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Pediatric
Infect Dis J. 1991 Mar;10(3):209-13.
Aseptic meningitis as a complication of mumps vaccination.
Sugiura A, Yamada A.
Department of Measles Virus, National Institute of Health, Tokyo,
Japan.
In 1989 a nationwide
surveillance of neurologic complications after the administration
of mumps vaccine was conducted in Japan, based on the notification
of cases and the testing of mumps viruses isolated from cerebrospinal
fluid for their relatedness to the vaccine by nucleotide sequence
analysis. Among 630,157 recipients of measles-mumps-rubella trivalent
(MMR) vaccine containing the Urabe Am9 mumps vaccine, there were
at least 311 meningitis cases suspected to be vaccine-related. In
96 of these 311 cases, mumps virus related to the vaccine was isolated
from cerebrospinal fluid. The unusually high incidence may have
been partly a result of the adverse media publicity of the problem
at the time of surveillance. We analyzed clinical features of 165
and 27 laboratory-confirmed mumps vaccine-related meningitis cases
that occurred among the recipients of MMR and monovalent mumps vaccines,
respectively, during a 1-year period after the introduction of MMR
vaccine. The incidence of vaccine-related meningitis was similar
among the recipients of MMR and monovalent Urabe Am9 mumps vaccines.
Meningitis was generally mild and there were no sequelae from the
illness. The complication was more frequent among male than among
female children.
PMID: 2041668
New England Journal of Medicine Study on Autism-MMR Vaccine in
Denmark NOT Definitive
WILMETTE, Ill., Nov. 6 /PRNewswire/ -- The new epidemiological study
appearing in the latest New England Journal of Medicine issue ("A
Population Based Study of Measles, Mumps and Rubella Vaccination
and Autism" by Kreesten Meldgaard, M.D., et al) does not demonstrate
that there
is no connection between MMR and autism. Rather it emphasizes the
fact that MMR cannot be the cause of all autism, a conclusion with
which Medical Interventions for Autism supported researchers will
wholeheartedly agree.
Medical Interventions
for Autism is a US charity that generates funds, co-ordinates and
administers biomedical and clinical research into autism, inflammatory
bowel disease and measles containing vaccines. Andrew
Wakefield, M.D. whose research is supported through Medical
Interventions for Autism grants, makes the following points.
"This is
a good study as far as it goes and the authors should be congratulated
for making a thorough attempt to approach this complex subject in
an epidemiological study. However, there are a number of
problems with this study that limit the conclusions that can be
drawn. "
"It has
become increasingly clear in recent years that autism is an umbrella
term for a collection of closely related disorders, whose causation
is likely to prove as varied and complex as the autistic spectrum
itself. Our own research has always concentrated on a subset of
children specifically with a regressive autistic developmental disorder
who simultaneously suffer persistent measles infection at key sites
in the bowel and a well-documented bowel disease. This subset is
of unknown size.
What the new study does suggest is that the proportion of Danish
children, specifically, with the form of autism described in our
studies, may be small, probably no more than 10% of diagnoses."
"I hope
the authors will continue their analysis of this cohort to establish
and describe the various subsets of autistic spectrum disorder that
make up their study population."
Elizabeth
Birt, Founder of Medical Interventions for Autism and a board member,
says: "The study proves nothing about the relationship between
regressive autism and MMR. The study participants were selected
from psychiatric clinics and hospitals; no child was evaluated for
immune system
dysfunction, inflammatory bowel disease or the presence of measles
RNA in their blood, intestines and cerebral spinal fluid. It is
time that we start looking for the biological basis of this disorder
which has been well documented in US and UK children and stop using
epidemiology to declare 'no
relationship' when study after study fails to be designed to even
look at this issue. When will the public health authorities stop
their 'ostrich like' behaviors and take a hard look at the peer
reviewed published
science? I am afraid that this generation of children may be permanently
lost if action is not taken now. We owe it to the children and their
families who kept their part of the public health bargain and immunized
their children for the 'greater good.' These children are being
treated like the Vietnam Veterans; they are being ignored because
of a fear that researchers like Dr. Wakefield may be right. It is
unconscionable and the parents will not stop until we have answers
as to what happened to our
children."
Measles mumps rubella vaccine: Through a glass, darkly
Andrew J Wakefield and Scott M Montgomery
Department of Medicine
Royal Free and University College Medical School, UK
(NB. excludes figures and diagrams)
Introduction
In the face of mounting enthusiasm for new, multiple antigen (polyvalent)
childhood vaccines (1) concerns have been raised over safety, particularly
for the measles mumps rubella (MMR) vaccine. Delayed adverse events
involving chronic inflammation of the gastrointestinal tract and
regressive autistic spectrum disorder are subjects of both continuing
debate and ongoing litigation, in this respect (2-6). These concerns
are unlikely to abate in the foreseeable future, and certainly not
until both the medical profession and the public can be reassured
about the integrity of the foundations that were laid in the original
safety trials, and upon which current dogma rests. The official
position is that MMR vaccine is safe (7); this paper examines the
evidence.
The
principal focus of this paper is pre-licensure studies of MMR. It
is the conduct of these trials, where inclusion of appropriate controls
is possible, that provides the best opportunity for not only identifying
acute adverse events, but also, for putting in place the appropriate
mechanisms for long term surveillance of safety. It becomes increasingly
difficult to identify appropriate control groups beyond the point
of widespread introduction of a vaccine. The first thing to note
is that these were short-term safety studies, with periods of observation
lasting at most 28 days, and often considerably less (8-10). For
live viral vaccines - particularly when combined - delayed, unpredictable,
and insidious adverse events should also have been a concern. When
considering how short-term safety studies of live viral vaccines
might act as a sentinel for identifying unexpected long-term adverse
events, we are provided with a model par excellence in measles virus.
Measles virus, and to a lesser extent, measles containing vaccines,
are causally associated with both acute and delayed encephalopathic
events (11-14). For measles virus, this association was evident
at the time MMR vaccines were developed, particularly since the
discovery of this agent as the cause of subacute sclerosing panencephalitis
(SSPE) in the mid- to late 1960's (15,16). Accordingly, in order
to monitor the impact of monovalent measles vaccine upon this condition,
SSPE case-registers were established in both the UK and US circa
1968.
Beyond
1968, therefore, it was known that measles virus could produce both
acute and persistent infection of the central nervous system, and
that this infection could cause acute and delayed encephalitis,
respectively. In pre-licensure trials of MMR, acute adverse events
involving alternative anatomical sites might have alerted the authorities
to the potential for delayed pathology. For example, since measles
is an enteropathic virus, capable of causing acute gastroenteritis,
mesenteric adenitis, and acute appendicitis (11,17-19), the gastrointestinal
tract would be one such site. Had complications such as acute gastroenteritis
been identified in these trials, the potential for delayed pathology
might have been considered equally plausible. The potential for
delayed intestinal pathology is borne out by Fournier et al's demonstration
of persistent measles virus infection of the diseased appendix in
1968 (20).
Pre-licensure
safety trials of MMR
Prior to its licensure in the US in 1975, trials of combined MMR
vaccine safety were the subject of 2 relatively small-scale controlled
studies (8,9). These studies were preceded by a smaller pilot study
of MMR in 1969 (21), which will be referred to later in this paper.
In 1971, Stokes et al reported a comparison of 228 children who
received MMR vaccine (Moraten strain measles) with 106 unvaccinated
controls (8). Two geographically distinct populations were examined,
one from a developed country (Philadelphia, US), and one from developing
countries (Costa Rica and San Salvador). Data on adverse events
in both groups were gathered for 28 days post vaccination and combined
for the purpose of statistical analysis.
Given the current concerns over possible gastrointestinal adverse
events following MMR vaccine, these merit particular attention when
reviewing the data. Gastroenteritis, although specifically recorded,
did not emerge as a cause for concern in the analysis, as presented
(8). Clearly, when interpreting these data one must first address
the first question of the comparability of two culturally, economically,
and geographically distinct groups and consider, therefore, whether
a combined analysis may obscure some relationships? For example,
it is evident from the data that, over the 28-day period of clinical
reporting, the difference in the background rate of gastroenteritis
in unvaccinated controls from Costa Rica-San Salvador (44%) compared
with Philadelphia (5.6%) was highly statistically significant (Odds
ratio 13.1; CI 5.19-35.06; p<0.001).
In the absence of an appropriate placebo-control group, these findings
cannot be dismissed as placebo effect. Indeed, the findings come
as no surprise, being entirely consistent with the marked difference
in patterns of childhood enteric infection between developed and
developing countries (22,23). This difference in the background
rate of gastroenteritis - an analysis not presented in the original
study - may be important to the interpretation of the possible adverse
effects of MMR. When data for children from Philadelphia are analysed
independently of those from Costa Rica-San Salvador, gastroenteritis
is statistically significantly more common in vaccinees (22.4%)
compared with unvaccinated controls (5.6%) (Odds ratio 4.8; CI 1.89-12.92;
p <0.001; unaltered by Fisher's exact test. Figure 1). In contrast,
in the Costa-Rica-San Salvador cohort there was no difference in
the rate of gastroenteritis between recipients of MMR vaccine (50%)
and unvaccinated controls (44%) (Odds ratio 1.27; CI 0.88-1.83;
p>0.1). Combination of the data sets, as presented, obscured
these facts. Moreover, it is biologically plausible that measles,
a virus that readily causes enteric infection (11,17-19,24) is responsible
for the clinical pathology that was observed.
Perhaps even more striking in the Philadelphia children, was the
frequency of "unrelated illness" (including otitis, allergy,
viral infection, and abdominal pain) which was seen in 39% of vaccinees
versus 12.2% of controls. This difference is highly statistically
significant (Odds ratio 4.58 CI 2.33-9.15; p<0.0001. Figure 2).
The absence of a placebo group makes its difficult to interpret
these data, but imprudent to ignore them. Clearly, a more detailed
sub-analysis should have been presented, and beyond this point these
events should have been a focus of specific attention in studies
of MMR in developed countries. Some of these events have since been
associated with exposure to measles containing vaccines (25,26).
Availed of this information, Schwarz et al - representing commercial
competitors - conducted a study of MMR vaccine (Schwarz strain measles)
that was reported in 1975 (9). Like the Stokes study (8) it comprised
two socio-economically distinct populations: first, 282 children
from Ohio and, second, 926 children from Santo Domingo in the Dominican
Republic and 373 children from Panama. The groups were randomised
to receive MMR vaccine (1,232 - of whom only 36.2% were susceptible
to all 3 infections) or placebo (249). As with the Stokes study
(8), data from all countries were combined for the purpose of statistical
analysis. Unlike the Stokes study, however, no data were provided
that allowed for independent analysis of the adverse events from
Ohio and Santo Domingo-Panama. However, there is no reason to suspect
that Schwarz's MMR vaccine should behave qualitatively differently
from that used by Stokes et al. A comparative analysis of 3 monovalent
measles vaccines showed no statistically significant difference
in the rate of gastrointestinal symptoms, by 28 days, between recipients
of either Schwarz strain (22/284 {8%}), Stokes' Moraten strain (28/273
{10.2%}), or Enders Edmonston strain (28/256 {10.9%}) (27).
In a small post-licensure study in the U.K, reported in 1991, that
compared reactions to MMR (Schwarz strain measles, Urabe AM/9 strain
mumps) with those of monovalent measles vaccine (Schwarz), Eddes
identified a very high rate of "gastrointestinal disorders"
occurring in 41.9% and 37.8% of children receiving the respective
vaccines (27). This reaction was as frequent as the established
clinical features of rash and pyrexia. Without reference to the
American pre-licensure studies (8,9), the authors dismissed the
gastrointestinal problems as representing normal "background"
illness. Unfortunately, without an unvaccinated control group, it
is very difficult to assess what proportion of these gastrointestinal
symptoms represent the "background" rate. Differences
in definitions and surveillance practice make it difficult to compare
background rates, but without detailed investigation the rates reported
by Eddes et al appear comparable to those for children in developing
countries in the early 1970's (8).
It is evident that the numbers of children included in these studies
(8,9,10,28) were too small to detect uncommon adverse events in
susceptible children receiving MMR. Combining two distinct groups
with widely differing background morbidities, in both pre-licensure
safety studies of MMR vaccine (8,9), may have masked gastroenteritis
as a significant adverse event in children from developed countries.
Since the denominator population was skewed heavily in favour of
children from the developing countries in both studies (77% (8)
and 81% (9)), masking of gastroenteritis as a possible adverse event
in American children, is highly plausible.
In the year prior to its general introduction in the U.K in 1988,
when it replaced monovalent measles vaccine, a surveillance of adverse
reactions to MMR was conducted on approximately 10,000 children
(10). The trial was not controlled and follow up was 3 weeks. Although
acute gastrointestinal adverse events are described as common, occurring
in up to 26% of vaccinees, no comparison data are available. As
such, there is little further information that can be gathered from
the trial reports.
In the context of possible delayed gastrointestinal complications
from measles vaccines, warning shots were received from a series
of studies undertaken in Senegal (29), Gambia (30),Guinea Bissau
(31), Haiti (32) and Peru (33). In an effort to identify a measles
vaccine strategy for developing countries that could overcome the
effects of passive, maternal antibody - a biological barrier to
seroconversion in infants - high titre measles vaccines were administered
to babies under one year of age. Unexpectedly, there was significant
delayed excess mortality in female recipients of high titre - compared
with standard titre vaccine. Diarrhoea deaths were prominent. In
addition there was a delayed excess morbidity involving both wasting
and growth that was observed in males and females with both medium
and high titre measles vaccines when given at 9 months of age (34).
Insights into a possible mechanism for these delayed adverse events
were provided by a study from Leon et al in Peru (33). The authors
identified subtle but consistent aberrations in cellular immunity
in recipients of high titre compared with low titre measles vaccine.
The effect was observed in both sexes, although it was more pronounced
in females than males, consistent with the morbidity and mortality
data. Garenne, who was among the first to report the findings of
delayed excess mortality in west Africa, is revealing in his summary
of the events that led up to the WHO's withdrawal of high titre
measles vaccines, when he wrote; "there was early enthusiasm
[for this vaccine] and negative findings tended to be ignored."
(35). Hilleman of Merck, when reviewing these studies, highlighted
both the diarrhoea-associated deaths and persistent immunodeficiency
(36), stating that, "The process bears resemblance to AIDS".
It is notable that in children with autistic regression where the
parents suspect a link with MMR, immunodeficiency, enterocolitis,
and persistent measles virus infection of ileal lymphoid tissue
are emerging characteristics (3,4,37-39).
One important aspect of these acute safety studies was the period
of what may be loosely termed "clinical observation".
Griffin reminds us that replication and spread of the measles virus
occurs during a latent period of infection of up to 21 days, that
spans the time from exposure to appearance of clinical symptoms
(40). Therefore, periods of observation of less than 21 days would
not comprehensively cover even the latent period.
Stokes' original study recorded adverse events to day 28 post-vaccination
(8). It is evident that at 28 days, recipients of MMR in the Philadelphia
cohort still manifest an excess of gastrointestinal and "unrelated"
adverse events compared with unvaccinated controls (figures 1 and
2). While the rate of gastrointestinal events was declining towards
the end of the observation period (figure 1), the rate of "unrelated"
events showed a steady and sustained excess over controls (figure
2). In the absence of a placebo control group, it may be inferred
that 4 weeks of follow up was insufficient. Despite this, rather
than increasing the period of follow-up, 4 years later Schwarz et
al had reduced it to 21 days (9), the time frame that was subsequently
adopted in the UK study of Miller et al (10).
The restricted view that was provided by such a narrow window of
observation has been highlighted by studies on the association between
MMR and idiopathic thrombocytopenic purpura (ITP), the onset of
which may be up to 59 days post-vaccination (41). A further example
was provided by Farrington et al of the Public Health Laboratory
Service (PHLS), in their reporting of meningo-encephalitis caused
by the Urabe strain of mumps virus, as a component of the MMR vaccine
(42). The "at risk" period for this event is considered
to be 15-35 days, with the majority of cases in the original report
occurring either at or beyond 3 weeks post vaccination (43). The
full story of the "Urabe episode" has yet to be told.
Viral
interference and Compound effects
A major consideration in the context of polyvalent vaccines such
as MMR, is the potential for adverse interactions between the component
live viruses, particularly in view of the immunosuppressive properties
of measles virus (11). In addition to the elements of unnatural
age, route, dose, and strain of infectious exposure, the childhood
immune system must cope with a combination of viruses that it would
have been extremely unlikely to encounter under circumstances of
natural exposure. In an executive summary, members of the committee
to whom vaccine-related events were reported in the U.S, reiterated
this anxiety in the context of virus-induced immunosuppression and
polyvalent vaccines (44). They stated, "It may be asked, then,
whether the use of combination viral vaccines might exacerbate the
potential problem of immune suppression. The committee found no
report of a systematic comparison of the effects of monovalent and
polyvalent live attenuated vaccines on immunity".
In 1995 concerns over the potential for interference between the
components of vaccines were raised again at a meeting of US vaccine
officials (45). Specifically, Belshe (St Louis) stated that: "To
be confident that a particular vaccine had no effect on another
vaccine given simultaneously, comparative studies should be performed".
Halsey (Johns Hopkins) considered that such studies would be both
"too large" and "unnecessary". Halsey conceded,
however, that: "If there is a biological reason to suspect
that there may be interference or blunting or blocking, then comparative
studies should be done."
Is
there a "biological reason" to suspect that "interference"
may occur between the component viruses of MMR? It is evident from
a literature, prior to 1977, that the outcome from measles infection
may be influenced by close temporal exposure to another virus. A
close temporal exposure to measles virus and another infection,
including chickenpox (46) and an encephalitogenic enterovirus (47),
is associated with an excess risk for SSPE. Virological data suggest
that SSPE may actually be caused by concurrent cerebral infection
with measles and another viral agent (48,49). With respect to possible
adverse events that are currently topical, atypical patterns of
exposure to measles, mumps, rubella and chickenpox have been associated
with both autism (50,51) and, for measles virus, developmental regression
(14,52). In utero and infant exposures have been identified as periods
of apparent susceptibility, when both the brain and the immune system
are undergoing rapid development. It is notable that a close temporal
relationship in the exposure to more than one of these infections
during periods of susceptibility, may compound both the risk and
severity of autism (50). Similarly, atypical patterns of measles
infection, including a close temporal exposure to mumps infection,
but not other common childhood infections, has been identified as
a significant risk factor for classical inflammatory bowel disease,
Crohn's disease and ulcerative colitis (53,54).
Clues that the component viruses of MMR could interfere, one with
another, were provided in the very first pilot studies of this vaccine.
In 1969, Buynak et al sought to examine the effects, in humans,
of various combinations of measles, mumps and rubella strains (18).
Their stated purpose was to examine; "the least quantity of
virus required to induce effective immunity; the durability of antibody
response, and; the stability of the rubella vaccine". Safety
is not mentioned, although in addition to seroconversion, end-points
included the comparative frequency of measles rash and fever. Children
(7-38 per group) aged 10 months to 13 years, were given trivalent
MMR, bivalent measles and mumps, or monovalent measles (Enders or
Moraten strains), mumps (Jeryl-Lynn strain) or rubella (HPV-77 strain)
vaccines. Despite the fact that the study was further complicated
by the use of different viral doses in different combinations, some
interesting observations were made.
In terms of a measles rash, a feature that reflects the cellular
immune response to this virus (11), Enders measles vaccine combined
with mumps produced rash in 30.8% of children compared with 3.4%
using the Enders vaccine alone (OR 12.44; CI 1.00-633.91; p=0.026).
What is surprising about this result is that the titre of monovalent
Enders vaccine was 6-fold greater than that used in the bivalent
vaccine, and yet the frequency of measles rash was 10 times less.
A temperature of greater than 99o F was induced in 100% of those
receiving the bivalent vaccine but only 76% of those receiving monovalent
Enders vaccine, although this difference was not statistically significant.
In those receiving Moraten measles vaccine compared with those receiving
bivalent mumps and Moraten vaccine at an equivalent dose to the
monovalent vaccine, pyrexia was detected in 28.6% and 47% respectively.
With a relative odds of 3.17 this did not achieve statistical significance,
although the numbers studied were small. Taken together, these clinical
data suggest a possible influence of mumps vaccine upon the clinical
response to measles vaccine that, for the latter, is strain dependent.
Mumps seroconversion rates also differed, although the data are
difficult to interpret since the dose of mumps vaccine that was
used, varied markedly between the 3 combinations that were compared.
Despite evidence of the potential for dose- and strain-dependent
interactions between the component viruses in the MMR vaccine, in
the context of antiviral immune responses and, therefore, possible
adverse events, the matter was left in abeyance.
Six years after Buynak's study, in 1974, the potential for interference
in MMR was the subject of a more detailed follow up of the original
observations, by Minekawa et al (55). Once again, the most striking
observation was of a dose-dependent influence of the mumps vaccine
(Urabe AM-7 strain) upon not only clinical reactions to the measles
component (Figure 3), but also seroconversion to rubella vaccine.
This same pattern of interference was also indicated by the study
of Eddes et al that compared clinical reactions to monovalent measles
and MMR vaccines (28). Despite using a 10-fold higher titre of measles
virus in the MMR compared with the monovalent vaccine, the frequency
of measles rash was lower, with rates of 43.9% and 51%, respectively.
The ability of mumps virus to interfere with the cellular immune
response to certain strains of measles virus and, thereby, in particular
combinations potentially to reduce viral clearance and increase
the risk of persistent infection and/or initiate immune dysregulation,
is an intriguing hypothesis to some of those involved in the current
debate. Whatever the ultimate merits of these hypotheses, the contemporaneous
interpretation of the authors was that further studies were necessary
(55). However, it does not appear, from the published literature,
that these further studies were undertaken.
Further compelling evidence of viral interference - in this instance,
between the measles and rubella vaccines - comes from Crawford and
Gremillion's study of U.S. Airforce recruits in 1981, 7 years prior
to the introduction of MMR in the U.K (56). In a relatively large
prospective study, safety and efficacy of measles and rubella vaccines
(given either alone or in combination) were compared with unvaccinated
controls. Five hundred and twelve vaccinees were compared with 835
unvaccinated controls and data were stratified by sex. The authors
noted an increase in reports of fever and diarrhoea in those immunized
with both vaccines simultaneously. In women there was an increase
in complaints of myalgias after simultaneous immunisation. The data
merit more detailed consideration; in recruits receiving either
monovalent measles or rubella vaccines there was no significant
increase in diarrhoea compared with unvaccinated controls (measles
vaccinees versus controls [men] OR 2.51; CI 0.06-9.99) and [women]
OR 3.61; CI 0.26-50.42; p>0.5; OR for rubella vaccinees versus
controls cannot be calculated since there is zero in each cell for
men and women reporting diarrhoea after rubella vaccine alone. Figure
4). In contrast, compared with unvaccinated controls there is a
significantly increased risk of diarrhoea following simultaneous
measles and rubella vaccination in both men (OR 7.31; CI 1.11-34.64)
p<0.001) and women (OR 17.29; CI 1.14-247.09; p<0.001). It
can be seen from Figure 4 that, in the context of gastrointestinal
adverse events (diarrhoea), the effect of simultaneous measles and
rubella vaccination is not additive but apparently synergistic (compound).
Despite being remarked upon in the results, these observations received
no further consideration in Crawford and Gremillion's report (56).
Indications that novel adverse events might be associated with the
combined MMR vaccine, rather than the monovalent component vaccines,
have come from Plesner et al's study of gait disturbance following
MMR in Denmark (13). Several prior studies had indicated that gait
disturbance might occur in up to 1 in 1000-4000 recipients of MMR
(57,58). In Denmark this association had not been detected with
any other vaccine administered to children of the same age, prior
to the introduction of MMR in 1987. In a recent follow up of the
mandatory passive reporting system operated in Denmark, Plesner
not only confirmed this association but also indicated that the
more severe cerebellar ataxias following MMR may be associated with
residual cognitive deficits in some children (13). This association
is specifically relevant to the debate on MMR and autism, as parents
of autistic children who suspect a link with MMR, not infrequently
report gait disturbances.
None of this is to say that vaccine manufacturers do not recognize
that the problem of interference exists. Douglas of Merck stated
recently, "The complexity of vaccine delivery today in clinical
practice with 15-17 injections in the first two years of life emphasizes
the need for development of combination pediatric vaccines, for
example, putting DTaP, HBV, HIB and IPV together. This has proved
to be far more difficult than previously believed due to unpredicted
immune interference and incompatibilities on mixing of different
components, demonstrating again the inadequacy of our understanding
of how vaccines work and the empiric nature of the science."
(1)
Candidly, Douglas admits that we see through this particular glass,
darkly. Why, however, in spite of evidence provided by studies undertaken
two decades earlier, should such interference be considered "unpredictable"
and, indeed, remain unstudied?
Revaccination
with MR and MMR
Systematic revaccination with MMR, with the stated aim of measles
elimination, started in Sweden in 1982 (59). Christenson, as one
of the architects of this program, was contacted by one of the authors
(AJW) to inquire about safety studies of 2-dose MMR schedules. She
replied, "I must avow that I don't quite understand what you
mean with if there has been any safety studies of the 2-dose measles
vaccine schedule. We have followed the 12 -year old children with
blood specimens drawn before vaccination and 2 months after vaccination.
This is a form of safety study."
Clearly, measurement of serum antibodies following revaccination
of 12 year olds was not a safety study. Christenson later confirmed
that there had been no safety studies of 2 dose schedules from Sweden,
nor was she aware of any having been performed elsewhere. Nonetheless,
the Swedish "experience" has served as a template for
re-vaccination strategies elsewhere in the world. In 1994 in the
UK, a re-vaccination campaign using bivalent measles and rubella
(MR) vaccine was undertaken; this targeted all school-age children
from 4-18 years of age. Since that time a 2nd dose of MMR has become
routine as a pre-school booster at 4 years of age.
"Assumptions" (60) about the safety of re-vaccination
are compounded, as extrapolation from assumptions about safety that
were based upon the early studies of MMR vaccine. Anxieties about
these assumptions were emphasized in the proceedings of a meeting
of measles experts that was convened under the auspices of the European
Union in 1993, prior to the U.K re-vaccination campaign (61). In
addition, the experts identified the "main areas which require
epidemiological input include the evaluation of the safety and efficacy
of two dose schedules of standard titre vaccine".
This - a two dose schedule - was precisely the strategy that was
adopted in the UK, one year later, without comprehensive monitoring
of safety - a priority that was clearly endorsed by European measles
experts. Cutts, one of the two epidemiologists present at the EU
meeting of measles virus experts, in commenting on the November
'94 re-vaccination program in a BMJ editorial, in which she strongly
endorsed this program, wrote, "The need to appraise risks as
well as benefits is an obligation for vaccination programs."
(62). Such piety is to be commended. Nonetheless, other than passive
surveillance, a system that is acknowledged by the regulatory authorities
to have serious limitations (42,44,63), this "obligation"
was not met. Consequently, possible adverse events have become by
definition anecdotal and "coincidence". Parents of children
who may be vaccine damaged have been left to cope with the consequences.
In the absence of either medium- or long-term safety studies of
MMR vaccine Cutts, in her BMJ editorial, went on to state that,
"If the measles-rubella campaign had not been conducted large
numbers of children would have had measles, with a much higher risk
of long-term serious effects than that potentially associated with
vaccination" (62).
Recent data confirm that failure to induce an adequate cytotoxic
T cell response to measles virus, despite the generation of specific
antibody - the conventional measure of immunity - is associated
with immunopathology upon re-exposure (64). Failure to clear cells
expressing viral antigen may lead to immunopathology that is directed
against these viral epitopes upon re-exposure, a situation that
could make revaccination for measles particularly hazardous in the
presence of persistent infection.
Reflecting further upon the perception of the regulatory authorities,
Rawlins, as head of the U.K Medicines Control Agency (MCA), maintained
recently that, "MMR & its component parts have undergone
rigorous testing before being licensed for use in this country.
Efficacy and safety have been convincingly demonstrated in hundreds
of millions of children world wide who have been immunized with
these vaccines during the last 20 years. Published evidence for
safety is available in; [Stratton KR et al Adverse Events Associated
With Childhood Vaccines. Natl. Acad. Press 1994 (44)]." (Personal
communication: Barr R, Alexander Harris Solicitors).
In contradiction to the reassurances given by Rawlins, the authors
of his suggested reference state that, "In the course of its
review the committee encountered many gaps and limitations in knowledge
bearing directly and indirectly on the safety of vaccines. These
include: inadequate understanding of the biologic mechanisms underlying
adverse events, insufficient or inconsistent information from case
reports and case series, inadequate size or length of follow-up
of many population-based epidemiologic studies." They concluded
that, "Clearly, if research capacity and accomplishment in
these areas are not improved, future reviews of vaccine safety will
be similarly handicapped." Rawlins' response is not reassuring.
"The comments [Stratton et al] have been taken out of context
because they apply to research needed to provide further reassurance
about vaccine safety. We would not agree with the authors when they
criticize the low number of available experimental studies since
they underestimate the difficulties of performing such studies.
In conclusion we consider that the body of available evidence supports
the view that the benefits of MMR and MR vaccines outweigh their
risks." Surely, when a medical intervention is intended for
universal use, particularly in healthy infants, there is no limit
to the vigilance that should be exercised. Finally, Rawlins falls
back upon generic argument that seeks reassurance in "available
evidence". On reflection, this might be considered ill advised.
In summary, analysis of pre-licensure trials of MMR reveals that
gastrointestinal, and other possible adverse events were evident
in children from developed countries. Although evidence of gastrointestinal
adverse events was a recurring feature of post-licensure studies,
they were not considered to be of clinical significance. Follow
up for detection of adverse events was reduced from 4 weeks in the
initial controlled trial, to 3 weeks in subsequent studies. This
was despite the fact that, in the original controlled trial, possible
adverse events were still evident in American children at 4 weeks
(8). There was evidence beyond 1968, that the component viruses
of MMR could exert both dose- and strain-dependent interference
upon the clinical and immunological response of the host to the
individual constituent viruses. This effect, for which the influence
of mumps virus upon the measles virus component was particularly
evident, merits thorough investigation. Clearly, one plus one, plus
one never did equal three. There is more than a theoretical risk,
supported by more recent studies (53,54,65), that interference with
clearance of measles virus might increase the risk of persistent
infection and/or delayed disease. The official argument that the
mumps vaccine is less effective alone, but potentiated by combination
in MMR, is tacit admission of "interference". Finally,
two-dose MMR vaccine schedules appear to be unsatisfactorily tested
for safety.
The foundations to claims of MMR safety have failed this structural
survey. Since the temple was constructed, we have become aware of
the contamination of MMR vaccines with avian retrovirus (66), bovine
viral diarrhea virus (BVDV) (67) and the potential for their contamination
with bovine prions (68). The success of vaccination programs, the
goals and benefits of which are laudable, depends upon trust, specifically
of the public in those charged with the broad remit of "vaccine
safety". Loss of this trust has the very real potential to
compromise vaccination strategies across the board, rather than
just reducing the uptake of a particular vaccine that may be under
scrutiny. The U.K Department of Health's decision to withdraw the
licence for importation of monovalent measles vaccine, whether implemented
directly or indirectly, was wrong. If protection against measles
is a principal concern, surely it is important to continue to allow
parents to use the monovalent vaccines where they are concerned
- rightly or wrongly - about the safety of MMR. Those on both sides
of the debate will continue to publish hypothesis testing, peer
reviewed studies that seek to clarify this matter. However, until
such time as this matter is resolved to everyone's satisfaction,
the public must, at the very least, be offered a choice. As the
last Minister for Health, the Hon. Frank Dobson said recently, in
the context of another medical intervention, "If there is even
a hypothetical risk [of harm] and a safer alternative exists, we
should use it." For MMR, autism, and inflammatory bowel disease,
a significant index of suspicion exists without adequate evidence
of safety (2-4,69).
With time, what is now opaque - the complexities of host-vaccine/vaccine-vaccine
interactions - may become clear. In the meantime, the foregoing
might be perceived as an argument for, rather than against vaccination,
although with strategic modifications. If the risk of chronic immune-mediated
disease is increased by concurrent exposure to the component viruses
of MMR, either in their natural or vaccine form, then by the use
of, for example, spaced monovalent measles and mumps vaccination
we have the ability to artificially dissociate these exposures,
and the possible associated risks. Some may argue that delaying,
for example, mumps vaccination by one year increases the risk of
exposure and associated morbidity. This would be most unlikely if
herd immunity were maintained by monovalent vaccination of 2 year
olds. When calculating these risks, the PHLS may recall that its
own senior members were equivocal about the merits of a mumps vaccine
as recently as 1991 (70).
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PEDIATRICS Vol. 107 No. 2 February 2001, p. e27
ELECTRONIC ARTICLE:
Allergic Reactions to Measles-Mumps-Rubella Vaccination
Received Jul 14, 2000; accepted Sep 12, 2000.
Annamari Patja*, Soili Mäkinen-Kiljunen , Irja Davidkin§,
Mikko Paunio , and Heikki Peltola*
From the * Hospital for Children and Adolescents, Helsinki University
Central Hospital; Skin and Allergy Hospital, Helsinki University
Central Hospital; § National Public Health Institute; and the
Department of Public Health, University of Helsinki, Helsinki, Finland.
Objective. Immunization of egg-allergic children against measles,
mumps, and rubella (MMR) is often deferred or even denied, although
the safety of this vaccination has been clearly shown. Moreover,
the majority of severe allergic reactions have occurred in egg-tolerant
vaccinees. Other allergenic vaccine components have been sought,
and gelatin has been suggested as one cause of allergic adverse
events. The aim of this study was to further characterize the actual
allergenic vaccine components.
Methods. Serum samples from 36 recipients of MMR vaccine with anaphylaxis,
urticaria with or without angioedema, asthmatic symptoms, or Henoch-Schönlein
purpura were analyzed by CAP System radioallergosorbent test (RAST)
and immunospot methods to detect the allergenic vaccine component.
To evaluate the correspondence between the findings in the CAP System
RAST or the immunospot and clinical symptoms, histories of allergies
and present hypersensitivity symptoms were assessed.
Results. Of the 36 participants, 10 were demonstrated to be allergic
to gelatin. Seven of them had persistent allergic symptoms, possibly
attributable to foods containing gelatin or cross-reactive allergens.
The results of the immunospot suggested concomitant allergy to gelatin
and egg, chicken, and feathers, as well as cow's milk, or they reflected
allergen cross-reactivity.
Conclusions. Although severe allergic adverse events attributable
to MMR vaccination are extremely rare, all serious allergic reactions
should be further assessed to detect the likely causative vaccine
component, including gelatin. The current recommendation for immunization
of egg-allergic persons according to standard MMR vaccination schedules
is reinforced. measles, mumps, and rubella vaccine, immunization,
adverse effects, allergic reactions, gelatin allergy, CAP System,
radioallergosorbent test, immunospot, immunoglobulin E. .
PEDIATRICS Vol. 110 No. 6 December 2002, pp. e71
ELECTRONIC ARTICLE
Prevalence of Anti-Gelatin IgE Antibodies in People With Anaphylaxis
After Measles-Mumps-Rubella Vaccine in the United States
Vitali Pool, MD*, M. Miles Braun, MD, MPH , John M. Kelso, MD ,
Gina Mootrey, DO, MPH*, Robert T. Chen, MD, MA*, John W. Yunginger,
MD||, Robert M. Jacobson, MD and Paul M. Gargiullo, PhD# the VAERS
Team
* Epidemiology and Surveillance Division, National Immunization
Program, Centers for Disease Control and Prevention, Atlanta, Georgia
Division of Epidemiology, Office of Biostatistics and Epidemiology,
Center for Biologics Evaluation and Research, Food and Drug Administration,
Rockville, Maryland
Department of Internal Medicine (Allergy Division), Naval Medical
Center, San Diego, California
|| Allergic Diseases Research Laboratory
Mayo Vaccine Research Group, Mayo Clinic and Foundation, Rochester,
Minnesota
# Division of Cancer Prevention and Control, National Center for
Chronic Disease Prevention and Health Promotion, Centers for Disease
Control and Prevention, Atlanta, Georgia
Objective. Anaphylaxis after immunization, although rare, is serious
and potentially life-threatening. Understanding risk factors for
this reaction is therefore important. Gelatin is added to many vaccines
as a heat stabilizer. Japanes
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