The laboratory control of vaccines.
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Biomedical subjects
Publications and source records attributed to F T Perkins.
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Accelerated stability tests on lyophilized measles vaccines show two distinct mechanisms of virus inactivation. A rapid initial loss of infectivity occurs only on exposure to temperatures above the ambient temperature. This loss is temperature related and may be attributable to the movement of residual moisture from the virus pellet into the void space of the vial. Subsequent inactivation of virus occurs at all temperatures as a first-order reaction that follows Arrhenius kinetics. Integration of values for these two components allows precise prediction of vaccine stability at any temperature. Analysis of the results obtained for greater than 30 vaccines shows that those which are stable for one week at 37 C have a predicted life of more than one year at 8 C. This simple test is now being applied to the identification of unstable products. The rate of this reaction is closely, if conservatively, matched by a time-temperature color indicator, which may be useful for monitoring vaccine quality.
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Many changes have been made in the World Health Organization's (WHO) requirements for the production and control of both the killed and live (oral) poliovirus vaccines since their initial formulations in 1959 and 1962, respectively. The major changes in the production of killed vaccine concern the cell substrates used from primary tissue to passaged primary tissue or even a continuous cell line such as Vero. It has been shown also that there is no longer the necessity to test for residual infectious virus by the inoculation of monkeys, since cell cultures are much more sensitive for this purpose. For the live vaccine, a more uniform test for the titration of virus content has been introduced. Furthermore, international agreement on the details of the test for neurovirulence in monkeys has been reached. The expression of the immunogen of poliovirus in eukaryotic cells has been achieved, but whether it becomes a commercial proposition replacing one or both of our present vaccines remains to be seen.
The cell substrate, virus strain, route of administration, and safety of the rubella vaccines were all considered given the experience with other vaccines. Tissues from closed colonies of ducks, rabbits, and quails-in addition to human diploid cells-are now well established as suitable substrates. Production of rubella vaccine is now based on the principle that the vaccine virus is a live attenuated strain. RA27/3, Cendehill, Takahashi, Matsuura, and HPV-77 were initially licensed in 1969-1970; HPV-77 grown in dog kidney cells has since been withdrawn. The subcutaneous route of administration is the most acceptable. Safe and effective vaccines include RA27/3 and Cendehill, which are widely available, and five other vaccines grown in two tissues available only in Japan. The key issue is the extent to which the vaccines should be used alone or together with other vaccines in individual countries. The World Health Organization's requirements for the vaccines, first formulated in 1976, are open to revision. These requirements did not include a test for stability, which will be especially pertinent in the developing world.
Optimal conditions for the detection of malignant cells substrates were investigated. Three approaches were used: (1) neonatally thymectomized, antithymocyte serum (ATS) treated mice, (2) thymectomized, lethally irriadiated, bone marrow reconstituted (T-B+mice, and (3) congenitally athymic nu/nu (nude) mice. All three systems successfully distinguished between normal and malignant cell lines. However, differences were observed between different colonies of nude mice as to their capacity to support progressive growth of certain tumours. Advantages and disadvantages of the immunosuppressed mouse model system will be discussed. They will include: (a) detection of malignant cells in mixed populations, (b) need for different routes of inoculation for different cell types, (c) comparison with other malignancy testing systems, (d) long term versus short term immunosuppression.
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