CORRESPONDENCE

RESPONSE: Re: Cancer Incidence in Denmark Following Exposure to Poliovirus Vaccine Contaminated With Simian Virus 40

Eric A. Engels, Hormuzd A. Katki, Philip S. Rosenberg, Morten Frisch

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 1955–1961 birth cohort (exposed as infants) with the 1946–1952 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 1946–1952 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, AGo). Overall, ependymoma incidence decreased with age (Fig. 1, BGo). Therefore, the paucity of data for infancy and early childhood in the 1946–1952 birth cohort strongly biases crude comparisons with this cohort. Indeed, when we adjusted for age using regression splines (1), the 1955–1961 and 1946–1952 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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Fig. 1. A) Amount of follow-up time (person-years) by age, for three Danish birth cohorts with varying exposure to simian virus 40 (SV40)-contaminated poliovirus vaccine. The three birth cohorts are 1946–1952 (exposed to SV40-contaminated poliovirus vaccine as children, beginning in 1955) (gray line with circles), 1955–1961 (exposed to SV40-contaminated poliovirus vaccine as infants) (black line with squares), and 1964–1970 (unexposed) (dashed line with diamonds). Data for the 1946–1952 birth cohort include only calendar years beginning in 1955, the year when poliovirus vaccine was introduced in Denmark. Hence, there were no data for this cohort before age 2 years and limited data for ages 2–8 years. B) Ependymoma incidence by age, for three Danish birth cohorts with varying exposure to SV40-contaminated poliovirus vaccine. The three birth cohorts are 1946–1952 (exposed to SV40-contaminated poliovirus vaccine as children, beginning in 1955) (gray lines with diamonds), 1955–1961 (exposed to SV40-contaminated poliovirus vaccine as infants) (black lines), and 1964–1970 (unexposed) (dashed lines). Observed incidence (thin lines) and fitted estimates (thick lines), which were calculated using a Poisson model that used regression splines to smooth age-specific incidence [see (1)], are shown. There were no data for the 1946–1952 birth cohort before age 2 years and limited data for ages 2–8 years (see A).

 
Contrary to the comments by Puntoni et al., our further analysis of ependymoma incidence in 0- to 4-year-old children over time also provided no evidence of an effect of SV40 infection (1). In that analysis, we carefully considered the birth years of children in each period, so that for the 1963–1966 period, only children born before 1963 were categorized as SV40-exposed [Table 2 of our original article (1)]. Puntoni et al. point out that ependymoma incidence was higher in the post-exposed period compared with the unexposed period. However, this increase in incidence among children who never received SV40-contaminated vaccine suggests a broad increase in ependymoma risk over time, rather than an effect attributable to the time-limited use of SV40-contaminated vaccine (1).

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

Editor’s 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;95:532–9.[Abstract/Free Full Text]

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. 91–5.

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;2:229–35.[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;95:38–45.[Abstract/Free Full Text]



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