Finnish Trial Research Articles

The good initial response to therapy with a combination of traditional disease‐modifying antirheumatic drugs is sustained over time: The eleven‐year results of the Finnish rheumatoid arthritis combination therapy trial

To evaluate the evolution of functional and clinical outcomes over 11 years in patients with early rheumatoid arthritis (RA) initially treated with a combination of 3 disease-modifying antirheumatic drugs (DMARDs) or with a single DMARD. A cohort of 199 patients with early active RA were initially randomized to receive treatment with a combination of methotrexate, sulfasalazine, and hydroxychloroquine with prednisolone or treatment with a single DMARD (initially, sulfasalazine) with or without prednisolone. After 2 years, the drug treatment strategy became unrestricted, but still targeted remission. At 11 years, function was assessed with the Health Assessment Questionnaire (HAQ), and clinical outcomes were assessed with the modified Minimal Disease Activity (MDA) measure and the American College of Rheumatology (ACR) criteria for remission. At 11 years, 138 patients were assessed (68 in the combination-DMARD group and 70 in the single-DMARD group). The mean+/-SD HAQ scores were 0.34+/-0.54 in the combination-DMARD group and 0.38+/-0.58 in the single-DMARD group (P=0.88). Modified MDA was achieved by 63% (95% confidence interval [95% CI] 51, 77) and by 43% (95% CI 32, 55) (P=0.016) of the combination-DMARD group and the single-DMARD group, respectively, and ACR remission by 37% (95% CI 26, 49) and by 19% (95% CI 11, 29) (P=0.017), respectively. Initial therapy with a combination of DMARDs in early RA results in higher rates of patients achieving modified MDA and strict ACR remission even over the long term than initial single-DMARD therapy. Targeting remission with tight clinical controls results in good functional and clinical outcomes in most RA patients.

Biological aggressiveness of prostate cancer in the Finnish screening trial

Prostate cancer aggressiveness was evaluated based on pathologic characterization of cases detected in the Finnish prostate cancer screening trial. The trial population consists of 80,458 men aged 55-67 years. A total of 32,000 men were randomized to the screening arm. The remaining 48,000 men formed the control arm. The interval cases and cancers among nonparticipants and in the control arm were identified from the Finnish Cancer Registry. Random samples were selected from screen-detected cases (126 of 543 in the first and 133 of 508 in the second round) and control arm cancers (133 out of 863), in addition to all 92 interval cancers and 106 cases among nonparticipants. All the biopsies were regraded according to the Gleason system. The expression of the proliferation antigen Ki-67 was determined in 479 cases (72%). More than half of the tumors diagnosed in the first round of screening were high-grade cancers (Gleason 7 or higher). In the second round, the proportion of low-grade cancers increased from 47% to 70%. Cancers in the screening arm were more commonly focal and fewer bilateral cancers were detected. The cancers among nonparticipants were the most aggressive group. The aggressiveness of the interval cancers was between the cancers detected in the first and the second round. Our results indicate that prostate cancers detected through screening are less biologically aggressive. This was most notable after the first screening round. Nonparticipants had more aggressive cancers.

BS04 TRASTUZUMAB (HERCEPTIN): REVIEW OF ADJUVANT TRIALS IN EARLY BREAST CANCER

Trastuzumab (Herceptin) is a humanized, monoclonal antibody to the Her2 neu receptor which is over‐expressed in approximately 15 to 20% of patients with breast cancer. The presence of this growth factor gene over‐expression is associated with more aggressive disease. The pivotal trials in metastatic breast cancer in the late 1990s demonstrated that Herceptin combined with chemotherapy produced significantly higher response rates, improved time to progression and superior overall survival compared to chemotherapy alone. There have been five clinical trials conducted to evaluate the effectiveness of Herceptin when used in combination with chemotherapy in women with early breast cancer. For the four larger trials, more than 13,000 women were essentially randomly assigned to either standard chemotherapy alone or the same chemotherapy plus Herceptin for one or two years. A small Finnish trial of 232 women, evaluated 9 weeks of Herceptin given with chemotherapy. Each trial confirmed a statistically improved disease‐free survival with a 42% to 50% reduction in the risk of relapse. In the four larger trials, a statistically significant overall survival benefit with a 33% to 41% reduction in the risk of death was seen. The only significant side effect associated with the inclusion of Herceptin was a higher incidence of cardiac dysfunction. This ranged from 1.7% to 4.1% in those patients receiving Herceptin, compared to <1% in the control group.

Specificity of serum prostate-specific antigen determination in the Finnish prostate cancer screening trial

Specificity constitutes a component of validity for a screening test. The number of false-positive (FP) results has been regarded as one of major shortcomings in prostate cancer screening. We estimated the specificity of serum prostate-specific antigen (PSA) determination in prostate cancer screening using data from a randomised, controlled screening trial conducted in Finland with 32 000 men in the screening arm. We calculated the specificity as the proportion of men with negative findings (screen negatives, SN) relative to those with negative and FP results (SN/(SN+FP)). A SN finding was defined as either PSA⩽4 ng ml−1 or PSA 3.0–3.9 ng ml−1 combined with a negative ancillary test (digital rectal examination, DRE or free/total, F/T PSA ratio). False positives were those with positive screening test followed by a negative diagnostic examination. Of the 30 194 eligible men, 20 794 (69%) attended the first screening round and 1968 (9.5%) had a screen-positive finding. A total of 508 prostate cancers were detected at screening (2.4%). Hence, the number of SN findings was 18 825 and the number of FP results 1358. Specificity was estimated as 0.933 (18 825 out of 20 183) with 95% confidence interval (CI) 0.929–0.936. Specificity decreased with age. Digital rectal examination as ancillary examination had similar or higher specificity than F/T PSA. In the second screening round, specificity was slightly lower (0.912, 95% CI 0.908–0.916). The specificity of PSA screening in the Finnish screening trial is acceptable. Further improvement in specificity could, however, improve acceptability of screening and decrease screening costs.

Adjuvant Trastuzumab: A Milestone in the Treatment of HER-2-Positive Early Breast Cancer

Up to one fourth of women diagnosed with early breast cancer (EBC) have tumors that are human epidermal growth factor receptor 2 (HER-2) positive. This is associated with a high risk of relapse and death from meta-static disease. Trastuzumab, a monoclonal antibody directed against the extracellular domain of HER-2, improves survival and quality of life in women with HER-2-positive metastatic breast cancer receiving chemotherapy. Four major adjuvant trials-Herceptin Adjuvant (HERA), National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31, North Central Cancer Treatment Group (NCCTG) N9831, and Breast Cancer International Research Group (BCIRG) 006-including between them >13,000 women with HER-2-positive EBC, have investigated different adjuvant treatment approaches with trastuzumab. These trials have shown that trastuzumab reduces the 3-year risk of recurrence by about half in this population. The benefit was similar across the trials despite differences in patient populations, chemotherapy regimens, and sequencing of treatment. At a 2-year follow-up, interim results from the combined analysis of the NSABP B-31 and NCCTG N9831 trials showed a one third lower mortality for trastuzumab, and there was a trend toward an overall survival benefit in the HERA and BCIRG trials. A small Finnish trial, FinHer, investigating another regimen of trastuzumab, has also shown similarly positive results. Further follow-up of the major adjuvant trials will clarify the survival benefit for women receiving trastuzumab, as well as the optimal treatment duration (1 or 2 years). Notably, cardiac events in the trastuzumab-containing arms of these trials have remained within acceptable levels, with a slightly higher (0.6%-3.3%) incidence of congestive heart failure that mostly responded to treatment. Further follow-up will provide information on long-term cardiac safety. Overall, results from clinical trials are sufficiently compelling to consider 1 year of adjuvant trastuzumab treatment for women with HER-2-positive EBC based on the risk:benefit ratio demonstrated in these studies.

Characteristics of prostate cancer in the finnish screening trial with Prostate-Specific Antigen (PSA)

Characteristics of prostate cancer in the finnish screening trial with Prostate-Specific Antigen (PSA)

Variation in the promoter region of the myeloperoxidase gene is not directly related to lung cancer risk among male smokers in Finland

In order to examine whether a polymorphism in the promoter region of the myeloperoxidase (MPO) gene is associated with lung cancer among male smokers, we conducted a case–control study nested within a Finnish clinical trial cohort. Although we found no evidence of an overall association between lung cancer risk and MPO genotype, the variant MPO genotype was associated with an increased risk of lung cancer among a subset of older men. These findings contrast with those from previous studies that report decreased lung cancer risk among MPO variant individuals.

USE OF THE COMPLEX BETWEEN PROSTATE SPECIFIC ANTIGEN AND α1-PROTEASE INHIBITOR FOR SCREENING PROSTATE CANCER

We assess whether the complex between prostate specific antigen (PSA) and alpha1-protease inhibitor in serum can be used to reduce further the number of false-positive PSA screen results independent of total and free PSA. Sera from 304 consecutive screen positive subjects, including 78 with and 226 without prostate cancer, and serum PSA of 4 to 10 microg./l. or higher in the Finnish, randomized, population based prostate cancer screening trial were analyzed for PSA-alpha-protease inhibitor, and total and free PSA. Main outcome measures were specificity, sensitivity and area under receiver operating characteristics curve for proportions of free PSA and PSA-alpha 1-protease inhibitor, and for a combination of these among screen positive cases. The proportion of serum PSA-alpha 1-protease inhibitor of total PSA was lower in cancer cases than in controls (0.9% versus 1.6%, p <0.001). Logistic regression analysis of total PSA, free PSA and PSA-alpha 1-protease inhibitor showed that PSA-alpha 1-protease inhibitor in serum was an independent variable for discrimination between subjects with and without prostate cancer (p = 0.006) in the PSA range of 4 to 10 microg./l. The proportion of PSA-alpha 1-protease inhibitor alone improved specificity less than the proportion of free PSA but when these were combined by logistic regression they performed better than the proportion of free PSA alone at sensitivities of 85% to 95% (p <0.001). Serum PSA-alpha 1-protease inhibitor improves the specificity of total and free PSA in a screening population with total PSA 4 to 10 microg./l.

Polysaccharide vaccines for preventing serogroup A meningococcal meningitis.

Controlled trials over two decades ago showed that the polysaccharide vaccine prevented serogroup A meningococcal meningitis. Subsequent non-experimental studies suggested age-specific variations in the duration of protection among young children. To determine the effect of polysaccharide serogroup A vaccine for preventing serogroup A meningococcal meningitis. MEDLINE and the Cochrane Controlled Trials Register. The first stage of the review included prospective controlled trials. The second stage included non-experimental studies that addressed questions unanswered by the trials, i.e. the duration of protection and the effect of a booster dose in children under 2 years of age. One reviewer assessed the methodological quality of the trials, and two reviewers independently identified and assessed the non-experimental studies. Data from the trials were pooled using the Exact method to assess vaccine efficacy at 1, 2 and 3 years post- vaccination. The protective effect within the first year was consistent across all 8 trials, vaccine efficacy was 95% (Exact 95% CI 87%, 99%). Protection extended into the second and third year after vaccination, but the results did not attain statistical significance. The only trial that assessed the effect of a booster dose in children less than 18 months old, lacked adequate statistical power. In the three other trials that included children less than 6 years old (one in Sudan and two in Nigeria), none of the vaccinated children developed meningitis, but the results did not attain statistical significance. Data from the two non-experimental studies included in this review were not pooled with the trial data because of methodological limitations. For the first year after vaccination, the vaccine was strongly protective in participants over 5 years of age. It was also protective beyond the first year after vaccination, but the level of vaccine efficacy could not be determined with precision. Children aged 1 to 5 years in developing countries were protected, but the level of efficacy among the youngest children could not be determined. While the vaccine was strongly protective among children aged 3 months and over in developed countries, the number of participants aged under 2 years was too small to draw firm conclusions on the protective effect of, or need for, a booster dose of vaccine.

Characterization and determination of the complex between prostate-specific antigen and α1-protease inhibitor in benign and malignant prostatic diseases

Prostate-specific antigen (PSA) is a tissue-specific serine protease which forms complexes with protease inhibitors such as f 1 -antichymotrypsin and f 2 - macroglobulin. We have studied the interaction between PSA and f 1 -protease inhibitor (API) in vitro and found that 15% of the added PSA binds to API while the majority of API is cleaved between Met358 and Ser359 when PSA is incubated with a 5-fold excess of API at 37 C for 7 days. The complex between PSA and API (PSA- API) formed in vitro displays the same chromatographic behavior, molecular size and immunoreactivity as endogenous PSA- API occurring in serum, indicating that they are identical. PSA- API can be detected in serum by a time-resolved immunofluorometric assay (IFMA), in which a monoclonal antibody to PSA is used as a catcher and a polyclonal antibody to API labeled with a Eu-chelate is used as a tracer. Purified PSA- API formed in vitro is used as a calibrator. PSA- API in serum represents 1.0- 7.9% (median 2.4%) of total PSA (tPSA) in prostate cancer (PCa, n= 82) and 1.3- 12.2% (median 3.6%, p<0.01) in patients with benign prostatic hyperplasia (BPH, n= 66). The IFMA for PSA- API in serum is hampered by a variable background, which is caused by non-specific adsorption of the huge excess of API in serum to the solid phase. The background can be determined by an assay using the same tracer as in the IFMA for PSA- API but PSA-unrelated antibody on the solid phase. The background signal is subtracted from the PSA- API signal. The clinical utility of PSA- API in serum has been evaluated in PSA-positive subjects from the Finnish PCa screening trial. After subtraction of the background, the proportion of PSA- API in relation to tPSA is lower in PCa than in controls, 0.9% vs. 1.6%, respectively (p<0.001). Logistic regression analysis showed that the concentration of PSA- API was independent of the proportion of free PSA as a diagnostic variable among subjects with a tPSA of 4- 10 w g/l (p= 0.009). The probability of PCa calculated by logistic regression using the concentration of PSA- API and the proportion of free PSA in serum significantly improved cancer specificity at high sensitivity levels (85 - 95%) as compared to the proportion of free PSA alone.

Interactions between common root rot (Aphanomyces euteiches) and peas (Pisum sativum) in Finland

Interactions were characterized for the first time between pea cultivars and the fungus Aphanomyces euteiches at Finnish trial sites on soils with and without common root rot caused by the fungus. Seed yield, protein content, growing time, duration of flowering and stalk length were all significantly influenced by the fungus. An average of 35% yield reduction was obtained in trial fields infected with Aphanomyces euteiches. On average, protein content was decreased by 1.4%, growing time was reduced by 9 days, duration of flowering was prolonged by 2 days and the stem length was reduced by 20%. Differences between cultivars were observed. The pea breeding line Jo 1085 showed the best tolerance.

Serum levels of vitamin D metabolites and the subsequent risk of colon and rectal cancer in Finnish men.

Experimental and human epidemiologic data suggest a protective role for vitamin D in large bowel cancer. To investigate this association, we conducted a nested case-control study within a Finnish clinical trial cohort. Cases (n = 146) were participants diagnosed with primary adenocarcinoma of the large bowel. Controls were matched (2:1) to cases on age, date of baseline blood draw, and study clinic. Prediagnostic serum levels of the vitamin D metabolites, 25-hydroxyvitamin D (25-OH D), and 1,25-dihydroxyvitamin D (1,25-DIOH D) were used as primary exposure measures. The baseline geometric-mean serum level of 25-OH D was 11.6 percent lower in cases than in controls (12.2 cf 13.8 ug/l, P = 0.01) while serum levels of 1,25-DIOH D did not differ by case-control status. No association was seen between serum levels of 1,25-DIOH D and large bowel cancer risk. However, the estimated relative risk (RR) of large bowel cancer decreased with increasing level of serum 25-OH D and the association was more pronounced for rectal cancer (55 cases; RR by quartile = 1.00, 0.93, 0.77, 0.37; trend P = 0.06). Neither exclusion of early cases nor multivariate adjustment for potential confounders materially altered these estimates. There was no evidence of effect modification by level of 1,25-dihydroxyvitamin D or with other known risk-factors for large bowel cancer.

Beta-carotene and cancer chemoprevention.

Evidence supports the potential role of beta-carotene in cancer prevention. Basic research has demonstrated that beta-carotene can trap organic free radicals and/or deactivate excited oxygen molecules which may have an anticancer effect by preventing tissue damage. Although observational epidemiologic studies are not entirely consistent, many show an inverse association between dietary intake or blood levels of beta-carotene and subsequent cancer risk. Two large-scale randomized trials of beta-carotene have been completed. A Finnish trial demonstrated no benefit of beta-carotene among middle-aged male smokers, with those assigned to this supplement in fact experiencing an increased risk of lung cancer. However, because of the long latency period for cancer, which may be a decade or more, the six-year duration of treatment in this trial may have been inadequate to detect an anticancer effect. A Chinese trial demonstrated a modest reduction in cancer mortality from a combined regimen of beta-carotene, vitamin E, and selenium. The effect of the individual agents could not be assessed, and because the trial was carried out among a nutritionally deficient population, its results may not have direct relevance to well-nourished individuals. Several additional large-scale trials of beta-carotene are ongoing. The Physicians' Health Study, which is testing beta-carotene among 22,071 US male physicians, will have an average duration of treatment of 12.5 years at its scheduled termination in late 1995. Data in women will be available from the Women's Health Study, which began in 1992, and will randomize approximately 40,000 US female health professionals.(ABSTRACT TRUNCATED AT 250 WORDS)

BED REST, EXERCISE, OR NORMAL ACTIVITY FOR ACUTE LOW BACK PAIN?

The optimal approach to treating acute low back pain is quite controversial. This Finnish trial randomized 186 sufferers to either two days of bed rest, back-mobilizing exercises, or routine activity as tolerated (the control group). …

All that glitters is not beta carotene

After a long series of increasingly optimistic reports about the potential health benefits of dietary antioxidants, two reports of randomized trials considerably dampened the enthusiasm for these nutrients. The Finnish trial of beta carotene and vitamin E failed to show a reduction in lung cancer or cardiovascular disease among heavy smokers,¹and the Dartmouth trial showed no benefit of antioxidants for prevention of colon polyp recurrence.²Now, in this issue ofTHE JOURNAL, two reports appear that link high antioxidant intake with reduced risk of coronary disease and age-related macular degeneration (AMD).^3,4What are we to make of these findings? See also pp 1413 and 1439. Morris et al³observed a strong inverse association between total plasma carotenoids and subsequent risk of coronary heart disease (CHD) (relative risk, 0.64 between highest and lowest quartiles). Individual carotenoids were not assayed; thus, the authors appropriately caution against attributing

Subgroup and cost‐benefit analysis of the Finnish multicentre trial of clodronate in multiple myeloma

Osteolytic lesions and pathological fractures are the major problems in the clinical management of multiple myeloma. We previously reported the main results of a randomized, controlled multicentre trial in 350 Finnish patients with multiple myeloma. All patients received standard melphalan-prednisolone treatment and were randomized to receive either clodronate 2.4 g daily or a placebo for 24 months. The proportion of patients with progression of osteolytic bone lesions was twice as high in the placebo group as in the clodronate group (24.0% v 12.0%, P = 0.026). The purpose of the present study was to investigate factors associated with the progression of osteolytic lesions and to identify subgroups of patients who would benefit most from clodronate treatment. In univariate logistic regression analysis, including treatment (placebo, clodronate), sex, age, pain index, serum calcium and creatinine, myeloma stage, number of osteolytic lesions at baseline, and number of vertebral fractures at baseline as independent variables and the progression of osteolytic lesions as a dependent variable, only the treatment with a placebo was associated with the progression of osteolytic bone lesions. Separate analyses with respect to the progression of osteolytic bone lesions were carried out in the following subgroups: male v female, < or = 64 v > 64 years, stage I v stage II-III myeloma, no osteolytic lesions at baseline versus osteolytic lesions at baseline, no vertebral fractures at baseline versus vertebral fractures at baseline. and a 50% treatment response to cytotoxic drugs versus no treatment response to cytotoxic drugs. The treatment with clodronate delayed the progression of osteolytic lesions similarly in these subgroups, with the exception of a subgroup of patients who did not have a 50% treatment response to cytotoxic drugs. The treatment with clodronate did not significantly increase treatment costs. We conclude that the treatment effect of clodronate seems to be independent of sex and age of the patients, the stage of myeloma, and the severity of bone lesions at diagnosis, but not of treatment response to cytotoxic drugs.

Finnish Efficacy Trials with Haemophilus influenzae Type b Vaccines

The first Finnish trial with Haemophilus influenzae type b vaccine was conducted during 1973-1974. It demonstrated that the polysaccharide vaccine was 90% efficacious in children greater than or equal to 18-24 months old. The immunologically superior polysaccharide-protein conjugate vaccines have been used since 1986 in randomized trials. The PRP-D vaccine (polysaccharide conjugated to diphtheria toxoid) was 90% efficacious when given at 3, 4, and 6 months of age to 58,000 infants. In 1988-1989, the PRP-D vaccine was compared with the HbOC vaccine (oligosaccharide conjugated to CRM197 protein). Follow-up is continuing, but both vaccines seem to be efficacious after two doses in infancy.

Commentary: Results of Efficacy Trials in Alaska and Finland of Haemophilus influenzae Type b Conjugate Vaccine

One of the currently licensed Haemophilus influenzae type b polysaccharide conjugate vaccines currently recommended for use in children 18 months of age and older, polyribosylribitol-phosphate-diphtheria toxoid (PRP-D, Connaught Laboratories), has been evaluated in two studies for its protective efficacy in children immunized before 6 months of age.1 The peak incidence of invasive disease caused by H. influenzae type b occurs in children 6 to 18 months of age; therefore, prevention of this disease depends on the efficacy of vaccines in this younger age group. In a large, randomized, unblinded trial conducted in Finland, relatively low levels of antibody were induced after a series of three primary PRP-D immunizations at 3, 4, and 6 months of age. Despite these limited immunogenicity results, a high level of protective efficacy was shown during a 3-year period (protective efficacy of 87%, 95% confidence intervals 50% to 96%). Another trial, which was randomized, double blind, and placebo controlled, was conducted among 2113 Native Alaskan infants immunized (20 µg/0.5 mL) at 2, 4, and 6 months of age as part of their routine childhood immunizations. This population was chosen for the trial because it has the highest known incidence of invasive disease caused by H influenzae type b, and a trial in such a high-risk population could be conducted more carefully, with fewer study subjects, and in a shorter period of time. As in the Finnish trial, in this younger age group immune responses to PRP-D vaccine were meager, apparent only after the third dose of vaccine at 6 months of age.

Haemophilus influenzae Type b Conjugate Vaccines: Update

The purpose of this statement is to update previous information and recommendations provided by the Committee for the use of Haemophilus influenzae type b conjugate vaccines in view of the licensure of a new product. Our initial recommendations concerned the use of PRP-D, a vaccine consisting of the capsular polysacchanide of H influenzae type b conjugated to diphtheria toxoid, which was licensed for use in December 1987. On December 22, 1988, a second conjugate vaccine was licensed by the US Food and Drug Administration for the prevention of infections caused by H influenzae type b in children 18 months of age or olden. This newly licensed vaccine is a conjugate of H influenzae type b capsular oligosaccharide and a nontoxic mutant diphtheria toxin protein molecule called CRM197. The official designation of this vaccine is "Haemophilus b conjugate vaccine (diphtheria CRM197 protein conjugate)" and it is often referred to as HbOC. No serious adverse reactions have been reported in clinical trials to date. Among 265 infants in the United States between 16 and 23 months of age who received HbOC, 7.2% had temperatures exceeding 38°C, 1.5% had erythema and warmth at the injection site, and 0.8% had localized swelling. Like PRP-D, HbOC is more immunogenic in 18-month-old children than are the unconjugated polysacchanide vaccines (PRP). Among 212 HbOC recipients in the study, the geometric mean anticapsular antibody concentration 1 month after immunization was 13.11 µg/mL. Moreover, 98.1% of these infants had an antibody concentration in excess of 1µg/mL, a concentration associated with protection in a Finnish field trial of unconjugated PRP.

Haemophilus influenzae Type b Polysaccharide Vaccine: An Efficacy Study

The Haemophilus influenzae type b polysaccharide vaccine was licensed for use in the United States in April 1985. Postlicensure case-control efficacy studies have yielded markedly different estimates of efficacy, leading to contradictory recommendations to practicing physicians. To obtain additional information about the efficacy of the vaccine, we studied cases of invasive Haemophilus influenzae type b disease ascertained through active surveillance in areas with a total population of 34 million. We enrolled children 24 to 59 months of age who did not attend day-care centers. (Data from our day-care study have been published elsewhere.) For each case child, as many as three 24- to 59-month-old control children were chosen from a roster of acquaintances supplied by the child's parent. Conditional logistic regression was used, and vaccine efficacy was estimated to be 62% (95% confidence interval = 0%, 85%), which did not change significantly after adjusting for age and parental smoking, variables that were significantly different for case and control children. Results of this study support our previous finding of a positive protective efficacy, albeit lower than the efficacy of 90% found in children 18 to 71 months of age in the Finnish prelicensure trial.