Mikko Paunio

The Elimination of Indigenous Measles, Mumps, and Rubella from Finland by a 12-Year, Two-Dose Vaccination Program

BACKGROUND In the 1970s measles, mumps, and rubella were rampant in Finland, and rates of immunization were inadequate. In 1982 a comprehensive national vaccination program began in which two doses of a combined live-virus vaccine were used. METHODS Public health nurses at 1036 child health centers administered the vaccine to children at 14 to 18 months of age and again at 6 years, and also to selected groups of older children and young adults. Vaccination was voluntary and free of charge. In follow-up studies, we focused on rates of vaccination, reasons for noncompliance, adverse reactions, immunogenicity, persistence of antibody, and incidence of the three diseases. Since 1987, paired serum samples have been collected from all patients with suspected cases of measles, mumps, or rubella. RESULTS Over a period of 12 years, 1.5 million of the 5 million people in Finland were vaccinated. Coverage now exceeds 95 percent. The vaccine was efficient and safe, even in those with a history of severe allergy. No deaths or persistent sequelae were attributable to vaccination. The most frequent complication requiring hospitalization was acute thrombocytopenic purpura, which occurred at a rate of 3.3 per 100,000 vaccinated persons. The 99 percent decrease in the incidence of the three diseases was accompanied by an increasing rate of false positive clinical diagnoses. In 655 vaccinated patients with clinically diagnosed disease, serologic studies confirmed the presence of measles in only 0.8 percent, mumps in 2.0 percent, and rubella in 1.2 percent. The few localized outbreaks were confined to patients in the partially vaccinated age groups. There are now fewer than 30 sporadic cases of each of the three diseases per year, and those are probably imported. CONCLUSIONS Over a 12-year period, an immunization program using two doses of combined live-virus vaccine has eliminated indigenous measles, mumps, and rubella from Finland. Serologic studies show that most reported sporadic cases are now due to other causes, but a continued high rate of vaccination coverage is essential to prevent outbreaks resulting from exposure to imported disease.

No evidence for measles, mumps, and rubella vaccine-associated inflammatory bowel disease or autism in a 14-year prospective study

Concern of potential loss of confidence in measles, mumps, and rubella (MMR) vaccine has been raised by a recent paper that suggested a causal association between this vaccine (or another environmental trigger) and a new syndrome of chronic inflammatory bowel disease and autism. Characteristically, all children described developed intestinal symptoms within days or soon after vaccination. The National Board of Health and National Public Health Institute launched a long-term vaccination project in 1982, which aimed at the elimination of MMR diseases from Finland. All children are vaccinated twice, at age 14–18 months and 6 years; further vaccinations are carried out among recruits of the defence forces and in some schools of nursing. Only one type of live-virus vaccine (MMR or Virivac [Merck, West Point, PA, USA]) consisting of the more attenuated Enders Edmonston, Jeryl Lynn, and Wistar RA 27/3 strains for measles, mumps, and rubella, respectively, has been used since beginning of the project. Adverse events in temporal relation to MMR vaccine were reported prospectively to the Institute. A form was filled and posted to us, followed by another form with further information 2–3 weeks later. We traced those vaccinees who developed gastrointestinal symptoms or signs lasting 24 h or more at any time after MMR vaccination (apart from within the first hour). We checked hospital or health centre records or interviewed the local public-health nurses. By the end of 1996, about three million vaccine doses had been delivered by the Institute. 31 children developed gastrointestinal symptoms after vaccination (table); all except one after the first vaccine dose. Haemophilus influenzae type b conjugate vaccine was given concomitantly in four cases. 20 patients were admitted to hospital. Antibiotics were given in 11 cases, symptomatic relief in nine, and intravenous -globulin was given to one child with Guillain Barre syndrome. The time between the reported event and our check on their health varied from 1 year and 4 months to 15 years and 1 month. The mean interval was 9 years 3 months, the median being 10 years and 8 months. Diarrhoea, frequently with vomiting, was the most common symptom (55%, n=17), followed by gingivostomatitis (23%, n=7), vomiting only (16%, n=5), and abdominal pains (n=2). The time from MMR vaccine to onset of symptoms varied from 20 h to 15 days. Duration of symptoms was not always stated or recalled by nurses, but subsidence within a week was usual, except in a 1-year-old boy (patient 23) whose diarrhoea lasted for 6 weeks. The child recovered and was healthy when checked almost 6 years later. Most symptoms and signs of the central nervous system were those one would expect in conjunction with acute gastrointestinal disease: five (16%) children had febrile seizures and two had headache. One child developed ataxia

Mumps Outbreaks in Canada and the United States: Time for New Thinking on Mumps Vaccines

Mumps epidemics in Canada and the United States prompted us to review evidence for the effectiveness of 5 different vaccine strains. Early trials with the Jeryl Lynn vaccine strain demonstrated an efficacy of approximately 95%, but in epidemic conditions, the effectiveness has been as low as 62%; this is still considerably better than the effectiveness of another safe strain, Rubini (which has an effectiveness of close to 0% in epidemic conditions). The Urabe vaccine strain has an effectiveness of 54%-87% but is prone to cause aseptic meningitis. Little epidemiological information is available for other vaccines. The Leningrad-Zagreb vaccine strain, which is widely used in developing countries and costs a fraction of what vaccines cost in the developed world, seems to have encouraging results; in 1 study, the effectiveness of this vaccine exceeded 95%. Aseptic meningitis has also been reported in association with this vaccine, but the benign nature of the associated meningitis was shown recently in Croatia. Also, the Leningrad-3 strain seems to be effective but causes less-benign meningitis. No mumps vaccine equals the best vaccines in quality, but the virtually complete safety of some strains may not offset their low effectiveness. Epidemiological data are pivotal in mumps, because serological testing is subject to many interpretation problems.

Alcohol Consumption and Stroke Incidence in Male Smokers

BACKGROUND Studies on alcohol consumption and incidences of stroke subtypes have suggested distinct dose-response relationships. Blood pressure and HDL cholesterol mediate the effect of alcohol on coronary heart disease, but similar evidence on cerebrovascular diseases is not available. METHODS AND RESULTS We studied the risk of stroke in 26 556 male cigarette smokers 50 to 69 years of age without history of stroke. The men were categorized as nondrinkers, light (</=24 g/d), moderate (25 to 60 g/d), or heavy (>60 g/d) drinkers. A total of 960 men suffered from incident stroke: 83 with subarachnoid and 95 with intracerebral hemorrhage, 733 with cerebral infarction, and 49 with unspecified stroke. The adjusted relative risk of subarachnoid hemorrhage was 1.0 in light drinkers, 1.3 in moderate drinkers, and 1.6 in heavy drinkers compared with nondrinkers. The respective relative risks of intracerebral hemorrhage were 0.8, 0.6, and 1.8; of cerebral infarction, 0.9, 1.2, and 1.5. Systolic blood pressure attenuated the effect of alcohol consumption in all subtypes of stroke, whereas HDL cholesterol strengthened the effect of alcohol in subarachnoid hemorrhage and cerebral infarction but attenuated the effect in intracerebral hemorrhage. CONCLUSIONS Alcohol consumption may have a distinct dose-response relationship within each stroke subtype-linear in subarachnoid hemorrhage, U-shaped in intracerebral hemorrhage, and J-shaped in cerebral infarction-but further studies are warranted. Systolic blood pressure and HDL cholesterol seem to mediate the effect of alcohol on stroke incidence, but evidently additional mechanisms are involved.

Secondary measles vaccine failures identified by measurement of IgG avidity: high occurrence among teenagers vaccinated at a young age.

Failure to seroconvert (primary vaccine failure) is believed to be the principal reason (approx. > 95%) why some vaccinees remain susceptible to measles and is often attributed to the persistence of maternal antibodies in children vaccinated at a young age. Avidity testing is able to separate primary from secondary vaccine failures (waning and/or incomplete immunity), but has not been utilized in measles epidemiology. Low-avidity (LA) and high-avidity (HA) virus-specific IgG antibodies indicate primary and secondary failure, respectively. Measles vaccine failures (n = 142; mean age 10.1 years, range 2-22 years) from an outbreak in 1988-9 in Finland were tested for measles-virus IgG avidity using a protein denaturating EIA. Severity of measles was recorded in 89 failures and 169 non-vaccinees (mean age 16.2 years, range 2-22 years). The patients with HA antibodies (n = 28) tended to have clinically mild measles and rapid IgG response. Among failures vaccinated at < 12, 12-15 and > 15 months of age with single doses of Schwarz-strain vaccine in the 1970s, 50 (95% CI 1-99), 36 (CI 16-56) and 25% (CI 8-42) had HA antibodies, respectively. When a single measles, mumps and rubella (MMR) vaccine had been given after 1982 at 15 months of age, only 7% (CI 0-14) showed HA antibodies. Omitting re-vaccinees and those vaccinated at < 15 months, Schwarz-strain recipients had 3.6 (CI 1.1-11.5) higher occurrence of HA responses compared to MMR recipients. Apart from one municipality, where even re-vaccinees had high risk of primary infection, 89% (CI 69 to approximately 100) of the infected re-vaccinees had an HA response. Secondary measles-vaccine failures are more common than was more previously thought, particularly among individuals vaccinated in early life, long ago, and among re-vaccinees. Waning immunity even among individuals vaccinated after 15 months of age, without the boosting effect of natural infections should be considered a relevant possibility in future planning of vaccination against measles.

Day-to-Day Reactogenicity and the Healthy Vaccinee Effect of Measles-Mumps-Rubella Vaccination

Objective. Revaccination policies adopted in many countries to control measles have raised various safety issues including those concerning the second vaccine dose. We performed a prospective, double-blind, crossover trial among twins receiving a measles-mumps-rubella (MMR) vaccine. Study Design. The study comprised 1162 monozygous and heterozygous twins, each of whom randomly received placebo and then vaccine, or vice versa, 3 weeks apart, at 14 to 83 months of age. Most of the oldest children had previously been vaccinated against measles, and one half of the remainder of children had had the disease. Symptoms and signs were recorded daily on structured forms. Statistical methods included a complex analysis of the vaccine attributability of the symptoms and conditional logistic regression. Results. Vaccination-attributable events occurred in 6% overall. At 14 to 18 months of age, reactions developed between days 6 and 14, peaking at day 10. The clearest vaccine-attributable effect was fever exceeding 101.3 °F (38.5°C; odds ratio: 3.28; 95% confidence interval: 2.23–4.82; P < .001), but the same trend was found for rash, arthralgia, conjunctivitis, staying in bed, drowsiness, and irritability. At 6 years of age, systemic reactions occurred 5 to 15 times less frequently, only arthralgia being associated with vaccination. Zygocity, gender, history of allergy, or infections did not modify reactions. Instead, respiratory symptoms developed within days postinjection to a level of 15% to 20% without subsequent decline and with no difference between vaccinees and placebo recipients. Conclusion. Vaccination was avoided during infections, but many small children became mildly ill within a week or so with no relation to vaccination (the healthy vaccinee effect). MMR vaccine was virtually nonreactogenic when given at 6 years of age. vaccine, measles, mumps, rubella, reactogenicity, adverse events, zygocity, healthy vaccinee effect.

HDL cholesterol and mortality in Finnish men with special reference to alcohol intake.

BackgroundThere is substantial evidence that a low serum level of HDL cholesterol (HDLC) is a risk factor for coronary deaths. However, data on older people are scarce, and previous studies have not examined this association in relation to alcohol intake. Methods and ResultsCoronary mortality, all-cause mortality, and mortality due to alcohol and violence were related to HDLC levels among 7052 male smokers 50 to 69 years old in south and west Finland enrolled from 1984 to 1988 in the ATBC (AT, alpha-tocopherol; BC, beta-carotene) Study placebo group. During the average follow-up period of 4.7 years, 620 men died; 222 of these deaths were from coronary heart disease and 82 from causes related alcohol and violence. HDLC levels were inversely associated with coronary mortality, irrespective of age, whereas high total cholesterol was positively associated with coronary mortality among the younger men, 50 to 59 years of age, but not among the older men, 60 to 69 years old. Correction for temporal variation in HDLC measurement indicated a 43% stronger inverse association between HDLC and coronary mortality compared with that based only on a single value. The inverse association of HDLC and coronary mortality was less marked at higher levels of alcohol intake. All-cause and alcohol- and violence-related mortality were positively associated with HDLC among the younger men. All-cause mortality showed a U-shaped dose response among men ≥ 60 years old. ConclusionsPrevious studies may have underestimated the beneficial effect of high HDLC because of regression-dilution bias and the confounding effect of heavy alcohol intake. This study supports the view that, particularly among older men, lipoprotein fractions may be more appropriate for screening than total cholesterol.

Measles, mumps, and rubella in Finland: 25 years of a nationwide elimination programme.

A nationwide programme to eliminate indigenous measles, mumps, and rubella, mainly by vaccinating children twice, was launched in Finland in 1982. Strong scientific methods to examine the immunological, clinical, and epidemiological variables have accompanied the programme. Measles was eliminated in 1996, and mumps and rubella in 1997. Now, 25 years from the start of this programme, Finland is facing new challenges. Since elimination, eight, 32, and six cases of measles, mumps, and rubella, respectively, have been reported. Of those, seven cases were failures of mumps vaccinations and one case was a rubella vaccination failure. Although outbreaks have been averted, the risks are increasing because the unvaccinated population is growing, epidemics occur in nearby countries, breakthrough cases arise, and declining antibodies suggest waning immunity. The chances for natural boosters are now at a minimum, and individuals are increasingly protected solely by vaccination. To maintain the absence of these diseases, the adopted policy should continue, but the country should also be prepared for prompt supplementary vaccinations in the case of epidemic outbreaks.

Waning Antibody Levels and Avidity: Implications for MMR Vaccine-Induced Protection

BACKGROUND The measles-mumps-rubella (MMR) vaccine is effective in eliciting a good antibody response. In addition to the amount of antibodies, the avidity of these antibodies might be important in protecting against disease. METHODS The amount of circulating antibodies for measles, mumps, and rubella was measured with enzyme immunoassays, and the avidity of these antibodies was determined by urea dissociation. Three groups of twice-MMR-vaccinated individuals and 1 group of naturally infected individuals were studied. One vaccinated group (n = 71) was studied 6 months and 20 years after a second MMR vaccination. RESULTS The antibody avidity indexes were high for measles and rubella but low for mumps. Twenty years after a second MMR vaccination, antibody levels for all 3 viruses waned. Also, the mean avidity index decreased by 8% for measles, 24% for mumps, and remained unchanged for rubella. Antibody avidity correlated with antibody concentration for measles. There was partial correlation for rubella and no correlation for mumps. CONCLUSIONS Measles and rubella induced high-avidity antibodies and mumps induced low-avidity antibodies after both vaccination and natural infection. Waning of both the concentration as well as the avidity of antibodies might contribute to measles and mumps infections in twice-MMR-vaccinated individuals.

MMR vaccination and disease elimination: the Finnish experience.

Measles, mumps and rubella (MMR) vaccinations have been included in Finland’s national vaccination program as a two-dose schedule since 1982. Owing to the high (>95%) coverage of vaccinations, indigenous MMR diseases were eliminated from Finland by the mid-1990s. In 1982, the incidence of measles, mumps and rubella was 105, 43 and 64 per 100,000 population, respectively, but declined to 0.1 per 100,000 population for all MMR diseases in 1995. Since then, the few cases of measles, mumps and rubella imported annually have not caused any outbreaks. Several research projects that started along with the vaccination campaign have provided important support throughout the program. The vaccine was proven to be safe, immunogenic and effective. Antibody follow-up has revealed that MMR vaccine-induced antibodies wane over time, and concerns have arisen about the continuation of this good situation. High vaccination coverage, enhanced surveillance and preparedness to administer additional doses when needed are key factors for future success. Here we present an overview of MMR vaccinations and the Finnish experience of the MMR disease elimination process, and we describe surveillance activities in the era following elimination in Finland.