COVID-19 vaccine is getting closer and closer to us.

Recently, Wu Yuanbin, director of the Department of Social Development Science and Technology of the Ministry of Science and Technology, told the media that 11 COVID-19 vaccines in China have entered clinical trials, four of which have entered phase III clinical trials and are progressing smoothly.

Usually, after the completion of phase III clinical trials, a domestic vaccine needs to be reviewed and approved before it can be put on the market, a process that often takes about a year.

However, in order to effectively deal with the COVID-19 epidemic, the State Drug Administration will conduct a simultaneous review, and the domestic COVID-19 vaccine will be put on the market much earlier.

From the investment point of view, COVID-19 vaccine is obviously a tuyere. The huge audience determines that the market scale of COVID-19 vaccine will be extremely large. According to the calculation caliber of various securities firms, the domestic market alone may exceed 50 billion, and it is naturally not a problem for the global market to exceed 100 billion.

At present, there are more than 200 vaccines in the preclinical or clinical stage, which are more or less related to "Qianjing".

But it is clear that not all participants get a piece of the pie. For COVID-19 vaccine research and development enterprises, time is money. The vaccine that is first put on the market will not only capture more markets, but will also have more dominant pricing.

According to WHO data, there are nine COVID-19 vaccines in the world that have entered the third phase of clinical trials. These nine leading vaccines are undoubtedly the most interesting.

Of course, entering the third phase of the clinical does not mean taking the first place. Generally speaking, the first and second phase of the clinical trial is only a small test, the third phase of the clinical ushered in the real challenge. Therefore, it will take time to see who can stand out.

In addition to the time factor, the choice of the "route" of vaccine technology is also important. The reason is very simple: different technological "routes" directly affect the success rate of R & D and even the competitiveness after listing.

Generally speaking, the global COVID-19 vaccine research and development enterprises are roughly divided into "five gate schools", which are inactivated vaccine, vector vaccine, recombinant protein vaccine, mRNA vaccine and DNA vaccine under nucleic acid vaccine. Specifically:

Inactivated vaccine is the most conservative and mature technical route, but it is expensive to produce and prone to mild side effects.

The adenovirus vector vaccine is safe and persistent, but it has the problem of pre-existing immunity, that is, it neutralizes the original antibody of the human body. COVID-19 vaccine developed by CANSINOBIO has the above problems.

The recombinant protein vaccine has good safety, effectiveness and few side effects. Although the speed of research and development is slow in the early stage, it is easy to form scale advantage in the later stage. However, the recombinant protein vaccine itself is also divided into "schools" and has different technical routes. at present, there is a certain gap between domestic and foreign enterprises in R & D path.

The effectiveness of mRNA vaccine is good, but the stability is too poor to preserve; DNA vaccine is effective, but the safety and immune persistence remain to be solved.

At present, there are 3 inactivated vaccines, 4 adenovirus vector vaccines and 2 mRNA vaccines among the 9 clinical vaccines in the world. It is said that birth determines fate. So, under different technological routes, who can win?

1. Inactivated vaccine, the least difficult and safest vaccine to develop

Inactivated vaccine is a kind of vaccine that loses its toxicity by physical or chemical methods, but retains its immunogenicity.

As one of the most traditional vaccine preparation methods, inactivated vaccine is often used as a priority vaccine strategy in the outbreak of acute infectious diseases because of its simple process.

At present, of the 4 vaccines that have entered the third phase of clinical practice in China, 3 are inactivated vaccines, and the R & D units are Wuhan Institute, Beijing Institute of National Pharmaceutical Group and Sinovac Biotech. In addition, companies such as Kangtai Biology and Hualan Biology are also preparing clinical work for inactivated vaccines.

From the perspective of immune effect, the inactivated vaccine is not bad.In mid-August, Henan CDC, Wuhan Institute of Biological products and Zhongsheng Group published the results of phase 1 phase 2 clinical trials of inactivated virus vaccine in JAMA.

The results released the data of neutralizing antibody titer after injection. Neutralizing antibody titer, you can understand as antibody concentration, the larger the number, the higher the concentration, the better the performance of the vaccine.

In the phase 1 clinical trial of inactivated vaccine in Wuhan Institute, high, medium and low doses were set up. The neutralizing antibody titers of different doses at 14 days after 3 injections were 297, 206 and 316 respectively.

By contrast, the vaccine developed by Pfizer Inc had a neutralization titer of 267, while the vaccine developed by Oxford University and AstraZeneca PLC had a neutralization titer of 218. Of course, the neutralization titer measurement methods of different companies are different, and direct comparison may not be fair.

But there is no doubt that the immune performance of different vaccines will be different, and inactivated vaccines are no exception. After 28 days of inoculation, the neutralization titer of Sinovac Biotech's inactivated virus vaccine was between 23.8 and 65.4, which was significantly lower than that of Wuhan Institute.

Since the difficulty of development and immune effect look good, will inactivated vaccine be the best route for COVID-19 vaccine development? The answer is not absolute.

There are two sides to everything. The technical threshold of inactivated vaccine itself is low, but the cost of large-scale production is very high. As it is related to virus culture, inactivated vaccine requires a high level of biosafety in the workshop, and the corresponding investment will be large.At present, Sinopharmaceutical Group has built two high-level biosafety production workshops, with an investment of about 2 billion yuan.

In addition, inactivated vaccines need to inactivate all viruses, and virus culture, inactivation and testing is a slow process.The whole process of vaccine production takes 3 months from the beginning of the cell to the qualified. The annual output of the two workshops adds up to 300 million doses.And the production capacity of some emerging technologies has been arranged to 1 billion doses. Therefore, in terms of production capacity, there are "hard wounds" in inactivated vaccines.

As the most primitive vaccine, inactivated vaccine also has some disadvantages in terms of "performance".

First of all, multiple vaccinations are needed to achieve the immune effect.The first dose of vaccination only "initializes" the immune system and does not produce protective immunity. Protective immunity can only be produced after the second or third dose.

Sinopharm's new crown inactivated vaccine requires a total of two doses, with an interval of 2 Mel for 4 weeks. According to information disclosed by the National Pharmaceutical Group, after the first dose and 28 days after the second dose, all people produced high titers of antibodies against novel coronavirus.

According to the minimum interval of 2 weeks between the two doses, the time from inoculation to the production of high concentration of virus in the body takes about 6 weeks.

Secondly, the immune response induced by inactivated vaccine is usually humoral immunity, with little or no cellular immunity. Because it is unable to induce cellular immunity, the immune effect is general.

Finally, inactivated vaccines need to add inactivating agents in the process of inactivation, and adjuvants are also needed in the process of use, which make the side effects of inactivated vaccines have a higher probability.

Of course, the blemish outweighs the excess. Generally speaking, the inactivated vaccine has the greatest probability of success, which is not the most advanced, but the safest path.

2. Vector vaccine, or the problem of pre-existing immunity.

In addition to the three inactivated vaccines, another vaccine in China that has entered the third clinical stage is the vector vaccine jointly developed by Academician Chen Wei and CANSINOBIO.

The principle of vector vaccine is that the gene fragments that can cause human immunity in the virus are grafted onto some kind of small harm virus that we are familiar with, so that the small harm virus enters the human body with pathogenic gene fragments, and induces the human body to produce immune response.

Compared with inactivated vaccine, vector vaccine can express antigen protein stably and long in vivo, which can induce lasting immune response.

At present, the rapid global progress is the Ad5 vector novel coronavirus vaccine developed by Academician Chen Wei and CANSINOBIO and the gorilla adenovirus vector novel coronavirus vaccine developed by Oxford University.

The mechanism of action of the two adenovirus vaccines is the same.The only difference is that the different sources of adenoviruses may affect the immune effect to some extent.

Although adenovirus is less harmful, the human body can still recognize and produce immune response.If people who have been infected with the virus before are vaccinated with the vaccine, the efficacy of the vaccine will be very low.

Oxford University adenovirus vaccine vectors come from non-primate chimpanzees. Adenovirus from chimpanzees, which basically does not appear in humans before, is a "strange" enemy to the human body, so it has a good immune effect.

CANSINOBIO Ad5 virus comes from the human body, and adenovirus is a common virus in China. More than 50% of people have been infected with adenovirus.

This may be the reason why the neutralizing antibody titer of CANSINOBIO vaccine is the lowest among the vaccines that have officially published clinical data.

The antibody titers produced by the Kang Nuo vaccine ranged from 18.3 to 19.5. With the exception of Sinovac Biotech, the other vaccines that published the results of clinical trials basically exceeded 100. Of course, as mentioned above, the neutralization titer measurement methods of different companies may be different, and a simple horizontal comparison may not be reliable.

However, it is a fact that the efficacy of Kang Nuo vaccine is affected by adenovirus infection rate. In phase II clinical trials in China, the older the vaccinated population is, the more difficult it is to produce an efficient immune response. It is speculated that the older the age, the higher the possibility of exposure to Ad5.

It is also worth noting that the proportion of adenovirus infection varies among different races, so the choice of clinical race will also have an impact on the actual effectiveness of the vaccine.

The specific results of CANSINOBIO vaccine also depend on the data of phase III clinical trials.

3. the recombinant protein vaccine has a slow progress in the early stage but has the advantage of scale in the later stage.

At present, the global research and development of recombinant protein vaccines are mainly NVX-CoV2373 developed by Novavax, SCB-2019 jointly developed by clover, GSK and Dynavax, and recombinant novel coronavirus vaccine (CHO cells) jointly developed by Zhifei and microorganisms.

Recombinant protein vaccine, also known as genetic engineering recombinant subunit vaccine, is based on the principle that genes encoding protective antigens of pathogenic microorganisms are introduced into recipient bacteria or cells to make them highly expressed in the receptor and secrete protective antigen peptide chains; researchers extract protective antigen peptide chains and add adjuvants to make genetically engineered subunit vaccines.

Using genetic engineering method, we can not only clone the genes encoding protective antigens, but also modify or modify them in vitro, so the effect may be more prominent.

At present, the highest antibody neutralization titer is the trimer recombinant protein vaccine of Novavax, which reaches 3906. Without taking into account the differences in statistical methods, this is obviously a BUG-like existence.

The technology and technology of recombinant protein vaccine is quite mature in the field of vaccine, easy to mass production and low cost. Although the screening of "receptors" drags down the progress in the early stage, it can form a significant cost advantage in the later stage.

However, the competition for recombinant protein vaccines is affected by "technical routes" and "adjuvants".

First of all, let's look at the technical route. At present, the recombinant protein vaccine is mainly divided into the antigen design based on the conformational stable S protein or the key part of S protein and the receptor binding region RBD protein.

The advantage of designing antigen for "RBD protein" lies in its simplicity, but because RBD protein is not a complete S protein, its immunogenicity is not as good as S protein, while "targeting" S protein is more complex and difficult, but the advantage is that the immune effect is better.

At present, the development route of Zhifei is relatively simple RBD protein vaccine, while clover and Novavax are based on S protein.

Let's look at the adjuvant factor. The deficiency of recombinant protein vaccine is that it has low immunogenicity and needs to be used in combination with adjuvants to produce better immune effect.

At present, the adjuvants of foreign enterprises are relatively advanced, and Zhifei's RBD protein vaccine does not have the advantage of vaccine adjuvants. Chengdu clover S protein vaccine adjuvants rely on foreign Dynavax and GSK adjuvants, which will have more advantages.

4. Nucleic acid vaccine is the most advanced in technology, but there is no precedent for approval.

Nucleic acid vaccine is the third generation vaccine, the principle is that the viral gene fragment (DNA or RNA) encoding a certain antigen protein is directly introduced into animal cells, and the antigen protein is produced through the host cell protein synthesis system to induce the host to produce immune response to the antigen protein, so as to achieve the effect of prevention.

From this point of view, nucleic acid vaccines have the advantages of vector vaccines, but they are not live viruses and are not so "delicate".

Nucleic acid vaccine is divided into plasmid DNA vaccine and mRNA vaccine. The difference between them is that DNA is first transcribed into mRNA and then synthesized protein, while mRNA is synthesized directly.

1) mRNA vaccine

At present, the vaccines that have made rapid progress in research and development in the world are mRNA-1273\ BioNtech developed by Moderna Inc and BNT162b1 developed in cooperation with Pfizer Inc and Shanghai Fosun Pharmaceutical. Domestic vaccines that are faster are ARCoV, which is jointly developed by Watson Biology and Aibo Biology, and COVID-19 mRNA Vaccine, which is jointly developed by Si Microbe and Tibet Pharmaceutical Industry.

MRNA vaccine can induce strong humoral and cellular immunity, and the production cost is low. In addition, one of the biggest advantages of mRNA vaccine is flexibility and rapidity.

The mRNA vaccine developed by Moderna Inc completed sequence identification within 45 days and entered clinical trials.

But mRNA vaccine also has a core problem, "poor stability, easy to degrade".

Perhaps you have noticed that the storage and transportation temperature requirements of two foreign star products, BNT162b2 and mRNA-1273, are stringent. The former needs to be transported and stored in an environment of about-70 ℃, while the latter is not much better and may need about-20 ℃ to maintain the long-term stability of the vaccine.

Must be stored and transported in ultra-low temperatures, not to mention developing countries, the United States will also worry. In real life, only large hospitals and laboratories have this condition, so small hospitals, pharmacies and doctors' clinics cannot vaccinate patients.

Theoretically, this BUG can be "alleviated" by means of sequence modification. Recently, the head of Abel Biology issued a public statement saying that its mRNA vaccine can be stored at 2-8 ℃ for at least 3 months. But whether it is feasible or not, we still need to look at the follow-up data.

2) DNA vaccine

DNA vaccine is a circular DNA plasmid that encodes antigens or antigenic epitopes. It enters the host nucleus through specific delivery, and the antigen genes carried are transcribed. MRNA is then transferred to the cytoplasm and translated into antigenic proteins.

Compared with the traditional vaccine, the preparation process of DNA vaccine is simple and the cost is low. Compared with mRNA vaccine, the biggest advantage of DNA vaccine is that the vaccine is stable and can be stored at room temperature for a long time.

At present, the rapid progress of global research and development of DNA vaccines are mainly INO-4800 developed by Inovio and Aidi Weixin, GX-19 developed by Genexine and so on. INO-4800 can be stored stably at room temperature for more than a year, so that it does not need to be frozen during distribution.

However, not a single DNA vaccine has been approved for sale. The core reason is that there are still some problems to be solved in DNA vaccine.

First, the issue of security.DNA vaccine is extreme, equivalent to a patch to the genes in the body, from then on the human body brings its own anti-coronavirus Buff, which may be the most efficient. However, considering that it will become a permanent patch for the human body, it is basically impossible to uninstall it. If there is a BUG, there is a risk of "crashing".

Second, the problem of persistence.The continuous expression of pathogen antigen protein in the body of DNA vaccine may disrupt the immune balance, cause immune tolerance and reduce the immune effect. Therefore, how to improve the immune effect of DNA vaccine is still a difficult point in research and development.

So it remains to be seen how the DNA vaccine will debut.

5. Summary

Different from the rapid control of COVID-19 epidemic in China, the epidemic situation in foreign countries continues to spread, and the number of new confirmed cases in the United States, India, Brazil and other countries hit record highs every day.

Under the circumstances that the global epidemic continues to spread, the future market space of COVID-19 vaccine is worth looking forward to. Fortunately, domestic enterprises have not lagged far behind in this arms race.

With the continuous progress of a number of COVID-19 vaccine phase 3 clinical trials, it has also attracted more and more attention and expectations of investors.

However, there are many schools of domestic players, and different technical routes have distinct advantages and disadvantages. The speed of research and development is different, the effect on the human body is different, and the production cost is different. Under the influence of these factors, it is destined that different players will eventually be given different sizes of cake. Among the many players, which one do you like most?