The development of rabies vaccine for human has gone through the process from the traditional nerve tissue vaccine to the current tissue culture vaccine, and it has been continuously improved and developed by using modern biotechnology.
:: Early use of traditional vaccines;
1882, Pasteur isolated a rabies virus from bovine brain, which has spread in rabbit brain for 90 generations. When the virus was transmitted to the 50th generation, the incubation period was shortened from 15 days to 7 days, and its virulence weakened, making it a fixed virus. 1885, pasteur tried to infect rabbits with a fixed virus. Seven days after onset, the spinal cord was taken out and dried to make attenuated live vaccine. The vaccine successfully cured a 9-year-old boy. 1908, Fermi improved Pasteur's method, but the residual toxicity was still as high as 100MLD50. Causing acute encephalomyelitis caused by fixed virus. 1973, who rabies expert Committee suggested that rabies vaccine containing live virus should not be used in human body, therefore, attenuated live vaccine ended its historical mission. 19 1 1 year, semple further improved on this basis, inactivated brain tissue, and prepared non-toxic inactivated vaccine for brain tissue in semple. Although the safety has been greatly improved compared with the attenuated live vaccine, there are still serious nerve paralysis accidents after using semple vaccine, and the incidence rate is between 1/500 ~ 1/2000. This vaccine is still widely used in developing countries. Semple vaccine prepared from sheep brain has been used in China since 1949, and 1980 stopped using it, and it was replaced by primary hamster kidney cell vaccine. 1955, Fuenjalida and Palacios prepared neonatal rat brain (SMBV) vaccine. This vaccine has been widely used in South America for more than 40 years. However, the incidence of neurological complications is still as high as 1/8000. Summarize the following problems of nerve tissue vaccine: weak immunogenicity, containing nerve paralysis factor, and some containing residual live virus. In addition, goats and sheep used in vaccine production may be infected with latent virus. Therefore, in its seventh report (1984), the WHO Expert Committee supported the restriction and abandonment of the production of brain tissue vaccines, and strongly advocated the use of inactivated cell culture vaccines. :: Avian embryo vaccine:
In order to reduce the occurrence of nerve paralysis, 1956 peck studied and prepared duck embryo seedlings (DEV). The vaccine has been widely used in the United States and other countries for 27 years after rabies exposure, and almost no serious side effects have been observed, but the level of neutralizing antibody is not as good as that of brain tissue vaccine. After the advent of human diploid cell vaccine, the comparison shows that the safety and immune effect are better than DEV, and many countries stopped using DEV vaccine in 1982. Cell culture vaccine-vaccine recommended by WHO;
1. Human diploid cell vaccine (HDCV):
1964, American Wistar adapted PM rabies virus strain used for semple vaccine production to WI-38 human diploid cell line, and later French Merieun Institute adapted it to MRC-5 cell line to produce vaccine. The virus was cultured, clarified, heated, inactivated by β -propiolactone and freeze-dried to prepare vaccine. The vaccine was first approved for production in 1974 and commercialized in 1978. HDCV is currently used in the United States, Canada, most European countries and several Asian countries because of its high immunogenicity and good tolerance. The disadvantage of HDCV is that HDC is not easy to culture, and the virus titer of rabies virus cultured on HDC is relatively low, which makes the vaccine very expensive and limits its use in developing countries. 2. Primary cell culture vaccine:
One of the advantages of primary cell culture vaccine is that it does not need to be frozen to preserve cell species. However, every batch of vaccine must check the impurities (bacteria, mycoplasma, virus) in the cultured organs, and the availability of animal organs is a factor limiting industrial production. Hamster kidney cell vaccine (PHKCV): 1958 was put forward by Kissling, and Fenje developed it further, and adapted the rabies virus fixed virus to hamster kidney cell (PHKC) to produce inactivated vaccine, which was successful. 1968 The vaccine was approved for human amplification and pre-exposure vaccination in Canada. The vaccine obtained the production number 1980 approved by the Ministry of Health of China, replacing the semple vaccine. Dog kidney cell vaccine: 1978, Van Wezal et al. used rabies virus PM strain to adapt to dog kidney cells, and used microcarriers to mass-produce vaccines. The human inoculation experiment before and after the vaccine exposure was carried out in the Netherlands, and the immune response obtained was equivalent to HKCV, which was approved for production in the Netherlands on 1980. Chicken embryo cell vaccine: In Kando 1965, Flary HEP strain adapted to chicken embryo cells, and the cultured virus was inactivated by β-propiolactone, concentrated and freeze-dried (improved by zonal centrifugation) to make vaccine, which was commercialized in Japan. In 1983, Barth et al. differentiated a purified chicken embryo cell vaccine (PCECV) suitable for chicken embryo cells with Flary LEP strain from the above Japanese vaccine. The vaccine is currently produced by Chiro Behring GmbH in Germany. 3. Cell line vaccine:
Advances in biotechnology, such as subculturing cells on microcarriers in fermentors, have made the industrialized production of rabies vaccine a reality. 1984 Vero cell vaccine was successfully developed by French Merion Institute. In the preparation process, the microcarrier technology (cell attachment suspension culture) was used for industrial large tank culture. A large number of experiments in 1980s and recently confirmed that Vero vaccine has good immune effect whether it is used as pre-exposure human immunity or post-exposure treatment. 1984165438+10. In October, WHO cooperated with RF to infuse Vero cells with microcarrier technology at high density. The industrialized production of rabies vaccine lasted 15 years and was successful. At present, Vero cell vaccine has gained safe and effective experience in many countries in the world.