Vero cell: Most productive Safest and Widely cell in vaccine production

Vero cell: Most productive Safest and Widely cell in vaccine production.  The continuous cell line (CCL) Vero cell line is the most widely used and most reliable cell line in the global virus vaccine production. It is the most cost-effective in terms of quality, yield and safety.

Since 1986, the Vero cell line has been officially approved by the World Health Organization (WHO), Europe, China and many other regions or countries for the production of virus vaccines.

In less than two months after the new coronavirus began to spread, the inactivated new coronavirus vaccine prepared with Vero cells began animal experiments and obtained conditional marketing approval in less than a year. It is unlikely to be possible on other cells.

The relationship between Vero cells and virus vaccines

Viral vaccines have been widely used to prevent many diseases. However, many vulnerable people in virus-endemic areas still cannot afford vaccines. The cost of vaccines and the frequent shortage of vaccines worldwide are the main obstacles to the promotion of viral vaccines worldwide. Vero cells were found to be highly sensitive to many types of viruses shortly after they were established. The cells are used as a matrix for Japanese encephalitis, hemorrhagic fever with renal syndrome, rabies, polio, EV71, rotavirus, and smallpox. Vaccines such as, influenza, etc. have been marketed successively, including both live attenuated vaccines and whole virus inactivated vaccines. The Vero cell platform is being used to develop vaccines against a series of new virulent diseases, such as vaccines against West Nile Virus, Severe Acute Respiratory Syndrome, Chikungunya Fever and New Coronavirus.

The source of Vero cells

Vero cells (also known as African green monkey kidney cells) are an aneuploidy passage cell line (CCL), which was originally isolated from normal adult African green monkey kidney cells in 1962 by Yasumura of Chiba University in Japan. The cell line was transferred to the US NIH (National Institutes of Health) at the 93rd generation and submitted to the ATCC (American type culture collection) by the NIH at the 113th passage. Then, the 124th generation was provided to the Mérieux Institute in France to establish the WHO Vero cell bank. It is the first aneuploidy adherent cell used to produce human biological products and establish cell lines and cell banks of different generations.

In 2014, Japanese researchers determined the entire genome sequence of the Vero cell line. Vero cells are a continuous aneuploid cell line, which means that it has an abnormal number of chromosomes, and it is known that a continuous cell line can go through many division cycles without aging. Vero cells cannot express the antiviral protein interferon due to their inherent genetic defects. Therefore, the wide susceptibility of Vero cells promotes the development of vaccine production using Vero cells as a substrate.

Safety of Vero cells

A large amount of research data has shown that Vero cells below a certain passage number are not carcinogenic.

CCL (passage cell lines) have the potential for unlimited passages, even though they may be derived from normal cell populations. Therefore, Vero cells have theoretically carcinogenic potential. However, with the development of new technologies in immunology, virology and molecular biology, it has become possible to detect the potential carcinogenic properties of viral vaccine cell substrates in a more critical way, thereby effectively avoiding its potential carcinogenic effects. In 1986, based on a large amount of research data, a WHO research team considered several issues related to the acceptability of new cell substrates for the production of biological agents. Their definite conclusion is that CCL is acceptable for the production of human vaccines. However, when deciding to use a specific CCL in the production of a specific product, the differences in the characteristics of the product and the production process must be considered. Therefore, in 1987, WHO officially announced the detailed technical requirements and specifications for CCL used in the production of biological products.

Cooperative research conducted by 10 laboratories around the world on carcinogenicity, exogenous pollution, existence and identification of reverse transcriptase, etc., shows that the Vero cell bank established by the WHO meets WHO’s requirements for CCL used in the production of biological agents. Different laboratories have been using Vero cells of different pedigrees, which multiply under very different conditions. Therefore, although Vero cells have become a common substrate for human vaccine production, it is still crucial to fully identify the cell bank used for vaccine production. Safety issues related to residual DNA and Vero cell proteins have also been specifically reviewed. Although these are now considered to be only impurities and not carcinogens, the purification process still needs to be verified to prove that the removal level of cellular DNA is equivalent to no more than 10 ng per single human dose. The Chinese Pharmacopoeia has increased the DNA residue standard by 100 times, requiring that each single human dose not exceed 100 pg, or 0.1 ng. Moreover, the fragment size of the remaining DNA must also be identified to ensure sufficient degradation during the purification process steps.

For many years, Vero cells have also been used to produce live oral poliovirus vaccines. As a result, there have been more than 35 years of experience in human vaccines derived from Vero cells, and a total of hundreds of millions of doses of various vaccines produced with Vero cells have been distributed globally. A large number of statistics prove that these vaccines did not increase carcinogenicity compared with other control vaccines.

On the other hand, it is recognized that over the past 30 years, compared with CCL, the regulatory opinions regarding the risks and benefits of primary culture have completely changed. With the development of new detection technologies, the theoretical carcinogenic risk of Vero and other cell lines has been eliminated, and the introduction of screening technologies such as PCR has proved that the primary cell line has a series of theoretical risks of foreign virus contamination. These cell lines are usually very dangerous. May not be fully identified. The well-characterized Vero cell line may actually be safer than the primary cell line. These regulatory considerations, coupled with the many advantages of the Vero cell line platform, will continue to promote the expansion of Vero cell line vaccine development and production.

Advantages of Vero cells compared to primary cell lines and diploid cell lines

First of all, the source of Vero cells is convenient, the cell bank is easy to establish and maintain, at the same time, it can be passaged continuously and grow fast. The diploid cell line has a limited number of passages, and when the passage reaches a certain number of passages, it will senescence and apoptosis, making the production process unable to be put into large-scale production.

Secondly, Vero cells have stable genetic characteristics and low malignant probability, no exogenous pollution, and good biosafety characteristics;

Third, Vero cells are sensitive to a variety of viruses, with high virus titer, which can significantly reduce vaccine production costs.

Finally, Vero cells have strong resistance or tolerance to various culture conditions, and have low requirements for their good growth on the surface of microcarriers. They can quickly adhere to the surface of microcarriers and grow, and are easy to scale up in bioreactors. Cultivation facilitates large-scale production of vaccines.

Of particular importance is that Vero microcarrier technology can be established in safe facilities at any time, and can be operated under the conditions of enhanced biosafety level 3, which is the level of containment required to deal with several highly pathogenic viruses, such as the new coronavirus. Therefore, wild-type viruses can be directly used for vaccine development and production on Vero cells, while such experiments and production under the increased level of biosafety cannot be carried out on a large scale on other production platforms such as chicken embryos. The ability of Vero cells to adapt to the proliferation of wild-type viruses has further shortened the development time of vaccines for new onset virulent diseases.

These relative advantages prove that Vero cells have important value in the development of a series of virus vaccines. The primary and diploid cell culture systems are now being replaced by the use of Vero cells.

Development and application of new coronavirus vaccine (COVID-19) based on Vero cell platform

In the context of a global pandemic caused by the new coronavirus, the Vero cell platform is particularly valuable in responding to such emerging threats.

The susceptibility of the Vero cell line to various viruses increases the possibility of obtaining high virus yields with newly emerging viruses. The SARS coronavirus can grow to high titers in Vero, which allowed the candidate vaccine to complete preclinical development within an 18-month time frame.

In less than two months after the new coronavirus began to spread, the experimental vaccine prepared with Vero cells began animal experiments. This is unlikely to be done on any other cell.

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