Lesson 6, Part 2B - Mumps Vaccines Reactions
Posted: Fri Feb 11, 2005 4:40 pm
Start with this page and read further at this site for all the reactions to
the vaccines
Lesson 6, Part 2B - Mumps Vaccines Reactions
"Urabe" strain markedly caused meningitis and was withdrawn..........see below
http://books.nap.edu/books/0309048958/h ... ml#pagetop
Mumps
Following the administration of mumps vaccine, seroconversion is slower and
the antibody titers achieved are lower than those following natural
infection. A neutralizing antibody response can be detected in some
recipients 2 weeks after vaccine administration; in others, it can be
delayed for up to 6 weeks (Hilleman et al., 1968a,b). It is assumed that
this immunity is long-lasting, but this has not yet been established.
http://books.nap.edu/books/0309048958/h ... ml#pagetop
ASEPTIC MENINGITIS
Clinical Description
Aseptic meningitis is defined as an inflammation of the meninges associated
with pleocytosis of the CSF. In the early stage of aseptic meningitis
polymorphonuclear leukocytes predominate, but within 8 to 16 hours this
changes to a predominance of mononuclear cells. There may be some elevation
of protein, but in general, the glucose level is normal. In patients with
aseptic meningitis associated with mumps, there may be hypoglycorrhachia.
Bacterial cultures are negative. The description of aseptic meningitis in
the wake of mumps vaccine administration follows this pattern, except that
hypoglycorrhachia was not mentioned in the reports.
The yearly incidence of aseptic meningitis for the years 1950 to 1981 in
Olmsted County, Minnesota, was 10.9 per 100,000 people (Nicolosi et al.,
1986). The annual incidence was markedly higher in children less than age 1
year (82.4 per 100,000) and slightly higher in children between ages 1 and
4 years (16.2 per 100,000) and in children between ages 5 and 9 years (18.8
per 100,000).
History of Suspected Association
Mumps disease is clearly associated with aseptic meningitis. The committee
was charged with investigating a possible causal relation between only
mumps vaccine and aseptic meningitis.
http://books.nap.edu/books/0309048958/h ... ml#pagetop
Evidence for Association
Biologic Plausibility
Mumps disease has been found to be clearly associated with aseptic
meningitis. Mumps virus (both wild-type and vaccine strains) has been
isolated from the CSF of patients with aseptic meningitis.
Case Reports, Case Series, and Uncontrolled Observational Studies
The ability to isolate mumps virus from the CSF of patients presenting with
symptoms of meningitis and to determine the type of the isolate as a
wild-type or a vaccine strain indicates that mumps vaccine can cause
aseptic meningitis. Many case series and observational studies have
documented cases of meningitis after vaccination with mumps
virus-containing vaccine. Of particular interest are the cases in which the
vaccine strain was identified. This has been done extensively with the
Urabe strain. Data concerning the Urabe strain mumps vaccine will be
presented first. Data related to the Jeryl Lynn strain (that used in the
United States) are presented last.
In 1989, Gray and Bums published two letters (Gray and Bums, 1989a,b) in
The Lancet concerning a 3-year-old girl presenting with aseptic meningitis
21 days after vaccination with MMR. Fluorescent-antibody tests identified
the isolated virus as mumps virus (Gray and Bums, 1989a), and soon
thereafter, this virus was identified by nucleotide sequencing analysis as
the Urabe strain (Gray and Burns, 1989b).
Identification of the mumps virus as the Urabe vaccine strain by nucleotide
sequence analysis of the isolates from eight patients with meningitis in
Canada led to suspension of the sale of that vaccine in Canada in May 1990
(Brown et al., 1991). Using the polymerase chain reaction to amplify the
genetic signal, investigators from Japan also typed mumps virus isolated
from patients with meningitis as a vaccine strain, most probably Urabe
(Mori et al., 1991; Yamada et al., 1990).
Most recently, the Nottingham (United Kingdom) Public Health Laboratory
isolated mumps virus from the CSF of eight children following
administration of Urabe-containing MMR (Colville and Pugh, 1992). Seven of
the isolates resembled the vaccine strain (the sample from the eighth
patient could not be typed). Vaccination occurred 17 to 24 days prior to
the lumbar puncture. The rate of virologically confirmed and suspected
MMR-associated meningitis was calculated to be 1 case per 3,800 doses. None
of the children had severe illness, and no sequelae were seen. Colville and
Pugh (1992) reviewed laboratory records from an approximately 3-year period
and determined that there were excess cases of lymphocytic meningitis in
the group that recently received MMR compared with the incidence in those
who had not recently been vaccinated with MMR. More cases of Urabe
strain-related meningitis have been identified in the United Kingdom, and
use of the Urabe vaccine strain has been suspended in that country.
A Urabe strain-containing MMR was released in Canada in 1986. Soon after
that, cases of mumps meningitis began to appear. In an investigation at
Montreal Children's Hospital of four patients with meningitis that appeared
within 19 to 26 days after receipt of the Urabe-containing vaccine, mumps
virus was isolated from the patients' CSF, as detected by hemadsorption
inhibition with mumps antisera (McDonald et al., 1989). This did not
distinguish the vaccine strain from the wild-type strain; however, none of
the four patients were known to have had contact with an individual with
natural mumps virus infection. The illnesses were not severe, and all
patients recovered without sequelae.
Retrospective studies of mumps-associated meningitis and reports from
surveillance systems provide more data regarding a relation between mumps
vaccine and meningitis. Cizman et al. (1989) retrospectively reviewed the
medical records of 2,418 children hospitalized and treated for aseptic
meningitis at University Medical Center in Ljubljana, Yugoslavia, between
1979 and 1986. The etiology of the aseptic meningitis was assessed by
serologic tests and isolation of the virus from CSF, urine, feces, or
throat swabs. They confirmed the presence of mumps virus strains by the
complement fixation test with a specific antiserum. They also tested for
poliovirus, Central European tick-borne encephalitis virus, and herpes
simplex virus. In 115 children, the onset of aseptic meningitis occurred
within 30 days of vaccination against measles and mumps (Leningrad 3
strain), leading to an attack rate of approximately 1 per 1,000 immunized
children, as calculated by the authors. Most of the cases occurred between
11 and 25 days after vaccination. The attack rate in immunized 6- to
8-year-old children was 3.5 times greater than that in immunized 1- to
3-year-old children. None of the children had sequelae. Signs of parotitis
and virologic findings suggestive of mumps infection were found in 65 of
the children, although only 1 child had a history of exposure to mumps.
Much more enterovirus was isolated from children with nonvaccine-associated
aseptic meningitis than from the 115 children with vaccine-associated
aseptic meningitis. Although the authors did not calculate a rate of
aseptic meningitis and they did not report how many cases of aseptic
meningitis they finally attributed specifically to mumps vaccination, they
were clearly concerned about the high incidence and, on the basis of in
vitro tests, believed that their vaccine was inadequately attenuated
compared with the Jeryl Lynn strain.
Introduction of vaccination for measles, mumps, and rubella (using the
Urabe strain mumps vaccine) in Japan in 1989 coincided with early reports
of mumps vaccine-associated meningitis. This prompted surveillance efforts
in Japan to study the problem. Pediatricians at 24 hospitals in the Gunma
Prefecture were asked to fill out a questionnaire regarding clinical
details and laboratory findings for patients with aseptic meningitis
without a history of vaccination with MMR and for patients with parotitis
and convulsive disorders within 2 months of vaccination with MMR during an
8-month period in 1989 (Fujinaga et al., 1991). There were 35 cases of
aseptic meningitis within 2 months of vaccination with MMR. These patients
had no history of contact with individuals with natural mumps virus
infection. Mumps meningitis was seen in 38 patients with no history of
vaccination, and meningitis resulting from other causes was seen in 46
patients. Mumps virus, but no other viral isolates, was detected by
indirect immunofluorescence in 13 patients with aseptic meningitis who had
been vaccinated within the 2 previous months, but who were negative for
contact with wild-type mumps virus. Characterization of virus in samples
from 13 patients by the polymerase chain reaction and nucleotide sequence
determination or by restriction enzyme analysis determined that all 13
viruses were of the Urabe strain. They referred to these as the
virus-positive group. They divided the remaining 22 patients into two
groups: 11 patients who seroconverted (the serum-positive group) and 11
patients who had clinical signs of meningitis but from whom virus was not
isolated and who had not seroconverted. They calculated incidence rates for
the virus-positive group, the serum-positive group, and the clinical
meningitis group for the 2-month period of 3, 2.5, and 1.5 cases per 1,000
children vaccinated with MMR, respectively. The estimated background
incidence of acute neurologic diseases in the Gunma Prefecture for the
years 1987 and 1988, by comparison, was 0.37 per 1,000 children.
A nationwide surveillance of neurologic complications after mumps vaccine
administration in Japan during 1989 (which presumably included the data
from the report described above [Fujinaga et al., 1991]) revealed 311
suspected cases of vaccine-related meningitis among 630,157 vaccinations
with MMR (Sugiura and Yamada, 1991). Of 222 CSF samples examined, 99
samples contained mumps virus, and 96 of these were shown by molecular
biology techniques to be the Urabe strain. The incidence rates of suspected
or laboratory-confirmed aseptic meningitis were 1 in 2,026 and 1 in 6,564
people administered MMR, respectively. The authors noted that these
incidence rates were higher than the estimated incidence rate among those
who received monovalent Urabe strain mumps vaccine before or during the
survey period. They also noted that all patients with aseptic meningitis
recovered without sequelae.
Data concerning aseptic meningitis in association with the Jeryl Lynn
strain mumps virus are more scarce than those related to the Urabe strain.
Virus was isolated from a patient with symptoms of meningitis beginning 20
days after vaccination with the Jeryl Lynn strain of mumps vaccine (that
used in the United States) (Ehrengut and Zastrow, 1989). The isolated
virus, obtained from a swab of the orifice of Stenson's duct and from the
CSF, was identified as the vaccine strain on the basis of the morphology of
the cytopathic effect but not by molecular analysis. Fescharek and
colleagues (1990) described the isolation of mumps virus from two patients
with meningitis reported to the pharmaceutical firm Behringwerke AG in the
former West Germany. The mumps vaccine administered was Jeryl Lynn (that
used in the United States), but identification of the virus as wild-type or
vaccine strain was not attempted.
Eleven cases of meningitis following receipt of MMR in the United States
(the Jeryl Lynn strain of mumps vaccine) reported in VAERS (submitted
between November 1990 and July 1992) were examined by the committee. In no
case was the strain identified or the virus isolated. The latencies from
vaccination to symptoms ranged from 3 days to 2 weeks. In some patients the
clinical symptoms seemed supportive of a diagnosis of meningitis, but
intercurrent infections were seen in two of the patients, insufficient
information was available for three patients, and encephalopathy was
possible for another patient.
Controlled Observational Studies
None.
Controlled Clinical Trials
None.
Causality Argument
There is strong biologic plausibility that mumps virus could cause aseptic
meningitis. Wild-type mumps virus clearly does so. Isolation of the virus
and typing by molecular biologic techniques as the vaccine strain of mumps
virus from patients who developed aseptic meningitis following immunization
with mumps vaccine provide evidence of a causal relation. This relation is
firmly established for the Urabe strain. The incidence appears to be
approximately 1 case per few thousand vaccine recipients. The matter is
unclear with regard to the Jeryl Lynn strain (that used in the United
States), because in the sole reported case in which the virus was
identified as the "vaccine strain," the isolated virus was typed by the
older morphologic technique and not by molecular analysis. In the two other
published cases of Jeryl Lynn-associated mumps meningitis, the virus was
not typed as the vaccine or wild-type strain. VAERS contains several
reports of what probably is meningitis after administration of Jeryl Lynn
mumps vaccine-containing preparations, but the reports do not describe
virus isolation or typing. A recent study of various commercial mumps
vaccine preparations demonstrates the existence of two populations of Jeryl
Lynn strain virus in commercial vaccine preparations, with sequence
variation of up to 4.4 percent for some genes (Afzal et al., 1992). Only
one population of the Urabe strain was detected. The authors hypothesized
that one of the populations could interfere with the growth of the other,
thus influencing rates of adverse reactions. There are no data to
substantiate this hypothesis directly.
Conclusion
The evidence is inadequate to accept or reject a causal relation between
the Jeryl Lynn strain mumps vaccine and aseptic meningitis.
[Non-text portions of this message have been removed]
the vaccines
Lesson 6, Part 2B - Mumps Vaccines Reactions
"Urabe" strain markedly caused meningitis and was withdrawn..........see below
http://books.nap.edu/books/0309048958/h ... ml#pagetop
Mumps
Following the administration of mumps vaccine, seroconversion is slower and
the antibody titers achieved are lower than those following natural
infection. A neutralizing antibody response can be detected in some
recipients 2 weeks after vaccine administration; in others, it can be
delayed for up to 6 weeks (Hilleman et al., 1968a,b). It is assumed that
this immunity is long-lasting, but this has not yet been established.
http://books.nap.edu/books/0309048958/h ... ml#pagetop
ASEPTIC MENINGITIS
Clinical Description
Aseptic meningitis is defined as an inflammation of the meninges associated
with pleocytosis of the CSF. In the early stage of aseptic meningitis
polymorphonuclear leukocytes predominate, but within 8 to 16 hours this
changes to a predominance of mononuclear cells. There may be some elevation
of protein, but in general, the glucose level is normal. In patients with
aseptic meningitis associated with mumps, there may be hypoglycorrhachia.
Bacterial cultures are negative. The description of aseptic meningitis in
the wake of mumps vaccine administration follows this pattern, except that
hypoglycorrhachia was not mentioned in the reports.
The yearly incidence of aseptic meningitis for the years 1950 to 1981 in
Olmsted County, Minnesota, was 10.9 per 100,000 people (Nicolosi et al.,
1986). The annual incidence was markedly higher in children less than age 1
year (82.4 per 100,000) and slightly higher in children between ages 1 and
4 years (16.2 per 100,000) and in children between ages 5 and 9 years (18.8
per 100,000).
History of Suspected Association
Mumps disease is clearly associated with aseptic meningitis. The committee
was charged with investigating a possible causal relation between only
mumps vaccine and aseptic meningitis.
http://books.nap.edu/books/0309048958/h ... ml#pagetop
Evidence for Association
Biologic Plausibility
Mumps disease has been found to be clearly associated with aseptic
meningitis. Mumps virus (both wild-type and vaccine strains) has been
isolated from the CSF of patients with aseptic meningitis.
Case Reports, Case Series, and Uncontrolled Observational Studies
The ability to isolate mumps virus from the CSF of patients presenting with
symptoms of meningitis and to determine the type of the isolate as a
wild-type or a vaccine strain indicates that mumps vaccine can cause
aseptic meningitis. Many case series and observational studies have
documented cases of meningitis after vaccination with mumps
virus-containing vaccine. Of particular interest are the cases in which the
vaccine strain was identified. This has been done extensively with the
Urabe strain. Data concerning the Urabe strain mumps vaccine will be
presented first. Data related to the Jeryl Lynn strain (that used in the
United States) are presented last.
In 1989, Gray and Bums published two letters (Gray and Bums, 1989a,b) in
The Lancet concerning a 3-year-old girl presenting with aseptic meningitis
21 days after vaccination with MMR. Fluorescent-antibody tests identified
the isolated virus as mumps virus (Gray and Bums, 1989a), and soon
thereafter, this virus was identified by nucleotide sequencing analysis as
the Urabe strain (Gray and Burns, 1989b).
Identification of the mumps virus as the Urabe vaccine strain by nucleotide
sequence analysis of the isolates from eight patients with meningitis in
Canada led to suspension of the sale of that vaccine in Canada in May 1990
(Brown et al., 1991). Using the polymerase chain reaction to amplify the
genetic signal, investigators from Japan also typed mumps virus isolated
from patients with meningitis as a vaccine strain, most probably Urabe
(Mori et al., 1991; Yamada et al., 1990).
Most recently, the Nottingham (United Kingdom) Public Health Laboratory
isolated mumps virus from the CSF of eight children following
administration of Urabe-containing MMR (Colville and Pugh, 1992). Seven of
the isolates resembled the vaccine strain (the sample from the eighth
patient could not be typed). Vaccination occurred 17 to 24 days prior to
the lumbar puncture. The rate of virologically confirmed and suspected
MMR-associated meningitis was calculated to be 1 case per 3,800 doses. None
of the children had severe illness, and no sequelae were seen. Colville and
Pugh (1992) reviewed laboratory records from an approximately 3-year period
and determined that there were excess cases of lymphocytic meningitis in
the group that recently received MMR compared with the incidence in those
who had not recently been vaccinated with MMR. More cases of Urabe
strain-related meningitis have been identified in the United Kingdom, and
use of the Urabe vaccine strain has been suspended in that country.
A Urabe strain-containing MMR was released in Canada in 1986. Soon after
that, cases of mumps meningitis began to appear. In an investigation at
Montreal Children's Hospital of four patients with meningitis that appeared
within 19 to 26 days after receipt of the Urabe-containing vaccine, mumps
virus was isolated from the patients' CSF, as detected by hemadsorption
inhibition with mumps antisera (McDonald et al., 1989). This did not
distinguish the vaccine strain from the wild-type strain; however, none of
the four patients were known to have had contact with an individual with
natural mumps virus infection. The illnesses were not severe, and all
patients recovered without sequelae.
Retrospective studies of mumps-associated meningitis and reports from
surveillance systems provide more data regarding a relation between mumps
vaccine and meningitis. Cizman et al. (1989) retrospectively reviewed the
medical records of 2,418 children hospitalized and treated for aseptic
meningitis at University Medical Center in Ljubljana, Yugoslavia, between
1979 and 1986. The etiology of the aseptic meningitis was assessed by
serologic tests and isolation of the virus from CSF, urine, feces, or
throat swabs. They confirmed the presence of mumps virus strains by the
complement fixation test with a specific antiserum. They also tested for
poliovirus, Central European tick-borne encephalitis virus, and herpes
simplex virus. In 115 children, the onset of aseptic meningitis occurred
within 30 days of vaccination against measles and mumps (Leningrad 3
strain), leading to an attack rate of approximately 1 per 1,000 immunized
children, as calculated by the authors. Most of the cases occurred between
11 and 25 days after vaccination. The attack rate in immunized 6- to
8-year-old children was 3.5 times greater than that in immunized 1- to
3-year-old children. None of the children had sequelae. Signs of parotitis
and virologic findings suggestive of mumps infection were found in 65 of
the children, although only 1 child had a history of exposure to mumps.
Much more enterovirus was isolated from children with nonvaccine-associated
aseptic meningitis than from the 115 children with vaccine-associated
aseptic meningitis. Although the authors did not calculate a rate of
aseptic meningitis and they did not report how many cases of aseptic
meningitis they finally attributed specifically to mumps vaccination, they
were clearly concerned about the high incidence and, on the basis of in
vitro tests, believed that their vaccine was inadequately attenuated
compared with the Jeryl Lynn strain.
Introduction of vaccination for measles, mumps, and rubella (using the
Urabe strain mumps vaccine) in Japan in 1989 coincided with early reports
of mumps vaccine-associated meningitis. This prompted surveillance efforts
in Japan to study the problem. Pediatricians at 24 hospitals in the Gunma
Prefecture were asked to fill out a questionnaire regarding clinical
details and laboratory findings for patients with aseptic meningitis
without a history of vaccination with MMR and for patients with parotitis
and convulsive disorders within 2 months of vaccination with MMR during an
8-month period in 1989 (Fujinaga et al., 1991). There were 35 cases of
aseptic meningitis within 2 months of vaccination with MMR. These patients
had no history of contact with individuals with natural mumps virus
infection. Mumps meningitis was seen in 38 patients with no history of
vaccination, and meningitis resulting from other causes was seen in 46
patients. Mumps virus, but no other viral isolates, was detected by
indirect immunofluorescence in 13 patients with aseptic meningitis who had
been vaccinated within the 2 previous months, but who were negative for
contact with wild-type mumps virus. Characterization of virus in samples
from 13 patients by the polymerase chain reaction and nucleotide sequence
determination or by restriction enzyme analysis determined that all 13
viruses were of the Urabe strain. They referred to these as the
virus-positive group. They divided the remaining 22 patients into two
groups: 11 patients who seroconverted (the serum-positive group) and 11
patients who had clinical signs of meningitis but from whom virus was not
isolated and who had not seroconverted. They calculated incidence rates for
the virus-positive group, the serum-positive group, and the clinical
meningitis group for the 2-month period of 3, 2.5, and 1.5 cases per 1,000
children vaccinated with MMR, respectively. The estimated background
incidence of acute neurologic diseases in the Gunma Prefecture for the
years 1987 and 1988, by comparison, was 0.37 per 1,000 children.
A nationwide surveillance of neurologic complications after mumps vaccine
administration in Japan during 1989 (which presumably included the data
from the report described above [Fujinaga et al., 1991]) revealed 311
suspected cases of vaccine-related meningitis among 630,157 vaccinations
with MMR (Sugiura and Yamada, 1991). Of 222 CSF samples examined, 99
samples contained mumps virus, and 96 of these were shown by molecular
biology techniques to be the Urabe strain. The incidence rates of suspected
or laboratory-confirmed aseptic meningitis were 1 in 2,026 and 1 in 6,564
people administered MMR, respectively. The authors noted that these
incidence rates were higher than the estimated incidence rate among those
who received monovalent Urabe strain mumps vaccine before or during the
survey period. They also noted that all patients with aseptic meningitis
recovered without sequelae.
Data concerning aseptic meningitis in association with the Jeryl Lynn
strain mumps virus are more scarce than those related to the Urabe strain.
Virus was isolated from a patient with symptoms of meningitis beginning 20
days after vaccination with the Jeryl Lynn strain of mumps vaccine (that
used in the United States) (Ehrengut and Zastrow, 1989). The isolated
virus, obtained from a swab of the orifice of Stenson's duct and from the
CSF, was identified as the vaccine strain on the basis of the morphology of
the cytopathic effect but not by molecular analysis. Fescharek and
colleagues (1990) described the isolation of mumps virus from two patients
with meningitis reported to the pharmaceutical firm Behringwerke AG in the
former West Germany. The mumps vaccine administered was Jeryl Lynn (that
used in the United States), but identification of the virus as wild-type or
vaccine strain was not attempted.
Eleven cases of meningitis following receipt of MMR in the United States
(the Jeryl Lynn strain of mumps vaccine) reported in VAERS (submitted
between November 1990 and July 1992) were examined by the committee. In no
case was the strain identified or the virus isolated. The latencies from
vaccination to symptoms ranged from 3 days to 2 weeks. In some patients the
clinical symptoms seemed supportive of a diagnosis of meningitis, but
intercurrent infections were seen in two of the patients, insufficient
information was available for three patients, and encephalopathy was
possible for another patient.
Controlled Observational Studies
None.
Controlled Clinical Trials
None.
Causality Argument
There is strong biologic plausibility that mumps virus could cause aseptic
meningitis. Wild-type mumps virus clearly does so. Isolation of the virus
and typing by molecular biologic techniques as the vaccine strain of mumps
virus from patients who developed aseptic meningitis following immunization
with mumps vaccine provide evidence of a causal relation. This relation is
firmly established for the Urabe strain. The incidence appears to be
approximately 1 case per few thousand vaccine recipients. The matter is
unclear with regard to the Jeryl Lynn strain (that used in the United
States), because in the sole reported case in which the virus was
identified as the "vaccine strain," the isolated virus was typed by the
older morphologic technique and not by molecular analysis. In the two other
published cases of Jeryl Lynn-associated mumps meningitis, the virus was
not typed as the vaccine or wild-type strain. VAERS contains several
reports of what probably is meningitis after administration of Jeryl Lynn
mumps vaccine-containing preparations, but the reports do not describe
virus isolation or typing. A recent study of various commercial mumps
vaccine preparations demonstrates the existence of two populations of Jeryl
Lynn strain virus in commercial vaccine preparations, with sequence
variation of up to 4.4 percent for some genes (Afzal et al., 1992). Only
one population of the Urabe strain was detected. The authors hypothesized
that one of the populations could interfere with the growth of the other,
thus influencing rates of adverse reactions. There are no data to
substantiate this hypothesis directly.
Conclusion
The evidence is inadequate to accept or reject a causal relation between
the Jeryl Lynn strain mumps vaccine and aseptic meningitis.
[Non-text portions of this message have been removed]