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The quality control of the BCG vaccine lacks the requirements of exact statistical methods, although the principles of bioassay have been required in the control of other biological products for a long time. For a remedy and to eliminate controversies in the interpretation of the laboratory results of BCG products valid statistical control is needed. In the four major laboratory test systems generally used to control: the viability of the BCG products, the residual virulence of the BCG strains, the allergenic potency and 4) the immunogenic potency of the BCG vaccines the following statistical methods should be required: estimations of the unbiased point and 95% confidence interval of the viable units 10(6)/ml, the mean residual virulence, the mean allergizing and protective capacity in appropriate models, the expressions of the relative potency of the in vitro viability and the in vivo test systems to a Reference Preparation, hypothesis tests using the unbiased estimates for the comparison of the estimated parameters of the controlled vaccines (Anova) and testing the stability of the viability (Regranal), multiple comparison with the ranked estimates to diminish Type I error in rejected null hypotheses, test of concordance between the sets of ranked parameters of the different test systems. Valid models will promote the standardization of the BCG vaccine, will ensure the objective statistical inference of the control results, the interpretation of the immunogenicity and reactogenicity of the BCG vaccines and the understanding of the epidemiological processes in tuberculosis.

The efficacy of BCG vaccine in preventing the clinical manifestations of leprosy in a tuberculosis-free area of Papua New Guinea is reported. Between 1963 and 1966 a total of 5356 subjects, randomized to receive BCG or saline inoculations, were examined for leprosy before the vaccination and surveillance was continued until 1979. BCG afforded 48% protection against clinical leprosy, being most effective against borderline tuberculoid leprosy and in children vaccinated when under 15 years old. Protection was evident within 12 months in those vaccinated between the ages of 10 and 15 years but was delayed in other age groups. There was evidence for accelerated manifestations of tuberculoid leprosy in children vaccinated when under 5 years of age. Tuberculin sensitivity was more likely to be sustained following multiple BCG inoculations; vaccinees with sustained tuberculin sensitivity had the lowest incidence of leprosy, but protection was also evident in tuberculin-negative vaccinees. These results may have implications for ongoing trials of leprosy vaccine incorporating BCG.

Between 1950 to 1971 6 758 cases of active tuberculosis were registered among children under 15 years of age in Hamburg. 33 of them died, mostly due to tuberculous meningitis. In spite of a general decrease in tuberculosis during that period a relative increase of cases of pleurisy, nodular tuberculosis and tuberculous infiltrations of the lung were seen. On the other hand, cases of tuberculous meningitis and miliary tuberculosis as well as cases of glandular tuberculosis decreased. Rarely BCG-vaccinated children suffered from miliary tuberculosis, tuberculous meningitis and pleurisy. A statistical comparison between BCG-vaccinated and unvaccinated children of the birth cohorts 1954 and 1963 revealed that unvaccinated children suffered significantly more often from tuberculosis than the vaccinated. The duration of the protection by BCG-vaccination has been calculated for 7 years. BCG-vaccination after school age of the tuberculin negative persons is still debatable.

BCG vaccination with the vaccine "1331 Copenhagen" in various concentrations was carried out in 129 newborns. Control examinations were conducted to establish the complication rate and the percentage of tuberculin-positive children. Complications, either locally or in regional lymphatic areas, did not appear. The conversion rate increased with the number of viable units pro dose of vaccine. A vaccine with a concentration of about 250,000 units of vaccine pro dose is recommended for additional clinical testing.

In vitro parameters of BCG vaccine, such as colony-forming units or bacterial weight, are significant with respect to efficacy and occurrence of side effects only for vaccines which are made by one manufacturer according to one method and tested in one laboratory. With respect to colony-forming units from different products, widely varying doses must be applied to gain comparable effects. Similar effects can be expected from the human dose, recommended for each particular product. These conclusions, derived from experiences in vaccination against tuberculosis can also be considered essential for comparative immunotherapy with BCG vaccines.

The results of research on the immunogenicity of experimental mycobacterial vaccines are characterized by a remarkable lack of agreement about which substances are most immunogenic. The disagreement has usually been attributed to the differences in the methods of preparing the vaccines. An alternative hypothesis is that the conflicting results are a product of the different methods used to assess the potency of the vaccines.To determine if the method by which a vaccine is tested is a major factor contributing to the disagreement, an experiment was conducted in which a series of five different vaccines was distributed to each of nine participating laboratories. Each investigator evaluated the potency of the vaccines in one or more animal models of his own choosing. This in effect held the method of vaccine preparation constant while permitting all other variables to change.The ranking of the five vaccines was random, thus demonstrating that the method by which a vaccine is tested influences the apparent potency of a vaccine. These results cast doubt on the conclusions about the relative potency of tuberculosis vaccines evaluated by different methods.

A study was made of the responses of schoolchildren to tuberculin testing 2 months and 5 years after vaccination with one of 11 different BCG vaccines prepared by several laboratories from different strains. The fact that the allergenic response was almost unchanged after 5 years shows that a long-term follow-up adds nothing of any significance to the information obtained 2 months after vaccination. The study also showed that postvaccinal tuberculin testing is only of value in determining the level of the allergy in groups of persons. It yields little information on the level in individuals since several factors, including unavoidable experimental errors and unknown personal factors, greatly influence the reaction.

Although the injection of a large dose of BCG causes progressive, fatal disease in the Syrian golden hamster, not all BCG strains are equally active in this respect. It has been suggested that a strain to be used for vaccinating human beings should not be too weakly virulent in the hamster.Nine BCG strains, some of them widely used for BCG production, were compared with regard to their virulence for hamsters. Five of the strains were found to be of about the same high virulence; the other 4 were less virulent.Of the strains derived from the BCG that was used with success in the BCG trial conducted in Great Britain more than 15 years ago, some are more virulent for hamsters than others. It is suggested that virulence is easily lost but not gained when strains are maintained in vitro. Thus, less virulent strains would have deviated from the original protective strain, and for this reason may be less acceptable for vaccine production.

A method is described for counting viable units of Mycobacterium microti (vole bacillus) suspensions after 21 days of culture on an oleic-albumin agar medium containing 5% defibrinated horse blood, with a tight seal to maintain humidity. This method is important because vole bacillus is an alternative to BCG in the prevention of tuberculosis.