The kits to be used to test the efficacy of the new crown vaccine are here. Can multiple listed companies take this to "fly into the air"?

Is it still possible to get the new crown after vaccination? On March 18, a medical worker in Xi'an was diagnosed with new coronary pneumonia. In fact, the medical worker had been vaccinated with 2 doses of new crown pneumonia as early as early February. This case was once widely discussed. Is there a way to evaluate the protective efficacy of vaccines on individuals? A new kit has entered people's field of vision-the new coronavirus neutralizing antibody detection kit. It is used to detect neutralizing antibodies in the human body, allowing subjects to see how much neutralizing antibodies are in their body and how long they can last. The level of neutralizing antibodies is closely related to the body's immunity to the new coronavirus. At present, the kit is intended to be used to evaluate the protective efficacy of the new crown vaccine after vaccination. As the global vaccination rate continues to rise, this means greater application prospects. Nowadays, many companies have deployed neutralizing antibody kits, including GenScript, China Biotech, Mindray Medical, Wantai Biotech, etc. Each company has adopted different technical routes, and the progress of product approval is different, but the above-mentioned several All companies have obtained the European Union CE certification and have been able to enter the European market. Among them, GenScript has gone a long way. Among them, the antibody kit cPass sVNT Kit (hereinafter referred to as "cPass") was approved by the US FDA for emergency use authorization in November 2020 for the recovery of patients with new coronary pneumonia. It is currently applying for neutralizing antibody level testing after vaccination. Dr. Zhu Li, Executive Director and Chief Strategy Officer of GenScript, said in an interview with a reporter from China Times: “We are ready for the commercial production of cPass kits. If there is more demand for neutralizing antibody kits in the future, In addition to the production base in China, it will also consider commissioning production in Singapore, the United States and other places." However, whether the neutralizing antibody kit can be approved for the evaluation of the effectiveness of the new crown vaccine still needs more data to support However, the Chinese regulatory authorities are more cautious about this, and have published the article "Current Considerations on New Coronavirus Neutralizing Antibody Detection Reagents" to express their attitude. Vaccine expert Tao Lina (Vaccines and Science) told the reporter of China Times: "(If it is to be used to evaluate the efficacy of the new crown vaccine) First of all, this kit must ensure a certain accuracy rate, and there should be no too high false positive and false negative rates. Secondly, which line the neutralizing antibody value is more appropriate. At present, there may not be a recognized standard. For example, if it is above 100, I believe that you have protective power. At this point, it is better to be internationally unified." Companies deploy neutralizing antibody kits As the new crown epidemic is raging around the world, nucleic acid testing and IgM/IgG antibody testing are already well-known. Nucleic acid testing can directly detect the presence of new coronaviruses in the body, which is mainly used for immediate diagnosis of new coronary pneumonia; IgM/IgG antibody testing is to detect the presence of total antibodies in the body to determine whether you have been infected with new coronaviruses, but these antibodies are present, and Not all have the ability to resist re-infection with the new coronavirus. The neutralizing antibody detection is fundamentally different from them. Neutralizing antibodies can block the binding of the new coronavirus to receptors on the cell surface, thereby directly blocking the virus from infecting cells. This means that with neutralizing antibodies, the human body can resist new infections in the future. Therefore, compared with the IgM/IgG antibody test, it does not detect the total antibodies in the body, but accurately detects the presence and level of neutralizing antibodies, and then determines whether the human body has established immunity against the new coronavirus. There is a real-world case: In 2020, a fishing boat in Seattle, the United States went to sea for 20 days, 121 people on board, 108 people on the return trip were positive for new coronary pneumonia. Although 6 people tested positive for total antibodies before boarding, 3 people were still infected. After testing, these 3 people did not have neutralizing antibodies. "This incident vividly illustrates that only with neutralizing antibodies can you have immunity from reinfection." Zhu Li said. (The picture is a screenshot of the news report of this case) Traditional neutralizing antibody detection is generally cumbersome and complicated. The industry-recognized detection method uses live virus to count the plaque reduction of infected cells to determine the level of neutralizing antibody, but it must be used For live viruses, the biosafety level of the laboratory needs to reach P3 or higher, the test procedures are complicated, the requirements for operators are high, and the sensitivity is low, and it takes 3 days or longer, which makes the detection cost very high, and it is completely impossible to do large-scale testing. Industrial applications. Although the pseudovirus detection method that replaces the live virus has improved in complexity, it still needs to use live cells, so it still cannot reach the level of industrialization. On July 23, 2020, Nature Biotechnology published a paper, introducing for the first time the world's first revolutionary rapid and effective method for detecting neutralizing antibodies against the new coronavirus, and published it in China and Singapore. Clinical trial data. The lead and corresponding author of the article is Wang Linfa, director of the Joint Institute of Emerging Infectious Diseases of Duke University School of Medicine and National University of Singapore. The research was completed by GenScript and Nanjing Infectious Disease Hospital, and GenScript also obtained the only commercial license right for this method in the world. The cPass kit using this method does not need to use live viruses or any cells, which reduces the requirements on the laboratory and can reduce the detection time to less than 1 hour. It is based on the specific recognition and binding between the receptor binding part of the virus surface spike protein (S1) and the human receptor protein (ACE-2) as the detection basis. It uses an enzyme-labeled display that can be operated by general medical institutions. Color as a test platform. Tests conducted on Singapore (175 COVID-19 recovered patients and 200 healthy controls) and Nanjing (50 COVID-19 recovered patients and 200 healthy controls) new coronary pneumonia patients have shown that this method achieves 100% positive correlation rate. According to our reporter, the cPass kit has been authorized by the US FDA for emergency use, and has been approved in Europe, Singapore, Brazil, Argentina, and the UAE. At the same time, many companies are entering this market, and their products have obtained EU CE certification. On March 21, the new coronavirus neutralizing antibody detection kit jointly developed by Zhongsheng Genuo and Mindray Medical announced that it has obtained the European Union CE certification. The kit uses enzyme-linked immunoassay. On February 25, Wantai Biotech announced that the new crown neutralizing antibody test kit produced by its subsidiary Wantai Kerry obtained the EU CE certification. The kit uses magnetic particle chemiluminescence method. In addition, the Shenwan Hongyuan research report shows that the neutralizing antibody kits of companies such as Rejing Bio, BGI's subsidiary BGI Biai have also obtained the EU CE certification. However, according to our reporter, it is easier for new coronavirus in vitro diagnostic products to obtain EU CE certification than in the US market, which has a higher entry barrier. The European Union divides medical devices into four categories: List A, List B, Self-testing, and Other, with the regulatory level decreasing in order. COVID-19 diagnostic products are medical devices that perform CE certification procedures in the category of "Other (Other)". The evaluation process of such products is "self-declaration", that is, the manufacturer itself tests according to the directive standards, submits the application materials and makes CE compliance Standard declaration of conformity, thus obtaining the "Declaration of Conformity" CE certificate. The biggest market lies in the evaluation of the effectiveness of the new crown vaccine. The new crown epidemic has directly spawned a market of tens of billions of nucleic acid tests, which will increase the net profit of related companies by several times in 2020. Can the neutralizing antibody kit reproduce the popularity of nucleic acid detection? According to the research report of China International Financial Securities, the United States has already received more than 100 million doses of COVID-19 vaccine, with a daily dose of 2.5 million doses. The time for herd immunity is expected to arrive ahead of schedule. China has now received 64.98 million doses, and the amount of inoculation continues to increase. The research report of Shenwan Hongyuan predicts that as the global new crown vaccine continues to spread, the demand for neutralizing antibody testing for testing the effect of the vaccine will also increase. In this context, neutralizing antibody kits have more room for imagination. Zhu Li said frankly that one of the biggest application scenarios of the kit is to evaluate the protective efficacy of the new crown vaccine. Due to the relatively short period of time for the emergence of new coronary pneumonia, each vaccine has not yet accumulated enough data to prove how long the validity period can be, and whether the vaccine has the same validity period in people of different ages, races, and health levels. Neutralizing antibody testing is expected to fill this gap. Many companies that have launched neutralizing antibody kits have also mentioned this point. For example, China Biosciences stated on its official public account that the Zhongsheng Genuo New Coronavirus Neutralizing Antibody Kit "provides a powerful evaluation of the immune effect of vaccines. Support, it can guide the testing population whether to strengthen injections, strengthen vaccination, etc." "The effect of vaccination after vaccination can be evaluated objectively." In this regard, Tao Lina said in an interview with this reporter that neutralizing antibody testing can be used as A measure of the protective efficacy of the new crown vaccine. "In principle, there is no problem, because our existing vaccines are generally based on the level of neutralizing antibody to evaluate the effect after vaccination." The flu vaccine, EV71 vaccine, rabies vaccine, polio vaccine, etc. are all the same. However, it is worth noting that no neutralizing antibody kit has been approved for the evaluation of the efficacy of the new crown vaccine. GenScript's cPass kit is authorized for emergency use in the United States for the indication of convalescent plasma screening for patients recovering from new coronary pneumonia. "Because there are not enough clinical trial data and real-world evidence to support it, but the data is becoming more and more, we are also applying for this indication, and hope to get the US FDA approval in the future." Zhu Li said. Although there is no certificate, many third-party testing agencies in the United States can provide neutralizing antibody testing services for the public in need through the LDT model, and objectively evaluate their immunity after being vaccinated with the new crown vaccine. Some US insurance companies have also announced This item can be reimbursed. "Through the neutralizing antibody test, people can see whether they have produced neutralizing antibodies, how much neutralizing antibodies are, and how long they can last. So we predict that if they are approved for vaccine efficacy evaluation, they will be aligned in the future. And antibody kits will be in great demand." Zhu Li said. However, if the neutralizing antibody kit is like nucleic acid detection and IgM/IgG antibody detection, it is still difficult to achieve large-scale promotion at the national level, and the entire city will be tested at every turn, bringing an incremental market of tens of billions. . Tao Lina admitted to our reporter that not everyone who has received the new crown vaccine needs to be tested for neutralizing antibodies. "According to the current clinical data disclosed by several new coronavirus vaccines, the positive conversion rate of neutralizing antibodies is very high, reaching more than 95%. In this case, every person who has been vaccinated should be treated as if there is no The cost is too high to test the antibodies and antibodies one by one. Moreover, the neutralizing antibody test requires blood draw, unlike the nasal swab and throat swab for nucleic acid detection, it is an invasive operation after all, and it is relatively more complicated." The State Food and Drug Administration is cautious about this. At present, the Chinese regulatory level is more cautious about whether the neutralizing antibody kit can be approved for the evaluation of the efficacy of the new crown vaccine. On February 18th, the Medical Device Technology Evaluation Center of the State Food and Drug Administration (hereinafter referred to as "Medical Device Evaluation Center") issued "Current Considerations on New Coronavirus Neutralizing Antibody Detection Reagents" (hereinafter referred to as "Considerations"). After investigating the opinions of experts in the fields of vaccine research and development, vaccine evaluation, neutralizing antibody test research and evaluation, clinicians, etc., respond to related issues such as whether in vitro diagnostic reagents can be tested for neutralizing antibodies and whether they can be used for vaccine effectiveness evaluation. . The article "Consideration" stated: "In the process of vaccine development and effectiveness evaluation, the scientific research of various neutralizing antibody detection alternative methods is worthy of encouragement; however, the marketing of products for the management of in vitro diagnostic reagents should be established on a sufficient basis On the basis of research results and sufficient clinical evidence, it should meet the definitions and uses prescribed by laws and regulations." The "Consideration" also lists four main problems with neutralizing antibody kits to be used for effectiveness evaluation after COVID-19 vaccination. . The first is that reagents need to select one or more epitopes for neutralizing antibody detection, and the choice of epitope determines whether the detected antibodies are neutralizing antibodies, and whether the neutralizing antibodies that can play a protective role are fully tested Arrived. At present, the basic research of the new coronavirus is not sufficient. Neutralizing antibodies may involve multiple protein domains on the surface of the virus; and studies have shown that the spectrum of neutralizing antibodies may change at different time stages after vaccination, such as neutralizing antibodies. The ratio of RBD antibody to NTD antibody may change; at the same time, the mutation of virus epitope occurs frequently, and the rule is not clear. Therefore, no matter whether it is a single epitope or multiple epitope detection products, it is not guaranteed to cover all neutralizing antibodies. In addition, the differences in the process routes of different vaccines result in different neutralizing antibodies. The uncertainty caused by these differences makes it difficult for reagents to achieve good representativeness and coverage in the selection of neutralizing antibody epitopes. . Secondly, there is insufficient clinical evidence for the correlation between the concentration of neutralizing antibody and the protective efficacy of the vaccine in vitro, and a reliable Cut-off value cannot be established, and the recognized standardized method of "neutralization test of virus culture in vitro" has not yet been established. In the absence of a reliable Cut-off value, the test results of the reagents are difficult to describe the protective power of the vaccine, and cannot provide clinically valuable judgments and results prompts, that is, positive does not mean that there is certain protection, and negative or A weak positive does not mean that there is no protection. In addition, humoral immunity is not the only way to produce protection after vaccination. In addition to neutralizing antibodies (humoral immunity), other immune pathways such as cellular immunity also play a role. Therefore, after vaccination, the level of neutralizing antibody is low or the test is negative, and it is not clear that there is no protective conclusion. The evaluation of vaccine protection should be combined with humoral immunity and cellular immunity to make a comprehensive judgment. Furthermore, vaccine evaluation is to judge whether a certain protection rate can be achieved from the perspective of the group, and to prove that the vaccine can effectively block the spread of the virus from the perspective of infectious disease prevention and control, rather than judging whether the vaccine is effective for each individual. The research conclusions on the protective power come from the large-scale clinical research data of the vaccine before and after the market. Therefore, in the absence of sufficient data support and the research on the immune mechanism of the new crown vaccine and the neutralizing mechanism of neutralizing antibodies are not yet thorough, neutralizing antibody testing for vaccinated individuals cannot provide effective support for vaccine evaluation, nor can it provide effective support for vaccine evaluation. It is not necessary to provide effective information to individual vaccinators. However, with the increasing human understanding of the new coronavirus and rapid progress in research and development, given time, the above four points are not unavoidable difficulties. For example, the World Health Organization recently released the first international standard for anti-SARS-CoV-2 immunoglobulin (NIBSC code 20/136), which assigned values ​​for the activity of neutralizing antibodies against SARS-CoV-2 in order to determine whether this material is in antigen Work is still underway to combine the effectiveness of the standardization process. This means that internationally recognized standards are expected to be released in the near future. Regarding the new crown vaccine can trigger humoral immunity and cellular immunity at the same time, neutralizing antibodies are only related to the former, and it is impossible to comprehensively judge the protection of vaccines. Many people in the industry told this reporter that cellular immunity is often difficult to measure, and neutralizing antibodies are detected. The representative humoral immunity is both basic, effective, easy to promote, and can be commercialized. Taolina stated that the humoral immune standard represented by neutralizing antibodies is single and clear, while the cellular immune test is very complicated, costly, and the indicators cannot be completely unified. There is no uniform standard for which indicator is the weight. "So usually comeIt is said that we rarely test cellular immunity, and it is impossible to do it in terms of cost. "So, on the whole, the market for neutralizing antibody kits is still small, and they are mostly used for scientific research purposes. The regulatory level is more cautious. However, once the relevant standards for neutralizing antibody testing are established, they will be approved for use in evaluating the effectiveness of the new crown vaccine. The kits that will be opened, with short detection time, high safety and high sensitivity, are expected to increase in volume and become a growth point for related companies.