Licensed vaccines.

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Takahashi, Matsuura, and HPV-77 were initially licensed in 1969-1970; HPV-77 grown in dog kidney cells has since been withdrawn.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.

The standardization of vaccines: a discussion.

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.

Stability of further-attenuated measles vaccines.

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.

Stability of human diploid-cell-strain rabies vaccine at high ambient temperatures.

A batch of lyophilised human diploid-cell-strain rabies vaccine was divided into three batches, which were exposed to different temperatures during their distribution to and storage at three centres in Pakistan. Vaccine potency after exposure to these temperatures was tested by measuring antibody response in those given the vaccine, and by three different laboratory tests. The results indicate that the vaccine retains its antigenicity for man and for laboratory tests despite continuous exposure to high ambient temperatures for up to 11 weeks. These findings, together with current developments in vaccine manufacture and treatment schedules, offer considerable hope to many countries with low budgets for health care and where rabies is poorly controlled.

The need for quality control in the developing countries.

In the developing countries there is a need for greater activity in the quality control of vaccines used in immunization programmes. The establishment of a quality control facility can give assistance not only in the checking of vaccines at the time of release, but also in monitoring the efficacy of the cold chain. Furthermore, the antibody responses of the local child population to the vaccines can be measured. Quality control should be established before vaccine manufacturer, therefore, and the economics of importing vaccine in the bulk concentrated form with dilution, blending and filling locally is worthy of consideration.

Tumourigenicity testing in immunosuppressed mice: advantages and disadvantages.

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.

The response to oral poliovaccine in persons aged 16-18 years.

Serum neutralizing antibodies to polioviruses were titrated in serum samples from 182 police cadets aged 16-18 years before and, in 168 of the cadets, 6 weeks after vaccination with a single dose of oral polio vaccine (OPV). Faecal excretion of poliovirus was also followed. Vaccination histories were obtained and confirmed whenever possible. Pre-vaccination antibody could not be detected against type 1 in 9-3% cadets, against type 2 in 2-7% and against type 3 in 7-7%. Absence of antibody to at least one virus type was found in 14-3% of the cadets. In 93 cadets in whom vaccination histories could be confirmed 40 had received only inactivated polio vaccine (IPV) previously; of these 23% lacked antibody to at least one virus type, and they had less intestinal immunity to a challenge dose of OPV than those previously given OPV. Only two of the cadets known to have had OPV were non-immune - both had received a single dose following full courses of IPV. However, cadets who had received OPV had their last dose of vaccine more recently (average 4-6 years) than those who had received only IPV (all 12 years or more). The serum antibody response to a single booster dose of OPV, and the faecal excretion of each type of virus after vaccination, showed an inverse relation to the corresponding pre-vaccination antibody concentration. A single dose of OPV did not reliably boost the immunity of those who possessed adequate immunity, and a failure to respond was also observed in a proportion of the cadets with no detectable antibody, mostly in the case of type 3 antibody and particularly if antibody to types 1 or 2 virus was also absent. No evidence was obtained that intestinal immunity could be expected in the absence of detectable circulating antibody. The reasons for the absence of a serological response to OPV in some subjects are discussed and consideration is given to the practical significance of the findings. It is suggested that reinforcement of polio immunity at school-leaving is important, particularly at the present time when many of those aged 16-18 years will have been vaccinated only with IPV. A single dose of OPV is not ideal for this purpose, not only because a small proportion of persons are liable to be left unprotected, but also because failure to produce a reliable boost in persons with adequate immunity at the time of vaccination gives rise to the possibility that they may become susceptible later in adult life.

Optimal conditions for the growth of malignant human and animal cell populations in immunosuppressed mice.

Immunosuppressed mice have been used to support the growth of xenogeneic human and animal malignant cell populations. The optimal conditions for tumor growth are neonatal thymectomy coupled with antithymocyte serum or thymectomy, followed by whole-body irradiation and bone marrow reconstitution. When mice are inoculated with a mixture of normal and malignant cells, the malignant cells have a selective advantage. No such selectivity is found when the mixed populations are grown in vitro. Human tumors may also be grown in immunosuppressed mice. These tumors retain the organization of the original tumor in the human host. The advantages of this system to cancer researchers are discussed.