Achievements at the initial stage of vaccine development
The development of vaccines at this stage is attributed to Louis Pasteur's pioneering role and outstanding contributions in the field of vaccine development at the end of the 19th century. The great contribution of Pasteur, known as the father of vaccines, is that he selects pathogenic microorganisms with strong immunogenicity to be cultured, inactivated by physical or chemical methods, and then purified. Inactivated vaccines generally use strong strains, but attenuated weak strains also have good immunogenicity, such as the inactivated polio vaccine produced with Sabin attenuated strains. Live attenuated vaccine is a kind of vaccine which is made of live microorganisms with highly weakened virulence or basically non-toxic selected from nature by means of artificial directional mutation, and is used to inoculate people to prevent infectious diseases.
Figure 2 Louis Pasteur
At the end of the 19th century, Koch invented the method of isolating bacterial cultures on solid culture media, which laid the foundation for Pasteur to develop vaccines. Pasteur first found that the growth toxicity of bacteria on artificial culture medium was weakened for a long time, such as Vibrio cholerae in chickens after two weeks, which could not cause disease in chickens after being injected into chickens. What's more, if fresh Vibrio cholerae is used to attack these injected chickens, they will not have cholera. Pasteur believed that this was due to the reduced virulence of Vibrio cholerae in the old culture, but the immunogenicity still existed, so that chickens had immunity against Vibrio cholerae. Based on this theory, Pasteur cultured the anthrax bacillus at 42~43 ℃ for two weeks to make an artificial live attenuated anthrax vaccine.
On May 5, 1881, Pasteur selected 24 sheep, 1 goat and 6 cattle for experiment. The animals were vaccinated with anthrax vaccine, and then immunized again with anthrax vaccine after an interval of 12 days. On May 31, the experimental group and the control group were attacked with pathogenic anthrax. The results were as follows: ① All sheep and goats in the control group died, 2 cows died and 4 cows were seriously ill; ② Only one sheep died in the test group. The results showed that anthrax vaccine had protective effect on animals. Since the live attenuated anthrax vaccine was officially used for the first time in 1881, to the beginning of 1882, a total of 85000 sheep were immunized, and achieved an unprecedented immune protection effect.
After the success of anthrax vaccine and chicken cholera vaccine, Pasteur began to study rabies vaccine again. Although rabies virus can not be isolated and cultured like bacteria, it has been confirmed that the pathogenic microorganism causing rabies exists in the spinal cord or brain tissue of diseased animals. Therefore, Pasteur chose rabbits to pass on their brains in order to obtain attenuated strains, and then made a live vaccine. With this vaccine, he successfully saved the life of Jacob Meister who was bitten by rabies dogs.
According to Pasteur's principle of vaccine preparation, Vibrio cholerae could be continuously cultured in the air at 39 ℃ in 1891 to produce a live attenuated vaccine. Later, clinical trials in India proved that live cholera vaccine has protective effect. Kolle et al. heated and inactivated Vibrio cholerae in 1896 to prepare an inactivated vaccine, which was widely used in cholera endemic areas in Japan in 1902, and then carried out clinical trials in Bangladesh, the Philippines and India, respectively. The conclusion shows that the vaccine has a good short-term protective effect.
Inspired by Pasteur's brilliant achievements, in 1908, Calmette and Guerin cultured a strain of bovine tuberculosis bacilli on a medium containing bile for 13 consecutive years and 213 generations, and finally obtained a attenuated BCG vaccine in 1921. At first, BCG was taken orally, but it was changed to intradermal injection at the end of the 1920s. BCG has a good effect in resisting miliary tuberculosis and tuberculous meningitis in newborns. Since 1928, BCG has still been widely used in children's immunization programs all over the world, and more than 4 billion people have been vaccinated.