494 Archives of Disease in Childhood

Freeze-dried B.C.G. of British manufacture became available for experimental work in 1955. The main reason for introducing it was the need for a vaccine which would retain its potency under conditions of prolonged storage. On reconstitution for injection the vaccine should produce a uniform suspension with minimal clumping, resulting in a uniform viable bacterial count. These properties mean that tests for potency and for sterility can be performed on samples of each batch before distribution, which will be more leisurely as only surface transport is required. Centres using B.C.G. can store stocks instead of depending on week to week supplies and finally, the vaccination lesions can be more uniform and predictable, if the viable count of the vaccines remains constant for anything up to a year or longer. Experimental work in the laboratory has shown that the vaccines made in this country have fulfilled all these requirements (Ungar, Farmer and Muggleton, 1956; Ungar, 1958; Medical Research Council, 1958). It was essential to show that freeze-dried B.C.G. was safe, would produce acceptable vaccination lesions, a high degree of tuberculin conversion within eight to 12 weeks and a positive tuberculin reaction over prolonged periods in vaccinated subjects. The optimal number of viable organisms to be injected had to be determined in order to achieve a minimal vaccination lesion with practically 100% conversion rate. The most suitable subjects for the initial clinical trials were non-contacts, because failure of conversion or a rapid reversion would not result in serious inconvenience. Clinical trials using the technique of intradermal injection were conducted in infants by Lorber, Hart, Farmer and Muggleton (1956); Lorber, Farmer, Muggleton, Hart and Menneer (1957); Griffiths and Gaisford (1956), and in children of various ages by Lorber and Menneer (1958) and Alston, Cowell and O'Meara (1958), and in school children (13-14 years) by the Medical Research Council (1958). These clinical trials established that there was a close correlation between the number of viable organisms injected and the size of the vaccination lesions, the incidence of regional lymph-node involvement and the degree of tuberculin sensitivity following vaccination. It was apparent that reconstituted vaccines containing 10 x 106 organisms per ml. or more were unnecessarily potent and that those containing less than 1 x 106 were not sufficiently antigenic for routine use. It was also shown on controlled trials that the immediate results obtained with freeze-dried vaccines were as good as with the standard Danish liquid vaccine (Lorber et al., 1957; Medical Research Council, 1958) or with the Swedish liquid vaccine (Alston et al., 1958). When the number of viable organisms injected was of similar order, the vaccination lesions and the conversion rates differed very little in subjects given the dry or the liquid vaccines. As the Danish liquid vaccine had proved to be excellent both with regard to the duration of tuberculin sensitivity after vaccination (Griffiths and Gaisford, 1956; Lorber and Menneer, 1959) and its protective value against tuberculous disease in children in intimate contact with infectious tuberculosis (Lorber and Menneer, 1959), it was hoped that the freeze-dried vaccine would eventually prove to be equally efficient in these respects. The clinical trials quoted above were concerned with the demonstration of tuberculin conversion some weeks after vaccination and with the appearance of the lesions at this stage. Since the research suggested that the best results might be obtained by a vaccine containing between 1 x 106 and 10 x 106 viable organisms per ml. of reconstituted vaccine, the manufacturers marketed such a vaccine. The Ministry accepted this vaccine as suitable for the vaccination of contacts and others and it is estimated that at present this freeze-dried vaccine is used by about half the authorities using B.C.G. in this country.