Martti Valle

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

Influenza vaccination in 22 developed countries: An update to 1995

This study expands and updates through 1995 our earlier report on influenza vaccine use in 18 developed countries. Five of the six countries with high levels of vaccine use in 1992 (> or = 130 doses/1000 population) showed little change or slight declines over the subsequent 3 years. The exception was the United States, where a new federal program for vaccination reimbursement for the elderly helped to increase vaccine distribution from 144 to 239 doses/1000 population. The six countries with medium levels of vaccine use in 1992 (76-96 doses/1000 population) increased to > or = 100 doses/1000 population by 1995. Among the six low-use countries in 1992 (< or = 65 doses/1000 population), only Finland showed substantial improvement (96 doses/1000 population) in 1995. Four new countries were added to the study. In Germany, vaccine use increased to 80 doses/1000 population in 1995, but in Ireland it remained at a low level (48 doses/1000 population). In Korea, vaccine use increased from 17 to 95 doses/ 1000 population during the period 1987-1995. In Japan, very high levels of vaccine use (approximately 280 doses/1000 population) in the early 1980s were associated with vaccination programs for school children. However, vaccine use fell precipitously when these programs were discontinued, and only 2 and 8 doses/1000 population were used in 1994 and 1995, respectively. In all 22 countries, higher levels of vaccine use were associated with vaccination reimbursement programs under national or social health insurance and were not correlated with different levels of economic development. Excluding Japan, in 1995 there was still a greater than fourfold difference between the highest and lowest levels of vaccine use among the other 21 countries in the study. Given its well established clinical effectiveness and cost-effectiveness, none of these countries has yet achieved the full benefits of its programs for influenza vaccination.

Vaccine-induced measles virus antibodies after two doses of combined measles, mumps, and rubella vaccine : a 12-year follow-up in two cohorts

In Finland, a two-dose vaccination programme against measles, mumps and rubella (MMR) was begun in 1982. The programme with high coverage (97-98%) has eliminated these three diseases from Finland. The aim of the present study was to follow up the kinetics of measles virus antibodies in MMR vaccinated cohorts. We have followed the kinetics of measles virus antibody levels induced by vaccination in the same individuals immunized with their first MMR vaccine in 1982. After 12 years 80% of the original children remained available for sampling. Antibodies to measles virus were measured by haemagglutination inhibition (HI) and plaque reduction neutralization (NT) techniques. The primary dose induced 99.4% seroconversion for measles with a geometric mean HI antibody titre (GMT) of 1/269 (+/- 219), equivalent to 4304 mIU (milli-International Units) ml-1 in group A. The 12-year follow-up specimens showed a measles seropositivity rate of 100% as assayed with the HI and NT tests with a mean HI antibody titre of 1/39 (+/- 54), equivalent to 624 mIU ml-1. The vaccination-induced measles virus antibodies decline in the absence of natural booster infections. It is important to follow how long the protection achieved by the present vaccine programme will last after elimination of indigenous measles.

Duration of rubella immunity induced by two-dose measles, mumps and rubella (MMR) vaccination. A 15-year follow-up in Finland

A national two-dose vaccination program with a combined measles, mumps and rubella (MMR-II) vaccine was introduced in Finland, in 1982, immunizing children at the ages of 14-18 months and 6 years. Antibody levels were determined from serial samples from a group of originally 350 children during 15 years. The latest samples were taken 15.5 years after the first vaccination and 70% of the children could still be reached. The aim of this study was to determine the kinetics of rubella antibodies induced by the MMR-II vaccine in these individuals. Rubella antibodies were analyzed from three different cohorts: Group I seronegative children (n=166) vaccinated at 14-18 months and 6 years, Group II seronegative children (n=139) and Group III seropositive children (n=16) vaccinated at 6 and 11-13 years. Samples collected 0-9 years after vaccination were analyzed by hemolysis-in-gel (HIG) and later samples by enzyme immunoassay (EIA) techniques. The primary vaccination induced 100% seropositivity in vaccinees with a mean zone diameter of 10 (+/-1.3), 10.2 (+/-1.1) and 11.5 (+/-0.9) mm, in Groups I, II and III, respectively. The seropositivity rate was still high at 15 years, 99%, 100% and 100% with the geometric mean titer 23, 46 and 105 IU/ml, respectively. At 15 years, antibody levels <15 IU/ml which is the suggested protective level, were found in 31, 9 and 0% of children in Groups I, II and III, respectively. Because almost a third of the individuals in Group I now, at the age of 17 years, had low levels of rubella antibodies, it is possible that rubella infections may re-emerge during pregnancy. A careful surveillance including serological follow-up is therefore very important.

Influenza vaccination in 18 developed countries, 1980-1992

Influenza continues to be an important cause of preventable morbidity and mortality. Although influenza vaccine is widely recommended for older high-risk individuals, no studies have compared its use in different countries. We gathered information on influenza vaccine distribution in 18 developed countries for the period 1980-1992. During the 1980s there was a > or = 10-fold difference in annual per capita vaccine distribution among these countries, and in 1992 the difference was still more than 7-fold. Several countries demonstrated large increases in vaccine use over the study period, some showing substantial increases in specific years. Thirteen of the 18 countries recommend influenza vaccination for all elderly persons and 11 countries provide reimbursement for vaccination through national or social health insurance. These countries tend to have higher levels of vaccine use. Historical, economic and political factors also affect vaccination practices and policies, but their relationships to differences in vaccine use between countries are not known. A better understanding of why the use of influenza vaccine varies among countries will be important if its protective benefits are to be fully realized.

Persistence of anti-mumps virus antibodies after a two-dose MMR vaccination. A nine-year follow-up

A two-dose vaccination program against measles, mumps, and rubella (MMR) viruses was started in Finland in 1982. In this program the trivalent MMR-II vaccine (MSD, USA) was offered to children at the ages of 14-18 months and 6 years followed by revaccination 4-5 years later. The vaccination coverage has been high (97%) and MMR infections have practically been eliminated in the Finnish population. In a serological follow-up program sequential serum samples were obtained from 254 children (127 14-18-month-old vaccinees and 127 6-year-old vaccinees) during a 9-year follow-up period. Anti-mumps virus antibody titers were determined by enzyme immunoassay using purified whole mumps viruses as the antigen. In seronegative (n = 120) 14-18-month-old vaccinees the seroconversion rate was 86% (geometric mean titer 1/1670 +/- 1/270). The antibody levels fell rapidly (significance p < 0.01) within the first year of follow-up (mean titer 1/1080 +/- 1/190), but remained relatively stable in subsequent years. After revaccination the seropositivity rate was 95% (mean titer 1/2310 +/- 1/260) and declined more slowly thereafter to 86% (mean titer 1/1510 +/- 1/210) at year 9 of follow-up. The mean antibody titer was significantly (p < 0.05) higher 4 years after the second MMR vaccination when compared with the corresponding time point after the first vaccination. In 6-year-old seronegative vaccinees the increase and decay of anti-mumps virus antibodies after the first MMR vaccination was similar to that seen in the group of younger vaccinees. A two-dose MMR vaccination protocol resulted in a high mumps immunity level in the vaccinated population.

Hepatitis A outbreak amongst intravenous amphetamine abusers in Finland

This article describes a widespread outbreak of hepatitis A virus (HAV) infection amongst drug abusers in Finland. Although attempts to demonstrate the virus in amphetamines failed, the infection was assumed to be linked to intravenous use of the drug. The unusual mode of transmission prompted us to analyse possible atypical clinical features as well as the spread of the virus to the general population, nowadays practically without protective immunity. Serologically verified cases that occurred in Helsinki were interviewed, their hospital records were analysed and their contacts were serology tested. Amphetamine lots, as well as faecal samples from patients, were examined with RT-PCR. Detailed information was obtained from 238 subjects, among whom 131 admitted drug abuse and 67 cases were classified as secondary cases. Phylogenetic analysis of virus strains from HAV-infected cases suggested a common origin, and epidemiological observations linked it with particular lots of amphetamine. Three cases died, and 3 presented with severe clinical disease. Icterus was more common among i.v. drug abusers than others. Infection with hepatitis A virus was probably related to the faecal contamination of amphetamine associated with the transportation of the drugs in the gastrointestinal tract.

Twice vaccinated recipients are better protected against epidemic measles than are single dose recipients of measles containing vaccine

OBJECTIVE: To study measles risk after revaccination. DESIGN: A population-based case-control study during an epidemic season. MAIN OUTCOME MEASURE: Relative serologically confirmed measles risk. PARTICIPANTS AND METHODS: 153 vaccinated cases, mostly from rural areas, were serologically confirmed as measles at the central laboratory in 1988-89. A randomly selected group of 453 controls from either municipalities of vaccinated cases or from areas where measles attack rate was > 600/10(5), was identified via the population registry. Vaccination and measles histories of cases and controls were determined from official vaccination cards. RESULTS: Once and twice vaccinated had crude relative risk 15.6 and 2.3 compared with thrice vaccinated. When cases who had received their first vaccination at less than 14 months of age were omitted from analysis, once vaccinated had 4.0 (95% CI 1.2, 16.6) times higher age adjusted measles risk compared with twice vaccinated. When, omission was extended to cases from one particular municipality where even revaccinees had high measles risk during an explosive outbreak the corresponding risk ratio was 17.8 (2.8, 67.8). CONCLUSIONS: Twice vaccinated have better protection against epidemic measles compared with single dose recipients.

No measles in Finland

1364 Vol 350 • November 8, 1997 remained in complete clinical remission for 1 year. The liposomal doxorubicin infusions were well tolerated, with mild fatigue 24–48 h postinfusion as the only side-effect. No bone-marrow suppression and no cardiac toxicity, as measured by left-ventricular ejection fraction, was seen. He subsequently developed prostate cancer which has been treated with local radiation therapy. During treatment, he developed a Kaposi’s sarcoma lesion on the left arm. The development of liposomal doxorubicin allows targeted tumour localisation and the delivery of a smaller systemic dose. This results in a lower incidence of adverse effects normally associated with non-encapsulated doxorubicin, most notably cardiac toxicity and myelosuppression. The efficacy of this drug and its reduced adverse effects would appear to make it an appropriate agent for treating resistant classic Kaposi’s sarcoma in which the patient population is often elderly and debilitated.