CANSINOBIO's stock price has fallen nearly 30 per cent recently because of the failure of Oxford University's ChAdOx1 nCoV-19 vaccine in animal experiments. On the evening of May 22nd, the phase I trial results of the recombinant adenovirus type 5 vector COVID-19 vaccine (Ad5-nCoV) developed by Chinese Chen Wei team were published online in the international academic journal the Lancet. The vaccine showed safe tolerance and immunoreactivity, and the overall results were satisfactory, laying a good foundation for later clinic. However, CANSINOBIO's stock price is still falling. Why? Is it because people have lost faith in the vaccine data?

This article will focus on the analysis of the difference between Cancino adenovirus vaccine and Oxford adenovirus vaccine, and will also focus on the interpretation of CANSINOBIO's phase I experimental results.

On May 13, Professor Sarah C. Gilbert of Oxford University published a preprint version of the results of ChAdOx1 nCoV-19 vaccine in animal models, which showed that both mice and rhesus monkeys produced humoral and cellular immune responses after vaccination. In the rhesus monkey experimentVaccination could significantly reduce the viral load in tracheo-alveolar lavage fluid and respiratory tissues, and there was no pulmonary inflammation and immune enhancement.

On May 21, a report from the business magazine Business Standard claimed that Oxford University vaccine candidates had failed in animal trials. Why do two groups of different conclusions come to the same set of data? Who is real and who is fake?

1. Effective vaccine standards:

To prove what kind of vaccine is effective? First, we need to know what are the core criteria for successful vaccine development.

1) completely killing the virus by activating the immune response is the gold standard for evaluating the vaccine.

2) in the titer of virus antibody, the neutralizing antibody produced by an effective vaccine remains active after being diluted more than 1000 times.

According to the above two criteria, has the ChAdOx1 nCoV-19 vaccine compound standard been published by Professor Sarah C. Gilbert of the University of Oxford?

First of all, the ChAdOx1 nCoV-19 vaccine in the laboratory of Professor Sarah C. Gilbert of the University of Oxford only significantly reduced the viral load in trachea-bronchoalveolar lavage fluid and respiratory tissues. RNA could be detected in the bronchi of some vaccinated and unvaccinated animals, but the inflammation of the lungs of vaccinated animals was weaker than that of unvaccinated animals.To put it simply, the vaccine may be effective in humans, but it does not completely kill the virus and can still be detected in the lungs.Novel coronavirus, but fewer viruses were detected than those who did not receive the vaccine.

Secondly, in the experiment, the animal serum was inactivated when the animal serum was diluted only 4-40 times, which was too different from the standard of 1000 times diluted.

Second, the action mechanism of Oxford adenovirus vaccine in human body.

COVID-19 is easy to stimulate Th1-type immune response (helper T cell response), leading to pulmonary inflammation and other symptoms. Then vaccination of the Oxford adenovirus vaccine (it can be simply understood that the vaccine is a non-toxic COVID-19 virus, which is not supposed to cause disease in the human body) also causes a Th1 immune response. In theory, Oxford adenovirus should reduce the production of inflammatory factors and prevent pneumonia.

Unfortunately, the results of the Oxford adenovirus vaccine do not meet the criteria for becoming our vaccine:

1) after inoculating the vaccine, COVID-19 can still be detected in rhesus monkeys.

2) in the experiment, the animal serum was inactivated when it was diluted only 4-40 times.

3. The difference between Oxford adenovirus vaccine and Cancino adenovirus vaccine.

1) similarities:

Both the Oxford adenovirus vaccine and the Cancino adenovirus vaccine choose the full-length S protein as the vaccine (pictured below). The inactivated vaccine is a whole virus capsid protein and also produces high titers of neutralizing antibodies against S protein and RBD protein.Therefore, the mechanism of their two adenoviruses is the same. Adenoviruses with target protein genes invade cells through their own infection mechanism, triggering an immune response.

2) differences:

The Oxford University adenovirus vaccine vector comes from non-primate chimpanzees, and the human pre-existing immunity is small. However, CANSINOBIO Ad5 adenovirus has a large pre-stored immunity, so the company needs to modify the adenovirus vector to reduce the pre-stored immunity. People have generally developed antibodies to adenoviruses, so adenoviral vectors are not fatal to most people and are relatively safe.

Note: adenovirus, usually weakly toxic, is a virus that generally causes small colds.

The latest clinical results of Kangxino adenovirus vaccine

On the evening of May 22, the phase I trial results of the recombinant adenovirus type 5 vector COVID-19 vaccine (Ad5-nCoV) developed by Chinese Chen Wei team were published online in the international academic journal the Lancet. The results showed that the vaccine was tolerant and immunoreactive, and the data laid a good foundation for follow-up research and later clinic.

1) Experimental design:

According to age and sex, 108 healthy people participated in the vaccine injection experiment of low, middle and high dose groups. Objective to observe the safety and immunogenicity of vaccinated healthy people between 18 and 60 years old.

2) the conclusion of phase I experiment:

A) CANSINOBIO's Ad5-nCoV vaccine was tolerable and immunogenic 28 days after vaccination

b）The humoral immunity reached the peak on the 28th day after inoculation.It is very important whether the antibodies produced after vaccination target the S protein as desired. In this experiment, the immune response to S protein was shown 14 days after injection of the vaccine. on the 28th day, the proportion of quadruple antibody titer in each dose group reached more than 90%, and 100% in the high dose group showed four times antibody titer. According to the absolute index theory, it is not high until it reaches at least 1000. In this experiment, the average titer of the high dose group is 1445.8, which is much higher than the standard of 1000.

c）The specific T cell response reached the peak on the 14th day after inoculation.INF γ (cytokine) was detected in CD4+ (activated cytotoxic T cells and macrophages) and CD8+ T cells (cytotoxic T cells) in all dose groups on the 14th and 28th day after inoculation.To put it simply, the Kangxinuo adenovirus vaccine is effective in the human body and can stimulate the body's immune system to kill novel coronavirus without COVID-19.

The results of phase I experiment generally achieve the purpose of experimental design, and the preliminary results support the further study of Ad5-nCoV vaccine.

3) side effects:

Safety results: the main adverse reactions were mild to moderate, no serious adverse events were found within 28 days after vaccination, and the middle and low dose groups were well tolerated.

(note: we do not pursue 100% safety in drugs, because the cost of life is too high, and there is basically no absolutely safe drug in this world. For example, many advanced cancer patients do not need 100% safe drugs at all, but can use relatively safe and effective drugs. It is most important for them to be able to prolong their lives now. Just like cancer patients know that chemotherapy has serious side effects such as hair loss, vomiting, diarrhea and fever, but cancer patients still choose to take chemotherapy. Because it may take 30-50 years or more to develop 100% safe and effective drugs, 10 patients may need to be sacrificed in order to reduce the cost of losing a life, because patients are more likely to race against time and cannot afford to wait. )

The incidence of grade 3 adverse reactions was high in the high dose group, but the overall incidence of grade 3 adverse reactions could be controlled.The incidence of grade 3 adverse reactions was 6% in the low-dose group and the middle-dose group at 7 days and 28 days, and 17% in the high-dose group. The third grade adverse reactions were mainly in the high dose group, including severe fever, severe fatigue, severe muscle pain and severe dyspnea.The overall incidence of grade 3 adverse reactions can be controlled.

(note: 91% of the adverse reactions of imported Merck & Co Inc's 9-valent HPV vaccine injected by most women are not serious side effects, such as dizziness, fatigue, pain and swelling of the vaccination site, fever and nausea; 9% are serious adverse events, such as death, disability and serious illness. )

4) follow-up clinical trials:

CANSINOBIO launched a phase II clinical trial on April 12, becoming the only novel coronavirus vaccine in the world to enter a phase II clinical trial at that time. The clinical II phase is to determine the immune procedure and immune dose, to obtain the highest antibody titer in the experimental group and to make a comprehensive comparison of other indicators.To determine the optimal dose.This dose was then applied to the clinical phase of III, that is, to vaccinate and assess side effects on a larger scale, requiring at least tens of thousands of volunteers.

Due to the lack of new cases in China, Chen Wei's team's III trial is expected to be carried out abroad. CANSINOBIO announcement shows that on May 15, 2020, it was approved by Health Canada on the recombinant vaccine (adenovirus vector) "Ad5-nCoV" clinical trial application. However, how the specific III phase clinical will be carried out depends on the results of the II phase clinical.

Other vaccines:

1) Moderna Inc:

At present, the fastest progress abroad is Moderna Inc's mRNA-1273.The data of phase I results are incomplete and controversial, and the data quality is much lower than that of Cancino adenovirus vaccine data.Moderna Inc only announced that among the initial 8 subjects (the top four in 25 ug and 100 ug groups), neutralizing antibodies were produced, which could effectively prevent the virus from infecting cells, but the results of the remaining 37 were not announced. In addition, the company announced that patients produced antibody levels similar to or higher than those recovered from natural infections, but did not disclose antibody levels.

2) Oxford adenovirus vaccine:

Oxford adenovirus Vaccine in Rhesus MonkeyVaccination could significantly reduce the viral load in tracheo-alveolar lavage fluid and respiratory tissues, and there was no pulmonary inflammation and immune enhancement.The good result was that three of the monkeys had shortness of breath, but there was no significant lung damage, so the vaccine may reduce the damage caused by the virus, but does not prevent pneumonia.

3) other COVID-19 vaccine processes around the world:

According to WHO data, as of May 22, 2020, a total of 124 new coronal vaccine research and development projects worldwide are under way, of which 10 COVID-19 vaccines have entered the clinical research stage, while the other 114 COVID-19 vaccine projects are still in the preclinical research stage.The phase I experimental results of the adenovirus vector COVID-19 vaccine developed by CANSINOBIO in China are effective as a whole, and it is the first to enter the phase 2 clinical trial. It is expected to uncover the blindness in June, and more extensive phase III clinical trials are expected to be conducted overseas in the future.

Summary:

Recently, animal experiments of Oxford adenovirus vaccine can significantly reduce the viral load in trachea-alveolar lavage fluid and respiratory tissues, but there is no immune enhancement effect in human body, so on the whole, the research and development of Oxford adenovirus vaccine is a failure. does not meet the criteria for becoming a vaccine. It is precisely because the mechanism of CANSINOBIO's adenovirus vaccine is the same as that of Oxford adenovirus, which causes people to question CANSINOBIO adenovirus. On the evening of May 22nd, CANSINOBIO announced that his Phase I vaccine showed safe tolerance and immune response, and the overall results were satisfactory, which still could not alleviate the recent skeptical attitude towards the vaccine.

The market usually has two ways of thinking about the valuation system of new drugs. First, new drugs that do not yet exist in the world, and are urgent drugs, then the biggest winner is likely to be the drug that can be approved to market as soon as possible. In the second valuation system, there are already 2-3 drugs of the same kind on the market, so who is the biggest winner? It may be the best of its kind or the cheapest, but it is a drug that can enter the national health insurance catalogue in China. Obviously, we should now be the first kind of valuation for CANSINOBIO (assuming a price of 100,000,000 yuan per injection, the conservative income of the Chinese market is estimated to be 100,000,000,000 people = 10 billion yuan).

According to WHO data, a total of 124 new coronal vaccine research and development projects are under way worldwide.The phase I trial results of the adenovirus vector COVID-19 vaccine developed by CANSINOBIO in China are effective as a whole. It has first entered the phase 2 clinical trial on April 12 and is expected to be blinded in June. In the future, it is expected to conduct more extensive phase III clinical trials overseas.