Adverse Events Associated with Childhood Vaccines Evidence Bearing on Causality (1994) / Chapter Skim
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6 Measles and Mumps Vaccines
6 Measles and Mumps Vaccines
Pages 118-186
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From page 118... ...
Conventionally, the diagnosis of measles is made clinically on the basis of its signs and symptoms, which include a characteristic rash. The diagnosis can be confirmed by a laboratory test that detects antibodies to the measles virus.
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From page 119... ...
Development of a live attenuated measles vaccine began a new era in the prevention of this disease. The initial vaccine was derived from the Edmonston strain, which was attenuated by serial passage in various tissue cultures and ultimately grown in chicken embryo cells.
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Table 6-1 lists the measles vaccines used in the United States. TABLE 6-1 Measles Vaccines Used in the United States Attenuation Strain Years Trade Name Manufacturer in Use Live attenuated Edmonston B Live, more attenuated Rubeovax M-Vac Pfizer-vax; Measles-L Generic Schwarz (derived from Edmonston A)
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From page 121... ...
The Jeryl Lynn strain, the mumps virus strain used in mumps vaccines in the United States, came about by numerous passages in vitro, first in embryonated hen's eggs and then in chicken embryo cells (Buynak and Hilleman, 1966~. The seroconversion rate was nearly 97 percent.
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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)
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measles virus infection is associated with a well-described, frequently very severe encephalitis. Case Reports, Case Series, and Uncontrolled Observational Studies Many uncontrolled observational studies in the literature describe the occurrence of encephalopathy after administration of measles vaccine.
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Table 6-2 summarizes case series and uncontrolled observational studies in which the incidence rates of encephalopathy or encephalitis following administration of measles vaccine were calculated by the authors. Two case series addressed early concerns in the United States that measles vaccine might cause encephalitis.
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, but provided no details. The incidence rate for "encephalopathy" and "encephalitis" following measles vaccination appeared to be lower than the observed incidence of encephalitis from all causes among age-matched controls (Hirayama, 1983; Isomura, 19881.
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From page 127... ...
, 6 of 16 reports of "meningitis" or "encephalitis" were thought by the authors to be possibly related to measles, measles-mumps, or measles-mumpsrubella vaccine, leading to a rate of 1 case per 1 million doses distributed, as calculated by the authors. The vaccine strains are those currently licensed in the United States, that is, the more attenuated measles vaccine and Jeryl Lynn mumps vaccine.
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No further details are given. Several reports of encephalopathy following measles vaccination can be found in the Vaccine Adverse Event Reporting System (VAERS)
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In one case of a 7-year-old girl with acute lymphoblastic leukemia (Valmari et al., 1987) , measles virus was isolated from her CSF approximately 10 weeks after she received MMR (which contains the more attenuated measles vaccine used in the United States)
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Conclusion The evidence is inadequate to accept or reject a causal relation between measles or mumps vaccine and encephalitis or encephalopathy. ASEPTIC MENINGITIS Clinical Description Aseptic meningitis is defined as an inflammation of the meninges associated with pleocytosis of the CSF.
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From page 131... ...
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.
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From page 132... ...
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)
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From page 133... ...
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.
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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.
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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.
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The committee was charged with investigating a possible causal relation between measles vaccine only and SSPE. Evidence for Association Biologic Plausibility SSPEis a recognized sequela of measles infection, and it is biologically plausible that it could occur after administration of the live attenuated viral vaccine.
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From page 137... ...
to 5 years (Cho et al., 1973~. The absence of prevaccination serology and the inability to characterize the cause of SSPE as wild-type or vaccine-strain measles virus in all cases preclude, as discussed below, a determination that the SSPE was caused by administration of the live attenuated measles vaccine.
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From page 138... ...
Eleven of 215 patients with SSPE identified in Japan between 1966 and 1985 had received measles vaccine but had not had measles virus infection by history. A total of 184 patients had a history of measles virus infection but not vaccination against measles (Okuno et al., 19891.
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The age of infection with measles virus for children with SSPE was significantly less than that for controls who had measles. There was no difference in age at the time of vaccination between those subjects and controls who did not have a prior measles infection.
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Causality Argument There is no question that measles virus is causally related to SSPE. Therefore, it is biologically plausible that there is a link between receipt of live attenuated measles vaccine and SSPE.
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The National Registry for Subacute Sclerosing Panencephalitis contained records of nine patients who received attenuated or killed measles vaccine after the onset of SSPE symptoms. Four of the nine patients died an average of 3.6 years after the onset of SSPE symptoms and 2.4 years after vaccination.
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From page 142... ...
There are no specific data bearing on the biologic plausibility of an association between measles or mumps vaccine and RSD. Case Reports, Case Series, and Uncontrolled Observational Studies The National Collaborative Perinatal Project followed about 54,000 pregnant women, living in 13 cities in the United States, between 1959 and 1966 (Hirtz et al., 19831.
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From page 143... ...
In a study of voluntary reporting of reactions to vaccination in the North West Thames region of England between 1975 and 1981, when approximately 170,000 children received live measles vaccine (as well as other childhood vaccines) , there were 26 reports of convulsions without evidence of necrologic damage following measles vaccination (Pollock and Morris, 1983~.
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From page 144... ...
It is not clear whether any of the convulsions represented the early signs of an RSD. A report from the passive surveillance system used to detect adverse events following immunization in Canada provided the rates of occurrence of adverse events but not long-term outcomes (Koch et al., 1989~.
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There is no evidence bearing on a causal relation between mumps vaccine and residual seizure disorder. The evidence is inadequate to accept or reject a causal relation between multivalent measles or mumps vaccines and residual seizure disorder.
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Sensorineural deafness can be a complication of natural mumps virus infection. Case Reports, Case Series, and Uncontrolled Observational Studies A 7-year-old girl who had audiometry 2 years earlier for an unstated reason developed total deafness in the left ear 11 days after an injection of MMR.
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From page 147... ...
Although cases of sensorineural deafness following administration of mumps and measles vaccines have been reported, the timing of onset and other nonspecific features make it impossible to distinguish vaccine from nonvaccine causation. Virus isolation would be helpful in assessing causality when the data are as scarce as described for the causal relation between measles and mumps vaccines and sensorineural deafness; however, such data are lacking.
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Controlled Clinical Trials None. Causality Argument There is demonstrated biologic plausibility of a causal relation between optic neuritis and measles vaccine, in that measles virus is associated with demyelinating disorders.
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linking transverse myelitis with live attenuated measles vaccine was identified (Clark et al., 1977~. Thirteen days after vaccination with Schwarz strain measles vaccine, a 16-year-old girl developed symptoms of transverse myelitis.
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Controlled Clinical Trials None. Causality Argument There is demonstrated biologic plausibility for a causal relation between measles vaccine and transverse myelitis, in that measles virus is well associated with demyelinating disorders.
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There is no specific information suggesting an association between measles vaccine and GBS. The committee was charged with investigating a possible causal relation between only measles vaccine and GBS.
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From page 152... ...
From 1963 to 1971, 84 cases of necrologic disorders with onset less than 30 days after live attenuated measles virus vaccination were reported in the United States, but these did not include GBS. In a review of adverse event reports submitted between 1976 and 1989 to the Behringwerke AG pharmaceutical firm in the former West Germany, Fescharek and colleagues (1990)
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GBS has been shown to follow natural measles virus infection. As described in Chapter 3, several vaccines and viruses are suspected of playing a role in GBS.
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Suspicion of an association between mumps vaccine and IDDM is based on the ability of the wild-type mumps virus to cause pancreatitis (Association for the Study of Infectious Disease, 1974; Craighead, 1975; Prince et al., 1978) , individual cases of IDDM with onset shortly following acute clinical mumps infections (Gamble et al., 1980; Harris, 1899; Hinden, 1962; Kremer, 1947; McCrae, 1963; Messaritakis, 1 97 1; Otten et al., 1 984; Patrick, 1 924; Peig et al., 1 98 1 )
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There have been numerous case reports of IDDM following infection with viruses other than the mumps virus, the most common being coxsackievirus and rubella virus. One of the most convincing reports of the ability of viruses to induce acute-onset IDDM was published by Yoon and colleagues in 1979.
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Case Reports, Case Series, and Uncontrolled Observational Studies The case reports implicating measles vaccine as a potential cause of IDDM involve administration of the mumps vaccine at the same time. There have been several cases of IDDM reported following MMR, measles
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In 1979, Quast and colleagues noted that in the first 2 years after mumps and measles-mumps vaccines were introduced in the former West Germany, two cases of IDDM with onset 7 and 10 days after immunization with measles-mumps and mumps vaccines, respectively, were reported to the manufacturer, Behringwerke AG. In 1990, Fescharek and colleagues noted that 20 cases of IDDM were reported to the manufacturer, Behringwerke AG, from 1976 through 1989, a period during which about 5 million doses of mumps vaccine were distributed in the former West Germany, giving a rate of 1 for every 250,000 doses distributed.
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From page 158... ...
, and noted that IDDM was preceded by mumps disease or exposure to mumps virus in almost 50 percent of the children and by mumps vaccination in an additional 11 percent. The median lag time was 3 years (mean, 3.8 years)
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From page 159... ...
Even if the vaccine virus were to cause IDDM by direct cytolysis of pancreatic beta cells, it will be difficult to document this by isolating the virus from pancreatic tissue since, currently, there is a very low mortality early in the course of IDDM, when the virus would most likely be present. Conclusion The evidence is inadequate to accept or reject a causal relation between measles or mumps vaccine and IDDM.
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From page 160... ...
Evidence for Association Biologic Plausibility There are no data bearing directly on the biologic plausibility of an association of orchitis or sterility with measles vaccine. The most compelling argument for biologic plausibility regarding orchitis following mumps vaccine are the reports of orchitis following infection with the wild-type mumps virus.
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. Case Reports, Case Series, and Uncontrolled Observational Studies The data regarding mumps vaccine-associated orchitis in the literature are in two reports of surveillance for adverse reactions to immunization in other countries.
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From page 162... ...
In another, the patient had a swollen left testicle that was not red or hot to the touch and was diagnosed as having "testis disease." In 1976, Borsche reported that after about 1,000 vaccinations with monovalent mumps vaccine, no side effects were noted. A study of live attenuated mumps vaccine (Rubini strain)
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From page 163... ...
Because there are case reports of bilateral orchitis following administration of mumps vaccine, there is a possibility of sterility, and thus, a causal relation between mumps vaccine and sterility has not been fully studied. Conclusion There is no evidence bearing on a causal relation between measles vaccine and orchitis or sterility.
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From page 164... ...
Evidence for Association Biologic Plausibility There is demonstrated biologic plausibility that measles or mumps vaccines could be associated with thrombocytopenia on the basis of experience with wild-type virus infections. Early case reports of purpura and bleeding associated with measles did not provide sufficient data to indicate the cause of bleeding.
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In addition to the case noted above following administration of live attenuated measles vaccine (Katz, 1965) , there have been other cases following administration of mumps vaccine (Dosik and Tricarico, 1970)
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From page 166... ...
reported 11 cases of thrombocytopenia following administration of measles vaccine between 1976 and December 1989, over which period an estimated 5.5 million doses of measles and measles-mumps vaccines and MMR were sold in the former West Germany. All cases of thrombocytopenia occurred following immunization with vaccines containing the measles virus antigen (the same strain that is used in the United States)
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, who found decreases in platelet counts in most subjects following administration of live attenuated measles vaccine (this vaccine is no longer used in the United States)
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From page 168... ...
Although Oski and colleagues (1966) speculated that the vaccine virus may replicate in the bone marrow since the onset of the vaccine-induced thrombocytopenia occurred during the incubation period of the live attenuated measles virus infection following immunization, they were unable to isolate the virus from the bone marrow on either of two occasions.
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From page 169... ...
The evidence is inadequate to accept or reject a causal relation between monovalent measles and mumps vaccines and thrombocytopenia. Risk-Modifying Factors Because so little information is available, the committee does not have the means to recommend any precautions to prevent clinically significant thrombocytopenia from occurring after administration of live attenuated measles vaccine or MMR.
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From page 170... ...
History of Suspected Association The suspected relation between measles and mumps vaccines and anaphylaxis is based on several reports of anaphylactic reactions following administration of measles or measles-mumps vaccines or MMR in the literature and VAERS (Aukrust et al., 1980; Fescharek et al., 1990; Herman et al., 1983; McEwen, 1983; Pollock and Morris, 1983; Taranger and Wiholm, 1987; Thurston, 1987; Van Asperen et al., 19811. No reports of anaphylaxis following administration of monovalent mumps vaccine have been published, but the 1991 Red Book states that since 1967 there have been rare, isolated reports of allergic reactions (American Academy of Pediatrics, Committee on Infectious Diseases, 19911.
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Case Reports, Case Series, and Uncontrolled Observational Studies In 1981, Van Asperen et al. reported immediate reactions following administration of live attenuated measles vaccine (Rimevax)
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In Germany, five reports of so-called immediate reactions were received after distribution of approximately 5.5 million doses of measles, mumps, and measles-mumps vaccines and MMR (Fescharek et al., 1990~. Three
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No details of these reactions were given. Nine cases of possible anaphylactic reactions following administration of measles or mumps vaccines have been reported to VAERS (submitted between November 1990 and July 1992~.
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reported systemic reactions after just intradermal skin testing with MMR in two patients with severe systemic reactions to egg. Fasano and colleagues (1992)
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From page 175... ...
In 1983, Pollock and Morris estimated that anaphylaxis or collapse within 24 hours of vaccination occurred with a frequency of about 9 cases per 170,000 doses of measles vaccine administered in a large region of England over 7 years. In children with a history of anaphylactic reactions to egg, only five cases of immediate allergic reaction had been reported after distribution of more than 174 million doses of measles vaccine in the United States (American Academy of Pediatrics, Committee on Infectious Diseases, 1991~.
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From page 176... ...
Patients who have demonstrated severe systemic reactions to egg protein or neomycin may be at increased risk of anaphylaxis following receipt of measles or mumps vaccines, and guidelines for immunizing such patients have been provided by the Committee on Infectious Diseases of the American Academy of Pediatrics (1991~. Patients with allergies to other antigens, including chickens and feathers, are not at increased risk of severe allergic reactions to these vaccines.
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Thrombocytopenic purpura following vaccination with attenuated measles virus. American Journal of Diseases of Children 1968;115:111-113.
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Brodsky L, Stanievich J Sensorineural hearing loss following live measles virus vaccination.
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Live attenuated mumps virus vaccine.
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From page 180... ...
Hoskins JM, Wegmann A, Just M, Germanier R Rubini, a new live attenuated mumps vaccine virus strain for human diploid cells.
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From page 181... ...
Risk of subacute sclerosing panencephalitis from measles vaccination. Pediatric Infectious Disease Journal 1990;9:857-858.
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From page 182... ...
Katz SL. Immunization with live attenuated measles virus vaccine: five years' experience.
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From page 183... ...
Epidemiologic studies of measles, measles vaccine, and subacute sclerosing panencephalitis. Pediatrics 1977;59:505-512.
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et al. Incidence of subacute sclerosing panencephalitis following measles and measles vaccination in Japan.
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From page 185... ...
Schwarz AJ, Anderson JT. Immunization with a further attenuated live measles virus vaccine.
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Cerebellar ataxia presumed due to live, attenuated measles virus vaccine. Journal of the American Medical Association 1967;199:129-130.
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