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Home , MMR vaccine and autism, Side Effects (Bass book), Tetanus vaccine, Vaccine adverse event

REPORT BRIEF AUGUST 2011

.For more information visit www.iom.edu/vaccineadverseeffects

Adverse Effects of Evidence and Causality

Immunizations are a cornerstone of the nation’s efforts to protect people from a host of infectious diseases. As required by the Food and Drug Admin- istration, vaccines are tested for safety before they enter the market, and their performance is continually evaluated to identify any risks that might appear over time. Vaccines are not free from side effects, or “adverse effects,” but most are very rare or very mild. Importantly, some adverse health problems following a may be due to coincidence and are not caused by the vaccine. As part of the evaluation of vaccines over time, researchers assess evidence to deter- As part of the evaluation of mine if adverse events following are causally linked to a specific vaccines over time, researchers vaccine, and if so, they are referred to as adverse effects. Under the National assess evidence to determine if Childhood Vaccine Injury Act of 1986, Congress established the National Vac- adverse events following cine Injury Compensation Program (VICP) to provide compensation to peo- vaccination are causally linked to ple injured by vaccines. Anyone who thinks they or a family member—often a a specific vaccine, and if so, they are referred to as adverse effects. child—has been injured can file a claim. The Health Resources and Services Administration (HRSA), the agency within the Department of Health and Human Services that administers VICP, can use evidence that demonstrates a causal link between an adverse event and a vaccine to streamline the claim process. As such, HRSA asked the Institute of (IOM) to review a list of adverse events associated with vaccines covered by VICP and to evaluate the scientific evidence about the event—vac- cine relationship. The vaccines covered by VICP include all vaccines recom- mended by the Centers for Disease Control and Prevention (CDC) for routine administration in children. Adults who experience an adverse event follow- ing one of these childhood vaccines also are covered by the program. HRSA asked the IOM to review 8 of the 12 covered vac- vides an explanation of how the evidence influ- cines. These eight are the varicella enced the causality conclusions. (used against chickenpox); the influenza vaccines Based on the totality of the evidence, the com- (except for the H1N1 distributed mittee assigned each relationship to one of four in 2009); the vaccine; the human pap- categories of causation in which the evidence: illomavirus (HPV) vaccine; the , , Examining the evidence • convincingly supports a causal relationship; and rubella (MMR) vaccine; the hepatitis A vac- cine; the meningococcal vaccines, and - • favors acceptance of a causal relationship; containing vaccines that do not carry the whole- • favors rejection of a causal relationship; or cell pertussis component. • is inadequate to accept or reject a causal relationship.

Examining the Evidence The committee did not use a category to des- ignate evidence that convincingly supports no The adverse events selected by HRSA for IOM causal relationship, because it is virtually impos- review are ones for which people have submitted sible to prove the absence of a very rare relation- claims—successful or not—to VICP. The commit- ship with the same certainty that is possible to tee appointed to this study was not asked to assess establish the presence of one. the benefits or effectiveness of vaccines but only the risk of specific adverse events. Its conclusions reflect the best evidence available at the time. Some Evidence Convincingly Supports of the adverse events the committee examined already are accepted in the medical community, a Causal Relationship but they are minor or manageable—for example, The committee concludes that the evidence con- a sudden allergic reaction called that vincingly supports a causal relationship between can follow the administration of some vaccines. some vaccines and some adverse events. In its report, the committee explains its pro- As a live vaccine, the varicella zoster vaccine cess for evaluating the list of adverse events and is linked to four specific adverse events, all due to provides a set of 158 causality conclusions. The from the vaccine virus strain: committee examined two types of evidence: epi- • Disseminated varicella infection (widespread demiologic evidence, which derives from studies chickenpox rash shortly after vaccination) of populations, and mechanistic evidence, which • Disseminated varicella infection with sub- draws from biological and clinical studies. The sequent infection resulting in pneumonia, committee evaluated each scientific article for , or hepatitis in individuals with its strengths and weaknesses and then assigned a demonstrated immunodeficiencies “weight of evidence” ranking to both the epide- miologic and mechanistic bodies of studies. • Vaccine strain viral reactivation (appear- The committee considered the weights of ance of chickenpox rash months to years evidence and then reached a conclusion about after vaccination) the causal relationship between each vaccine and • Vaccine strain viral reactivation with sub- adverse health problem pairing. The commit- sequent infection resulting in meningitis or tee began from a position of neutrality, presum- encephalitis (inflammation of the brain) ing neither causation nor lack of causation, and moved from that position only when the combi- The MMR vaccine is linked to a disease called nation of evidence suggested a more definitive measles inclusion body encephalitis, which in assessment regarding causation. The figure pro- very rare cases can affect people whose immune

2 The committee began from a position of neutrality, presum- ing neither causation nor lack of causation, and moved from that position only when the combina- tion of evidence suggested a more definitive assessment regarding causation.

systems are compromised and usually occurs and a mild and temporary oculorespiratory within a year of acute measles infection or vacci- syndrome, which is characterized by con- nation. The MMR vaccine also is linked to febrile junctivitis, facial swelling, and upper respi- seizures, which are a type of seizure that occurs ratory symptoms, including coughing and in infants and young children in association with wheezing. fever. Febrile seizures are generally benign and hold no long-term consequences. Six types of vaccines—MMR, varicella zoster, Evidence Favors Rejection of a influenza, hepatitis B, meningococcal, and tetanus- containing vaccines—are linked to anaphylaxis. Causal Relationship The committee also found convincing evi- The evidence favors rejection of five vaccine– dence of a causal relationship between injection of adverse event relationships: vaccine, independent of the involved, and • MMR vaccine and two types of adverse events, including syncope, or fainting, and deltoid bursitis, or frozen shoulder, • MMR vaccine and type 1 diabetes characterized by shoulder pain and loss of motion. • DTaP (tetanus) vaccine and type 1 diabetes • Inactivated influenza vaccine and Bell’s palsy (weakness of the facial nerve) Evidence Favors Acceptance of • Inactivated influenza vaccine and exacer- a Causal Relationship bation of asthma or reactive airway disease The evidence favors acceptance of four vaccine– episodes in children and adults adverse event relationships. In these cases, the evidence is strong and generally suggestive, but not firm enough to be described as convincing. These relationships include: Evidence Inadequate to Accept or Reject a Causal Relationship • HPV vaccine and anaphylaxis; For the vast majority, (135 vaccine-adverse event • MMR vaccine and transient arthralgia (tem- pairs), the evidence is inadequate to accept or reject porary joint pain) in female adults; a causal relationship. In many cases, the adverse • MMR vaccine and transient arthralgia in event being examined is an extremely rare condi- children; and tion, making it hard to study. In these cases, there • certain trivalent inactivated influenza vac- was not adequate evidence to determine if the vac- cines used in Canada in some recent years cine was or was not causally associated.

3 Committee to Review Adverse Effects of Vaccines Susceptibility

Ellen Wright Clayton (Chair) Anthony L. Komaroff As some of the conclusions suggest, individuals with Craig-Weaver Professor of Steven P. Simcox, Patrick ; Director, Center for A. Clifford, and James H. certain characteristics are more likely to suffer cer- Biomedical Ethics and Society; Higby Professor of Medicine; Professor of Law; Vanderbilt Senior , Brigham and tain adverse effects from particular . University Women’s Hospital; Harvard Inmaculada B. Aban Individuals who have serious immunodeficiencies Associate Professor, Depart- B. Paige Lawrence ment of , University Associate Professor of are clearly at increased risk for specific adverse of Alabama, Birmingham Environmental Medicine; reactions to live viral vaccines, such as MMR and Douglas J. Barrett Associate Professor of Professor, Departments of Microbiology and , varicella vaccines. Thus, the committee was able Pediatrics, Molecular Genetics University of Rochester School & Microbiology, and , of Medicine and at times to reach more limited conclusions for sub- Immunology, & Laboratory M. Louise Markert Medicine at the University Of Associate Professor of groups of the population. Florida College Of Medicine Pediatrics and Immunology, Martina Bebin Division of Pediatric Associate Professor of Neurol- and Immunology, Department ogy and Pediatrics, University of Pediatrics, Duke University of Alabama at Birmingham Medical Center Conclusion Kirsten Bibbins-Domingo Ruby H.N. Nguyen (Resigned Associate Professor and March 2010) In applying consistent standards across all the evi- Attending Physician, University Assistant Professor, Division of of California, San Francisco and , University of Minnesota dence, the committee found that some conclusions Graham A. Colditz (Resigned School of August 2010) were easy to reach: the evidence was clear and con- Associate Director for Preven- Marc C. Patterson tion and Control, Alvin J. Chair, Division of Child and sistent or, in the extreme, completely absent. Others Siteman Cancer, and Niess- Adolescent ; Gain Professor in the School Professor of Neurology, required substantial discussion and debate. of Medicine, Department of Pediatrics, and Medical , Washington University Genetics; Director, Child The committee was not charged with making Neurology Training Martha Constantine-Paton Program, Mayo Clinic recommendations, and it did not pinpoint any par- Investigator, McGovern Institute for Brain Research; Professor Hugh A. Sampson ticular areas for continued research. Much research of Biology, Department of Biol- Professor of Pediatrics and ogy, Department of Brain and Immunology; Dean for Trans- already occurs to determine the safety of vaccines for Cognitive Sciences, Massachu- lational Biomedical Sciences; setts Institute of Technology Director of the Jaffe Food the populations for whom they are recommended. Allergy Institute, Mount Sinai Deborah J. del Junco School of Medicine Senior Epidemiologist and However, there is much to learn about the human Associate Professor of Bio- Pauline A. Thomas , autoimmunity, and the effects of statistics, Epidemiology, and Associate Professor, Depart- Research Design, University of ment of Preventive Medicine genetic variation, all of which may influence how Texas Health Science Center at and Community Health, New Houston Jersey Medical School; and Associate Professor, School people respond to vaccines. Betty A. Diamond of Public Health, University of Head, Center for Autoimmune Medicine and Dentistry of New Vaccines offer the promise of protection against and Musculoskeletal Disease, Jersey The Feinstein Institute for a variety of infectious diseases. Despite much media Medical Research, North Shore- Leslie P. Weiner LIJ Richard Angus Grant, Sr. Chair attention and strong opinions from many quarters, in Neurology; Professor of S. Claiborne Johnston Neurology and Molecular vaccines remain one of the greatest tools in the pub- Associate Vice Chancellor of Microbiology and Immunology, Research; Director, Clinical and Keck School of Medicine, lic health arsenal. Certainly, some vaccines result in Translational Science, Institute University of Southern Professor of Neurology and California adverse effects that must be acknowledged. But the Epidemiology; Director, Neurovascular Disease and latest evidence shows that few adverse effects are Stroke Center; University of California, San Francisco caused by the vaccines reviewed in this report.

Study Staff

Kathleen Stratton William McLeod Study Director Senior Research Librarian Andrew Ford Hope Hare Program Officer Administrative Assistant Erin Rusch Amy Pryzbocki Research Associate Financial Associate Trevonne Walford Rose Marie Martinez Research Assistant (from Director, Board on Population 500 Fifth Street, NW August 2009) Health and Public Health Practice Washington, DC 20001 TEL 202.334.2352 Study Sponsor FAX 202.334.1412 The Health Resources and Services Administration www.iom.edu The Centers for Disease Control and Prevention The National Vaccine Program Office The Institute of Medicine serves as adviser to the nation to improve health. Established in 1970 under the charter of the National Academy of Sciences, the Institute of Medicine provides independent, objective, evidence-based advice to policy makers, health professionals, the private sector, and the public. Copyright 2011 by the National Academy of Sciences. All rights reserved. DETAILED INFORMATION

Advising the nation / Improving health

For more information visit www.iom.edu/vaccineadverseffects

Adverse Effects of Vaccines Evidence and Causality

FIGURE

Strength of Evidence that Determined the Causality Conclusions EPIDEMIOLOGIC ASSESSMENT MECHANISTIC ASSESSMENTCAUSALITY CONCLUSION Low- Inadequate High Moderate High (decreased risk Moderate (decreased risk Inter- Inter- to Accept Favors Favors Convincingly (increased risk) or no eect) (increased risk) or no eect) LimitedSInsucient trong mediate mediate Weak Lacking or Reject Rejection Acceptance Supports

High (increased risk) Convincingly Supports

Strong

Moderate (increased risk) Favors Acceptance Inter- mediate

High (decreased risk Favors or no e ect)* Rejection

Moderate (decreased risk or no e ect), Limited, or Insu‹cient** Inadequate to Accept or Reject Low-Intermediate, Weak, or Lacking***

* Causality conclusion is favors rejection only if mechanistic assessment is not strong or intermediate. ** Causality conclusion is inadequate to accept or reject only if mechanistic assessment is not strong or intermediate. *** Causality conclusion is inadequate to accept or reject only if epidemiologic assessment is not high (increased risk), high (decreased risk or no eect), or moderate (increased risk).

The Institute of Medicine serves as adviser to the nation to improve health. Established in 1970 under the charter of the National Academy of Sciences, the Institute of Medicine provides independent, objective, evidence-based advice to policy makers, health professionals, the private sector, and the public. TABLE: Summary of Causality Conclusions

Vaccine Adverse Event Causality Conclusion

Varicella Disseminated varicella infection (widespread chickenpox rash shortly after vaccination) Convincingly Supports

Disseminated varicella infection with subsequent infection resulting in pneumonia, Varicella Convincingly Supports a meningitis, or hepatitis

Vaccine strain viral reactivation (appearance of chickenpox rash months to years after Varicella Convincingly Supports vaccination)

Vaccine strain viral reactivation with subsequent infection resulting in meningitis or Varicella Convincingly Supports encephalitis (inflammation of the brain)

MMR Measles inclusion body encephalitis Convincingly Supports a, b

Febrile seizures (a type of seizure that occurs in association with fever and is generally MMR Convincingly Supports regarded as benign)

MMR Anaphylaxis (a very rare but sudden allergic reaction) Convincingly Supports

Varicella Anaphylaxis Convincingly Supports

Influenza Anaphylaxis Convincingly Supports

Hepatitis B Anaphylaxis Convincingly Supports c

Tetanus Anaphylaxis Convincingly Supports

Meningococcal Anaphylaxis Convincingly Supports

Injection-Related Event Deltoid bursitis (frozen shoulder, characterized by shoulder pain and loss of motion) Convincingly Supports

Injection-Related Event Syncope (fainting) Convincingly Supports

HPV Anaphylaxis Favors Acceptance

MMR Transient arthralgia (temporary joint pain) in women Favors Acceptance d

MMR Transient arthralgia in children Favors Acceptance

Oculorespiratory syndrome (a mild and temporary syndrome characterized by conjunc- Influenza Favors Acceptance e tivitis, facial swelling, and upper respiratory symptoms)

MMR Autism Favors Rejection

Influenza Inactivated influenza vaccine and Bell’s palsy (weakness or paralysis of the facial nerve) Favors Rejection

Inactivated influenza vaccine and asthma exacerbation or reactive airway disease epi- Influenza Favors Rejection sodes in children and adults

MMR Type 1 diabetes Favors Rejection

DT, TT, or aP containing Type 1 diabetes Favors Rejection a The committee attributes causation to individuals with demonstrated immunodeficiencies. b The committee attributes causation to the measles component of the vaccine. c The committee attributes causation to yeast-sensitive individuals. d The committee attributes causation to the rubella component of the vaccine. e The committee attributes causation to two particular vaccines used in three particular years in Canada.

All other causality conclusions are the evidence is inadequate to accept or reject a causal relationship.