Difficulties in polio eradication.
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Fresh Water↗
Biomedical subjects
J Furesz
Publications and source records attributed to J Furesz.
Telomerase activity is not altered by regular strenuous exercise in skeletal muscle or by sarcoma in liver of rats.
Telomerase is a specialized ribonucleoprotein enzyme complex which prevents the loss of the telomere. The activity of telomerase can be up- and down-regulated by various oxidative stresses but the effect of physical exercise is not known, whereas the modifying effect of cancer on telomerase activity is well documented. In the first study, we investigated the effect of mild and strenuous exercise training on telomerase activity, assessed by a PCR ELISA kit. No alteration in telomerase activity was detected. In the second investigation, solid sarcoma cells were transplanted to control, exercise trained or exercise trained and still exercising mice. On the 16th day after the transplantation, the size of tumors in the exercise trained group was 72% and in the exercising group 57% (P < 0.05) of that in the controls. Telomerase activity and 8-hydroxy-2'-deoxyguanosine levels in the liver were not significantly altered by exercise and/or sarcoma. We conclude that mild and strenuous exercise training does not significantly affect the activity of telomerase in the systems studied. Exercise training during sarcoma significantly retards the development of tumors and could possibly serve as a positive adjunct to treatment.
8-Hydroxy-2'-Deoxyguanosine↗
New assays for the quality control of live oral poliovirus vaccine.
The strains of all three types of poliovirus used in the production of live oral poliomyelitis vaccine have been shown to yield vaccines that are both immunogenic and highly attenuated when administered orally to susceptible children and adults. Experience obtained for close to four decades with the vaccines prepared from these strains indicates that laboratory and animal tests described in the World Health Organization's (WHO) Requirements for Poliomyelitis Vaccines (Oral) do ensure the consistency of virus characteristics during vaccine production. Major advances in our understanding of the molecular basis of attenuation and reversion of polioviruses resulted in the development of a new generation of tests. These include an alternative in vivo neurovirulence test in transgenic mice that express the human poliovirus receptor and a new in vitro assay (mutant analysis by polymerase chain reaction and restriction enzyme cleavage, shortly MAPREC) that assess the consistency of vaccine production at a molecular level. A WHO collaborative study was initiated in 1993 with the objective of assessing transgenic mice as potential models for evaluation of the neurovirulence of type 3 vaccines. The results of the study showed that there is a very good correlation between the TgPVR21 mouse assay and the monkey neurovirulence test. Further studies are in progress to develop a statistical model for making regulatory decisions on accepting or rejecting batches of type 3 vaccine. A WHO collaborative study was initiated in 1991 to evaluate the MAPREC assay for type 3 vaccines. The results of this study showed that the MAPREC test was a sensitive, robust and standardized molecular assay suitable for process development for new manufacturers and for monitoring the consistency of existing vaccine production. Screening single virus harvests with MAPREC before pooling them into monovalent bulk vaccine will also improve the quality of the final product.
Adult↗
Elimination of measles in the Americas.
Of the 5551 confirmed measles cases reported in 1995 in the Americas, 2301 (41%) occurred in Canada. In this issue (see pages 1407 to 1413) Drs. Penny A. Sutcliffe and Elizabeth Rea describe a measles outbreak that occurred during that year in a highly vaccinated secondary school population in Toronto. Their findings support the use of a two-dose measles vaccination strategy. In this editorial the author explains how a two-dose strategy lowers the incidence of primary and secondary vaccine failures and thus reduces the number of susceptible people to below the outbreak threshold. Two-dose programs in Finland, Sweden and the United States have dramatically reduced the incidence rates of measles in those countries, and it is expected that the implementation of two-dose programs and "catch-up" campaigns in Canada and the remaining countries of the Americas will eliminate measles from the Western Hemisphere by the year 2000.
Child↗
Safety and effectiveness of the new inactivated hepatitis A virus vaccine.
PURPOSE: To examine the evidence concerning the safety and effectiveness of the inactivated hepatitis A virus vaccine recently licensed for use in Canada. DATA SOURCES: The main source of information were papers presented at the International Symposium on Active Immunization against Hepatitis A, held in Vienna, Austria, Jan. 27-29, 1992. The bibliographies of these papers were searched for additional references. Recent articles describing the new vaccine and the epidemiologic aspects of infection with hepatitis A virus (HAV) were also reviewed. STUDY SELECTION: Peer-reviewed reports of trials approved by a government regulatory agency on the safety, immunogenic properties and efficacy of the vaccine. DATA EXTRACTION: The authors assembled key reports on adverse reactions, protection from disease and serologic assessment of immune response in vaccine recipients; data from these reports were tabulated and analysed. RESULTS OF DATA SYNTHESIS: The new vaccine contains the HM175 strain of HAV, which is adapted to grow in tissue culture. The virus is purified, inactivated with the use of formaldehyde and adsorbed onto aluminum hydroxide. The recommended dose for adults is 720 enzyme-linked immunosorbent assay (ELISA) units in a 1.0-mL dose and for children 360 ELISA units in a 0.5-mL dose, injected intramuscularly. The usual schedule is three serial doses, the second given 1 month and the third 6 to 12 months after the initial dose. Reported side effects are infrequent and minor. In healthy persons who have received two doses, the seroconversion rate is almost 100%. Protective efficacy after two doses is estimated to be 94%. However, the persistence of protective antibodies has been studied only over the short term (3 years). CONCLUSIONS: The new HAV vaccine is safe, effective and best suited to pre-exposure prophylaxis in people with an increased risk of infection for an extended period, such as travellers to areas where the disease is endemic. Further studies are needed to determine whether infants respond well to the vaccine and whether the vaccine protects recipients from subclinical infection and associated fecal shedding of HAV. Controlled trials to determine the duration of protection beyond 3 years and the effects of more rapid dosage schedules are also needed.
Clinical Trials as Topic↗
Some aspects of the monkey neurovirulence test used for the assessment of oral poliovirus vaccines.
Twelve years of experience in three control laboratories with 8,000 macaca monkeys for the testing of 204 monovalent lots of the three types of oral poliovirus vaccine (OPV), have shown that the new monkey neurovirulence test (MNVT) adopted by the World Health Organization (WHO) is a reproducible and sensitive assay likely to ensure the safety of this vaccine in humans. When the test vaccine and the appropriate homotypic reference vaccine were tested in a single group of monkeys, the concurrent use of the reference vaccine considerably increased the reproducibility of the test. The usefulness of the WHO MNVT was further demonstrated in our laboratory when the test was applied to types 1 and 3 vaccine strains that were passaged serially in the intestinal tract of infants. The test was suitable for detecting increased monkey neurovirulence in these human passage strains that did not reach the level of neurovirulence of the "wild" types 1 and 3 strains tested concurrently (except human passage no. 7 of the type 3 vaccine that multiplied for a cumulative 109 days in seven infants). The statistical analysis of the data showed that the old intrathalamic (IT) assay used for many years in our laboratory was considerably less sensitive than the intraspinal WHO MNVT; a test vaccine with a two-fold increase in monkey neurovirulence showed a 41% chance of failing in the IT test (using 30 monkeys per vaccine), while this chance increased to 99% in the WHO assay (using 12 monkeys for types 1 and 2 vaccines and 20 monkeys for type 3 vaccine). Indeed, three of seven type 3 lots tested in our laboratory with both assays failed in the WHO assay but all lots passed in the IT test. Since the introduction of the WHO MNVT in Canada and the United Kingdom, the number of vaccine-associated paralytic poliomyelitis cases in the population continued to remain at a low level.
Animals↗
Genetic characterization of Sabin types 1 and 3 poliovaccine virus following serial passage in the human intestinal tract.
Poliovirus isolates types 1 and 3 were obtained from five and seven successive passages respectively, in infants who had been fed monovalent OPV in two separate clinical trials conducted in 1960. The purpose of these trials was to answer the question how much the vaccine virus would revert to its original neurovirulent phenotype following multiplication in the intestinal tract. Human passages were performed either by contact exposure or by feeding the excreted virus while the infants were maintained in isolation. Several virus isolates were obtained at each passage level. Infants participating in both studies showed no symptoms of disease. Antigenic studies (McBride, van Wezel) and protein analysis (PAGE) of the isolates, reported earlier from this laboratory, had shown that the isolates remained vaccine-like, although isolates from the later passages revealed some differences. Monkey neurovirulence test results showed that for both types 1 and 3 viruses the loss of attenuation of the vaccine strain upon passage was gradual, although the loss was faster for type 3. Examination of the oligonucleotide maps demonstrated that the oligonucleotide configuration of the isolates remained the same as for the vaccine strain but there was an increase of individual spot differences with increasing passage. The nucleotide sequence analysis of selected regions of the virus genomes revealed that there was no change from a G to A in nucleotide 480 of type 1 isolates; however, nucleotide 476 changed from a U to an A in type 1 passages 3, 4 and 5. Conversely, for type 3 the change of nucleotide 472 from a U to a C changed at the early first passage (4 days following administration of OPV), and remained a C in the six following passages; type 3 nucleotide 2034 did not change in the first passage from a U to a C, but it became a C in all further passages tested. The nucleotide changes mentioned for both virus types remained stable in successive passages. However, there was another nucleotide change for type 3 from a U to a C at position 1973 only for passages 5 and 6 which reverted to a U for passages 7L and 7LL. Study of selected human passage virus strains could further contribute to the identification of the critical nucleotides that are responsible for the attenuation of these two polio types of vaccine viruses.
Base Sequence↗
Possible influence of measles virus infection of cynomolgus monkeys on the outcome of the neurovirulence test for oral poliovirus vaccine.
Macaque monkeys are susceptible to measles infection which triggers temporary immuno-depression similar to the well known phenomenon in humans. It is known that feral monkeys become infected with measles virus when they are exposed to humans. Since Macaca mulatta and M. fascicularis are species used to assay the neurovirulence of oral poliovirus vaccine, the immunodepression caused by measles infection of the test monkeys could significantly alter the results of the neurovirulence test. The serum titers of measles-neutralizing antibodies were studied in over 1500 monkeys used for neurovirulence tests. A high proportion of the feral monkeys had measles antibodies (51-100%); in contrast, none of 493 M. fascicularis monkeys which had been bred in a primate colony under strict isolation measures was found positive for measles antibodies. An increase in the prevalence of measles in the population of Ontario and Quebec provinces was accompanied with an increase in the proportion of measles-positive monkey and their serum antibody titers were found higher. It was observed that monkeys used in tests that had been performed during high measles prevalence presented with a poliomyelitis of more pronounced severity clinically and histologically. The analysis of 29 tests conducted on type 1 vaccines over several years showed a positive correlation (correlation coefficient = 0.5141, P less than 0.0022) between severity of poliomyelitis and the presence of measles serum antibodies in test monkeys (some animals seroconverted during the test). A similar observation, when type 3 Sabin vaccines were tested in M. fascicularis, was recently reported from another laboratory in Ontario.
Animal Husbandry↗
Nucleotide sequence analysis of Urabe mumps vaccine strain that caused meningitis in vaccine recipients.
Mumps virus was isolated from the cerebrospinal fluid of eight patients who acquired meningitis within 4 weeks of immunization with live Trivirix vaccine that contains mumps (Urabe Am 9), measles (Schwarz), and rubella (RA 27/3) viruses. Part of the haemagglutinin-neuraminidase (HN) gene from three postvaccination isolates of mumps virus, three wild strains and the Urabe and Jeryl Lynn vaccine strains was cloned following polymerase chain reaction (PCR) amplification, for the purpose of sequence analysis. A 200-nucleotide portion of the cloned HN genes was sequenced and compared to published sequences of two other strains (RW and SBL-1). The postvaccination mumps strains were identical in sequence to Urabe and were distinguishable from the wild and the Jeryl Lynn vaccine strains. Twenty-two out of 200 positions were seen to vary among the group of viruses. It was concluded that the Urabe vaccine strain was the cause of postvaccination meningitis. Therefore, with effect from 1990, Trivirix measles, mumps and rubella vaccine is no longer licensed for sale in Canada.
Base Sequence↗
Vaccine-related mumps meningitis--Canada.
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Canada↗
Evaluation of Canadian poliovirus-related cases.
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Canada↗
Tumorigenicity testing of various cell substrates for production of biologicals.
The data presented in this paper confirm earlier findings that the antithymocyte globulin (ATG) treated newborn Wistar rat is more sensitive than the nude mouse in allowing the metastatic potential of a cell substrate to be displayed. Several human neoplastic cell lines such as HeLa, FL, Hep-2, KB and WiDr cells as well as monkey kidney cell lines such as Vero and BSC-1 cells, which failed to metastasize in nude mice, formed metastases in ATG-treated newborn rats. Earlier studies on the tumorigenicity of Vero monkey kidney cells were extended to various passage levels of BSC-1 aneuploid and CV-1 diploid monkey kidney cells in order to establish the effect of prolonged in vitro culture on the oncogenic potential of African green monkey kidney cells. It was found that BSC-1 and CV-1 cells--like Vero cells--showed increased tumorigenicity in the rat model with increasing cell passage. Cells of all three cell lines passaged 146 to 257 times formed invasive adenocarcinomas in the muscle (inoculation site) of the animals. Considering the passage levels, at which the adenocarcinomas appeared and lung metastases were detected, the malignant potential was most pronounced in CV-1 cells, followed by Vero cells and was lowest in BSC-1 cells. Results obtained from the in vitro tumorigenicity assay of cell colony formation in soft agar confirmed the rat test results: increased cell passage of all three monkey kidney cell lines resulted in higher cell colony formation. The in vitro chick embryo skin culture assay was found unsuitable for the differentiation of various passage levels of these cell lines.
Animals↗
Mumps meningitis, possibly vaccine-related--Ontario.
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Humans↗
Experience in Canada with the new revised monkey neurovirulence test for oral poliovirus vaccine.
Nine years of experience in our laboratory, using more than 1500 cynomolgus monkeys in 138 tests, has shown that the new neurovirulence test (NVT) adopted by the World Health Organization (WHO) for live, oral monovalent vaccine of each poliovirus type, was a reproducible and sensitive assay likely to ensure the safety of this vaccine in humans. Our findings were the following: (1) when the test vaccine and the appropriate homotypic reference vaccine were tested in a single group of monkeys, the concurrent use of the reference vaccine considerably increased the reproducibility of the NVT; (2) in the assessment of the degree of attenuation of each lot of vaccine, the use of 12 monkeys for types 1 and 2 vaccines and 20 monkeys for type 3 vaccine (inoculated intraspinally each for reference and test vaccine) was satisfactory; (3) the virus dose used per monkey (10(5.6) to 10(6.6) pfu per monkey) was found not to be critical, i.e. the lower virus dose yielded mean lesion scores in the central nervous system of monkeys at least as high or higher than the tenfold higher virus dose; (4) the statistical analysis of our data showed that the old intrathalamic (IT) assay was considerably less sensitive than the new intraspinal (IS) assay, i.e., a test vaccine with a twofold increase in monkey neurovirulence would have a 41% chance of failing in the IT test (using 30 monkeys per vaccine), while this chance increased to 99% in the WHO IS assay (using 12 or 20 monkeys per vaccine). Since the introduction of the WHO NVT in Canada, the laboratory findings in monkeys were confirmed by vaccine experience in humans; the number of vaccine-associated paralytic poliomyelitis cases in the population showed a further decline.
Animals↗
Regulatory control of blood products in Canada.
Blood products are considered as biological drugs in Canada and are regulated under The Food and Drugs Act. Before a biological drug may be sold, the manufacturer must file a new drug submission with the Bureau of Biologics and receive a notice that the submission complies with the regulations. In addition the manufacturer must comply with the requirements for a license, including the detailed description of manufacturing facilities, qualifications of personnel, and standard operating procedures of all manufacturing steps. To verify the information provided by the manufacturer, senior scientists of the Bureau conduct an inspection of the manufacturing premises. In order to ensure the safety and potency of the product, the Bureau authorizes the sale of the product on a lot by lot basis. Samples of each lot are submitted to the Bureau laboratories for testing. In November 1984 the Bureau required manufacturers to treat coagulation products by a method proven to inactivate HTLV-III/LAV. While immune globulin preparations have not been associated with virus transmission in recipients, the Bureau tested 22 lots of various immune globulin products for HTLV-III/LAV antibodies. Using the Western Blot assay 9 lots were found antibody positive. Although these lots are not considered infectious, further studies are required from manufacturers to demonstrate by virus isolation attempts and virus "spiking" studies that the fractionation procedure eliminates potentially infectious virus.
Acquired Immunodeficiency Syndrome↗
Poliomyelitis in Finland.
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Disease Outbreaks↗
Activation of metastatic potential in African green monkey kidney cell lines by prolonged in vitro culture.
Studies on the tumorigenicity of Vero kidney cells of Cercopithecus aethiops monkey origin were extended to various passage levels of BSC-1 aneuploid cells and to low passage CV-1 diploid cells (derived also from C. aethiops monkey kidney). It was found that BSC-1 cells -- like Vero cells -- showed increased tumorigenicity with increasing passage level in antithymocyte globulin (ATG) treated newborn rats and in nude mice. Cells passaged over 250 times in cultures formed invasive adenocarcinomas in newborn rats. Their malignant tumor growth was further demonstrated around the 500 passage level when tumor metastases were detected in the lungs of four of the 14 inoculated rats. Vero cells induced such lung metastases in rats already at passage 227. CV-1 diploid cells at low passage level produced small nodules of epithelioid cells in newborn rats at 6th day after inoculation that had disappeared by the 21st day, and caused no local invasion nor lung metastasis. In vitro tumorigenicity tests on BSC-1 and CV-1 cells, using chick embryo skin, human muscle and colony formation in agarose, confirmed the animal test results. The results of this study indicate that BSC-1 and Vero cell lines at low and high passage levels may prove to be useful tools to study the molecular basis of malignancy.
Adenocarcinoma↗
Heterotransplantation studies with tissue culture cell lines in various animal and in vitro host systems.
The human amnion cell line FL was found to be more tumorigenic than HeLa cells when used as a positive control in heterotransplantation assays. FL cells formed significantly larger locally invasive tumors than HeLa cells in both Balb/c/nu/nu mice and ATG-treated newborn Wistar rats. In addition, FL cells resulted in metastatic growths in the lungs of two of 12 mice six weeks and in 10 of 36 rats three weeks after inoculation. HeLa cells did not produce metastases in either mice or rats. Both these cell lines were obtained from the American Type Culture Collection. Heterotransplantation experiments with a variety of animal host systems confirmed previous findings that newborn Wistar rats treated with rat ATG were the most sensitive to tumor growth. Vero and LLC-MK2 continuous monkey kidney cells formed small, non-progressively growing tumors showing tubule formation and occasional mitoses. LLC-MK2 cells were found to be more pleomorphic in appearance and with more mitoses than Vero cells but neither cell line showed any evidence of distant metastatic growth in any of several organs examined. The human lymphoblastoid cell line Namalwa produced large invasive tumors at the inoculation site but no distant metastases. In the chick embryo skin test it was found that MI values (mitotic index--percentage of cells in mitosis) gave more reproducible results and were less time-consuming than counting mean mitoses per section. Significant differences were found between Vero, LLC-MK2, HeLa and FL cells with Vero giving the lowest and FL the highest values. The use of MI values enhanced the sensitivity of the chick embryo skin test which was found to be a rapid and valuable screening test for tumorigenicity.
Animals↗