Affiliations of authors: E. A. Engels, H. A. Katki, P. S. Rosenberg, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD; M. Frisch, Department of Epidemiology Research, Danish Epidemiology Science Center, Statens Serum Institut, Copenhagen, Denmark.
Correspondence to: Eric A. Engels, MD, MPH, Viral Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., EPS 8010, Rockville, MD 20892 (e-mail: engelse{at}exchange.nih.gov).
We thank Puntoni et al. for their comments on our recent article (1); however, we disagree that our data demonstrate a relationship between early-life exposure to simian virus 40 (SV40)-contaminated poliovirus vaccine and ependymoma incidence. Puntoni et al. calculated a crude relative risk (RR) of 1.46 (95% confidence interval [CI] = 1.06 to 1.95) comparing the 19551961 birth cohort (exposed as infants) with the 19461952 birth cohort (exposed as children). However, this comparison is of uncertain relevance, because it contrasts two SV40-exposed cohorts rather than the exposed-as-infants and unexposed cohorts, as we did in our article (1). Furthermore, when we calculated a crude relative risk for this comparison (RR = 1.44), our confidence interval was wider than what Puntoni et al. report, regardless of the method we used to calculate it (95% CI = 0.86 to 2.42, assuming asymptotic normality and 95% CI = 0.84 to 2.55, using an exact method). These two confidence intervals, which appropriately incorporate the uncertainty in measured ependymoma incidence in both birth cohorts (2), do not indicate an increased incidence in the exposed-as-infants cohort.
More importantly, this crude comparison does not accurately capture the relationship between SV40 exposure and cancer risk, because the three birth cohorts differ in age composition. Specifically, the data for the 19461952 birth cohort do not cover years before 1955, when poliovirus vaccine was introduced. Thus, reflecting birth years for individuals in this cohort, there were no data for 0- to 1-year-old children and relatively few data for 2- to 8-year-old children (Fig. 1, A). Overall, ependymoma incidence decreased with age (Fig. 1, B
). Therefore, the paucity of data for infancy and early childhood in the 19461952 birth cohort strongly biases crude comparisons with this cohort. Indeed, when we adjusted for age using regression splines (1), the 19551961 and 19461952 birth cohorts did not differ in ependymoma incidence (age-adjusted RR = 1.06, 95% CI = 0.60 to 1.87; P = .84).
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Puntoni et al. suggest that the peak ependymoma incidence in 1964 could partly be due to SV40 infection acquired by children from their mothers as a result of vaccination during pregnancy. This interpretation is implausible for several reasons. First, the peak in incidence in 1964 was based on only seven ependymoma cases; thus, the single-year incidence estimate was unstable. When we smoothed the incidence data, the peak in incidence occurred in 1969. Second, no ependymoma cases were observed among 0- to 4-year-old children in 1962, even though mothers of all children followed in 1962 also could have received SV40-contaminated vaccine during pregnancy. Third, in the study (3) cited by Puntoni et al., children whose mothers had received poliovirus vaccine during pregnancy had an increased risk of cancer, but no child developed ependymoma. In addition, a subsequent serologic study found little evidence of SV40 infection occurring during pregnancy in vaccinated mothers (4), so the basis for the increased cancer risk in these children remains unknown.
Although we agree with Puntoni et al. that our results for mesothelioma and osteosarcoma were less conclusive, our study still provides relevant data on these cancer outcomes. Our data for mesothelioma were strongest for individuals aged 33 years or younger; however, although mesothelioma incidence increases most steeply for older individuals, the extreme rarity of mesothelioma in younger individuals illustrates the absence of an observable effect of SV40 infection on mesothelioma risk for three decades after childhood exposure. Furthermore, among older adults in the United States, Strickler et al. (5) found no evidence for increased mesothelioma risk related to exposure to SV40-con-taminated poliovirus vaccine. Finally, osteosarcoma comprises the majority of bone tumors in persons aged younger than 25 years (1). Therefore, the similarity in incidence of combined bone tumors across birth cohorts argues against an increased incidence of osteosarcoma in Danish children who received SV40-contaminated vaccines.
NOTES
Editors note: Dr. Frisch is employed by Statens Serum Institut, the manufacturer of inactivated poliovirus vaccine used in Denmark since 1955.
REFERENCES
1 Engels EA, Katki HA, Nielsen NM, Winther JF, Hjalgrim H, Gjerris F, et al. Cancer incidence in Denmark following exposure to poliovirus vaccine contaminated with simian virus 40. J Natl Cancer Inst 2003;95:5329.
2 Breslow NE, Day NE. Statistical methods in cancer research, Vol. II. Design and analysis of cohort studies. Lyon (France): International Agency for Research on Cancer; 1987. p. 915.
3 Heinonen OP, Shapiro S, Monson RR, Hartz SC, Rosenberg L, Slone D. Immunization during pregnancy against poliomyelitis and influenza in relation to childhood malignancy. Int J Epidemiol 1973;2:22935.[ISI][Medline]
4 Rosa FW, Sever JL, Madden DL. Absence of antibody response to simian virus 40 after inoculation with killed-poliovirus vaccine of mothers of offspring with neurologic tumors. N Engl J Med 1988;318:1469.[ISI][Medline]
5 Strickler HD, Goedert JJ, Devesa SS, Lahey J, Fraumeni JF Jr, Rosenberg PS. Trends in U.S. pleural mesothelioma incidence rates following simian virus 40 contamination of early poliovirus vaccines. J Natl Cancer Inst 2003;95:3845.
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