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s Vaccine Injury The occurrence of adverse reactions to vaccines raises numerous questions of the magnitude of risk to the individual compared with overall benefits to the population, of how to protect those at increased risk, of the potential for vaccine Improvement, or appr~- priate compensation for injuries, and of the effects of vaccine-related injury liability on vaccine production and utilization. The first section of this chapter focuses on the factors that impede efforts to establish cause-and-effect relationships in cases of vaccine-related injury, and the problem of determining the true frequencies of adverse effects among vaccinees. The second section consists of a review of scientific data on major adverse reactions to commonly used domestic vaccines for children and adults. Chapter 6 examines the legal ramifications of vaccine injury and compensation issues, and the effect of the current state of the law on vaccine production and innovation. The mechanisms most likely to ensure rapid identification of vaccine-related injuries and improved coordination of vaccine improvement efforts are discussed more fully in Chapter 7. Adverse reactions have been attributed to various vaccines ror many years, but until recently few scientifically acceptable efforts have been made to determine the frequency of these events. One reason for this situation is that many of the diseases for which effective vaccines have been developed were so feared by the public and the medical community that at first the side effects of immunization were ignored or accepted as a necessary evil. Fifty years ago, when an estimated 2 million or more cases of whooping cough with 7,000 deaths occurred annually in the United States, little attention was paid to the rare infant who displayed severe symptoms following inoculation with the newly developed vaccine. Similarly, the anxiety created by the specter of more than 20,000 new cases of paralytic poliomyelitis each year weighed heavily when compared with the possibility of an occasional case of vaccine-related poliomyelitis. Furthermore, the actual incidence of vaccine-related poliomyelitis could not be determined until the vaccine had been in use for several years. As serious vaccine-preventable diseases have become rarities in the United States, the attention focused on adverse reactions has 65

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66 increased. This situation will continue because the immunization programs must be maintained to prevent resurgence of the diseases.!' The nation's limited ability to deal with the consequences of vaccine injury derives partly from the lack of a unified approach to the problem. Responsibilities for identifying vaccine-associated risks, stimulating research to improve implicated vaccines, and testing and producing these improved products are diffused among the public and private components of the vaccine production enterprise (Chapter 2~. The Office of Biologics Research and Review (OBRR) of the Food and Drug Administration (FDA) is responsible for ensur ing the safety and efficacy of vaccine products for use in clinical trials or by the public. While extensive data are examined before licensing, it is not possible prior to widespread use to detect adverse reactions that occur at very low frequencies. In all approval processes for drugs and biological products, a balance must be established between increasing the stringency of testing requirements to ensure safety and placing much-needed products on the market without unreasonable delay. The committee believes that the quality control testing required by the FDA provides adequate safeguards against the risks of injury from an improperly manufactured vaccine. However, no practical mechanism is available for ensuring before licensing that a vaccine is totally free of possible adverse reactions for all individuals, nor is it reasonable to require this for continued licensing. Adverse events following immunization are reported to the FDA by manufacturers, pharmacists, physicians, and the military, and to the Centers for Disease Control {CDC) by the parents or guardians of children who receive federally funded vaccines.3 Although these reporting systems are useful, neither of them provides an adequate basis for estimation of the total number of events that occur, in part because most reporting is voluntary. Even if reporting were mandatory, however, the data would not allow determination of the number of events actually caused by, rather than coincidental to, the administration of vaccines because information on similar events in unvaccinated individuals is not collected. Use of licensed vaccines is guided by the recommendations of several groups, including the Immunization Practices Advisory Committee of the CDC, the Committee on Infectious Diseases of the American Academy of Pediatrics, and the American College of Physicians. Their recommendations generally attempt to identify two groups: those who would benefit from immunization with a specific vaccine and those for whom vaccination Is contraindicated because of increased risk of possible adverse reactions. Increasing the awareness of contraindications to specific vaccines among health care providers and the public is important in minimizing the potential for vaccine-related injury. This would be an important function of the vaccine commission proposed in Chapter 7 and of any entity established to oversee compensation to injured individuals. Identification of true vaccine-related injuries and the development of strategies to minimize their occurrence are made difficult by many factors:

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67 1. Serious or permanent reactions to vaccines are very rare, occurring once in many thousands or millions of doses administered; thus, inordinately large populations must be studied to identify these reactions and determine their incidence. 2. Many suspected vaccine reactions constitute or resemble disease syndromes that occur for other reasons, known or unknown. This problem was illustrated by the difficulty in determining how many of the cases of the Guillain-Barre syndrome that occurred during the swine flu episode were actually attributable to the vaccine and how many would have occurred anyway (the so-called background cases). 3. Preexisting abnormalities that evolve gradually or that are not yet clinically apparent when the vaccine is given may cause confusion. This problem is of particular importance in relation to vaccines given to young infants, in whom serious underlying neurological abnormalities may not become obvious until later stages of development. 4. Clinically and pathologically, the manifestations of many suspected reactions to vaccines are nonspecific and may be associated with a variety of disease entities. Therefore, the symptoms may be of little or no use in assigning causation. 5. Basic understanding of the pathogenesis of reactions to vaccines often is lacking. 6. Enormous problems exist in the ascertainment of reactions. Vaccines are administered by a wide variety of providers, whose interpretations of events following vaccine administration may vary. Over-reporting of alleged reactions often occurs as a result of publicity, but both over-reporting and under-reporting may occur for a variety of reasons. For example, selective reporting of problems in children who had a prior history of receipt of DTP may have occurred because of widespread publicity about the risks of the vaccine. 7. The costs and logistics necessary to overcome these problems for a prospective study of vaccine reactions may be prohibitive, making such studies of low public priority. 8. Even when studies are conducted on large populations, the number of individuals incurring reactions to a vaccine may be so few that estimates of rates are imprecise. For example, if a study involved 300,000 individuals receiving a given immunization and if it were found that eight developed serious reactions (of a type that did not occur in the unvaccinated control population), the reaction rate would be estimated to be approximately 27 per million doses. However, given the small number of individuals with reactions (eight), the so-called 9S percent confidence limits on that rate would be 12 and 53 per million. This means that there is a 95 percent probability that the true rate of reactions lies somewhere between 12 and 53 per million doses. Furthermore, there is a 5 percent chance that the rate might be either lower than 12 or greater than 53 per million doses. Consequently, the estimate of 27 per million is hardly precise. The Pertussis Controversy The controversy surrounding the pertussis component of the DTP {diphtheria-tetanus-pertussis) vaccine provides a good example of the

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68 difficulties in establishing a cause-and-effect relationship based on a temporal association between the vaccine and an untoward event. An alleged reaction to a vaccine may represent one of four events: (1) the vaccine may have caused the disorder; (2) the vaccine may have triggered or precipitated manifestations of an underlying disease destined to appear in the immediate future with or without the vaccine; (3) concern about minor reactions to a vaccine (such as discomfort and fever) may have prompted recognition of previously existing but unnoticed symptoms; or (4) the timing of administration of the vaccine simply may have coincided with the appearance of an unrelated disease problem. To provide maximum protection, the administration of vaccines to children customarily begins in the first few months of life, when many inherent developmental and neurological abnormalities, such as cerebral palsy or mental retardation of unknown cause, are not yet manifest. Infants and young children also are particularly susceptible to events that may cause death or future disability, such as the sudden infant death syndrome (SIDS) and infections leading to acquired central nervous system damage. The appearance of one of these conditions shortly after vaccination may be misinterpreted as a cause-and-effect situation, difficult to prove or disprove in an individual case. Many of the alleged severe injuries from pertussis vaccine, such as infantile spasms, have not been found to be caused by the vaccine, temporal associations notwithstanding.4'5 This distinction between temporal association and causation may not be grasped readily by lay jurors and others who are unaccustomed to dealing with the concept, and most explanations are based on complex epidemiology that is even more difficult to comprehend. Therefore, juries faced with a seriously damaged child and agonized family, who date the onset of disability from the approximate time of vaccination, are understandably sympathetic to the plaintiffs. Identifying Individuals at High Risk of Adverse Effects The effort to prevent adverse reactions by identifying high-risk individuals before immunization also is complicated by the time element. For example, live viral vaccines are contraindicated in children with certain immunodeficiency syndromes, but these hereditary syndromes are rarely recognized before 2 months of age (unless a sibling has been affected), the time at which routine immunization usually begins. Children with unrecognized congenital combined immunodeficiency syndrome may be among those who develop vaccine- induced paralytic poliomyelitis, for example. It is important to note, however, that they constitute a minority of those affected: the majority of the rare cases of vaccine-related paralytic poliomyelitis occur in persons who cannot be distinguished immunologically from normal persons even after the event. Thus, except for the rare immunodeficient child who is in jeopardy

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69 from any live viral vaccine, identification of individuals at high risk of disabling adverse reactions is not possible at present. Indeed, prior identification may never be possible because some or many of these reactions may be idiosyncratic. From the foregoing, it is clear that conclusions about cause and effect and rates of adverse reactions to vaccines should be drawn only from carefully designed, well-controlled, epidemiological studies. Until recently, few studies have approached these criteria, and available rate estimates have been characterized by wide confidence limits. Mechanisms dependent on the voluntary reporting of events associated with the administration of vaccines have not provided accurate or useful information about the frequency of vaccine-related adverse reactions. The following is a review of definitive studies and reports of reactions to commonly used vaccines for children and adults. Only major reactions sufficient to justify medical intervention or posing a risk of death or permanent disability are described in detail. Minor reactions, such as local tenderness at the site of injection, low- grade fever, and malaise, are largely ignored. VACCINES USED IN CHILDHOOD Pertussis Vaccine Pertussis vaccine is assumed to be the most reactive component of the familiar, triple-antigen DTP preparation. It also is the child- hood immunizing agent that has caused the greatest concern. Because the immunity-producing antigents) of the pertussis organism has eluded identification and purification for many years, the vaccine consists of the whole, killed organism. Reactions to DTP may be divided into three categories.6 The first comprises minor local and systemic effects, usually limited to the first 48 hours after inoculation. The second category includes certain responses that traditionally have caused parents and physi- cians some concern, but that have not been shown to have permanent consequences. These include excessive somnolence and protracted, inconsolable crying. More alarming to parents and providers are an unusual shock-like state with hypotonicity and hyporesponsiveness and short-lived convulsions, usually febrile. The third category includes major neurological reactions, often followed by permanent disability. Among the minor, expected reactions to DTP is fever (39C or more), which may occur~in up to 7 percent of children. Rarely, fever may exceed 40.5C, which is considered an indication to replace subsequent doses of DTP with DT. More severe local reactions occur occasionally, with considerable swelling and redness at the site of injection, sometimes followed by a ~knot" in the subcutaneous tissue that may persist for weeks. Rarely, a sterile abscess occurs. These more severe local reactions usually are attributed to the aluminum salts

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70 employed as adjutants in the vaccine, and occur more often with subcutaneous than with intramuscular injections of the material. A vaccine that contained two or three times the usual amount of aluminum adjuvant was withdrawn from the market when it was found to be associated with an excess of sterile abscesses.7 Rarely, small clusters of septic abscesses have occurred;8 these usually have been shown to be caused by inadvertent contamination of a single multiple-dose dial of vaccine during use. Cody et al. have provided the best data on the frequency of the more common reactions to DTP, especially those due to the pertussis component. In their study, symptoms occurring within 48 hours after inoculation in infants and children who received DTP were compared with those in infants and children who received DT. Drowsiness, irritability, and anorexia were observed frequently following both vaccines, though at least twice as often after DTP. Vomiting also was more frequent following DTP, occurring in about 6 percent of infants. Persistent crying occurred in about 3 percent of infants receiving DTP, which was more than four times as often as it occurred in recipients of DT. In about a third of the DTP recipients, crying persisted more than 3 hours and in a few it was described as high pitched and unusual. Recovery appeared to be complete in all cases. The study by Cody et al. involved the administration of almost 16,000 doses of DTP. Among those who received the vaccine, nine infants (0.06 percent) experienced short-lived convulsions within 24 hours after inoculation. In all but two, the episodes were associated with fever; none required hospitalization and all appeared to recover completely. For this and other reasons it is generally believed that a simple, short-lived febrile convulsion following DTP immunization does not produce permanent sequelae. In addition, nine infants exhibited the shock-like or collapse state for several hours following injection; all survived without apparent sequelae. Most public advisory committees concerned with general immunization recommendations agree that fever of 40.5C or more, excessive crying for 4 or more hours, a shock-like episode, or a convulsion following an injection of DTP contraindicates further use of preparations containing pertussis vaccine; DT (or Td, depending on the age of the child; see Diphtheria Toxoid, below) should be employed.l,ll Recently, the Surgeon General's Immunization Practices Advisory Committee (ACIP) has recommended delaying the initiation or continuation of DTP immunization in children with symptoms of underlying neurological disease until those symptoms have been clarified.12 Severe neurological disease, the third type of alleged untoward event following DTP, has been the subject of many reports, mostly anecdotal and uncontrolled.13 These reports describe an acute encephalopathy with convulsions and coma, often resulting in severe, permanent intellectual and neurological impairment. No characteristic picture has been recognized to differentiate post-vaccine encephalo- pathy from other acute central nervous system syndromes, nor has a unique pathology been identified. Confusion about the frequency of

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71 such a syndrome, and even whether it can be attributed to pertussis vaccine, has resulted because of difficulties in differentiating true vaccine-related encephalopathy from coincidental or pre-existing evolving neurological syndromes in these infants and children. Some clarification of these issues has been provided, however, by a recent National Childhood Encephalopathy Study (NCES) of acute encephalopathy in infants and children in the United Kingdom.l4~15 In the study, individuals with otherwise unexplained acute encepha- lopathy were about twice as likely to have received an injection of DTP in the previous week as normal, matched controls. The results may be interpreted as indicating that DTP is responsible for about two- thirds of all cases of acute encephalopathy (otherwise not explainable) occurring within a week of inoculation, and that the remainder must be ascribed to other causes. From these data the frequency of encephalopathy with residual brain damage 1 year after DTP is estimated to be 1 per 310,000 doses. Thy 95 percent confidence limits of this risk are 1 per 54,000 to 1 per 5,310,000 doses. This suggests that 1 in 100,000 infants who receive the three recommended doses in the first year of life incurs brain damage. However, it should be noted that children with encephalopathy ware less likely than unaffected controls to have received DTP 8 to 28 days prior to onset. This suggests that some of the observed excess risk of encephalopathy in the 7 days following administration of DTP reflects the accelerated appearance or recognition of underlying disorders that were destined to become manifest within a few weeks.l6 Because there do not appear to be substantive differences between DTP preparations in the United Kingdom and those in the United States, the results of this study suggest that 36 of the approximately 3,650,000 infants born in the United States in 1982 might have incurred permanent brain damage from DTP, if all infants received three doses in the first year of life. A lower rate is suggested by study from Sweden, which indicates that encephalopathy with residue occurs in approximately 1 child in 170,000 who receives three doses of the vaccine (i.e., 1 per 510,000 doses).17 Extrapolation of the Swedish data to the United States population indicates that permanent disability would occur in 22 infants in each annual birth cohort of 3,650,000, assuming all receive three doses in the first year. Further analysis of the data from the British encephalopathy study has clarified the relationship between DTP and infantile spasms, a syndrome that usually appears in the first 6 months of life and that frequently presages severe, permanent neurological disability. Some cases are caused by congenital or metabolic defects, but for others no cause is found. Occasional temporal associations between the admini- stration of DTP and the appearance of infantile spasms led to the concern that the two might be related. The NCES data clearly indicate that DTP does not cause infantile spasms; instead, overt manifestations of infantile spasms may be recognized 1 to 3 weeks earlier than usual because irritability and other minor symptoms secondary to the DTP attract attention to the child's preexisting neurological condition.4 Another problem of major importance is whether DTP might, in some

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72 cases, induce SIDS. About 5,000 infants succumb to SIDS annually in the United States. Because SIDS occurs most frequently in the first 6 months of life, when primary immunization with DTP is begun, questions have arisen about the possible relationship of DTP to this problem. This concern received added impetus from a cluster of cases of SIDS in Tennessee in 1979, but attribution of this cluster to DTP was confounded by enhanced immunization efforts in Tennessee directed at children of lower socioeconomic status who are at higher risk of SIDS, and by intensified surveillance. 8 More recently, a study in Los Angeles of infants who succumbed to SIDS seemed to show a causal connection.l9 On preliminary analysis, the time distribution of DTP vaccinations in the 28 days prior to death suggested a distinct temporal association between DTP and death. This study could have been affected by recall bias,\however, because families who incur a tragedy such as SIDS are much more likely to recall events that occurred immediately preceding the unfortunate episode. Further, the authors failed to take into consideration week-by-week age-specific incidence rates of SIDS, which are already declinin,Oby the time the first dose of DTP is given (approximately 2 months). Thus, such a temporal relationship would be expected even in the absence of causation. Paradoxically, a similar temporal association, though not as strong, was found between SIDS and a recent physician visit without administration of DTP. Definitive evidence that DTP is not causally related to SIDS has been provided by a case-control study conducted by the National Institute of Child Health and Human Development.2 In this study, infants succumbing to SIDS were, if anything, less apt to have been inoculated with DTP in the recent past than matched control infants. These findings have been confirmed by a case-control study from the United Kingdom.22 Thus, reasonable confidence can be expressed that SIDS is not a consequence of DTP. Although it is likely that the pertussis component of DTP is responsible for rare instances of encephalopathy, there is no evidence that other untoward, disabling neurological events can be attributed to the vaccine. Conditions such as transverse myelitis, Guillain-Barre syndrome, and peripheral neuropathy have not been reported to result from DTP, although occasionally they have been attributed to other vaccines. Advisory committees concerned with vaccine recommendations occasionally have alluded to thrombocytopenia and hemolytic anemia as rare sequelae of DTP immunization. Causative relationships have not been established, however, and it is likely that any apparent temporal associations are coincidental and can be explained by background rates of these conditions at the age when vaccinations are initiated. Diphtheria Toxoid Active immunization against diphtheria is accomplished with diphtheria toxoid, an inactivated toxin that retains immunizing potential. For primary immunization of children it is almost always

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73 administered in combination with tetanus toxoid and pertussis vaccine as DTP. DT, a combination of diphtheria and tetanus toxoids, is administered to children who should not receive pertussis vaccine. A combination containing less diphtheria toxoid, Td, is administered to children over the age of 7 and adults for primary and booster immunization. Diphtheria toxoid produces frequent minor local and systemic reactions, but these are transient and of no serious consequence. No doubt, both diphtheria and tetanus toxoids contribute to these types of reactions to DTP. In the past, however, less refined diphtheria toxoid preparations were responsible for more severe local and systemic reactions, presumably hypersensitive in nature. These reactions may have been caused, in part, by extraneous proteins present in the toxoid preparations. They also occurred more frequently in adults and in individuals already shown to be immune to diphtheria by Schick testing, including persons who had received repeated doses of toxoid.23 Elimination of these more severe, often temporarily disabling, reactions has been accomplished in two ways e First, better purification procedures probably have removed many of the extraneous proteins. Second, for primary and booster immunization of adults and older children, Td is employed; this preparation contains one-tenth to one-fifth as much diphtheria toxoid as DTP or DT.24 There is no evidence that diphtheria toxoid produces fatal or permanently disabling reactions. Tetanus Toxoid In a review of reactions to tetanus toxoid, it was stated that they "do not endanger life, do not leave any sequelae, and do not occur in more than about 1 percent of adults, mainly the over-immunized.825 For these reasons and in light of the remarkable efficacy of tetanus toxoid, the benefit-risk ratio of this preparation is considered to be unusually high. Local reactions (swelling, redness, pain, and sometimes a more severe Arthus-type response) occur, but these are transient and without sequelae. Similarly, fever and malaise lasting a day or two occasionally occur. Urticarial reactions also have been described. These untoward events appear to occur most often following the administration of toxoid as a booster to individuals who are already well immunized or hyperimmunized, particularly adults.26 Very rarely, true anaphylaxis involving tetanus toxoid does occur. In confidential material submitted to the Panel on Review of Bacterial Vaccines and Toxoids, Bureau of Biologics, FDA, by manufacturers, anaphylaxis was reported at a rate of 1 per 1.5 to 2 million doses. No fatal episode has been described. Single anecdotal reports of temporal associations between tetanus toxoid administration and other sequelae, such as peripheral neuropathy and serum sickness, have been difficult to evaluate and probably involve coincidence.

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74 Poliomyelitis Vaccines Two types of poliomyelitis vaccines are now available in the united States. The orally administered, live attenuated vaccine (OPV), contains all three types of poliovirus and is generally recommended for routine use. The inactivated poliovirus vaccine (IPV), which also contains all three strains, was used for routine immunization against poliomyelitis from the mid-1950s until the early 1960s, when OPV became widely available. OPV became the preferred vaccine because it was believed to provide more permanent immunity, to prevent transmission by creating intestinal immunity, and to offer better community protection by person-to-person transmission of vaccine virus.27 The only known untoward effect of OPV is the rare appearance of paralytic poliomyelitis in recipients of the vaccine or in nonimmune contacts of vaccinees.28 Induction of paralytic disease appears to be caused by a change in the vaccine virus to a more virulent form in the recipient or contact. Immunodeficient individuals are at special risk. Poliovirus recovered from affected persons usually can be classified as either vaccine-derived or "wild" type (naturally occurring) by special laboratory techniques. Between 1969 and 1982, about 320 million doses of OPV were distributed. Vaccine-associated paralytic poliomyelitis was recognized in 94 apparently normal individuals during those 14 years. Twenty-eight were recipients and the remainder were household or community contacts. Thus, for recipients the risk appears to be less than about 1 per 11 million doses. A numerical risk for household and community contacts cannot be determined because of the impossibility of estimating the denominator of individuals exposed. During the 14 years, an additional 15 immunodeficient individuals acquired paralytic poliomyelitis, 14 from vaccine virus as either recipients or contacts, and 1 from the wild virus. In contrast, the current inactivated poliovirus vaccine (IPV) is without risk of vaccine-related poliomyelitis. For this reason and because a more potent inactivated vaccine has been developed in Europe, the desirability of switching back from OPV to IPV for routine immunization against poliomyelitis in the United States is being examined.29 The complexity of such a decision has been emphasized by Alexander,30 including uncertainties about optimum dosage schedules and lingering doubts about the effects of IPV on the circu- lation of wild poliovirus in the population. of major importance is the fact that surveillance of untoward events following immunization with the newer IPV has been insufficient to determine the potential incidence of rare but disabling sequelae following its administration. Measles Vaccine The measles vaccine contains live, attenuated measles virus and is usually administered in combination with rubella and mumps vaccines (MMR). A single injection at 15 months of age is recommended. Five

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75 to 15 percent of recipients incur a mild, measles-like illness with fever of 39.4C or more about a week after immunization, and occasional transient rashes also occur.31 Rarely, a febrile seizure may ensue. These responses do not produce permanent sequelae. The importance of measles in the past was largely measured by pneumonia, which occurred in approximately 10 percent of cases and was often fatal, especially in malnourished and debilitated children. Even today it is estimated by the World Health Organization that about 1.5 million children worldwide succumb to measles annually, almost all in less technologically developed countries. In the United States and other developed countries, pneumonia secondary to measles became less of a threat, even prior to development of the vaccine. There are two important central nervous system complications of measles, acute encephalitis and subacute sclerosing panencephalitis (SSPE or Dawson's encephalitis).31 The former occurs in about 1 in 1,000 cases of measles, and results in death or permanent central nervous system disability in about 40 percent of affected individuals. Subacute sclerosing panencephalitis (SSPE) is a slowly progressive complication of measles, beginning months or years after the disease and associated with progressive central nervous system deterioration and, usually, death. There is convincing evidence that SSPE is a slow virus infection with the measles agent. Because measles vaccine is live, it is important to consider the possibility that it might produce measles encephalitis. Reports of encephalopathy following this vaccine in the United States are rare and anecdotal, and do not prove cause and effect. However, data from the NCES suggest that encephalitis with or without sequelae occurs in 1 in 87,000 immunizations (95 percent confidence limits 1 per 2S,000 to 1 per 830,000 immunizations).15 Reports of post-vaccination encephalitis submitted to the CDC suggest that the rate in the united States is much lower (less than 1 in a million). SSPE, which appears to occur at a rate of about 1 per 100,000 cases of measles disease, is more difficult to monitor. In particular, concern has been expressed about SSPE related to measles vaccine because the disease appears to occur more often following milder cases of clinical measles. Rare instances of SSPE following measles vaccine have been reported, but it is possible that these may have resulted from Unapparent, mild episodes of measles in infancy.3 Reported cases in the United States have declined steadily over the years that the vaccine has been used widely.31 Thus, it appears that the risk of SSPE from the vaccine, if any, is far less than that from the disease. The measles vaccine virus is grown in chick embryo culture, and traces of egg protein may be present in the vaccine. In the past, these minute amounts of egg protein were considered insufficient to cause allergic reactions, but recent reports have indicated that extremely rare anaphylactic-type reactions do occur, almost always in individuals with a strong history of similar reactions following the ingestion of eggs.31 A history of such reactions is now considered a contraindication to the administration of measles vaccine. Measles in pregnancy has been associated with excessive fetal

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76 wastage and, in one report, an excess of congenital anomalies.31 Although there is no report of problems following the administration of measles vaccine in pregnancy, on theoretical grounds and because of the possibility of confusion about causation if an unrelated fetal defect were to occur, the administration of measles vaccine during pregnancy is inadvisable. -Persons with immunodeficiencies, congenital or acquired through disease or pharmacological agents, should not receive measles vaccine because of the enhanced potential for viral replication. Rubella Vaccine Rubella vaccine, usually given in combination with measles and mumps vaccine (MMR), is a live, attenuated viral vaccine. It is also available in combination with measles vaccine and in monovalent form. Because it is a live vaccine, it is reasonable to consider whether complications of the disease also might follow administration of the vaccine to susceptible individuals. Important disease complications include post-rubella encephalitis, the congenital rubella syndrome, purpura, and arthritis.32 Encephalitis following rubella disease is rare, probably occurring in less than 1 per 5,000 cases.33 Though rubella encephalitis is occasionally fatal, sequelae in survivors appear to be uncommon. Experience over 15 years indicates that encephalitis is not a compli- cation of rubella vaccine. Of major concern is the theoretical possibility of vaccine-induced congenital rubella syndrome following administration of the vaccine to rubella-susceptible women in the first trimester of pregnancy. This concern was enhanced by the recovery of vaccine virus from the aborted fetuses and placentae of a few rubella-susceptible women who received the vaccine in the first trimester.34 However, from 1971 to 1983, 213 rubella-susceptible women who received rubella vaccine within 3 months before or after conception have been followed to term. All of these pregnancies resulted in normal infants, including two pairs of twins, without signs of the congenital rubella syndrome.35 This study indicates that the syndrome, if it ever occurs from the vaccine, does so at a far lower rate than that observed following natural disease. (Estimation of confidence limits indicates 95 percent probability that the rate of the syndrome following immunization is no more than 1.7 percent, if it occurs at all.) Nonetheless, authorities recommend deferring rubella immunization in pregnant women and the avoidance of pregnancy in nonpregnant women for 3 months following rubella immunization, if only because of possible confusion about cause and effect if an infant is born with a coincident anomaly. Because vaccine recipients rarely, if ever, transmit vaccine virus to susceptible contacts, 36 there is no reason to withhold rubella immunization from a child whose mother or other household contact is pregnant. There is no evidence that the transient purpura observed after natural rubella occurs following rubella immunization.

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77 As with the natural disease, rubella-susceptible individuals who receive the vaccine may exhibit transient joint pains 1 to 3 weeks following immunization.36 Occasionally, clinical arthritis or transient peripheral neuropathy with pain and paresthesia in the extremities occurs.36 Higher rates of these reactions appear in women, especially adolescents and young adults, than in children. These joint manifestations are almost always transient. Recently, however, it has been recognized that rare instances of persistent or recurrent arthropathy occur following rubella vaccine or the natural disease. Although some of these may represent temporal association of other joint conditions with rubella disease or receipt of rubella vaccine, it appears that at least some may be attributable to the infection or vaccine.37 The vast majority of cases apparently caused by the vaccine or illness have been reported in young adult women, which may be due in part to the fact that adult males may be less likely to receive the vaccine. Vaccine or wild virus has been recovered from lymphocytes and occasionally from joint fluids of such persons long after the original infection or inoculation. Curiously, it appears that this syndrome of persistent arthropathy may be a consequence of a secondary exposure to the rubella virus or vaccine. Whether the mechanism relates to circulating antibody-virus complexes or whether it is attributable to persistent virus in tissues, such as joints, is uncertain.38 Since 1979, the United States rubella vaccine has been grown in human cells, rather than in duck embryo cell cultures. Thus, the current rubella vaccine exhibits no risk of egg hypersensitivity, in contrast to measles and mumps vaccines. Mumps Vaccine Mumps vaccine, which contains live, attenuated mumps virus, usually is administered in combination with measles and rubella vaccines (MMR) The important complications of mumps disease (meningoencephalitis, permanent nerve deafness, and orchitis) rarely, if ever, occur following mumps immunization.39 The rare reports of transient neurological sequelae following receipt of mumps vaccine probably represent other coincidental diseases. Although natural mumps infection during pregnancy does not appear to cause congenital defects, avoidance of administration of mumps vaccine during pregnancy is recommended on theoretical grounds. Similarly, as with all live viruses, it is recommended that mumps vaccine be avoided in individuals with congenital or acquired immunodeficiencies. Mumps vaccine is propagated in chick embryo culture. It is possible that individuals who exhibit anaphylactic responses to elf products could experience similar episodes following the vaccine. Although there are contradictory data relating mumps to diabetes mellitus, there is no evidence that the vaccine is causatively related to the disease.39~40

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78 VACCINES FOR ADULTS The following vaccines are used primarily in adults, but are recommended for children and adolescents under certain circumstances. Influenza Vaccines Vaccines for viral influenza, types A and B. contain inactivated preparations produced in embryonated chicken eggs. Given that the antigenic constituents of prevalent influenza viruses vary from year to-year, viral strains incorporated into the vaccine must be changed annually.41 Transient local and systemic reactions to influenza vaccines occur at low but predictable rates, but these are usually minor and of no permanent consequence.41 Two types of reactions of major conse- quence have been described. The first of these comprises anaphylactic responses to traces of egg protein present in the vaccine.41 These reactions, though frightening and potentially life-endangering, are usually effectively treated pharmacologically and result in no sequelae. The second major putative reaction is Guillain-Barre syndrome, approximately 500 cases of which were reported following swine flu vaccine administration to almost 41.5 million people in 1976.42 This unprecedented experience appears to have been unique to that particular vaccine. No prior association between influenza vaccines and this syndrome had been recognized, and careful monitoring of recipients of influenza vaccine subsequently has demonstrated no excess of this disease in association with other influenza vac- cines.41 Why this sequela was unique to the swine flu vaccine is unknown. The incidence of Guillain-Barre syndrome peaked 2 to 3 weeks following administration of the swine flu vaccine.42 The precise incidence rate of the disease following the vaccine has been difficult to determine, however, because the syndrome occurs at low rates for other and unknown reasons throughout the year and, particularly for cases that occurred 6 or more weeks following vaccine administration, attribution of the disease to the vaccine has been difficult. Pneumococcal Vaccines Pneumococcal vaccine is used to prevent pneumonia and other severe pneumococcal diseases. It is prepared from the carbohydrate of the organism's capsule, which is the major virulence factor of the pneumococcus and also the antigen responsible for inducing clinical immunity. The vaccine contains capsular antigens from the 23 serotypes of pneumococci that are responsible for the majority of severe pneumo- coccal disease. Although the vaccine may be responsible for some annoying local reactions and rare systemic responses such as fever and

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79 possibly anaphylaxis, no permanent sequelae have been attributed to this preparation.43 Booster doses are not recommended, however, because they result in more severe, though transient, local and systemic reactions.43 Meningococcal Vaccines Vaccines against meningococcal infections contain the type-specific capsular carbohydrate of the organism. Ninety-five percent of meningococcal meningitis is caused by types A, B. and C. Type A, the epidemic strain, has been inexplicably rare in the United States for almost 30 years. Thus, current low rates of endemic meningococcal disease in the United States are due almost entirely to types B and C.44 To date, it has not been possible to produce a protective type B vaccine. Of the two preparations available, one includes types A and C, and the other types A, C, Y. and W-135 (the Y and W-135 strains are infrequently associated with disease). These vaccines are recommended only for use under special circumstances, such as travel to endemic areas and during local outbreaks in the United States.45 Minor local and systemic reactions occur at low rates following injections of meningococcal vaccine. One instance of anaphylaxiS following a booster dose has been reported, but otherwise there is no evidence of major risk from these vaccines.44 Rabies Vaccine Rabies vaccines, containing killed rabies virus, are used for two purposes in the United States: (1) post-exposure prophylaxis against the disease in individuals who have been bitten by an animal shown or suspected to have been rabid and (2) pre-exposure prophylaxis of individuals who are anticipated to be at high risk of exposure because of occupation or travel to areas of high endemicity.46 Until about 30 years ago in the United States, rabies vaccines were prepared in neurological tissues of various animals (this remains the practice in many other countries). These vaccines resulted in low but nonetheless unacceptable rates of serious reactions, often involving the nervous system. From the mid-1950s until 1980, killed rabies vaccine was prepared in embryonated duck eggs; this vaccine, though far safer than the former preparation, resulted in undesirable rates of severe allergic reactions.47 Since 1980, the vaccine of choice in the United States has been an inactivated vaccine prepared in human cell tissue culture; approximately 100,000 persons have received a total of about 400,000 doses.48 Reactivity is low in most persons. However, approximately 1 per 1,000 vaccinees has exhibited a systemic allergic reaction, usually of the serum sickness type and most often occurring with the fifth (booster) dose. Almost all have occurred in persons immunized electively because of potential occupational exposure, and all reactions have been followed by complete recovery.

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80 Hepatitis B Vaccine Hepatitis B vaccine, licensed for use in the united States in 1982, is prepared from human plasma that contains the infective antigen (HBsAg). The antigen is extracted from plasma and submitted to a series of procedures known to inactivate hepatitis B virus and representative viruses from all other groups.- Use of the vaccine is recommended for individuals at high risk of hepatitis49 because of occupation, specific medical problems, or life-style. As of February 1984, 1,400,000 doses of the vaccine had been distributed, and it is estimated that 450,000 individuals have received at least two of the three recommended doses.50 Although minor local reactions have been observed occasionally following the vaccine, there has been no evidence of severe or life-endangering sequelae. Because the vaccine has been prepared from plasma of individuals at high risk of acquired immune deficiency syndrome (AIDS), careful surveillance has been conducted for this compli- cation. The inactivation processes to which the vaccine is slubmitted make it highly unlikely that any viral agent could survive. Accumulating epidemiologic evidence further indicates that the vaccine does not serve as a risk factor for AIDS.51 Thus, there is no evidence that hepatitis B vaccine is associated with permanent or disabling sequelae. SUMMARY Vaccines licensed in the United States provide excellent protection to society against their target diseases and are safe for an over- whelming proportion of recipients. They are not, however, universally effective or completely safe. The judgment as to what is adequately safe is difficult, and decisions on the urgency with which improvement of vaccines needs to be pursued depends on the undesirability of the risks of vaccination in relation to the risks of disease, and on other health needs. Adverse events following immunization are reported to the FDA by manufacturers, pharmacists, physicians, and the military, and to the CDC by the parents or guardians of children who receive federally funded vaccines. Although these reporting systems are useful, neither of them provides an adequate basis for estimation of the total number of events that occur, in part because reporting is voluntary. Even if reporting were mandatory, however, the data would not allow determina- tion of the number of events actually caused by, rather than coinciden- tal to, the administration of vaccines because information on similar events in unvaccinated individuals is not collected. Conclusions about cause and effect and rates of adverse reactions to vaccines should be drawn only from carefully designed, well-controlled epidemiological studies. Responsibilities for identifying vaccine-associated risks, promoting awareness of contraindications to vaccination, and completing all of the steps required for vaccine improvement are now poorly defined and

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81 coordinated. Proposals outlined elsewhere in this report should ensure greater cooperation among the multiple public and private components of the vaccine innovation and immunization effort. REFERENCES AND NOTES 1. Centers for Disease Control. 1982. Pertussis-England and Wales. Morbid. Mortal. Weekly Rept. 31:629-631. 2. Kanai, K. 1980. Japan's experience in pertussis epidemiology and vaccination in the past 30 years. Jpn. J. Med. Sci. Biol. 33:107-143. 3. Centers for Disease Control. 1985. Adverse events following immunization. Morbid. Mortal. Weekly Rept. 34:43-47. 4. Bellman, M.H., Ross, E.M., and Miller, D.L. 1983. Infantile spasms and pertussis immunization. Lancet 1:1031-1033. 5. Melchior, J.C. 1977. Infantile spasms and early immunization against whooping cough: Danish survey from 1970 to 1975. Arch. Dis. Child. 52:134-137. 6. Mortimer, E.A., Jr., and Jones, P.K. 1979. An evaluation of pertussis vaccine. Rev. Infect. Dis. 1:927-932. Bernier, R.H., Frank, J.A., Jr., and Nolan, T.F., Jr. 1981. Abscesses complicating DTP vaccination. Am. J. Dis. Child. 135:826-828. 8. Centers for Disease Control. 1982. Group A streptococcal abscesses after DTP immunization-Georgia. Morbid. Mortal. Weekly Rept. 31:519-520, 525-526. 9. Cody, C.L., Baraff, L.J., Cherry, J.D., Marcy, S.M., and Manclark, C.R. 1981. Nature and rates of adverse reactions associated with DTP and DT immunizations in infants and children. Pediatrics 68:650-660. 10. Centers for Disease Control. 1981. Recommendations of th e Immunization Practices Advisory Committee (ACIP). Diphtheria, tetanus, and pertussis: guidelines for vaccine prophylaxis and other preventive measures. Morbid. Mortal. Weekly Rept. 30:392-407. 11. American Academy of Pediatrics. 1982. PertuSSiS. Pp. 198-202 in Report of the Committee on Infectious Diseases, J.O. Klein, P.A. Brunell, J.D. Cherry, and V.A. Fulginiti, eds. Evanston, I11.: American Academy of Pediatrics. 12. Centers for Disease Control. 1984. Supplementary statement of contraindications to receipt of pertussis vaccine. Morbid. Mortal. Weekly Rept. 33:169-171. 13. Griffith, A.H. 1978. Reactions after pertussis vaccine: a manufacturer's experiences and difficulties since 1964. Br. Med. J. 1:809-815. 14. Miller, D.L., Ross, E.M., Alderslade, R., Bellman, N.H., and Rawson, N.S.B. 1981. Pertussis immunisation and serious acute neurological illness in children. Br. Med. J. 282:1595-1599. 15. Department of Health and Social Security. 1981. Whooping cough: reports from the Committee on Safety of Medicines and the

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82 23. Joint Committee on Vaccination and Immunisation, Department of Health and Social Security. London: Her Majesty's Stationery Office. 16. Committee interpretation of material in reference 15. 17. Strom, J. 1967. Further experience of reactions, especially of a cerebral nature, in conjunction with triple vaccination: a study based on vaccinations in Sweden 1959-1965. Br. Med. J. 4:320-323. 18. Centers for Disease Control. 1979. DTP vaccination and sudden infant deaths-Tennessee. Morbid. Mortal. Weekly Rept. 28:131-132. 19. Baraff, L.J., Ablon, W.J., and Weiss, R.C. 1983. Possible temporal association between diphtheria-tetanus toxoid-pertussis vaccination and sudden infant death syndrome. Pediatr. Infect. Dis. 2:7-11. Mortimer, E.A., Jr., Jones, P.K., and Adelson, L. 1983. DTP and SIDS (letter). Pediatr. Infect. Dis. 2:492. 21. Hoffman, H.S., Hunter, J.C., and Hasselmeyer, E.G. 1982. SIDS and DTP. Pp. 79-88 in 17th Immunization Conference Proceedings, Atlanta, Gal, May 18-19, 1982. Atlanta, Gal: Centers for Disease Control. Taylor, E.M., and Emery, J.L. 1982. Immunization and cot deaths. Lancet II:721. Edsall, G. 1952. Immunization of adults against diphtheria and tetanus. Am. J. Public Health 42:393-400. 24. Edsall, G., Altman, J.S., and Gaspar, A.J. 1954. Combined tetanus-diphtheria immunization of adults: use of small doses of diphtheria toxoid. Am. J. Public Health 44:1537-1545. 25. Editorial. 1974. Reactions to tetanus toxoid. Br. Med. J. 1:48. 26. Edsall, G., Elliott, M.W., Peebles, T.C., Levine, L., and Eldred, M.C. 1967. Excessive use of tetanus toxoid boosters. JAMA 202:17-19. Institute of Medicine. 1977. Evaluation of Poliomyelitis Vaccines. Washington, D.C.: National Academy PresS. 28. Kim-Farley, R., Bart, K., Schonberger, L., Orenstein, W., Hinman, A., Rew, O., Hatch, M., and Kaplan, J. 1983. Has indigenous wild paralytic poliomyelitis been eliminated from the united States? Pp. 43-47 in 18th Immunization Conference Proceedings, Atlanta, Gal, May 16-19, 1983. Atlanta, Gal: Centers for Disease Control. . McBean, A.M., Thoms, M.L., Johnson, R.H., Gadless, B.R., MacDonald, B., Nerhood, L., Cummings, P., Hughes, J., Kinnear, J., Watts, C., Kraft, M., Albrecht, P., Boone, E.J., and Bernier, R. 1983. Preliminary results from a comparative trial of live and inactivated polio vaccines. Pp. 49-55 in 18th Immunization Conference Proceedings, Atlanta, Ga, May 16-19, 1983. Atlanta, Gal: Centers for Disease Control. 30. Alexander, E.R. 1984. Inactivated poliomyelitis vaccination. Issues reconsidered. J. AMA 251:2710-2712. 31. Centers for Disease Control. 1982. Recommendations of the Immunization Practices Advisory Committee (ACIP). Measles prevention. Morbid. Mortal. Weekly Rept. 31:217-231.

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83 32. 33. Krugman, S., and Katz, S.L. 1981. Infectious Diseases of Children. St. Louis: Mosby. Sherman, F.E., Michaels, R.H., and Kenny, F.M. 1965. Acute encephalopathy (encephalitis) complicating rubella. JAMA 192:91-97. 34. Horstmann, D.M. 1982. Rubella. Pp. 519-539 in viral Infections of Humans, A.S. Evans, ed. New York: Plenum. 35. Centers for Disease Control. 1984. Rubella vaccination during pregnancy-United States, 1971-1983. Morbid. Mortal. Weekly Rept. 33:365-368, 373. 36. Preblud, S.R., Serdula, M.K., Frank, J.A., Jr., Brandling-Bennett, A.D., and Hinman, A.R. 1980. Rubella vaccination in the united States: a ten-year review. Epidemiol. Rev. 2:171-194. 37. Tingle, A.J., Yang, T., Allen, M., Kettyls, G.D., Larke, R.P.B., and Schulze, M. 1983. Prospective immunological assessment of arthritis induced by rubella vaccine. Infect. Immun. 40:22-28. 38. Vergani, D., Morgan-Capner, P., Davies, E.T., Davies, A.W., Tee, D.E.H., and Pattison, J.R. 1980. Joint symptoms, immune complexes and rubella. Lancet II:321-322. 39. Centers for Disease Control. 1982. Recommendations of the Immunization Practices Advisory Committee (ACIP). Mumps vaccine. Morbid. Mortal. Weekly Rept. 31:617-625. 40. Feldman, H.A. 1982. Mumps. Pp. 419-440 in Viral InfectiOnS of Humans, A.S. Evans, ed. New York: Plenwn. 41. Centers for Disease Control. 1984. RecommendatiOns of the Immunization Practices Advisory Committee (ACIP). Prevention and control of influenza. Morbid. Mortal. Weekly Rept. 33:253-266. 42. Schonberger, L.B., Bregman, D.J., Sullivan-Bolyai, J.Z., Keenlyside, R.A., Ziegler, D.W., Retailliau, H.F., Eddins, D.L., and Bryan, J.A. 1979. Guillain-Barre syndrome following vaccination in the national influenza immunization program, United States, 1976-1977. Am. J. Epidemiol. 110:105-123. 43. Centers for Disease Control. 1978. Reconunendations of the Immunization Practices Advisory Committee (ACIP). Update: pneumococcal polysaccharide vaccine usage-United States. Morbid. Mortal. Weekly Rept. 35:273-281. 44. Gold, R., and Lepow, M.L. 1976. Present status of polyeaccharide vaccines in the prevention of meningococcal disease. Adv. Pediatr. 23:71-94. 45. Centers for Disease Control. 1978. Recommendations of the Immunization Practices Advisory Committee (ACIP). MeningOcoccal polysaccharide vaccines. Morbid. Mortal. Weekly Rept. 35:327-329. 46. Centers for Disease Control. 1980. Recommendations of the Immunization Practices Advisory Committee (ACIP) . Rabies prevention. Morbid. Mortal. Weekly Rept. 29:265-280. 47. Plotkin, S.A. 1980. Rabies vaccination in the 1980s. Hosp. Pract. 15:65-72. 48. Centers for Disease Control. 1984. Systemic allergic reactions following i~rununization with human diploid cell rabies vaccine. Morbid. Mortal. Weekly Rept. 33:185-187.

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84 49. Centers for Disease Control. 1982. Recommendations of the Immunization Practices Advisory Committee (ACIP). Inactivated hepatitis B virus vaccine. Morbid. Mortal. Weekly Rept. 31:317-328. 50. Surveillance, Investigations, and Research Branch, Division of Immunization, Center for Prevention Services, Centers for Disease Control. 1984. Unpublished data presented to the Surgeon General's Immunization Practices Advisory Committee (ACIP), February 7, 1984. 51. Centers for Disease Control. 1984. Hepatitis B vaccine: evidence confirming lack of AIDS transmission. Morbid. Mortal. Weekly Rept. 33:685-687.