Neurovirulence tests of type 3 oral poliovirus vaccine manufactured by Lederle Laboratories, 1964–1988

Abstract

Oral poliovirus vaccine (OPV) is tested for safety by evaluation of neurovirulence in rhesus and cynomolgus macaques. After intraspinal or intrathalamic injection of varying doses of vaccine, monkeys are followed for 17–21 days, killed, and a histopathological evaluation is made of the severity of poliomyelitis lesions in the spinal cord and brainstem. Each production lot of vaccine is compared with a type 1 OPV reference virus tested by the same method. Records of neurovirulence tests on production lots of type 3 OPV manufactured by Lederle Laboratories, during the period 1964–1988, have recently become available, together with the corresponding tests on type 1 reference vaccine. The cumulative data were collated, using a system under which each monkey was given a single grade according to the severity and spread of neuropathological poliomyelitis lesions. These raw data were assembled into frequency distributions (‘neurovirulence profiles’), and used to compare type 3 OPV with the reference vaccine. These comparisons included monkeys injected by intraspinal injection (three vaccine dose levels) and intrathalamic injection (one vaccine dose level), and comprised independent tests conducted by the Food and Drug Administration and by the vaccine manufacturer. A total of 13 different comparisons were made, each one consisting of a pair of profiles, on type 3 OPV and reference vaccine, respectively. In total, these comparisons represented tests on more than 12 000 monkeys. Based on these neurovirulence profiles, the type 3 OPV appeared to be no more virulent than the reference vaccine. In 12 13 comparisons, the type 3 OPV was statistically significantly ( p < 0.002) less virulent than the reference vaccine, and in the 13th comparison, although less virulent, it did not reach statistical significance ( p = 0.11). In one of the 13 comparisons the number of monkeys with severe neurovirulence scores (grades 3 3 and 4) was greater for the type 3 OPV ( 13 230 , 6%) than for the reference vaccine ( 1 340 , 0.3%). However, this difference was not seen in any of the other comparisons made, and it was therefore concluded that there was no consistent or statistically significant evidence that type 3 OPV exhibited greater monkey neurovirulence than did the reference vaccine. This comparison represents the first published large-scale evaluation of neurovirulence tests on OPV manufactured and tested in the United States. It is particularly significant since type 3 OPV is the virus most frequently associated with vaccine-related cases of poliomyelitis. The data indicate that the cumulative results of monkey tests meet the single most important provision for neurovirulence safety testing, as set forth in the Code of Federal Regulations for OPV manufactured in the United States.