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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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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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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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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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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 (39°C or more),
which may occur~in up to 7 percent of children. Rarely, fever may
exceed 40.5°C, 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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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 40.5°C 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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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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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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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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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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to 15 percent of recipients incur a mild, measles-like illness with
fever of 39.4°C 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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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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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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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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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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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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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
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2. Kanai, K. 1980. Japan's experience in pertussis epidemiology
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3. Centers for Disease Control. 1985. Adverse events following
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spasms and pertussis immunization. Lancet 1:1031-1033.
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Bernier, R.H., Frank, J.A., Jr., and Nolan, T.F., Jr. 1981.
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8. Centers for Disease Control. 1982. Group A streptococcal
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9. Cody, C.L., Baraff, L.J., Cherry, J.D., Marcy, S.M., and
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11. American Academy of Pediatrics. 1982. PertuSSiS. Pp. 198-202
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13. Griffith, A.H. 1978. Reactions after pertussis vaccine: a
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14. Miller, D.L., Ross, E.M., Alderslade, R., Bellman, N.H., and
Rawson, N.S.B. 1981. Pertussis immunisation and serious acute
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23.
Joint Committee on Vaccination and Immunisation, Department of
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16. Committee interpretation of material in reference 15.
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Mortimer, E.A., Jr., Jones, P.K., and Adelson, L. 1983. DTP and
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Institute of Medicine. 1977. Evaluation of Poliomyelitis
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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
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. McBean, A.M., Thoms, M.L., Johnson, R.H., Gadless, B.R.,
MacDonald, B., Nerhood, L., Cummings, P., Hughes, J., Kinnear,
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30. Alexander, E.R. 1984. Inactivated poliomyelitis vaccination.
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33.
Krugman, S., and Katz, S.L. 1981. Infectious Diseases of
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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
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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
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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
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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
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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.
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following i~rununization with human diploid cell rabies vaccine.
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49. Centers for Disease Control. 1982. Recommendations of the
Immunization Practices Advisory Committee (ACIP). Inactivated
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31:317-328.
50. Surveillance, Investigations, and Research Branch, Division of
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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.
Representative terms from entire chapter:
measles vaccine
