1

Introduction

Protecting health is a major priority of society, families, and individual parents. Over the past 100 years there has been a revolution in the ability to protect health in the developed world, where there are resources to enable this to happen. In 1900, among every 1,000 babies born in the United States, 100 would die before their first birthday, and five before 5 years of age (Guyer et al., 2000). By 2007, fewer than seven were expected to die before their first birthday, and only 0.29 per 1,000 before 5 years of age (HHS, 2010). Diseases severe enough to kill children and adults can also leave survivors disabled in some way, and as mortality has fallen, so has the chance of severe disability from these diseases.

Among the dangers for children and adults that have greatly diminished over the past century are infectious diseases. For bacterial diseases, antibiotics have been developed to treat infections before permanent harm can occur. For many viral and bacterial diseases, vaccines now exist.

In the early 20th century, smallpox (which has 30 percent mortality and a very high rate of disfigurement and other less common sequelae including blindness and encephalopathy) and rabies (virtually 100 percent fatal) could be prevented with immunization (CDC, 2001, 2008). With the fast growing understanding of microbes and immunity from 1920 onward, the development of immunizations became a race to “conquer” infectious disease. Beginning with the combination diphtheria, pertussis, and tetanus immunization during World War II and most recently with immunization to prevent cervical cancer (the human papillomavirus vaccine), immunizations have changed our expectations for child and adult health. Infections are less of a terror, and children are expected to survive to adulthood.



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1 Introduction Protecting health is a major priority of society, families, and individual parents. Over the past 100 years there has been a revolution in the ability to protect health in the developed world, where there are resources to en- able this to happen. In 1900, among every 1,000 babies born in the United States, 100 would die before their first birthday, and five before 5 years of age (Guyer et al., 2000). By 2007, fewer than seven were expected to die before their first birthday, and only 0.29 per 1,000 before 5 years of age (HHS, 2010). Diseases severe enough to kill children and adults can also leave survivors disabled in some way, and as mortality has fallen, so has the chance of severe disability from these diseases. Among the dangers for children and adults that have greatly diminished over the past century are infectious diseases. For bacterial diseases, antibi- otics have been developed to treat infections before permanent harm can occur. For many viral and bacterial diseases, vaccines now exist. In the early 20th century, smallpox (which has 30 percent mortality and a very high rate of disfigurement and other less common sequelae including blindness and encephalopathy) and rabies (virtually 100 percent fatal) could be prevented with immunization (CDC, 2001, 2008). With the fast growing understanding of microbes and immunity from 1920 onward, the development of immunizations became a race to “conquer” infectious disease. Beginning with the combination diphtheria, pertussis, and tetanus immunization during World War II and most recently with immunization to prevent cervical cancer (the human papillomavirus vaccine), immunizations have changed our expectations for child and adult health. Infections are less of a terror, and children are expected to survive to adulthood. 27

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28 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY Vaccines function by stimulating the immune system and prompt - ing a primary immune response to an infecting pathogen or to molecules derived from a particular pathogen. The immune response elicited by this primary exposure to vaccine pathogen creates immunological memory, which involves the generation of a pool of immune cells that will recognize the pathogen and mount a more robust or secondary response upon subse- quent exposure to the virus or bacterium. In successful immunization, the secondary immune response is sufficient to prevent disease in the infected individual, as well as prevent the transmission of the pathogen to others. For communicable diseases, immunizations protect not only the individual who receives the immunization, but also others with whom he or she has contact. High levels of vaccination in a community increase the number of people who are less susceptible or resistant to illness and propagation of the infectious agent. Unvaccinated individuals or those who have not developed immunity to this pathogen are afforded an indirect measure of protection because those with immunity reduce the spread of the pathogen throughout the entire population. The larger the proportion of people with immunity, the greater the protection of those without immunity. This effect is called “herd immunity.” Herd immunity is an important phenomenon as immunization programs rarely achieve 100 percent immunization in a population; and in some cases, previously vaccinated persons may not exhibit effective immunity and disease may result from exposure to the pathogen. For protection, immunization of not only ourselves but also our neighbors is important. The overwhelming safety and effectiveness of vaccines in current use in preventing serious disease has allowed them to gain their preeminent role in the routine protection of health. Before an immunization is introduced for population-wide use, it is tested for efficacy and safety. However, im- munization is not without risks. For example, it is well established that the oral polio vaccine on rare occasion causes paralytic polio and that vaccines sometimes lead to anaphylactic shock. Given the widespread use of vaccines; state mandates requiring vaccination of children for entry into school, college, or day care; and the importance of ensuring that trust in im- munization programs is justified, it is essential that safety concerns receive assiduous attention. Congress passed the National Childhood Vaccine Injury Act (NCVIA, P.L. 99-660) in 1986. The legislation was intended to bolster vaccine re- search and development through federal coordination of the vaccine ef- forts in government and by providing relief to vaccine manufacturers who reported at the time that financial burdens from awards in the tort system threatened their financial viability. The legislation was also intended to ad- dress concerns about the safety of vaccines by instituting a compensation program financed by an excise tax on covered vaccines, setting up a passive surveillance system for vaccine adverse events, and by providing informa-

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29 INTRODUCTION tion to consumers (CDC, 2010). Key provisions of the 1986 legislation include • The establishment of the National Vaccine Program Office, which coordinates immunization-related activities between all Depart- ment of Health and Human Services (HHS) agencies including the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration, the National Institutes of Health, and the Health Resources and Services Administration (HRSA). • The requirement that all health care providers who administer vaccines provide a vaccine information statement (VIS) to the vac- cine recipient, or his or her parent or legal guardian, prior to each dose. Each VIS contains a brief description of the disease as well as the risks and benefits of the vaccine. The CDC develops VISs and distributes them to state and local health departments as well as individual providers. • The requirement that health care providers must report certain and are encouraged to report other adverse events (health effects occurring after immunization that may or may not be related to the vaccine) following vaccination to the Vaccine Adverse Event Reporting System. • The creation of the National Vaccine Injury Compensation Pro- gram (VICP) to compensate those injured by vaccines on a no-fault basis. Importantly, this compensation system has two parts: ○ The Secretary of Health and Human Services has created a Vaccine Injury Table (Table) that “lists and explains injuries/ conditions that are presumed to be caused by vaccines. It also lists time periods in which the first symptom of these injuries/ conditions must occur after receiving the vaccine. If the first symptom of these injuries/conditions occurs within the listed time periods, it is presumed that the vaccine was the cause of the injury or condition unless another cause is found” (http:// www.hrsa.gov/vaccinecompensation/table.htm) and compensa- tion is awarded. ○ Individuals who assert that they suffered an injury from a vaccine that is not on the Table (“off-Table” or “causation-in- fact”) must pursue their claim before Special Masters, who are appointed by the United States Court of Federal Claims, which hears any appeals. Claimants bear the burden of proving that the vaccine caused their injury, although the burden of proof is lower than that in the tort system. A key component of the legislation, found in Sections 312 and 313, required the HHS secretary to consult with the Institute of Medicine (IOM)

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30 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY to review the scientific literature on vaccine safety. Two reports were issued (IOM, 1991, 1994). These reports contain a framework for causality as- sessment of vaccine adverse events.1 The reports addressed the vaccines covered by the VICP up to that point: diphtheria and tetanus toxoids and whole cell pertussis vaccine and other tetanus toxoid–containing vaccines; measles, mumps, and rubella (MMR) vaccines; Haemophilus influenzae type B vaccine; hepatitis B vaccine; and both inactivated and oral polio vaccines.2 The reports informed the secretary’s review of the Vaccine Injury Table. The reports have also been referenced extensively as a source of definitive scien- tific understanding of the evidence by Special Masters in decisions regarding injuries not listed on the Vaccine Injury Table. The IOM was subsequently asked to review specific vaccine safety concerns in a series of reports requested by the CDC. These reports (IOM, 2001a,b, 2002a,b, 2003a,b, 2004a,b) included causality assessments simi- lar to the previous IOM reports, but included other conclusions and recom- mendations regarding research, communications, and policy review. CHARGE TO THE COMMITTEE In 2009 HRSA requested that the IOM convene a committee of experts to review the epidemiological, clinical, and biological evidence regarding adverse health events associated with specific vaccines covered by the VICP. The committee was charged with developing a consensus report with con- clusions on the evidence bearing on causality and the evidence regarding the biological mechanisms that underlie specific theories for how a specific vaccine is related to a specific adverse event. The vaccines to be reviewed include varicella zoster vaccine, influenza vaccines (but not 2009 H1N1 vaccine), hepatitis B vaccine, human papillomavirus vaccine, tetanus-con- taining vaccines other than those containing the whole cell pertussis com- ponent, MMR vaccine, hepatitis A vaccine, and meningococcal vaccines. It is expected that the report will provide the scientific basis for review and adjudication of claims of vaccine injury by the VICP. HRSA presented a list of specific adverse events for the committee to review (see Table 1-1). The selection criteria were described at the first committee meeting (Johann-Liang, 2009) as including the vast majority of adverse events in the claims for compensation. The committee added ad- verse events to the list if it identified epidemiologic studies or case reports 1 Adverse events are distinguished from adverse effects in that an event is something that occurs but may not be causally associated, whereas an adverse “effect” implies causation. All adverse effects are adverse events, but not all adverse events are adverse effects. 2 Vaccines are included in the VICP if they are recommended by the CDC for routine admin- istration in children and are subject to an excise tax. Adults who experience an adverse reac- tion to one of these “childhood” vaccines are also covered by the program.

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TABLE 1-1 Adverse Events Included in the Vaccine Chapters DT–, TT–, and aP– Injected- MMR Varicella Influenza Hepatitis Hepatitis HPV Containing Meningococcal Related Vaccine Vaccine Vaccine A Vaccine B Vaccine Vaccine Vaccines Vaccine Events Adverse Event Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Chapter 9 Chapter 10 Chapter 11 Chapter 12 ● Disseminated Oka VZV without Other Organ Involvement ● Disseminated Oka VZV with Subsequent Infection Resulting in Pneumonia, Meningitis, or Hepatitis ● Vaccine Strain Viral Reactivation without Other Organ Involvement ● Vaccine Strain Viral Reactivation with Subsequent Infection Resulting in Meningitis or Encephalitis ● Measles Inclusion Body Encephalitis ● ● ● ● ● Encephalitis ● ● ● ● ● ● Encephalopathy ● Infantile Spasms 31 continued

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TABLE 1-1 Continued 32 DT–, TT–, and aP– Injected- MMR Varicella Influenza Hepatitis Hepatitis HPV Containing Meningococcal Related Vaccine Vaccine Vaccine A Vaccine B Vaccine Vaccine Vaccines Vaccine Events Adverse Event Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Chapter 9 Chapter 10 Chapter 11 Chapter 12 ● ● ❍ ● ● Seizures ❍ ● Meningitis ● Cerebellar Ataxia ● ● Ataxia ● ● Autism ● ● ● ● ● ● ● ● Acute Disseminated Encephalomyelitis ● ● ● ● ● ● ● ● Transverse Myelitis ❍ ❍ ❍ ❍ Optic Neuritis ❍ ● ● ● Neuromyelitis Optica ● ● ● ● ● ● ● Multiple Sclerosis ● First Demyelinating Event ● ● ● ● ● ● ● ● Guillain-Barré Syndrome ● ● ● ● ● ● ● Chronic Inflammatory Disseminated Polyneuropathy ● ● Opsoclonus Myoclonus Syndrome

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● ● ● Bell’s Palsy ● ● ● ● Brachial Neuritis ● Amyotrophic Lateral Sclerosis ❍ ● Small Fiber Neuropathy ● ● ● ● ● ● ● ● Anaphylaxis ● Chronic Urticaria ● Serum Sickness ● Asthma ❍ Erythema Nodosum ● ● Systemic Lupus Erythematous ● ● Vasculitis ● ● Polyarteritis Nodosa ● Psoriatic Arthritis ● Reactive Arthritis ● Rheumatoid Arthritis ● Juvenile Idiopathic Arthritis ● ● ● ● ● Arthropathy (Arthralgia and Arthritis) 33 continued

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TABLE 1-1 Continued 34 DT–, TT–, and aP– Injected- MMR Varicella Influenza Hepatitis Hepatitis HPV Containing Meningococcal Related Vaccine Vaccine Vaccine A Vaccine B Vaccine Vaccine Vaccines Vaccine Events Adverse Event Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Chapter 9 Chapter 10 Chapter 11 Chapter 12 ● ● ● Type 1 Diabetes ● Hepatitis (Autoimmune) ● Myocarditis ● Pancreatitis ● ● Hepatitis ● Thromboembolic Events ❍ ● Stroke ● Hypercoagulable States ● Myocardial Infarction ● Chronic Fatigue Syndrome ● Chronic Headaches ● ● ● ● Fibromyalgia ● Sudden Infant Death Syndrome ● Hearing Loss ❍ All-Cause Mortality ● Oculorespiratory Syndrome

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● Thrombocytopenia ● Immune Thrombocytopenic Purpura ● Complex Regional Pain Syndrome ● Deltoid Bursitis ● Syncope NOTE: Adverse events indicated by “❍” were added to the list by the committee. 35

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36 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY for an adverse event not originally assigned by HRSA. These additions were all-cause mortality and seizures following influenza vaccine; optic neuritis following MMR, influenza, hepatitis B, and diphtheria, tetanus, and pertus- sis (DTaP) vaccines; neuromyelitis optica and meningitis following MMR vaccine; erythema nodosum following hepatitis B vaccine; and stroke and small fiber neuropathy following varicella vaccine. The committee was also tasked with addressing, as time and evidence allowed, general considerations. These included: underlying (susceptible) populations, “immune dysfunction,” vaccine administration issues, appro- priate time intervals for anaphylaxis and autoimmune diseases, and sequen- tial vaccination issues. The committee addressed some of these, as described in Chapters 4–12. It is important to note that the committee was not tasked with assessing the benefits (effectiveness) of vaccines or any policy issues related to vaccination. The task is clearly focused on an assessment only of the risk of vaccines. COMMITTEE PROCESS The committee was composed of individuals with expertise in pediat- rics, internal medicine, neurology, immunology, immunotoxicology, neu- robiology, rheumatology, epidemiology, biostatistics, and law. Appendix F includes biographical sketches of the committee members. The committee met eight times between April 2009 and March 2011. The committee held open sessions at three of these meetings. Appendix G includes agendas of these open meetings. The committee’s methodology and approach to their task is described in Chapter 2. OUTLINE OF THE REPORT Chapter 2 details the committee’s methodology. Chapter 3 discusses generally possible mechanisms of vaccine injury. Chapters 4–11 present the evidence reviewed by the committee for each of the eight vaccines covered and the conclusions it reaches. Chapter 12 presents causality assessments for adverse events that can occur with any injected vaccine regardless of the vaccine antigen and components. The committee discusses some special considerations of its work in Chapter 13. REFERENCES CDC (Centers for Disease Control and Prevention). 2001. Vaccinia (smallpox) vaccine rec- ommendations of the Advisory Committee on Immunization Practices (ACIP), 2001. Morbidity & Mortality Weekly Report 50(RR-10). CDC. 2008. Human rabies prevention. Morbidity & Mortality Weekly Report 57(RR-3):1-36.

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37 INTRODUCTION CDC. 2010. History of vaccine safety. http://www.cdc.gov/vaccinesafety/Vaccine_Monitoring/ history.html (accessed August 1, 2011). Guyer, B., M. A. Freedman, D. M. Strobino, and E. J. Sondik. 2000. Annual summary of vital statistics: Trends in the health of Americans during the 20th century. Pediatrics 106(6):1307-1317. HHS (U.S. Department of Health and Human Services). 2010. Deaths: Final data for 2007. National Vital Statistics Reports 58(19). IOM (Institute of Medicine). 1991. Adverse effects of pertussis and rubella vaccines: A report of the committee to review the adverse consequences of pertussis and rubella vaccines. Washington, DC: National Academy Press. IOM. 1994. Adverse events associated with childhood vaccines: Evidence bearing on causality. Washington, DC: National Academy Press. IOM. 2001a. Immunization safety review: Measles-mumps-rubella vaccine and autism. Washington, DC: National Academy Press. IOM. 2001b. Immunization safety review: Thimerosal-containing vaccines and neuro- developmental disorders. Washington, DC: National Academy Press. IOM. 2002a. Immunization safety review: Hepatitis B vaccine and demyelinating neurological disorders. Washington, DC: The National Academies Press. IOM. 2002b. Immunization safety review: Multiple immunizations and immune dysfunction. Washington, DC: National Academy Press. IOM. 2003a. Immunization safety review: SV40 contamination of polio vaccine and cancer. Washington, DC: The National Academies Press. IOM. 2003b. Immunization safety review: Vaccinations and sudden unexpected death in infancy. Washington, DC: The National Academies Press. IOM. 2004a. Immunization safety review: Influenza vaccines and neurological complications. Washington, DC: The National Academies Press. IOM. 2004b. Immunization safety review: Vaccines and autism. Washington, DC: The National Academies Press. Johann-Liang, R. 2009. Charge to the Institute of Medicine Committee to Review Adverse Effects of Vaccines. Paper read at the Meeting of the Institute of Medicine Committee to Review of Adverse Effects of Vaccines, Washington, DC.

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