CORRESPONDENCE

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

Eric A. Engels, Morten Frisch

Affiliations of authors: E. A. Engels, 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).

Unfortunately, Vilchez et al. have incorrectly generalized from a recent Institute of Medicine (IOM) report (1) to criticize our study (2). That report noted that there were several limitations to previous U.S.-based retrospective cohort studies, most importantly that not all U.S. poliovirus vaccines between 1955 and 1962 contained live simian virus 40 (SV40) and that the extent of use of SV40-contaminated poliovirus vaccine in the United States was poorly documented.

Our retrospective cohort study in Denmark overcomes these limitations. As previously described (2), by April 1962, 84%–100% of Danish children had received at least one dose of poliovirus vaccine. In addition, SV40 contamination of poliovirus vaccine was much more frequent in Denmark than it was in the United States because Danish vaccines were manufactured in monolayer cultures that pooled kidney tissue from dozens of monkeys. We also described (2) frequent SV40 seroconversions following receipt of the Danish vaccine, further illustrating widespread contamination. We concluded that, by 1962, almost all Danish children had received one or more inoculations with poliovirus vaccine containing live SV40.

Why then, did these SV40-exposed children (i.e., born 1946–1961) have similar cancer incidence to children born later (i.e., born 1964–1970) who did not receive SV40-contaminated vaccine? The argument by Vilchez et al. on this matter is vague. They suggest that successful infection rates by live SV40 are unknown. This statement is true; however, in the absence of data on whether SV40 can be acquired by other routes, we suggest that direct injection of live SV40 early in life would be the most likely route and time course that could lead to SV40 infection.

In addition, Vilchez et al. comment that there is ample evidence that some individuals acquire SV40 infection from sources other than poliovirus vaccines. In fact, the data on this issue are somewhat contradictory, as reviewed by the IOM (1). Specifically, whereas some laboratories have reported detection of SV40 DNA in tumors from individuals too young to have received SV40-contaminated vaccines, other laboratories have not detected SV40 in any human tumors. SV40 antibodies found in asymptomatic individuals may represent cross-reactive antibodies to the human polyomaviruses BK and JC. Indeed, recognizing these issues, the IOM highlighted the need for the development and use of sensitive and specific standardized techniques for SV40 DNA detection, including masking of specimens, use of positive and negative control tissues, and replicate testing, and the development of sensitive and specific serologic tests.

Given the limitations of laboratory studies of SV40 in humans (1), the possibility that SV40 infection can be acquired by routes other than through SV40-contaminated vaccinations remains uncertain. Nevertheless, as we argue (2), if any SV40 infections occurred in Denmark after 1962, they would likely have been less frequent, have occurred at older ages, and have arisen from smaller inocula of virus than infections transmitted by SV40-contaminated vaccination. Vilchez et al. further suggest that changes in cancer registration, coding, or diagnosis could have obscured an effect of SV40 on cancer risk. However, as we note in our study (2), such an effect would likely be small and would not hide a large effect of SV40, if one were present. Therefore, our comparison of vaccine-exposed and unexposed individuals remains informative. The similar cancer incidence among these groups argues against a role for SV40 in human cancer.

Vilchez et al. also cite their own recently published study (3) to argue that, contrary to our results, SV40 infection is associated with increased cancer risk. Although they characterize this work as a case–control study and imply that it includes new data on 1793 cancer patients, their article is actually a meta-analysis of previously published laboratory studies on the detection of SV40 in human tumors. As reviewed elsewhere (1,4), many of these individual laboratory studies have important limitations, including an absence of appropriate negative control tissues and masking of specimens. Substantial variability among the results of these various studies is apparent. It is also surprising that Vilchez et al. did not comment on the fact that in the only multi-laboratory study that evaluated mesothelioma tumors under masked conditions, SV40 was not reproducibly detected in any specimen (5). Because the sensitivity, specificity, and reproducibility of molecular methods for detecting SV40 infection in human tumors remain uncertain, we concur with the IOM’s recommendations (1) that urge the improvement and standardization of laboratory methods.

NOTES

Editor’s note: Dr. Frisch is employed by Statens Serum Institut, the manufacturer of poliovirus vaccine used in Denmark since 1955.

References

1 Immunization safety review. SV40 contamination of polio vaccine and cancer. Washington (DC): National Academy Press; 2002.

2 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]

3 Vilchez RA, Kozinetz CA, Arrington AS, Madden CR, Butel JS. Simian virus 40 in human cancers. Am J Med 2003;114:675–84.[CrossRef][ISI][Medline]

4 Engels EA, Sarkar C, Daniel RW, Gravitt PE, Verma K, Quezado M, et al. Absence of simian virus 40 in human brain tumors from northern India. Int J Cancer 2002;101:348–52.[CrossRef][ISI][Medline]

5 Strickler HD, International SV40 Working Group. A multicenter evaluation of assays for detection of SV40 DNA and results in masked mesothelioma specimens. Cancer Epidemiol Biomarkers Prev 2001;10:523–32.[Abstract/Free Full Text]



             
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