Abstract
The outbreak of the coronavirus disease (COVID-19) had put vaccine research and development (R&D) on the urgent agenda. China had taken a diversified route in vaccine research and development. It had taken an approach of first producing inactivated vaccines and then tackling mRNA vaccines, and had achieved varying degrees of progress. At present, the scale of production and the number of vaccines in China is very large, which helped to form an immune barrier. However, China's participation in international vaccine cooperation and exporting vaccines still faced some challenges, and efforts were needed to improve the effectiveness of vaccines and ensure the improvement of vaccine upgrade.
A global COVID-19 pandemic began in 2020. The medical community was not able to quickly develop medicines specifically to treat this sudden and deadly novel coronavirus and could only adopt conventional symptomatic treatment methods, which put a great deal of pressure on the medical community to find other ways to control the pandemic. 1 Faced with the extremely rapid spread of the novel coronavirus and the risk of mutation, how to prevent more people from being infected became the focus of epidemic control, which meant relying on vaccination. 2 After the outbreak of the epidemic, China adopted emergency medical assistance and strict social isolation measures to ease the epidemic. Subsequently, China began to accelerate the research and production of various novel coronavirus vaccines, and used governmental authority and societiel norms to complete the vaccination of hundreds of millions of people. 3 Based on this, this article mainly discusses the technical route of China's novel coronavirus research and development (R&D), the vaccination strategy for the novel coronavirus vaccine, the principles of vaccination on a global scale, and the opportunities and challenges faced by China's novel coronavirus vaccine.
1. THE R&D CHARACTERISTICS OF CHINA'S NOVEL CORONAVIRUS VACCINE
(1) The development of multiple vaccine R&D routes
The R&D of the novel coronavirus vaccine reflected the achievements of the development of biotechnology, especially genetic technology, in recent years, as well as reflecting the competition between new and old technologies. At the beginning of the epidemic, based on the availability of vaccine production technology and in order to avoid excessively long research and development processes, China focused its efforts on inactivated vaccines with relatively simple technology but a relatively high success rate. But at the same time, China has tracked the research progress of mRNA vaccines and recombinant proteins vaccines.
The most traditional vaccine R&D route was to develop inactivated vaccines based on whole virus particles: to extract strains from the novel coronavirus, cultivate and reduce their toxicity, and finally prepare an inactivated vaccine. Even from an early stage of the COVID-19 outbreak, there were a large number of patients, making it easy to collect and isolate complete novel coronavirus strains, which laid the foundation for the development of inactivated vaccines. 4 China National Pharmaceutical Group used the complete novel coronavirus strain isolated from patients severely ill with COVID-19 admitted to Jinyintan Hospital in Wuhan City, Hubei to prepare vaccines. Sinovac Biotech cultured the novel coronavirus strain in Vero cells and selected a strain suitable for vaccine preparation—the CZ strain. This Vero cell was isolated and cultured from the kidney epithelial cells of African green monkeys. After the culture solution was inactivated, purified, and concentrated, it became the semi-finished product of vaccine. Both of the above Chinese companies' inactivated vaccines for the novel coronavirus had been successfully developed and put into commercial application. In addition, WIBP and Biokangtai's inactivated vaccine had also been launched. So far, China had embraced several kinds of inactivated vaccines.
Another route was to develop mRNA vaccines. Generally, when a virus invades the human body, the human body can use immune cells to launch an attack to destroy it. The premise is that the antibody can accurately recognize the virus's DNA. 5 This requires the RNA in the human immune cells to be dispatched to observe the characteristics of the virus's DNA, record it and eventually become mRNA that can guide the formation of antibody proteins. 6 The mRNA vaccine technology uses artificial methods to encode the antigen of a specific virus, produce the corresponding mRNA, and then inject it to guide the human body to produce the corresponding antibody. 7 The first mRNA vaccines launched by Pfizer and Moderna encoded the spike glycoprotein of the novel coronavirus, which induced an antibody response in the human body. After immunization with this vaccine, any novel coronavirus with the spike glycoprotein will be recognized by a subject's antibodies. 8 Recognition of the spike protein by the immune system reduces or eliminates the virus's ability to infect people. 9 Chinese pharmaceutical companies have also followed this R&D method, and have made adjustments according to the technical expertise of various R&D teams. Some companies choose to use the full-length spike protein to develop the technology route, and some companies choose to intercept receptor-binding domain (RBD) protein to develop vaccines. A total of 17 mRNA vaccines were under research in China, the most successful among them was the Comirnaty vaccine jointly launched by Fosun Pharma and BioNTech, though strictly speaking, it was not independently developed in China, but was created mainly using mature technology purchased from BioNTech for production or through cooperative authorized production. Two vaccines developed in China have been exported to foreign markets—Abogen and Walvax Biotechnology's mRNA vaccine AWcorna (exported to Indonesia) and the vaccine Sverk developed by Stemirna (exported to Laos)—but the global popularity of these vaccines is not great.
The third route was a recombinant protein vaccine. The recombinant protein vaccine integrated the spike protein gene of the virus into yeast, E. coli, and other microorganisms; a large quantity of culture expressed the virus' spike protein in vitro; and then the spike protein is harvested and purified to make a vaccine. 10 The CHO vaccine jointly developed by Zhifei Biological Products and the Chinese Academy of Sciences was the most representative of the class, though there also are RBD-Fc-based dimer sub-unit vaccines from the Institute of Pathogenic Microbiology of Fudan University and the Shanghai Pasteur Institute. Based upon many studies, Chinese researchers are very interested in the RBD protein vaccine route, because the researchers found that the SARS virus, MERS virus, and the novel coronavirus all had very similar RBD protein structures, so these vaccines had the potential to become universal coronavirus vaccines. 11 Also, the neutralizing antibody titers induced by RBD-based vaccines were much higher than those of mRNA vaccines and virus particle vaccines. But on the other hand, there is a weakness: the RBD protein has a small molecular weight and may not be able to trigger a sufficient immune response. 12 It needs to be made into a dimer or trimer by technology to improve its ability to induce neutralizing antibodies. At present, among these vaccines, Zhifei Biological's recombinant protein vaccine has been authorized for emergency use in China, Uzbekistan and other countries. The others were still in the R&D track or in clinical trials.
The fourth route is the adenovirus vector vaccine, which was to install nucleic acid fragments of the virus into an adenovirus that had been safely processed and then inject it into the human body. After the injection, the immune system will recognize this viral antigen and activate the body's response to obtain immunity, which can maximize the antigenic activity of viral nucleic acid and stimulate the body's immune function. 13 The advantages of this vaccine were that it only required administration once and that it was easy to store and transport. The initial adenovirus vector vaccine was jointly developed by the team of Academician Chen Wei of the Chinese Academy of Military Sciences and CanSinoBIO. In 2022, CanSinoBIO launched the second generation adenovirus vaccine Convidecia Wuyou which featured an innovation in the way of vaccine delivery; the vaccine was atomized into tiny particles with an atomizer, and inoculation was completed through oral inhalation. 14
(2) Cooperative development of vaccine clinical trials
China urgently initiated the R&D of the novel coronavirus vaccine in early 2020, and completed the first- and second-phase animal experiments in a very short time. By May 2020, the COVID-19 epidemic had rapidly subsided in China, and the Phase III vaccine clinical trials could not recruit enough volunteers. As a result, Chinese pharmaceutical companies began to cooperate with foreign hospitals to carry out Phase III clinical trials. 15 The CoronaVac vaccine of Sinovac Biotech had undergone clinical trials in Turkey, Brazil, Indonesia, Chile, and other countries. In April 2021, Sinovac Biotech announced the results of the Phase III clinical trial in Brazil, showing that compared with the unvaccinated population, the risk of infection of the trial group had been reduced 50.7% after receiving two doses of the vaccine. At the same time, satisfactory results have been achieved. 16 In July 2021, the Turkish Health Department announced the results of the Phase III clinical trial of CoronaVac vaccine. A total of 10,216 volunteers participated in the trial, and the vaccine protection rate was 83.5%. 17 In Chile, researchers followed people who had received two injections of CoronaVac vaccine for more than 14 days. The overall effectiveness against the novel coronavirus reached 65.9%, the effectiveness of preventing hospitalization was 87.5%, the risk of entering the intensive care unit was reduced by 90.3%, and the risk of death was reduced 86.3%. China National Pharmaceutical's vaccine, BBIBP-CorV, began a randomized human trial in 40,411 subjects in July 2020 and published the results of Phase III clinical trial in May 2021. The results showed that after 14 days of continuous vaccination with two doses of vaccine, the volunteers can produce high titers of antibodies in their bodies. The protective effect of a group of WIV04 vaccine was 72.8%, and the protective effect of another group of HB02 vaccine was 78.1%. 18 The data results meet the relevant technical standards of the World Health Organization (WHO) and the relevant standards in the “Guidelines for Clinical Evaluation of Novel Coronavirus Preventive Vaccines (Trial)” issued by the National Administration of Drug Products of China.
In terms of adenovirus vaccine, Ad5-nCoV vaccine's trial in Pakistan in February 2021 showed that after a single injection, the vaccine had generated 100% protection against severe COVID-19, the overall protection effect was 74.8%. 19
The clinical trials of mRNA vaccines in China were generally conducted jointly at home and abroad, especially in countries interested in vaccines. 20 Abogen and Walvax Biotechnology's ARCoV carried out Phase III clinical trials around the world, involving more than 20,819 volunteers, of which Indonesia was the country with the largest number of participants, involving more than 9,055 subjects. The comprehensive data shows that ARCoV had a high protection rate for COVID-19 wild strain and Omicron mutant with overall adequate safety.
(3) Progress in the marketing authority of vaccines
As vaccine development time, clinical trial data, and side effects data are not enough to fully support the effectiveness and safety of vaccines, according to the Drug Administration Law, Drug Registration Administration Measures, and Vaccine Administration Law, China currently implemented conditional listing or emergency use approval for 13 vaccines, of which five were inactivated, two were adenovirus vector, and five were recombinant protein (Table 1). These vaccines were first approved for emergency use for a period of one year; after monitoring the use, effect, and adverse reactions, they have the opportunity to enter conditional listing. This signifies that the vaccines will continue to wait for the final approval by the drug registration review agency.
List of vaccines already on the market in China
It can also be seen from the above list that the mRNA vaccine China is actively developing and for which it has great hopes has not yet passed the review of its domestic regulatory authorities. The biggest uncertainty should be based on safey concerns.
2. THE VACCINATION SCALE OF CHINA'S NOVEL CORONAVIRUS VACCINE
From the end of 2020, China has launched a novel coronavirus vaccination plan nationally. In order to ensure safety and priority, the National Health Commission of China divided vaccination into several stages.
The first group to be vaccinated was the key population, that is the population at high risk of exposure to the novel coronavirus, including customs inspection and quarantine officers; loading, handling, and transportation workers in ports and in the imported cold chain good yards; international and domestic transportation personnel; people going abroad for work and study; medical and healthcare personnel; government agencies' employees; policemen; firemen; community workers; relevant personnel of water supply, power supply, and heating supply companies; and logistics, sanitation, funeral, and communications-related staff. For these groups of people, vaccinations were given priority as they were required to perform their duties during the pandemic, in order to prevent loopholes in virus prevention and control. Between January and February 2021, this part of the population had basically completed vaccination.
In the second step, the Chinese government decided that all citizens in the 18–59 age group could be vaccinated free of charge. The health department, however, listed people (including those with certain diseases or conditions) who should not be vaccinated, including pregnant and breastfeeding women; patients with fevers; persons who had severe allergic reactions from previous vaccinations (such as acute allergic reactions, urticaria, skin eczema, dyspnea, angioedema, or abdominal pain); people with thrombocytopenia or bleeding disorders; people with convulsions, epilepsy, encephalopathy, and other progressive neurological diseases or a history of mental illness; persons with liver and kidney diseases, hypertension, diabetic complications, malignant tumors; those with various acute or chronic diseases in the acute onset period; and anyone who has been diagnosed with congenital or acquired immunodeficiency, HIV infection, lymphoma, leukemia, or other autoimmune diseases. All of the eligible people in this group received the first dose in time, and then the second dose two to four weeks later. Beginning in February 2021, China had widely set up vaccination sites in various places, and the weekly vaccination volume had reached a staggering 20 million doses. By the beginning of August 2021, 1.6 billion doses have been administered.
In the third step of the vaccination program, starting March 2021, the National Health Commission of China had approved vaccination of elderly people (over 60 years old). The approval was based on the previous implementation of the first and second clinical trials of the elderly group vaccination, as well as analysis of the feedback of foreign vaccines in the elderly. 21 These indicators showed that the incidence of adverse reactions in the elderly group after vaccination was not higher than that in the younger adult group. 22 Therefore, the elderly who are in good health could be vaccinated directly. For those who suffer from common diseases of aging, such as high blood pressure and diabetes, as long as they can maintain a stable physical condition through drug control, tcould also be vaccinated. 23
The fourth step in the vaccine program: at the end of July 2021, the Chinese government had decided to fully vaccinate persons between the ages of 12 and 17, and had planned to complete the vaccination before September. Among these minors, they first vaccinated those who were 15–17 years old and then those 12–14 years old. Prior to this, the United States, France, Australia, and other countries had vaccinated children 12–15 years old with the Pfizer vaccine, 24 which inspired China.
In addition, China had also launched a “Spring Vaccine Program” in some countries to vaccinate Chinese citizens who were engaged in commercial and educational activities overseas. These vaccines were provided by the Chinese government.
In order to realize this huge universal vaccination plan, it was estimated that two billion doses of vaccine would be expended. But this was not the final demand data. Preliminary studies had shown that various vaccines will help the body to produce antibodies after vaccination, but that over time, antibodies decline until they disappear. For some vaccines, it is estimated that the maintenance time of the antibodies is about six months. 25 In this regard, scientists had come up with several countermeasures. One was to inject a third dose of the vaccine after a period of time, to consolidate antibodies. 26 The second was sequential vaccination: that was, mixed vaccination or booster vaccination with vaccines of different components. 27 For example, first inoculate with one dose of inactivated vaccine, and then inoculate with one dose of adenovirus vector or mRNA vaccine in order to absorb the advantages of different types. If you had already received two doses of inactivated vaccines, you may also consider continuing with adenovirus vector or mRNA vaccines in order to strengthen your immunity. In the last few months of 2022, China again suffered a pandemic, reaching the highest level in nearly three years. A large number of vaccine breakthroughs showed that early immunization can no longer provide protection for the public. The Chinese government urgently arranged a new round of a vaccine enhancement plan to allow people to continue to receive recombinant protein or adenovirus vaccines. By the end of December 2022, the cumulative number of various types of COVID-19 vaccines administerd in China (excluding Hong Kong, Macao, and Taiwan) reached 3,475,387,000 doses.
3. INTERNATIONAL APPLICATION OF CHINA'S NOVEL CORONAVIRUS VACCINE
In the context of the rapid spread of the epidemic worldwide, China had proposed the idea of making novel coronavirus vaccines a global public product. This was an idea that went beyond drug intellectual property rights. On the one hand, it meant recognizing and protecting the efforts and exclusive rights of novel coronavirus vaccine's R&D and guaranteeing the economic returns of pharmaceutical companies. On the other hand, it meant that novel coronavirus vaccines could be used in countries and regions that did not themselves have any widely available due to reasons of affordability or adequate supply, so that the benefit of public vaccines was higher than that of commercial. Third, it also meant that the production, marketing, and inoculation of novel coronavirus immunizations must comply with the basic requirements for vaccines in the International Health Regulations led by the World Health Organization, as well as the drug management regulations and access regulations of countries around the world.
This new idea was constructive, but it was not without difficulties. First of all, China's own population was large, and the demand for novel coronavirus vaccines and the number of stockpiles were near three billion doses. This imposed high requirements for vaccine production, capacity, and manufacture scale. Secondly, novel coronavirus vaccines were drugs. Import licenses and drug marketing authority were required in every country. Since vaccine R&D time was less than one year, there was insufficient data accumulation on the safety and effectiveness of vaccines globally, which made many people skeptical about them. Thirdly, there was the question of whether China's plan was integrated with the plans launched by the United Nations and the World Health Organization. 28 The World Health Organization launched the “COVID-19 Vaccine Implementation Plan,” which planned to provide 2.5 billion doses of novel coronavirus vaccines to poor countries in 2021. The WHO intended to conduct inspections and evaluations of vaccines produced in various countries and include effective and safe vaccines on the emergency use list, recommended to countries all over the world. Since the launch of the plan, vaccines produced by Pfizer, Moderna, AstraZeneca, and Johnson & Johnson had been included in the “emergency use list.” If the vaccines produced in China are certified by the World Health Organization, they will be recommended and purchased by the United Nations, thus smoothly entering foreign markets.
Around the above challenges, several Chinese pharmaceutical companies had made certain progress in novel coronavirus vaccines. The first was production capacity. China's vaccine production facilities were also accelerating expansion, and the output was expected to reach five billion doses by the end of 2022. At present, China provided urgently needed vaccines to more than 100 countries and international organizations through gifts and sales, and had carried out technology transfer and production cooperation with Egypt, the United Arab Emirates, and other countries. The vaccine stock solution was provided by Chinese companies and filled and packaged locally. As of writing, the number of vaccines exported to foreign countries had reached 2.2 billion and covered more than 120 countries and international organizations worldwide.
The second was the qualification of the novel coronavirus vaccine. In November 2020, China National Pharmaceutical Group Corporation's vaccine started to apply to the WHO for evaluation, but it was not until May 2021 that it was finally approved. This delay caused some criticisms in China, because China National Pharmaceutical Group Corporation's vaccine was applied for evaluation at the same time as Pfizer's vaccine, but Pfizer's had been approved by the World Health Organization in less than two months. This may have been caused by two factors. One was the difference in technology. The China National Pharmaceutical Group vaccine was an inactivated vaccine, while the five vaccines previously approved by the WHO were all mRNA or adenovirus vector vaccines. The other was the basis of evaluation. The World Health Organization divided the drug administration agencies of member states into two categories, one of which was “strict regulatory agencies”: the drug regulatory agencies of the United States and some European countries were classified in this category. For the certification applications of companies registered in these countries, the WHO usually approved them quickly, based on the evaluation of the drug regulatory authority. 29 Pfizer's vaccine was approved by the World Health Organization within ten days after the U.S. Food and Drug Administration approved it. 30 In countries with other drug regulatory regimes, the WHO's review standards for applications for pharmaceutical companies would be more stringent: not only must the review start from the beginning, but it also includes on-site inspections of production facilities. In January 2021, the WHO expert group inspected the production facilities of China National Pharmaceutical Group Corporation and Sinovac Biotech Co., Ltd. Sinovac Biotech's inactivated vaccine had been included in the “emergency use list” by the World Health Organization in June 2021, and will be promoted globally based on temporary use recommendations. At the end of 2022, the Convidecia vaccines of CanSinoBIO had finally been included in the emergency use list by the World Health Organization. After the new drug approval process, Sinovac Biotech's vaccine had been authorized for use in more than 30 countries. The EU was also undergoing the review process.
The third was the price and competitiveness of novel coronavirus vaccines. The current government procurement price of China National Pharmaceutical Group and Sinovac Biotech's vaccines in mainland China is about 200 yuan per dose. In foreign markets, the price varies according to different dosage forms. According to official data disclosed by various countries, the price of Sinovac Biotech's vaccine was 650 pesos in the Philippines, 60 Singapore dollars in Singapore, and about 200,000 rupiah in Indonesia. Compared with the market prices of several vaccines recommended by the World Health Organization, the price of vaccines in China was relatively cheap. On the other hand, due to the requirements of some foreigners working in China for mRNA vaccines, the Chinese government agreed to import a batch for foreigners only.
4. OUTLOOK
The role of the novel coronavirus vaccine has become more and more critical. In addition to the vaccine sharing plan launched by the World Health Organization, the U.S. government announced that it would temporarily suspend the intellectual property patents of the novel coronavirus vaccine and begin to implement vaccine distribution. The European Parliament approved the implementation of the novel coronavirus vaccine passport within the EU, and gradually reopened the borders to low-risk countries and travelers who have been vaccinated. The Group of G20 Tourism Ministers' Meeting decided to promote the vaccine passport; this made the novel coronavirus vaccine like a mask and will become a public health necessity in the future. 31 Now more and more countries have released restrictions and tried to return to normal life, but the demand for vaccines, especially those against new virus variants and multivalent ones, is still strong, and the development of new vaccines has not stopped.
China's novel coronavirus vaccine R&D has begun to diversify. In addition to traditional technologies, China has gradually mastered the key technology of mRNA vaccines. While maintaining the huge production capacity of inactivated vaccines, China can also produce some mRNA vaccines with higher protection efficiency and greater resistance to mutation to deal with the elongated epidemic. In the future, the main risk for novel coronavirus vaccine R&D and production for Chinese pharmaceutical companies may be intellectual property issues. For example, some countries may use compulsory drug patent licenses to initiate vaccines, and some countries may break through vaccine patent protection and directly apply mature R&D technologies or use drug trail data for commercialization activities. A secondary risk involves vaccine production capacity, including output of production facilities, supply of biologically active materials, and even the availability of vaccine packaging and storage equipment. For example, consider the borosilicate medicinal glass bottles currently used in vaccine packaging. The global manufacturers of vaccine glass bottles mainly include German's SCHOTT, Japan's NEG, and USA's Corning. These three companies account for 90% of the global vaccine glass bottles market share. Due to the large demand for vaccines, there has been a tight supply of glass bottles. A third risk was the vaccine barrier between countries: China was a major producer, but in the past, vaccine products were basically self-produced and self-consumed; exports only accounted for a small part of the output, and accounted for less than 1% share in the global vaccine trade. The novel coronavirus vaccine produced in China had not yet been approved by the U.S. and European drug regulatory authorities, and there were no vaccine sales from Pfizer, AstraZeneca, and other companies in mainland China. This also affected consumers' choices.
Acknowledgment
This work was supported by Fujian Social Science Foundation Project (FJ2021BF031)