A combined vaccine comprising attenuated live measles, mumps and rubella (MMR) viruses was added to the schedule of voluntary and free of charge childhood immunization in Finland in November, 1982. Since then children have been vaccinated twice, at 14 to 18 months and 6 years of age. This comprehensive program has proved highly successful, and MMR diseases and their severe consequences have become rarities. As a result vaccine safety has become a more important issue than when these diseases were rampant.
With the launching of the vaccination policy, a countrywide prospective surveillance system was set up to clarify the incidence and nature of all serious events after MMR vaccination during 1982 through 1996. The aim was to distinguish events having a causal relation with MMR vaccination from those with only a temporal relation. We here report the results of >14 years of follow-up.
The passive surveillance system was launched by ad hoc personnel and a follow-up committee operating under the auspices of the National Board of Health and the National Public Health Institute. 1 A primary aim was to gather information about the incidence and nature of all the severe adverse events in a causal association with MMR vaccination. The surveillance system was designed to identify all such events that were too rare to have been detected by a double-blind crossover study conducted on 1200 twins. 2
It was anticipated that potentially serious and unpredictable events would be reported more reliably than the commonplace reactions.
All reports were sent to the central office by health care personnel, public health nurses, general practitioners or pediatricians in primary care and hospitals, who were provided with detailed information in a series of seminars held around the country before the project started. 1 All information was distributed in written form in Finnish and Swedish, the other official language. The public was informed by the media, 3 and several articles on the MMR project appeared in Finnish medical publications during the subsequent years.
Once a report arrived it was evaluated, and if needed the hospital or health center treating the vaccinee was contacted.
A potentially serious adverse event was defined as an event in any temporal association (no time limit was imposed) with MMR vaccination that fulfilled one or more of three characteristics: a potentially life-threatening disorder (e.g. anaphylaxis); possibility that a chronic disease had been triggered by the vaccination (e.g. rheumatoid arthritis, diabetes); or the vaccinee had been hospitalized for reasons possibly attributable to MMR vaccine. In case of such an event the first part of a special two part form was completed and mailed to the central office, whenever possible with a serum sample. The second part of the form and a second serum sample were sent 2 to 3 weeks later.
To facilitate reporting the forms with detailed instructions, tubes for serum samples, and prestamped padded envelopes were distributed to the 1000 child health centers and relevant hospitals.
Categorization of the cases (death, likely allergic reactions, neurologic disorders and miscellaneous events) was conducted by two of the authors (HP, specialist in pediatric infectious diseases, and AP). Likely allergic reactions were anaphylaxis, 4 urticaria 5 (sometimes accompanied by angioedema 6), asthma, 7 Henoch-Schönlein purpura 8 and Stevens-Johnson syndrome. 9
Neurologic disorders were divided into seizures (febrile seizures, 10 epilepsy, 11 and undefined seizures which did not meet any particular criterion and remained without accurate diagnosis), encephalitis, 12 meningitis, 13 Guillain-Barré syndrome, 14 gait disturbance and confusion during fever. A few cases of transient gait disturbance have been described before, 15, 16 but exact definition is lacking, as in the case of short lasting confusion during fever.
Finally the miscellaneous syndromes comprised pneumonia, 17 orchitis 18 and diabetes mellitus.
Judgment of the causal association with MMR vaccination was based on the clinical information obtained from medical records and notification forms and analysis of the serum samples. The incubation periods of measles (8 to 12 days), mumps and rubella (both 16 to 18 days) 19 were also used in the assessment of whether a nonallergic event was likely or unlikely to have been triggered by MMR vaccination. The incubation periods could not be applied to allergic events or those with unresolved etiology.
Serum samples were collected to trace possible concurrent infections manifesting with symptoms or signs mimicking those caused by vaccination. All samples were stored at −20°C until analyzed in 1998. Antibodies against Haemophilus influenzae, Moraxella catarrhalis, pneumococcus and adeno-, entero- and human parvoviruses were detected by enzyme immunoassay, whereas microimmunofluorescence was used for Chlamydia pneumoniae and indirect immunofluorescence for human herpesvirus 6. Details of the methodology are described elsewhere. 20–24
Vaccine and vaccinees
M-M-R®II (Merck & Co., Inc., West Point, PA), distributed as Virivac in Scandinavia, has been the only vaccine used in Finland except for the 2570 doses of Triviraten (Swiss Serum and Vaccine Institute, Berna, Switzerland) that were administered to individuals with severe hypersensitivity in 1992 through 1996.
M-M-R®II contains the more attenuated Enders-Edmonston strain of measles virus, the Jeryl Lynn B strain of mumps virus and the Wistar RA 27/3 strain of rubella virus. It also contains 25 μg of neomycin and traces of sorbitol and hydrolyzed gelatin. The vaccine is administered subcutaneously into the buttock (at age 14 to 18 months) or upper arm (subsequently).
Besides the main target groups, children at the age of 14 to 18 months and 6 years, intermediate age groups were immunized in various catch-up programs during the early years of the project. 1, 25 Recruits of the Defense Forces were included in 1986, whereas health care workers, nursing school students and once only vaccinated 11- to 13-year-old girls have been vaccinated since 1988. From 1988 to 1993 rubella-seronegative women were vaccinated after delivery. During outbreaks 3 vaccination was extended to unvaccinated adolescents.
The reports of potentially serious adverse events were categorized as death, likely allergic reactions, neurologic disorders and miscellaneous events.
However, the majority of the reports concerned innocuous symptoms and signs not fulfilling the above mentioned criteria and were excluded from further analysis (Table 1). Idiopathic thrombocytopenic purpura was also excluded because it has been analyzed previously. 26
The vaccination coverage has oscillated around 95%. 25, 27 By the end of 1996 2 990 000 vaccine doses had been distributed for 1.8 million vaccinees. During the entire 14-year period 437 vaccinees were reported to have a vaccine-associated untoward event (Table 1); 173 reactions among 169 vaccinees, of whom 79 (46.7%) were hospitalized, were considered potentially serious. These 173 events were further scrutinized, except for a possible anaphylactic reaction in a 6-year-old child, whose medical records were not traced. Paired sera were available from 83 and a single sample from 19 of these vaccinees.
As might be expected, more events were reported soon after the beginning of the project; a clear peak was observed in 1983 (Fig. 1). However, 43% (n = 19) of these 44 reports concerned febrile seizures. The reporting activity thereafter remained fairly static at 5 to 15 reports per year.
The age at the time of vaccination ranged from 13 months to 23 years; 57% of vaccinees were male and 43% were female. Simultaneous immunizations had been administered to 35 (20.7%) individuals;H. influenzae type b conjugate vaccine to 22, inactivated or live poliovirus vaccine to 9 and meningococcal polysaccharide vaccine to 1. In addition, 2 were vaccinated concurrently against tetanus, diphtheria, polio and meningococcal disease and 1 against H. influenzae type b and polio.
As illustrated in Fig. 2, the events developed in 2 peaks, within the first 24 h and on Days 7 to 10 postvaccination; 34% of cases occurred in each period (n = 59 and 60, respectively). Most events, 81% (n = 140), followed the first vaccination dose, but 16% (n = 28) occurred after revaccination [dose not stated in 5 reports (3%)]. An exception to this were the suspected anaphylactic reactions, 63% (n = 19) manifesting after the second dose.
Serious adverse events
Death. A previously healthy 13-month-old boy died during sleep 8 days after MMR vaccination. The parents had noticed transient flaccidity and faintness a few hours preceding the death, but the symptoms had subsided immediately, and the boy had seemed entirely healthy when put to bed. Forensic autopsy disclosed the cause of death as aspiration of vomit caused by acute gastritis. His older sister also had a history of flaccid attacks unrelated to vaccinations.
Allergic events. Thirty suspected cases of anaphylaxis were reported, at age from 15 months to 23 years, only 2 boys were younger than 5 years. Epinephrine or corticosteroids had been administered to only 18 of these 30 vaccinees, and in 15 of the 30 cases the physician ultimately diagnosed fainting, based on lack of other signs of hypersensitivity, evident fear before vaccination, a history of syncope after other vaccinations or blood tests or a full and rapid recovery without medication. All reactions appeared within 20 min of vaccination, except in a 20-year-old woman, who developed shortness of breath, dizziness, diarrhea and facial angioedema several hours after vaccination, shortly after a spicy meal. Allergy tests were never conducted, but allergy to spice was suspected. Full recovery within 1 h, and usually within a few minutes, was the rule.
Urticaria occurred in 30 vaccinees, in 12 cases accompanied by angioedema. The symptoms appeared within a few minutes to 15 days. The age at vaccination ranged from 13 months to 23 years.
Asthma-like symptoms and signs commencing 10 min to 13 days after vaccination were reported in 10 vaccinees at the ages of 17 months to 17 years. Asthma had previously been diagnosed in 2 vaccinees, and egg allergy had been diagnosed in 2. Symptoms appeared in conjunction with upper respiratory tract infection in 4 children, 3 of whom had histories of similar episodes.
A 2-year-old girl developed Henoch-Schönlein purpura 3 days after MMR vaccination. A 6-year-old boy was also diagnosed with this disease 24 days postvaccination, but a verified streptococcal tonsillitis preceded the diagnosis by a few days. Both children recovered completely.
A 16-year-old boy developed Stevens-Johnson syndrome 4 days postvaccination, and 6 relapses with milder manifestations occurred during the following 7 years. Respiratory infections with reappearance of labial herpes simplex lesions were observed in connection with most of the relapses.
Neurologic disorders. The events most commonly reported were febrile seizures, occurring in 52 vaccinees 12 h to 15 days after vaccination. Apart from 3 children at the ages of 3 to 6 years, all were <3 years old. In a 14-month-old girl with a febrile seizure occurring 10 days postvaccination, serology detected influenza A infection. Tympanocentesis revealed H. influenzae and pneumococcal infections in 2 children with concomitant otitis media.
Epilepsy was diagnosed in 2 boys and a girl, all 6 years old. Symptoms manifested for the first time 1, 10 and 21 days postvaccination. One of the boys was later diagnosed as having severe Lennox-Gastaut syndrome, whereas medical records subsequent to the acute phase were not available for the other. The electroencephalogram of the girl normalized during follow-up and medication was discontinued.
Undefined seizures were observed in 4 girls 2 to 12 days postvaccination. Histories of breath-holding spells in 2 girls were noted. Brief convulsions were reported in the 14- and 23-month-old girls. The other 2 vaccinees, 21 months and 7 years old, underwent transient loss of consciousness, accompanied by fever in the older child. All seizures subsided without medication or sequelae. An electroencephalography was conducted in 2 children and lumbar puncture was performed in 1; all results were normal. One of the events was deemed by a neurologist to have been a breath-holding spell.
Of the four cases of encephalitis reported, the first has been described earlier;28 acute lymphoblastic leukemia was diagnosed in a 6-year-old girl 23 days after MMR vaccination. During immunosuppressive treatment she developed severe measles encephalopathy 54 days postvaccination and interstitial pneumonia a few days later. In 1998, 14 years later, she had completed comprehensive school, and the leukemia had not relapsed, but she suffered from severe epilepsy. No factor indicated a causal connection between MMR vaccination and leukemia, because the symptoms that led to the diagnosis, pain in the extremities and back, were already present at the time of vaccination. 28
Laboratory confirmation of herpes simplex encephalitis developing 6 days postvaccination in a 14-month-old boy indicated only a temporal association between vaccination and encephalitis. In contrast in 2 girls at the ages of 15 and 18 months who developed encephalitis 9 and 13 days postvaccination, a causal relation could not be excluded because no specific etiology was detected.
Meningitis was reported in 4 children. H. influenzae and meningococcal meningitis were diagnosed in a 15-month-old boy and 14-month-old girl 2 and 7 days postvaccination, respectively. In 2 boys 6 and 7 years old, no agent was detected. Both developed symptoms 2 days after the second MMR vaccination. The very short interval between vaccination and onset of the disease almost certainly excludes a causal association with MMR vaccination.
Guillain-Barré syndrome was diagnosed in two 18-month-old boys 10 and 27 days after immunization. Both soon recovered without complications. A causal association with vaccination cannot be excluded in these cases.
Transient gait disturbances were reported in five vaccinees, four boys and a girl 14 to 18 months old. The only visible sign was enlargement of the inguinal lymph nodes in one child; fever was present in three children. The symptoms manifested 2 to 8 days postvaccination and subsided within a few days.
Confusion during fever was reported in 3 boys 18 months to 2 years old. This nonspecific sign developed 2 to 9 days postvaccination and subsided spontaneously within a few hours.
No cases of autism 29 were associated with MMR vaccination during this 14-year follow-up.
Miscellaneous complaints. Pneumonia occurred 3 to 58 days postvaccination in 12 vaccinees 15 months to 6 years old. In 1 case pneumonia was caused by aspiration during a febrile seizure. Concomitant otitis media, caused by H. influenzae and by M. catarrhalis, was diagnosed in 2 boys by tympanocentesis.
In four 17- to 18-month-old boys, orchitis was suspected 5 to 9 days postvaccination. Three additional cases were reported, but they turned out to be swelling of the scrotum caused by urticaria without involvement of the testicles, testicular cancer and scrotal hernia, at the ages of 16 months, 17 months and 4 years, respectively. The cancer was diagnosed 16 days postvaccination and had not relapsed after operative treatment when checked 5 years later.
Diabetes mellitus was reported in three children. A 15-month-old girl was healthy when vaccinated, but polydipsia, fever, vomiting and diarrhea were noticed a couple of days later. The symptoms subsided 6 days postvaccination but recurred on the eighth day, leading to hospitalization and diagnosis.
Polydipsia and polyuria were observed 7 days after MMR vaccination in a 6-year-old boy in whom diabetes was diagnosed 1 week later. Another boy, 19 months old when vaccinated, developed symptoms insidiously over weeks until the diagnosis was made 80 days postvaccination.
The incidence of type I diabetes in Finland is the highest worldwide; ∼30 new cases are expected in children aged 1 to 6 years during any 80-day period (J Tuomilehto, personal communication, 1998). 30 Because this is 10 times more than the incidence of diabetes found in this series, we deem a causal relation very unlikely.
No cases of ulcerative colitis, Crohn’s disease or any other chronic disorder affecting the gastrointestinal tract 29 were reported.
Documented causative or contributing factors
An infectious agent or other factor not related to MMR vaccine that was probably responsible for the reported event was identified in 11 cases by the examinations conducted shortly after the event; streptococcal infection preceding Henoch-Schönlein purpura, influenza A infection triggering a febrile seizure, H. influenzae and pneumococcal infections associated with febrile seizures and otitis, herpes simplex encephalitis, H. influenzae and meningococcal meningitis, H. influenzae and M. catarrhalis infections concomitantly with pneumonia and otitis and 2 noninfectious factors, testicular cancer and hernia.
The serum samples of 102 vaccinees, which were analyzed later, disclosed a probable cause, or at least a contributory factor, in a further 25 cases (Table 2): pneumococcus in 7; human herpesvirus 6 in 6;M. catarrhalis in 3; enterovirus in 3; and H. influenzae in 1; 5 vaccinees had multiple infections.
In summary our clinical, serologic and epidemiologic analyses suggest that factors not related to MMR vaccination probably caused or contributed to 45% (n = 78) of the serious events reported. The results of this assessment and the estimated incidences are listed in Table 3.
Large scale immunizations have sharply lowered the incidence of many vaccine-preventable diseases and their complications but raised the question of undesirable secondary effects of vaccination. 31–33 The risks in the community may change with time and compel changes in vaccination policy, as was the case in the US years ago, when all residual polio cases were vaccine-induced. 34
Passive notification systems are liable to the risk of underreporting, and relatively frequent but less severe events, such as febrile convulsions, are detected more reliably by active surveillance. 35 Clear awareness of this problem prompted the organization of an extensive campaign to motivate health care personnel and the public to report all serious events meticulously, and various efforts were made in subsequent years to maintain their interest. Because notification and sampling of paired sera were made as easy as possible, we do not regard underreporting as a major issue. Lack of a control group was realized to be another limitation but was unavoidable in an almost fully vaccinated population.
Various events were reported during the time of this study. Whether the single case of death or the chronic diseases such as asthma, epilepsy or diabetes were causally related to immunization is debatable. However, if the causality had been real, an accumulation of new cases should have occurred during the follow-up, and this did not happen. Our findings for diabetes are compatible with those of Fescharek et al., 16 who found no increase in the incidence of diabetes after mumps vaccination. These estimations do not, however, exclude the possibility of a causal link in an individual case, but such a connection is highly improbable.
If one were to accept MMR vaccination as a cause of encephalitis, the facts would have to be put into perspective. The incidence of encephalitis is 35, 150 and 12.5 per 100 000 cases of measles, 36, 37 clinical mumps 36, 38 and rubella, 36, 39 respectively. We found 3 cases likely or possibly caused by MMR vaccination, 1 of these being in an immunocompromised child, 28 giving an incidence of 0.1 per 100 000 vaccine doses for all 3 viral components combined. This almost 2000-fold difference from natural MMR diseases, even allowing for some unreported cases, still shows that the risks of vaccination are greatly outweighed by those of wild infections. In Finland MMR vaccination has reduced by one-third all cases of childhood encephalitis. 12
Aseptic meningitis develops in at least 1 per 1000 cases of clinical mumps. 36, 38 An association with MMR vaccine has also been identified, but virtually exclusively in recipients of the Urabe Am 9 mumps strain. 40, 41 In this study no case was attributable to the vaccine containing the Jeryl Lynn B strain, nor have cases of the invariably fatal subacute sclerosing panencephalitis caused by measles, with an incidence of 0.5 to 1 per 100 000 patients, 36, 42 occurred. Orchitis complicates 14 to 35% of mumps cases in postpubertal men, but in children it is rare. 18, 43 Our series disclosed only 1 suspected orchitis with possible causal relation to MMR vaccination. Approximately 50 cases a year 44 of congenital rubella infections have also been eliminated from Finland, not to mention all the less severe manifestations that so often required hospitalization.
No case of inflammatory bowel disease or autism was detected during this long follow-up study comprising 3 million vaccine doses. This finding is important because were there an association with MMR vaccination after such a short interval as suggested, 45, 46 this prospective study design would undoubtedly have disclosed at least some cases.
Some events were no doubt triggered by MMR vaccination. The estimated overall incidence of serious adverse events with a possible or unknown causal association with MMR vaccination was 3.2 per 100 000 vaccine doses or 5.3 per 100 000 vaccinees.
Revaccination caused fewer adverse events than the first vaccine dose, except for faintings, which understandably manifested among older vaccinees, and anaphylactic reactions reflecting hypersensitivity to a subsequent exposure. 47, 48
Febrile seizures were the most commonly reported events. Because up to 5% of children undergo febrile convulsions before the age of 5 years, 10 some concurrence with vaccinations is inevitable. Concurrence was also indicated in connection with several other events, for 45% of the serious events were probably caused, at least partially, by a factor unrelated to MMR vaccine. Clearly, post hoc non est propter hoc, a sequence does not prove consequence.
We thank the MMR follow-up group and Drs. Maija Leinonen, Pekka Saikku, Jaakko Tuomilehto and Kimmo Linnavuori for their contributions. We also thank Sini Kangas, Sari Jokinen and Anne Jaakkola for technical assistance. Richard Burton, M.Sc., checked the English text.
The study was supported by a grant from Merck & Co., USA.
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