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Since the earliest days of biological product manufacture, there have been a number of instances where laboratory studies provided evidence for the presence of adventitious agents in a marketed product. Lessons learned from such events can be used to strengthen regulatory preparedness for the future. We have therefore selected four instances where an adventitious agent, or a signal suggesting the presence of an agent, was found in a viral vaccine, and have developed a case study for each. The four cases are: a) SV40 in polio vaccines; b) bacteriophage in measles and polio vaccines; c) reverse transcriptase in measles and mumps vaccines; and d) porcine circovirus and porcine circovirus DNA sequences in rotavirus vaccines. The lessons learned from each event are discussed. Based in part on those experiences, certain scientific principles have been identified by WHO that should be considered in regulatory risk evaluation if an adventitious agent is found in a marketed vaccine in the future., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Analysis of publications about real and suggested contamination of polio vaccines produced in 1950s and 1960s with simian viruses--SV40 and SIV--is performed. Factual data are discussed and antivaccination fictions about calamitous consequences of really occurred contamination with SV40 and concocted contamination with SIV are refuted.

From the Croatian Cancer Registry (period 1991-1997) 194 malignant pleural mesothelioma patients were collected. According to participation in polio vaccination mass campaign in 1961 that covered the entire Croatian population aged 3 months to 20 years, mesothelioma patients were divided in vaccinated (N=58), and non-vaccinated (N=136) subjects. Significantly higher percentage of those with a history of occupational exposure to asbestos was found in vaccinated (79%) compared to non-vaccinated group (63%). This is the opposite to what would be expected if potential SV40 contamination of polio vaccine used had a causative role in the development of the tumour. On the other hand, shorter latency period reflected by very high percentage of 45-year-old or younger mesothelioma patients in vaccinated group (15 out of 58), with all of them having a history of occupational asbestos exposure, raises a question for a possible enhancing effect of the vaccine used to asbestos exposure, if it was contaminated with SV40.

The question of whether Simian Virus 40 (SV40) can cause human tumors has been one of the most highly controversial topics in cancer research during the last 50 years. The longstanding debate began with the discovery of SV40 as a contaminant in poliovirus vaccine stocks that were used to inoculate approximately 100 million children and adults in the United States between 1955 and 1963, and countless more throughout the world. Concerns regarding the potential health risk of SV40 exposure were reinforced by studies demonstrating SV40's potential to transform human cells and promote tumor growth in animal models. Many studies have attempted to assess the relationship between the potential exposure of humans to SV40 and cancer incidence. Reports of the detection of SV40 DNA in a variety of cancers have raised serious concerns as to whether the inadvertent inoculation with SV40 has led to the development of cancer in humans. However, inconsistent reports linking SV40 with various tumor types has led to conflicting views regarding the potential of SV40 as a human cancer virus. Several recent studies suggest that older detection methodologies were flawed, and the limitations of these methods could account for most, if not all, of the positive correlations of SV40 in human tumors to date. Although many people may have been exposed to SV40 by polio vaccination, there is inadequate evidence to support widespread SV40 infection in the population, increased tumor incidence in those individuals who received contaminated vaccine, or a direct role for SV40 in human cancer.

Between 1955 and 1963, an estimated number of 150 million people in various parts of the world, including Norway, received poliomyelitis vaccine possibly contaminated with infectious simian virus 40 (SV40). Human studies have investigated the hypothesised association between SV40 and various cancers, but the results have so far been contradicting. The aim of the present study was to examine Norwegian cancer incidence data to assess a possible association between birth cohorts assumed to have been subjected to the vaccine and the incidence rate of lymphoproliferative disorders (excluding Hodgkin's lymphoma), further subdivided into non-Hodgkin's lymphoma (NHL), lymphocytic leukemia and plasma cell neoplasms. Between 1953 and 1997, the incidence rate of lymphoproliferative diseases combined increased about 3-fold in both males and females. Subgroup analysis showed that this increase was largely attributable to NHL. Age-period-cohort modelling of the subgroups, as well as of all groups combined, showed that the cohort effect was more prominent than the period effect. However, the variations in incidence patterns across the birth cohorts did not fit with the trends that would be expected if a SV40 contaminated vaccine did play a causative role. Thus, our data do not support the hypothesis of an association between the vaccine and any subgroup of lymphoproliferative diseases., (Copyright (c) 2005 Wiley-Liss, Inc.)

Recent studies have linked simian virus 40 (SV40) to non-Hodgkin's lymphoma (NHL), especially in countries in which people were exposed to contaminated polio vaccines prior to 1963. In Taiwan, nearly all children were not exposed to contaminated polio vaccine during this period; the relationship between SV40 infection and hematological malignancies is unclear and deserves to be studied. Using PCR amplification of SV40 large T antigen DNA, confirmed by Southern blot hybridization and sequence analysis, 91 frozen lymph nodes from NHL patients were examined. Thirteen (14.3 percent) showed positive for SV40. All other test samples, including diagnostic bone marrow from patients with acute leukemia, peripheral blood from 10 relatives of SV40 positive-patients and 91 age-matched normal volunteers, and 5 reactive hyperplastic lymphoid tissues, showed negative. These results may reflect that human-to-human transmission of SV40 is independent of contaminated polio vaccines; and SV40 is possibly associated with the development of NHL in Taiwan (p = 0.0001). Prospective studies are needed to determine the prevalence of SV40 infections in our and other human populations and to explore the means of transmission of the virus.

Since the first studies on hepatitis C virus (HCV) prevalence were published, it has been evident that southern Italy is an area of hyperendemicity. A recent study conducted in southern Italy suggested that the high prevalence of HCV infection might be the result of past iatrogenic transmission. Polio vaccination with the parenteral Salk vaccine between 1956 and 1965 by multiple use of unsafe glass syringes may have been one of the major causes of the spread of HCV infection among southern Italian adults who are now older than 40 years of age. Persons born between the 1940s and early 1960s have a nearly 3-fold increased risk of HCV seropositivity than the younger age group. The findings are consistent with a cohort effect of exposure to the Salk parenteral vaccination., (Copyright 2003 Wiley-Liss, Inc.)

Early poliovirus vaccines, both inactivated and live attenuated, were inadvertently contaminated with simian virus 40 (SV40), a monkey virus known to be oncogenic for newborn hamsters. Although large epidemiologic studies have not identified an elevated cancer risk in persons who received SV40-contaminated vaccines, fragments of SV40 DNA have recently been identified in certain human tumours. We report the follow-up of a cohort of 1073 persons, unique because they received SV40-contaminated poliovirus vaccines as newborns in 1961-63. A previous report of the status of these subjects as of 1977-79 identified 15 deaths, none due to cancer. The present study utilized the National Death Index to identify deaths in the cohort for the years 1979-96. Expected deaths were calculated from Cleveland area sex-, age-, race- and year-specific mortality rates. Increased mortality from all causes was not found. 4 deaths from cancer were found compared to 3.16 expected (P = 0.77). However, 2 deaths from testicular cancer occurred, compared to 0.05 expected (P = 0.002), which may be a chance finding due to multiple comparisons. There were 2 deaths due to leukaemia, a non-significant finding, and no deaths due to tumours of the types putatively associated with SV40. Although these results are, for the most part, consistent with other negative epidemiologic investigations of risks from SV40-contaminated vaccines, further study of testicular cancer may be warranted, and it will be important to continue monitoring this cohort which is now reaching middle-age., (Copyright 2001 Cancer Research Campaign)