Development history of Japanese encephalitis vaccine in China

Japanese encephalitis (Japanese Encephalitis,JE, hereinafter referred to as Japanese encephalitis) is an acute infectious disease of the central nervous system damage caused by Japanese encephalitis virus vector mosquito bites. my country is a high-incidence area of Japanese encephalitis, and the number of cases is second only to India, ranking second in the world. Therefore, Japanese encephalitis is also a major public health problem in my country. At present, there is no specific therapeutic drug for Japanese encephalitis, and vaccine is the most effective protective measure to prevent Japanese encephalitis infection. Today, the editor will review the history of the development, production and use of Japanese encephalitis vaccine in China, and why it has become a Dalibao^®Is the latest generation of pure and safe Japanese encephalitis inactivated vaccine in China?

From 1950 to 1951, the Beijing Institute of Biological Products of the former Ministry of Health of China successively made inactivated Japanese encephalitis vaccine from rat brain and chicken embryo. The effect of the experimental stage was confirmed and approved by the state. In 1952, preventive injection was promoted in Beijing, Tianjin and other big cities. The epidemiological effect test showed that the protection of 3 needles, 2 needles and 1 needle was 1:27.1, 1:5.7 and 1:4 respectively. Because the vaccine contains more brain tissue components, severe allergic encephalomyelitis occurred in 1957. After that, the addition of clarification, filtration and ether treatment on the basis of the original vaccine failed to make a fundamental change in the vaccination response.

The vaccine produced from 1960 to 1966 using chicken embryo tissue culture, although the safety has been significantly improved, the immune effect is not good, and the epidemiological effect is always hovering around 1:2.

In 1967, the study of inactivated vaccine cultured by hamster kidney cells was successful. The efficacy of laboratory-verified vaccine was better than that of chicken embryo vaccine. Since 1968, it has been produced and applied in large quantities, with more than 70 million doses, which played an important role in reducing the incidence of Japanese encephalitis at that time and protecting the population in China.

1989 SA_14-14-2The live attenuated vaccine made by the strain is on the market, and the Vero cell inactivated Japanese encephalitis vaccine is on the market in 2004. The above vaccines are all based on the production technology based on the traditional transfer bottle cell culture.

Production workshop of traditional rotary bottle technology in China

Although the current vaccine manufacturing plant facilities, production equipment has extremely strict aseptic control requirements, there are clear cleanliness requirements, but even in the cleanliness of the highest A- level production workshop, the purified air also has a specified number of suspended particles within the number, therefore, the concept of aseptic is relative. In the traditional process of rotating flask cell culture, there are many links from inoculating culture cells, changing culture medium, inoculating virus, washing and removing bovine serum, harvesting virus and so on. In a certain period of time, there needs to be frequent operation of opening and capping the bottle mouth, and there will be a certain exposure time, so it is difficult to ensure that the whole process is in a closed culture environment, there is a direct or potential risk of contamination by bacteria, molds and other exogenous microorganisms. Therefore, a certain amount of antibiotics will be added in the production and preparation process. The commonly used antibiotics are: gentamicin sulfate, kanamycin, etc. Due to the limitation of the production process, the added antibiotics cannot be completely removed. Therefore, the current vaccines using the transfer bottle cell culture technology will have residual antibiotic components.

Chengdalibao of Chengda Biology in 2008^®It took the lead in establishing the "bioreactor large-scale cell culture technology" introduced from the United States. Through digestion, absorption and re innovation, it has formed a "bioreactor large-scale vaccine preparation process platform" with independent intellectual property rights, which has overcome the technical problems of large-scale cell culture in China for more than ten years, promoted the great progress of vaccine production technology in China, and become the leader of bioreactor technology.

The production workshop of Chengda Bioreactor Technology

High-density microcarrier bioreactor, the whole process of computer automation control, closed, pipeline, continuous perfusion production process, with industrial bioreactor technology to replace the traditional manual transfer bottle production, to overcome the traditional process, can not completely avoid bacteria, mold and other exogenous pollution and must add antibiotics technical bottleneck. Chengda Libao^®There is no need to add any antibiotics in the whole process of production and preparation of finished products, which makes the vaccine purer and safer, and eliminates all kinds of hazards that antibiotics may bring from the source.

At present, all cell-cultured vaccines need to be added with bovine serum in the production process, because bovine serum is an indispensable and important substance to promote cell adhesion and growth, but its residue can cause allergic reactions such as allergic rash. Therefore, the lower the residual amount of bovine serum albumin, the better. The national pharmacopoeia standard is ≤ 50 ng/dose. The large organisms use the advantages of bioreactor continuous perfusion technology, and the internal control standard of the enterprise is ≤ 30ng/dose, in fact, it is generally controlled below 10ng/dose, which greatly reduces the residual amount of bovine serum albumin to more than 40%-80%, making the vaccine safer.

According to the 2015 Pharmacopoeia and the current instructions for live attenuated Japanese encephalitis vaccine, live attenuated Japanese encephalitis vaccine contains antibiotics and is not recommended for people who are allergic to antibiotics. Moreover, live attenuated vaccines cannot be used for people with immunodeficiency, immunodeficiency or immunosuppression treatment. Therefore, from this point of view, inactivated Japanese encephalitis vaccine without antibiotics can cover more applicable people. Chengda Libao^®It does not contain any antibiotics, gelatin, formaldehyde, and preservatives. It has been safely vaccinated with more than 15 million doses. It is a new generation of pure and safe Japanese encephalitis vaccine.