Eve Of The Birth Of The New Crown Vaccine

The world's new crown vaccine development race day and night.

On September 18, at the Global Forum on science and life and health, Wang Zhigang, Minister of science and technology, revealed that China has 11 new crown vaccines in clinical trials, and 4 of them have entered phase III clinical trials.

Liu Jingzhen, chairman and Secretary of the Party committee of Sinopharm group, recently said that the new crown vaccine of Sinopharm Group China biological Co., Ltd. "can enter the final approval stage in about three months, and the vaccine is expected to be listed before the end of this year". At present, it has two new crown inactivated vaccine production workshops in Beijing and Wuhan, with a total annual production capacity of 300 million doses.

On September 15 and September 17 local time in the United States, Pfizer / biontech and Moderna announced the latest progress of phase 3 clinical trials on online investor activities and R & D days respectively. Pfizer also stated that it expected to obtain key data by the end of October and then submit its listing application. If approved, Pfizer is expected to supply 100 million globally by the end of 2020 About 1.3 billion doses will be provided by the end of 2021.

Nature Reviews drug discovery recently released a review on the development of new coronal vaccines. According to the review, as of September 2, 2020, the global covid-19 vaccine R & D pipeline includes 321 candidate vaccines. Among them, 33 candidate vaccines are in clinical trials, and more than 280000 subjects from at least 470 locations in 34 different countries are planned to be recruited.

In the face of the possible supply shortage of the new crown vaccine next year, developed countries have preemptively ordered more than 2 billion doses. On the other hand, international efforts to buy vaccines for low - and middle-income countries are poorly supported.

In any case, it seems that the vaccine development "catching up with the spread of the virus" is on the eve of its birth. Various signs and announcements show that the vaccine R & D and regulatory authorities may put the new vaccine on the market by the end of 2020 or early 2021 as soon as possible. Moreover, these fast-growing candidate vaccines have started mass production and can be quickly distributed if approved.

However, from the safety and effectiveness of vaccine research and development, unexpected adverse reactions, regulatory review and approval, large-scale production and distribution to the commercialization of enterprises, there are still many uncertainties and multi-dimensional tests before the real launch of new crown vaccine.

Clinical design test

The clinical trial progress of the new crown vaccine is under the anxious expectation of the whole world.

In the special period, in addition to R & D personnel and enterprises accelerating R & D day and night, regulatory agencies in various countries are also constantly "green light". Vaccines have become almost the only hope that people can return to the "pre epidemic era".

Since April, the biggest change in the general profile of new crown vaccine developers has been the increasing number of large multinational companies involved. Currently, among the clinical candidate vaccines, 11 are developed by Chinese institutions, and 7 are supported by the U.S. action warp program.

At present, most of the vaccine candidates in clinical trials use the spike (s) protein and its variants as the main antigens. Candidate drugs targeting other or multiple antigens are being developed, including targeting N protein, attenuated vaccine, inactivated vaccine and peptide vaccine.

In the pandemic of new infectious diseases, clinical trials from design to endpoint selection pose considerable challenges to developers, as there is limited understanding of pathogen specific disease manifestations and underlying pathophysiology. Researchers and regulators need to design and evaluate the vaccines according to the key points such as the mechanism of action, the mode of presentation and the type of induced immune response.

From the perspective of immune principle, "humoral immunity and cellular immunity are two favorable magic weapons for us to deal with viruses, which are actually the basic scientific basis for vaccine design. In addition to cellular immunity and humoral immune response, we can not divide them into two categories, namely, whether the vaccine can be activated or not Dong Chen, President of the school of medicine of Tsinghua University, said at the first Dawan District vaccine Summit on September 12 that the clinical symptoms of new crown patients were uneven, "80% were mild diseases, and about 20% were moderate to severe diseases, and even asymptomatic. What kind of factors lead to heterogeneous clinical symptoms, is it related to the immune system? This is the problem we need to solve, and the development of vaccines is more targeted. "

In addition, Dong Chen said that the strategy and adjuvant of vaccine, the formation and maintenance of adaptive immune memory, how to induce broad-spectrum neutralizing antibodies, the depletion of CD8 T cells, and how to achieve therapeutic effects are all key scientific issues of the new crown vaccine.

Safety and effectiveness

Before being approved, the vaccine must be evaluated for efficacy and safety through large-scale phase III clinical trials.

From the perspective of effectiveness, in June this year, the FDA issued the guidelines for the development of the new crown vaccine, saying that under the condition of ensuring safety, the vaccine can be approved for use when its effectiveness in clinical trials is at least 50%.

Since 2010, the efficacy of seasonal influenza vaccines has ranged from 19% to 60%, according to the Centers for Disease Control and Prevention (CDC). According to the World Health Organization (who), although some common childhood vaccines (such as measles vaccine) can achieve 85% to 95% efficiency, none of them can be 100% effective.

On August 14, the drug examination center of the State Food and Drug Administration of China issued a notice on five guiding principles, including the guiding principles for the development of new coronavirus vaccine for prevention (Trial Implementation), pointing out that "the main end point of effectiveness evaluation should be the prevention of covid-19". In the placebo-controlled trial, the protective effect of the target population should reach more than 70% (point estimated value), and at least 5% The lower limit of 95% confidence interval is not less than 30%.

Take Pfizer and biontech's bnt162b2 vaccine as an example, which is a nucleoside modified and codon optimized mRNA vaccine. The candidate vaccine has been clinically tested in the United States and other countries. On September 12, Pfizer plans to expand its recruitment of large-scale clinical trials from 30000 to 44000, and more than 29000 have been enrolled.

On August 20, according to the data published by the two companies, the geometric titer of neutralizing antibody against sars-cov-2 produced by bnt162b2 vaccine was very high, showing strong immunogenicity in young and old people.

In March 2020, Fosun Pharmaceutical spent 85 million license fee and was authorized by biontech to conduct clinical trial, market application and commercialization of the vaccine product in mainland China, Hong Kong, Macao and Taiwan.

At present, Fosun medicine has also carried out a phase I clinical trial on it in China, "the population coverage range is from 18 to 85 years old, and the humoral immunity and cell surface are comprehensively tested. On July 28, the first batch of 36 volunteers in phase I clinical trial were successfully vaccinated. " Hui Aimin, senior vice president of Fosun Pharmaceutical, President and chief medical officer of global R & D center, revealed in an interview with 21st century economic report that "up to now, 144 subjects in the phase I clinical trial of bnt162b1 in China have completed two injections of vaccine, and the response is good at present."

In addition to the baseline, the most important thing is the safety of the vaccine itself. The safety of the new crown vaccine may be a more eye-catching event at present.

According to the above-mentioned CDE documents, the safety risks of vaccines mainly come from the following aspects: first, the safety of the main active ingredients of the vaccine; second, the safety related to the process: such as carrier / delivery system, adjuvants, excipients, etc.; third, the safety problems brought by human immune response, such as antibody dependent enhancement effect (ADE) / vaccine enhanced disease (VED).

On September 8, clinical trials of the new crown vaccine jointly developed by the British pharmaceutical giant AstraZeneca and Oxford University were suspended on September 8 because of suspected serious adverse reactions in a vaccine subject. On September 12, clinical trials of azd1222, the New Oxford crown vaccine of AstraZeneca, were resumed in the UK.

Problems in clinical trials were referred to an independent committee to review whether it would continue to be routine, but considering that the vaccine was one of the most potential candidates at present, it raised public concerns about the safety of the vaccine.

Kathrin U. Jansen, Pfizer's head of vaccine research and development, also spoke about safety at the above-mentioned investor meeting. "Our trial design allows an independent external data monitoring team to conduct interim analysis and no blind review, and the Committee reviews the data weekly. If they feel that there is any potential safety hazard, we have not received any notice so far, so we will continue to recruit and register according to the plan. "

In terms of side effects, the data collected from about 6000 unblinded people so far show consistent tolerance, "we are pleased that in phase 3 studies of doses 1 and 2, our tolerance data show overall tolerability with the basic mild to moderate observed in phase 1 studies."

Hui Aimin explained that the results of phase 1 trials of bnt162 mRNA vaccine in the United States showed that bnt162b2 was well tolerated in terms of safety, and less than 20% of all subjects showed mild to moderate fever. At a dose of 30 micrograms, 16.7% of patients aged 18-55 years had adverse reactions, while patients aged 65-85 years had no adverse reactions.

Next step: vaccine approval and production competition?

The review and approval of new coronal vaccine under emergency state has attracted worldwide attention.

"Our new crown vaccine is clearly oriented to clinical needs, and our common goal is to promote the vaccine to be available as soon as possible." Li Yingli, the drug examination center of the State Food and drug administration, revealed at the above summit that CDE formulated a work plan for special review during the Spring Festival, and further developed a work plan for the review of the new crown vaccine. "But we can't lower the standard. We should stand the test of history and international peers, ensure the safety, control the quality of products, fully study the safety of animals, and have higher profit space in clinical trials. The most direct evidence of effectiveness is the protection efficiency."

At the same time, Li Yingli pointed out that in the emergency state, the challenges of the new crown vaccine also include "ensuring the safety of the subjects and complying with the compliance and scientificity of clinical trials; there may be situations where the procedures and doses are not the most appropriate; the final marketing of vaccines depends on the evaluation of clinical requirements and risk benefits; post marketing pharmacovigilance and risk management, which are our domestic ones We should pay more attention to the short board. In particular, we will speed up the supervision of ADE, the new coronal vaccine. "

In the domestic market, in addition to local enterprises, Fosun Pharmaceutical is also looking for time convergence with foreign countries. Wu Yifang, President and chief executive officer of Fosun Pharmaceutical, previously told the 21st century economic report that "we hope to complete the phase III clinical trials in foreign countries at the same time in China. China does not have the environment to do phase III clinical trials, so the domestic normal population after completion of the trial and form a comparison with foreign countries. If there is no ethnic difference, the global data can also be used as reference for listing application. "

Hui Aimin said that Fosun Pharmaceutical has submitted bnt162b2 application in China. "At present, it is waiting for the approval of the State Food and drug administration, so that it can bridge with foreign countries. It is hoped that when the third phase of clinical trials abroad are completed, our domestic bridging experiments can also be completed simultaneously. We hope to use this kind of research data with foreign research data, domestic research data and animal attack data Combined with the data of public experiments, the vaccine can be put on the domestic market as soon as possible. "

Although no regulatory authority has yet approved the launch of the new crown vaccine, a large number of orders have begun. As of mid August, the United States has ordered at least 800 million doses of six vaccines under development and may order another 1 billion doses, according to a news statistic from nature. The UK has the world's highest per capita purchases, with 340 million doses purchased: about 5 per citizen. EU countries are buying vaccines in groups, and Japan has ordered hundreds of millions of doses for its citizens.

For public health experts calling for a fair distribution of vaccines around the world, the rush is depressing. "Unless we can get rid of the epidemic in every corner of the world, we can't eliminate it." Mark Feinberg, director of the International AIDS vaccine initiative in New York City.

A major international initiative to secure vaccine supply is called the covax mechanism, which is co sponsored by GAVI, CEPI and who, a Geneva based foundation that supports the supply of vaccines to low-income countries. Covax aims to purchase two billion doses of vaccine, one billion of which will be given to 92 low - and middle-income countries and regions, and the other 1 billion doses will be prepared for 75 relatively rich countries and regions, which need to pay for their own vaccines.

If all the leading candidate vaccines can be approved, according to the estimation of vaccine enterprises on their production capacity, more than 10 billion doses of vaccines may be put on the market by the end of 2021. However, based on the stage of each vaccine manufacturer's candidate vaccine and the historical performance of their vaccine production technology, airfinity predicts that only one billion doses of vaccine will be available by the fourth quarter of 2021.

And the cost of each vaccine is different: from the purchase agreement, the price of AstraZeneca vaccine purchased in the United States is less than $4 per dose, but the price of Moderna vaccine is $25 per dose. However, many procurement agreements do not disclose cost data. If the effectiveness of vaccines is not up to standard, can countries withdraw from the procurement agreements? Or when can some purchasers give priority to purchase additional doses? None of this is known.

At the above summit, Gao Fu, academician of the Chinese Academy of Sciences and director of the Chinese Center for Disease Control and prevention, said that the biggest challenge facing the new crown vaccine is the cost, "can the price be reduced?"

In terms of commercialization, "new crown vaccine is a public health product. One of the basic principles of public health products is that its pricing cannot be based on the contradiction between supply and demand in the market. From a commercial point of view, we should not lose money, otherwise it will affect the normal operation of the company. These two enterprises certainly need to take into account, and we will make reasonable pricing according to the results of cost calculation. " Hui Aimin said, "at present, the first step must be to ensure supply, which is also a global consensus."

Liu Jingzhen, Secretary of the Party committee and chairman of Sinopharm group, revealed in an interview in August this year that the dose of a vaccine is 4 micrograms, and the protection rate is about 97% if one dose of vaccine is given, and the protection rate can reach 100% with two injections. After the new crown inactivated vaccine is put on the market, the price is expected to be several hundred yuan per injection. If two injections are given, the price should be 1 Within 1000 yuan.

Can the Chinese people accept this price?

Meng Qingyue, Dean of School of public health of Peking University, pointed out at the above summit that the display of vaccines in public policy discussion and research is low, the research on the economic and social characteristics of vaccines is insufficient, and the understanding and attention of vaccines from multi-disciplinary perspectives is lacking.

"Our country has a total health expenditure of more than 60000 billion yuan in 2018. How much is the cost of vaccine? Unfortunately, I didn't find the data. In the past decade, China's total health expenditure has experienced the fastest growth period in history, but does the flow of health expenditure reflect the guiding ideology of prevention first and health as the core? Attention should be paid to the research and analysis of vaccine economics at the macro level. " Meng Qingyue said that there is still a lot of room for improvement in vaccine economic evaluation, such as the dimensions of input and output analysis, cost information such as R & D, production, management and use, and its role in pricing. "If two doses of new crown vaccine cost 1000 yuan, and some data say that the monthly income of 600 million people in China is less than 1000 yuan, then how can we use such pricing? If there are 1 billion people using vaccines, that is 1 trillion. The total national health expenditure is only more than 60000 billion in 2018, which accounts for 1 / 6. Is this possible? How much is likely to be subsidized by the government? How do we account for this? Therefore, cost information is basic information. "