In recent years, China has made breakthrough progress in the development of rabies vaccines and achieved remarkable results in rabies prevention and control. However, there is still a long way to go before rabies can be completely eradicated. With the release and expansion of vaccine production capacity, the tight supply situation of rabies vaccines has been alleviated to some extent. Since the implementation of the Vaccine Administration Law of the People's Republic of China in December 2019, a series of regulatory requirements and detailed rules for the entire life cycle of vaccines, from research and development to circulation, have been gradually implemented, marking the entry of China's vaccine industry into a stage of high-quality development.
At the same time, due to the public's profound understanding of the important role of vaccines in prevention and control work in recent years, there is a strong demand for high-quality vaccines. The shift in the demand side also continuously sets higher requirements for vaccine research and development. Rabies vaccines with higher purity and more complete antigen structures may be able to meet this demand. In the future, with the launch of more high-quality rabies vaccine products, it will bring new growth momentum to the rabies vaccine market.
This article will conduct an in-depth analysis of the prevention and control system for rabies virus infection. Starting from practical clinical needs, it will track the iterative direction of rabies vaccine products and explore with industry participants the innovation and improvement of production processes for human rabies vaccines.
1. Rabies poses a significant social hazard, and the potential risk of virus exposure in our country remains constant
Introduction to Rabies
Viral etiology, transmission routes, and clinical manifestations
There are multiple serotypes of rabies virus. After a series of studies on the genetic evolution of rabies virus diversity, the International Committee on Taxonomy of VirusesICTVThe genus Lyssavirus was established. The latest classification results in 2021 identified 17 species of rabies viruses, including RABV, LBV, MOKV, DUVV, etc.
As a zoonotic virus, common carriers include dogs, cats, raccoons, skunks, bats, and foxes, among which domestic dogs are the most important source of infection for humans. Most rabies cases in humans are due to bites from infected animals, with a minority caused by scratches or contamination of wounds and mucous membranes. Clinically, it is often characterized by specific phobias such as fear of wind, water, pharyngeal muscle spasms, and progressive paralysis. Once infected, the mortality rate can reach nearly 100%.1.
Introduction to Rabies
Epidemiology and Disease Burden Analysis of Rabies
Rabies is a significant public health threat. According to WHO statistics, there are approximately 59,000 deaths from rabies worldwide each year, and the economic loss caused by rabies is estimated at $8.6 billion annually.2,3Among them, 95% of rabies deaths come from Asia and Africa. India is currently the country with the most severe rabies epidemic, followed by China in terms of human rabies incidence.
The presence of rabies is not unfamiliar to the Chinese people, having caused great fear among them. With the further popularization of medical knowledge related to rabies, and the improvement in disposable income and vaccine accessibility in rural areas, the number of new rabies cases in China dropped significantly from 516 in 2017 to 151 in 2021. Despite the continuous improvement in the domestic rabies epidemic situation, China, as a country with a high prevalence of rabies, has a large exposed population. According to data from the Chinese Center for Disease Control and Prevention, the annual number of rabies-exposed people in China is as high as 40 million.
The vast majority of rabies cases in our country are caused by bites or scratches from cats and dogs. However, at present, the implementation of a rabies prevention and control strategy starting from animals is not very satisfactory in our country. The increasing number of dogs that are large in size and poorly managed is one of the main obstacles to achieving the goal of 'completely eradicating rabies' in our country. With the gradual rise of pet ownership habits, our country is experiencing a pet boom. Against the backdrop of a gradually expanding pet population and rising numbers of pets, there is an obvious trend in the number of new rabies cases caused by bites from cats and dogs. Moreover, the vaccination rate of pet dogs with veterinary rabies vaccines is still at a low level, indicating that the source of rabies transmission will continue to exist. The high-risk level of virus exposure suggests the necessity of strengthening rabies prevention.4.
Figure: New Cases of Cat and Dog Bites in China (2017-2030E)
Source: Analysis by Frost & Sullivan
II. Establishing a comprehensive rabies prevention and control system requires multiple measures. Vaccination is a crucial preventive measure before and after exposure.
In recent years, China has taken a series of measures to contain rabies, striving to establish a comprehensive rabies prevention and control system. At the national level, regulatory capabilities and standards are continuously improved in line with international standards, including improving vaccine production and circulation supervision, strengthening adverse reaction monitoring, enhancing batch release risk management, and implementing strict supervision over the entire process, all aspects, and all dimensions of vaccine administration. At the social public level, social organizations actively popularize rabies prevention knowledge, raise awareness of rabies prevention and animal bite prevention, emphasize the scientific management of dogs, and highlight the importance of dog owners taking responsibility for raising dogs. Measures at the healthcare industry level include epidemic monitoring, epidemiological investigations, pre-exposure and post-exposure vaccination, and exposure management work in a wide range of forms.
The emphasis on the rabies prevention and control system is partly due to the current lack of effective clinical treatment methods for rabies. Some treatment approaches can delay the clinical progression but rarely affect the outcome of the disease. As a preventable viral disease, the most effective approach is to administer a vaccine promptly before exposure or after wound exposure. In human prevention and control, the development and use of human rabies vaccines have provided necessary technical conditions for the prevention and control of rabies. At the same time, an adequate supply of high-quality vaccines has also provided efficient and safe prevention and control measures for people at risk of exposure.
Reviewing the Development History of Human Rabies Vaccines
From neural tissue vaccines to cell culture vaccines
The development of modern biotechnology has provided more possibilities for vaccine research. To produce vaccines safely, efficiently, and at low cost, people are constantly exploring and improving in terms of culturing viral cell matrices and process optimization. The history of humans attempting to prevent and control rabies with human rabies vaccines has spanned over a hundred years, evolving from early animal nerve tissue vaccines, avian embryo vaccines, crude cell culture vaccines, to purified vaccines cultured from primary murine kidney cells, chicken embryo cells, human diploid cells, and Vero cells.
Figure: Development History of Rabies Vaccines
Source: Public information, Frost & Sullivan analysis
In 1885, Pasteur of France used the spinal fluid of rabbits infected with rabies virus to develop the first generation of attenuated rabies vaccine for post-exposure prophylaxis, also known as the Pasteur vaccine.5Pasteur's method has proven effective, but due to the high content of myelin components in vaccines, which often lead to allergic reactions associated with residual nervous system material, including subsequent improvements and refinements that led to the production of inactivated vaccines from other animal brain tissues. Therefore, the World Health Organization advocated the cessation of production and use of vaccines derived from nervous tissue in 1984. Subsequently, some countries around the world gradually stopped producing such vaccines, and the industry began to attempt using non-nervous tissue culture for rabies virus production.
The method of preparing rabies vaccine using cell and tissue embryonic culture technology has made significant progress and has gradually replaced early nerve tissue vaccines. In 1965, Kondo from Japan adapted the Flury HEP strain virus to chicken embryo cell culture and produced an inactivated vaccine.6Fenje et al. from Canada cultured the SAD virus on primary hamster kidney cells, and the vaccine produced by this technique was approved by Canada in 1968 for use before and after rabies exposure as a booster immunization.7.
To avoid usePrimary cell cultureIn addressing the inherent difficulties in quality control, foreign researchers have begun developing rabies vaccines based on human diploid cells. In 1961, Haytlick and others from the Wistar Institute in the United States pioneered the selection of the human diploid cell line WI-38 for virus propagation.8Subsequently, the French company Mérieux developed industrial cultivation of rabies virus in human diploid cells using MRC-5 cells, and the vaccine achieved good results. It was granted a production license in 1978 and has been officially marketed in countries such as North America and Europe since then.9Due to the difficulty in large-scale production of human diploid cell vaccines to meet industrialization needs, and the high cost that limits their use in developing countries, they are usually only available to a few developed nations.10.
The emergence of the Vero cell line has brought about a tremendous transformation in the large-scale production of rabies vaccines. Initially, the pioneering work on producing human vaccines using the Vero cell line was initiated by the French Mérieux Institute. In 1985, based on the Vero cell line established by Yasumura and Kawikata in 1962, the French Mérieux Institute successfully developed a purified rabies vaccine (Vera) using the fixed strain PM1503-3M through processes such as ultrafiltration concentration, gradient density centrifugation purification, and β-PL inactivation, and obtained production authorization.11Numerous studies have proven its good safety and immunogenicity before and after exposure12.
Review of the Development History of Rabies Vaccines in China
"Quantitative change" comes first, and "qualitative change" is still in progress.
Following the pace of Western developed countries, the production technology of rabies vaccines in our country is also undergoing rapid iteration. Similar to the Western development path, it has successively gone through two stages: tissue vaccine and cell culture vaccine. Among them, cell culture vaccines include unconcentrated primary cell vaccines, concentrated vaccines, and purified vaccines. Vaccines that have undergone refined purification and chemical processing possess a higher quality level and immune effect.
Before 1980, China used to prepare rabies vaccines from sheep brain tissue suspension inactivated with carbolic acid for use and production. However, there were frequent occurrences of serious adverse reactions after vaccination and poor immunization effects.13Since 1965, China has begun developing inactivated vaccines based on primary rat kidney cell culture. Led by the Wuhan Institute of Biological Products under the Ministry of Health, cooperation has been carried out by units such as the Changchun Institute of Biological Products, Lanzhou Institute of Biological Products, and the National Institutes for Pharmaceutical Control using the fixed rabies strain AG. The vaccine was officially produced and applied in 1980 through adaptation of the primary rat kidney cells to passaged vaccine strains.14,15.
At that time, the overall preventive effect of vaccines was good, but there were still some cases of immunization failure, which could be attributed to the low antigen content in unconcentrated vaccines. The vaccine titer did not reach the standard set by the WHO, which is 2.5 IU per dose. To further improve the quality of vaccines, the Ministry of Health decided in 1993 to adopt concentrated or concentrated purified vaccines. Subsequent vaccine manufacturers then concentrated the vaccine stock solution by 3 to 5 times.16Practice has shown that the immunogenicity of vaccines has been significantly improved from 'weak seedlings' to 'strong seedlings'.
However, since most commercially available concentrated vaccines are not purified, significant side effects have occurred after large-scale human vaccination, with a serious adverse reaction rate reaching 5% to 10%.17The reason for this may be due to the addition of heterogeneous proteins such as calf serum, virus-containing guinea pig brain tissue, and mouse kidney cells containing cultured viruses during the production process16In view of safety considerations, the National Medical Products Administration has required the purification of concentrated rabies vaccines. At the same time, to avoid affecting the timeliness of vaccine-induced immunity, rabies vaccines have been transitioning from adjuvant vaccines to non-adjuvant vaccines. Since 2005, the drug regulatory authority has explicitly required that rabies vaccine products remove aluminum hydroxide adjuvant.
From the practical experience of rabies vaccine research, development, production, and application, quality improvement is essential for enhancing vaccine protection and reducing the incidence of adverse reactions in vaccinated individuals. Continuous quality improvement stems from continuous innovation in production technology. To this day, manufacturers and research institutions of rabies vaccines in China are still striving on the path of 'qualitative change' and making progress.
In terms of cell culture media, Vero cell vaccines and human diploid cell vaccines have subsequently entered the Chinese market, providing diverse immunization options for the population. Since 1990, a large number of purified rabies vaccines based on Vero cells developed or introduced into China have been marketed. In 2002, Liaoning Chengda introduced microcarrier bioreactor cell culture technology, using the PV2061 strain of rabies virus from Pasteur vaccines and Vero cells for culture and antigen production. The rabies virus was purified using molecular sieve column chromatography technology, and the vaccine (SPEEDA PVRV) developed was approved for use in 2005.
The widespread adaptability of Vero cells has rapidly promoted the development of rabies vaccines using them as a viral culture medium, making the Vero cell-based rabies vaccine a representative of mainstream rabies vaccines in China. Over time, the state's quality requirements for rabies vaccines have continuously increased. In the 2015 edition of the 'Pharmacopoeia of the People's Republic of China', it was proposed that host DNA residue should not exceed 100 pg per dose, and host protein residue (HCP) should not exceed 4 ug per dose, with strict standards set for these two indicators. Subsequently, when domestic companies sought corresponding countermeasures, they turned their attention to the field of human diploid rabies vaccines. In 2014,Kanghua BiologyA human diploid cell vaccine has been launched in China.
III. The characteristics of the cell matrix vary, and its safety, effectiveness, ease of standardization, and scalability for mass production are important considerations for vaccine production.
Currently, the cell matrices widely used in China include hamster kidney cells, chicken embryo cells, Vero cells, and human diploid cells. In terms of the types of virus strains, the PM strain is mainly used for the production of rabies vaccines using human diploid cells, while the aG, CTN-1V, and PV-2061 strains are mainly used for the production of rabies vaccines using Vero cells. The production of hamster kidney cell vaccines and chicken embryo cell vaccines uses the aG strain and Flury-LEP strain respectively.
Cell matrix for vaccine production is the main raw material for developing and manufacturing candidate viral vaccines, directly affecting the quality, yield, and safety of vaccines. Under the current comprehensive vaccine drug regulatory mechanism, clinical experience and observations suggest that different types of rabies vaccines have good safety and efficacy. The main differences or concentrations are reflected in vaccine production technology. To ensure vaccine quality and sufficient supply, when selecting an appropriate cell matrix, it is necessary to comprehensively consider multiple key parameters, such as cell sensitivity, safety risks associated with related impurities, accessibility of cell sources, large-scale production, and quality control.
Figure: Types of human rabies vaccines currently available for marketing in China
Source: Public information, Frost & Sullivan analysis
For a long time, primary cells represented by chicken embryo cells and hamster kidney cells have been widely used in the production of attenuated and inactivated human vaccines. In vitro culture of primary cells typically involves growth in a adherent form, and the main technique used is the flask culture process, which is relatively mature and has a simple cell culture medium. Therefore, it has the advantage of being broadly sensitive to a variety of viruses and being simple to prepare. From the perspective of quality control, chicken embryo cells and hamster kidney cells have potential contamination issues with exogenous factors such as viruses, and the quality and virus sensitivity of animal cultures from different sources can vary. During production, aseptic control of the animals used is required, generally using SPF (Specific Pathogen Free) level animals to reduce the frequency of contamination of biological products by pathogenic microorganisms. In addition, since primary cells do not possess the characteristics of cell line propagation, a larger number of animal sources are often needed to achieve large-scale production.
Human diploid cells are cell lines established using human-derived cells (usually embryonic tissue), which solve the contamination risk associated with the relatively unstable cell matrix source in virus culture of traditional primary cell vaccines. This improves the quality and safety of vaccines. Additionally, human diploid cells can be produced using a cell seed bank system, which facilitates subsequent full identification and quality control, bringing more stable and controllable conditions to the vaccine production process.
However, during in vitro passage culture, due to the limited number of passages typically up to 50 generations, industrial scale-up is constrained; cells can only proliferate doublings, resulting in a low number of cells per batch; the adaptability of rabies virus in human diploid cells is not ideal, leading to a low virus concentration in the viral culture stock. These factors affect its large-scale production, and the process of deep purification of vaccine culture stocks becomes more difficult. The residual process proteins and cell DNA may lead to allergic reactions, and the genetic defects inherent in human cells also pose certain potential risks.
The most recently discovered cell culture medium in the development history of rabies vaccines is the Vero cell. This cell line can be continuously propagated in vitro as a subculture line, safely up to 150 passages in production, with a proliferation multiple greater than four times. It can also be produced using a seed cell bank system. These characteristics make Vero cells a highly adaptable culture medium for rabies virus, facilitating industrial production and large-scale cultivation to obtain large quantities of virus. In addition, deep purification can remove host proteins and residual host DNA, further reducing the incidence of adverse reactions in products.
IV. As people's living standards and cognition continue to improve, the pursuit of product quality follows
The development history of the rabies vaccine field over the past century is also a history of the evolution of human cognitive patterns. From the birth of the first vaccine product, to whether vaccine production can meet demand, to today's pursuit of vaccine efficacy and quality. With the outbreak of the COVID-19 pandemic, people's understanding of vaccine quality and efficacy has gradually deepened, and future market competition in the rabies vaccine industry may further escalate. Adhering to the principle of 'surviving by quality,' manufacturers' R&D capabilities and technological iteration speed will also face higher challenges.
Between 2017 and 2021, there were fluctuations in the batch release volume of rabies vaccines for human use in China due to multiple incidents. After the Changchun Changsheng incident in the vaccine industry in 2018, the batch release volume of rabies vaccines for human use in China showed a severe decline, hovering around 50 million doses. During this period, the rabies vaccine standard underwent updates from the 2015 edition of the 'Pharmacopoeia of the People's Republic of China' to the 2020 edition. With the implementation of the new pharmacopoeia, the batch release volume of rabies vaccines for human use in China quickly rose to around 80 million doses and has tended to stabilize in recent years. Based on a stable batch release volume of 88 million doses, the output value scale reached 9.4 billion yuan.
Figure: Batch issuance of rabies vaccines to Chinese people, 2017-2021
Source: Frost & Sullivan, compiled and analyzed based on public information from the China Inspection and Quarantine Administration (CIQ) and local inspection institutes, historical batch issuance numbers of corresponding manufacturers, and public information
Currently, according to batch issuance volume statistics, the mainstream rabies vaccine on the market in China uses Vero cell culture medium as the production process.
As a rabies vaccine product, regardless of the culture medium used in the production process, its active ingredient is an inactivated rabies virus. However, due to the current level of product purification being close to each other, cell culture media are commonly used as the classification basis for rabies vaccines on the market. If the vaccine batch release volume in China is split by culture cell type, in 2021, 88.8% of rabies vaccines were based on Vero cells, with human diploid cell vaccines and murine kidney cell vaccines accounting for 5.8% and 5.4% respectively.
In the future, Vero cells may continue to be the main type of cell culture matrix for rabies virus research and development. From the perspective of the R&D trends of key rabies vaccine manufacturers, Sanofi is further deepening its layout of Vero cell vaccines. According to Sanofi's 2022 annual report information disclosure, Sanofi is developing the next generation human rabies vaccine (VRVg) based on Vero cell culture medium and serum-free culture technology, aiming to replace two of Sanofi Pasteur's products that have entered the commercialization stage (Imovax and Verorab).
Figure: Batch release volume of rabies vaccine for Chinese people,By cell type, 2021
Source: Analysis by Frost & Sullivan
As of June 30, 2023, there are two human rabies vaccines on the market in the United States, namely Sanofi's human diploid rabies vaccine Imovax and Novartis' chicken embryo cell vaccine RabAvert.
In contrast, there are many manufacturers and product types in the field of rabies vaccines in China, with 21 manufacturers of human rabies vaccines approved. Among them, there are 14 manufacturers of human rabies vaccines (Vero cells), including Chengda Biological Products and Yisheng Biological Products; 6 manufacturers of human rabies vaccines (murine kidney cells), including Yatai Biological Products and Yuanda Biological Products; and 1 manufacturer of human rabies vaccines (human diploid cells), which is Kanghua Biological Products.
Figure: Licensed rabies vaccines in China, categorized by cell type
Note: As of June 30, 2023
Source: Analysis by Frost & Sullivan
V. New market entrants face high homogenization of products, and upgrading production processes and product quality is the 'sharp weapon' for differentiated competition.
R&D manufacturers are competing to deploy in the field of rabies vaccines. As of June 30, 2023, there are a total of 20 human rabies vaccines in clinical research stages in China. Classified by culture cell matrix, there are 12 Vero cells, 6 human diploid cells, and 2 chicken embryo cells. Representative R&D manufacturers include Rongsheng Biotech, Rebio, Jinsite, Jindik, etc., which have entered phase III clinical trials.
Currently, in most production processes, the virus culture step uses large-scale bioreactor culture techniques (except for chicken embryo matrices), or changes the degree of dependence on serum. The main difference is reflected in the total amount of virus in the single harvest of the virus; the purification processes for commercially available products are basically similar, with most separation principles belonging to molecular sieve properties, using differences in molecular weight or buoyant density to separate effective components from impurities in the virus harvest.
At the beginning of the 21st century, Liaoning Chengda took the lead in introducing bioreactor technology, giving its products a competitive edge that has enabled it to maintain its position as the market leader in rabies vaccines for nearly 20 years since their launch three years ago. At present, due to the scarcity of breakthrough research results in rabies vaccine technology, it is difficult to find new technological breakthroughs. The production processes adopted by manufacturers are highly homogeneous, and future competition may tend towards price wars.
However, in the long run, products that excel in 'quality' are less susceptible to price constraints and are more likely to stand out. In recent years, the tremendous leap in China's economic level has reversed the national consumption concept, which also means that the market potential for further penetration of high-quality products will stimulate a new growth curve.
Figure: Analysis of clinical investigational human rabies vaccines
Note: As of June 30, 2023, pipelines in the clinical application phase are not included.
Source: Public information, Frost & Sullivan analysis
VI. Innovating technical routes have led to an improvement in product quality, enabling us to 'stand out' in the fierce market competition
For rabies inactivated vaccines, the active ingredient is inactivated rabies virus. Obtaining 100% purity and intact structure of the inactivated rabies virus is the ideal goal pursued by manufacturers. Good process design, reasonable process steps, and complete production facilities and equipment are important foundations for achieving this ideal goal. Taking the Vero cell vaccine as an example, its preparation process flow includes seed cell preparation, large-scale cell culture, virus inoculation, virus cultivation, virus harvest, virus liquid concentration, virus inactivation, concentrated solution purification, semi-finished product formulation, sub-packaging, etc. Among them, the technological upgrading of core process steps such as culture, purification, and quality control is ongoing.
From the perspective of culture techniques, the main culture process used in China for preparing vaccines using Vero cells is the bioreactor microcarrier culture technique. It combines the advantages of both adherent and suspension culture techniques, with a stable culture environment and easy control of the production process. It allows for uniform transfer of gases, heat, and nutrients, facilitating large-scale high-density culture. Some manufacturers such as Rongsheng Biology, Jinstar, and BioTek have chosen the direct suspension culture technique, using Vero cells to adapt to suspension growth in serum-free culture medium before producing vaccines. As adherent cells, the changes in their biological characteristics during adaptation are an important concern for product safety.
At the same time, the suspension culture process of Vero cells relies on technological advancements in serum-free culture media. Currently, the total amount of virus harvest from cell serum-free culture media is limited by the high-density culture issues of large-scale cell cultivation. Another classification of culture processes is based on the different methods of virus harvest used by manufacturers, which include single or multiple harvests in one batch or multiple batches in one tank. The applied production culture techniques include multi-tank batch, single-tank single-batch, and single-tank multiple-batch variations.
Based on the ideal goal of obtaining 100% purity and intact structure of inactivated rabies virus, good separation and purification techniques will play a crucial role while ensuring the provision of large quantities of virus stock solutions. In line with international standards, China has higher quality requirements for finished human rabies vaccine products. According to the quality standards established in the 2020 edition of the 'Pharmacopoeia of the People's Republic of China', residual host cell DNA in human rabies vaccine (Vero vaccine) should not exceed 3 ng per dose. The FDA's 'Characteristics and Identification of Cell Substrates and Other Biological Materials Used in the Production of Viral Vaccines for Use in Infectious Disease Indications' and the CDE's 'Technical Guidelines for Pharmaceutical Research and Evaluation of Gene Therapy Products' recommend that residual cell host DNA fragments should not exceed the length of a functional gene, which is about 200 bp.
Due to the buoyant density and molecular weight of rabies virus, the purification process mainly involves chromatographic purification techniques to remove host DNA and proteins. Currently, many manufacturers use non-specific molecular sieve chromatography to purify viral harvests. Most of these manufacturers' purification techniques are either based on or derived from the molecular sieve chromatography method used by the Pasteur Institute, which is also the main technique for purifying Vero cell rabies vaccines in China. In addition, some manufacturers add nucleic acid endonucleases to degrade DNA in concentrate solutions to shorten DNA fragments.
How to introduce no new substances into the production process, while extracting active ingredients and removing impurities related to production technology and products, thereby improving product safety and quality. Currently, specific purification methods such as ion exchange chromatography and affinity chromatography are expected to achieve these goals. Among numerous declared projects, some enterprises have taken this critical step by differentiating their choice of ion exchange technology, which can further remove components from vaccine stocks.Bovine serumSoluble cellular proteins and small structural impurities such as additives added during the culture process. By applying this technology, there may be an iterative upgrade of rabies vaccine products.
China issues a large number of rabies vaccine batches each year for human use, which are widely applied. Based on national-level guiding principles and years of clinical practice, several safe and effective rabies vaccines have been developed, and manufacturers' response capabilities to vaccine demand have gradually strengthened.
However, innovation is not limited to this; vaccine manufacturers in the industry are still committed to using modern biotechnology to improve the quality of vaccine products and develop more scientifically applicable production process models, leading the focus of rabies vaccine research and development from quantity to quality. In terms of vaccine cell culture media, Vero cells, with their inherent characteristics, make it possible for manufacturers to pursue the vision of balancing 'quantity' and 'quality'.
Furthermore, in terms of process selection, some advanced enterprises have already adopted cutting-edge production processes and technologies. Based on thorough research into products, they have made improvements and enhancements, bringing high-quality 'vaccine seed' products to the market. At the same time, they have further enhanced the controllability and stability of production. During the manufacturing process, large-scale production equipment is used for continuous production across the entire process, enabling vaccine production to keep up with the development trend of modern pharmaceutical industry. These innovative processes will also promote the international competitiveness of China's overall vaccine industry and enhance China's status and influence in the global vaccine field.
Scroll to view references
[1] World Health Organization. (2017). The immunological basis for immunization series: Module 17: Rabies. World Health Organization. https://apps.who.int/iris/handle/10665/259511.
[2] Katie H, Laurent C, Tiziana L, et al. Estimating the global burden of endemic canine rabies.[J]. PLoS neglected tropical diseases, 2015,9(4).
[3] WHO. Rabies [EB/OL]. [2021-11-12]. https://www.whoi.nt/newsGroom/factsheets/detail/rabies
[4] Wang W, Wang Y, Wang Y, Yan F, Wang N, Fu C. Vaccine bidding, procurement and distribution management practices in China: A nationwide study. Vaccine. 2021 Dec 20;39(52):7584-7589. doi: 10.1016/j.vaccine.2021.11.020. Epub 2021 Nov 19. PMID: 34802784.
[5] Pasteur, L.; Chamberland, C.E.; Roux, E. Method for preventing rabies after bites (in French). C. R. Acad. Sci., 1885, 101, 765–774.
[6] Kondo A. (1965). Growth characteristics of rabies virus in primary chick embryo cells.. Virology(2).
[7] Sureau, P. Rabies vaccine production in animal cell cultures. Adv. Biochem. Engin./Biotechnol. 1987, 34, 111–128.
Hayflick, L.; Moorhead, P.S. Serial cultivation of human diploid cell strains. Exp. Cell Res. 1961, 25, 585-621.
[9] Jacobs, J.P.; Jones, C.M.; Baille, J.P. Characteristics of a human diploid cell designated MRC-5. Nature 1970, 227, 168–170.
[10] Wang Yue, Huang Sijia, Yan Jiaxin. Cells and vaccine strains for modern rabies vaccine production: current status and prospects [J]. International Journal of Biological Products, 2012, 35(5): 237-241.
[11] Fournier P, Montagnon B, Vincent-Falquet JC, et al. A new vaccine produced from rabies virus cultivated in VERO cells. In: Vodopija I, Nicholson KG, Smerdel S, et al., editors. Improvements in rabies post-exposure treatments. Zagreb: Institute of Public Health, 1985: 115–21
[12] Moulenat T, Petit C, Bosch Castells V, Houillon G. Purified Vero Cell Rabies Vaccine (PVRV, Verorab®): A Systematic Review of Intradermal Use Between 1985 and 2019. Trop Med Infect Dis. 2020 Mar 7;5(1):40. doi: 10.3390/tropicalmed5010040. PMID: 32156005; PMCID: PMC7157209.
Yu Yongxin (2006). Development and Current Status of Rabies Vaccines at Home and Abroad. Shanghai Journal of Preventive Medicine (05), 216-218+254. doi:10.19428/j.cnki.sjpm.2006.05.005.
[14] Lin F, Zeng F, Lu L, et al. The primary hamster kidney cell rabies vaccine: adaptation of viral strain, production of vaccine, and pre- and post-exposure treatment [J]. J Infect Dis, 1983, 147(3): 467-473.
[15] Lin F. The protective effects of the large-scale use of PHKC rabies vaccine in humans in China 'J]. Bull World Health Organ., 1990, 68(4): 449-454.
[16] Shao Yibin, Yang Zhongdong & Chen Ze. (2007). Clinical research and application of human rabies inactivated vaccine. International Journal of Biologicals (06), 259-263.
Yu Yongxin. Research and Application Prospects of Domestic Rabies Purified Vaccines [J]. China Program Immunization, 2000(03):50-51+62.
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