD and Tourette's syndrome,'' Journal of the American 
Academy of Child Adolescent Psychiatry 34, no. 3 (1995): 307-311.
---------------------------------------------------------------------------

    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.\79\
---------------------------------------------------------------------------

    \79\ Susan E. Swedo, James F. Leckman, and Noel R. Rose, ``From 
Research Subgroup to Clinical Syndrome: Modifying the PANDAS 
Criteria to Describe PANS (Pediatric Acute-onset Neuropsychiatric 
Syndrome),'' Pediatrics & Therapeutics 2, no. 2 (2012): 3.
---------------------------------------------------------------------------

    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.

[[Page 11480]]

    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.\80\ Some researchers question the autoimmune 
mechanism of PANDAS and no specific autoimmune antibody is agreed upon 
as a pathogenic mechanism for its symptoms.\81\
---------------------------------------------------------------------------

    \80\ Sonja Orlovska, Claus H[oslash]strup Vestergaard, Bodil 
Hammer Bech, et al., ``Association of Streptococcal Throat Infection 
with Mental Disorders: Testing Key Aspects of the PANDAS Hypothesis 
in a Nationwide Study,'' JAMA Psychiatry 74, no. 7 (2017): 741.
    \81\ Williams, ``Post-infectious autoimmune disorders: 
Sydenham's chorea, PANDAS and beyond,'' 145.
---------------------------------------------------------------------------

    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.\82\ 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.
---------------------------------------------------------------------------

    \82\ William J. Lindsey, ``EAE: History, Clinical Signs, and 
Disease Course,'' in Experimental Models of Multiple Sclerosis, 
eds..Ehud Lavi and Cris Constantinescu (New York: Springer 
Science+Business Media, Inc., 2005): 1.
---------------------------------------------------------------------------

    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.\83\ 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.
---------------------------------------------------------------------------

    \83\ IOM, Adverse Effects of Vaccines, 546-7.
---------------------------------------------------------------------------

    Multiple articles were submitted by the petitioner in support of 
adding ADEM/EAE to the 
Table.84 85 86 87 88 89 90 91 92 93 94 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.
---------------------------------------------------------------------------

    \84\ Harald H. Hofstetter, Carey L. Shive, and Thomas G. 
Forsthuber, ``Pertussis Toxin Modulates the Immune Response to 
Neuroantigens Injected in Incomplete Freund's Adjuvant: Induction of 
Th1 Cells and Experimental Autoimmune Encephalomyelitis in the 
Presence of High Frequencies of Th2 Cells,'' (animal model), The 
Journal of Immunology 169, no. 1 (2002) 117-125.
    \85\ B. Diamond, G. Honig, S. Mader, et al., ``Brain-Reactive 
Antibodies and Disease,'' Annual Review of Immunology 31 (2013): 
345-385.
    \86\ Hans Lassman, ``Acute disseminated encephalomyelitis and 
multiple sclerosis,'' Brain 133 (2010): 317-319.
    \87\ Kristina Leuner, Tanja Schutt, Christopher Kurz, et al., 
``Mitochondrion-Derived Reactive Oxygen Species Lead to Enhanced 
Amyloid Beta Formation,'' (animal study), Antioxidants and Redox 
Signaling 16, no. 12 (2012): 1421-1433.
    \88\ Dan Zhou, Rajneesh Srivastava, Stefan Nessler, et al., 
``Identification of a pathogenic antibody response to native myelin 
oligodendrocyte glycoprotein in multiple sclerosis,'' Proceedings of 
the National Academy of Sciences of the United States of America 
(PNAS) 103, no. 50 (2006): 19057-19062.
    \89\ Peter M. Clifford, Shabnam Zarrabi, Gilbert Siu, et al., 
``A[beta] peptides can enter the brain through a defective blood-
brain barrier and bind selectively to neurons,'' (animal study), 
Brain Research 1142 (2007): 223-236.
    \90\ Ralf A. Linker and De-Hyung Lee, ``Models of autoimmune 
demyelination in the central nervous system: on the way to 
translational medicine,'' Experimental & Translational Stroke 
Medicine 1, no. 5 (2009): 1-10.
    \91\ Kevin O'Connor, Katherine A. McLaughlin, Philip L. De 
Jager, et al., ``Self-antigen tetramers discriminate between myelin 
autoantibodies to native or denatured protein,'' Nature Medicine 13, 
no. 2 (2007): 211-217.
    \92\ Fabienne Brilot, Russell C. Dale, Rebecca C. Selter, et 
al., ``Antibodies to native myelinoligodendrocyte glycoprotein in 
children with inflammatory demyelinating central nervous system 
disease,'' Annals of Neurology 66, no.6 (2009): 833-42.
    \93\ Alan G. Baxter, ``The origin and application of 
experimental autoimmune encephalomyelitis,'' Nature Reviews 
Immunology 7 (2007): 904-912.
    \94\ Roberto Furlan, Elena Brambilla, Francesca Sanvito, et al., 
``Vaccination with amyloid[hyphen][beta] peptide induces autoimmune 
encephalomyelitis in C57/BL6 mice,'' Brain 126, no. 2 (2003): 285-
291.
---------------------------------------------------------------------------

    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.95 96
---------------------------------------------------------------------------

    \95\ Roger Baxter, Edwin Lewis, Kristin Goddard, et al., ``Acute 
Demyelinating Events Following Vaccines: A Case Centered Analysis,'' 
Clinical Infectious Diseases 63, no. 11 (2016): 1461.
    \96\ Joseph P. Romano, Azeem M. Shaikh, and Michael Wolf, 
``Multiple Testing,'' The New Palgrave Dictionary of Economics, 
Online Edition, eds. S.N. Durlauf and L.E. Blume (London: Palgrave 
Macmillan, 2010), 1. http://home.uchicago.edu/amshaikh/webfilespalgrave.pdf.

---------------------------------------------------------------------------

[[Page 11481]]

    Another study by Chang that analyzed post-licensure safety for 
diphtheria and acellular pertussis vaccines found no statistically 
significant adverse events including ADEM.\97\ 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.\98\ 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.
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    \97\ Soju Chang, Patrick M. O'Connor, Barbara A. Slade, and 
Emily Jane Woo, ``US post licensure safety surveillance for 
adolescent and adult tetanus diphtheria and acelluar pertussis 
vaccines: 2005-2007,'' Vaccine 31, no. 10 (2013): 1447-1452.
    \98\ Paolo Pellegrino, Carla Carnovale, Valentina Perrone, et 
al., ``Acute Disseminated Encephalomyelitis Onset: Evaluation Based 
on Vaccine Adverse Event Reporting Systems,'' PLoS One 8, no. 10 
(2013): 5.
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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.

    Dated: February 22, 2019.
George Sigounas,
Administrator, Health Resources and Services Administration.

    Approved: March 15, 2019.
Alex M. Azar II,
Secretary, Department of Health and Human Services.
[FR Doc. 2019-05618 Filed 3-26-19; 8:45 am]
 BILLING CODE 4150-28-P