key: cord-0921958-cil5q891
authors: Jiang, Hu-Da-Chuan; Tao, Yan-Yang; Jia, Si-Yue; Li, Jing-Xin; Zhu, Feng-Cai
title: Coronavirus disease 2019 vaccines: landscape of global studies and potential risks
date: 2021-09-05
journal: Chin Med J (Engl)
DOI: 10.1097/cm9.0000000000001688
sha: a7c61370f01423c8b04de3048dabb3d056a7e17c
doc_id: 921958
cord_uid: cil5q891

With the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, the importance of vaccines in epidemic prevention and public health has become even more obvious than ever. However, the emergence of multiple severe acute respiratory syndrome coronavirus 2 variants worldwide has raised concerns about the effectiveness of current COVID-19 vaccines. Here, we review the characteristics of COVID-19 vaccine candidates in five platforms and the latest clinical trial results of them. In addition, we further discuss future directions for the research and development of the next generation of COVID-19 vaccines. We also summarize the serious adverse events reported recently after the large-scale vaccination with the current COVID-19 vaccines, including the thromboembolism caused by the AstraZeneca and Johnson & Johnson vaccines.

Following severe acute respiratory syndrome coronavirus (SARS-CoV), which caused an outbreak in 2002, and Middle East respiratory syndrome coronavirus, which caused an outbreak in 2012, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third highly pathogenic coronavirus that has emerged in humans over the past 20 years. [1] Since the whole genome sequence of SARS-CoV-2 was released by Chinese scientists on January 11, 2020, there has been an upsurge in the research and development of vaccines against coronavirus disease 2019 (COVID- 19) worldwide. The World Health Organization (WHO) reported that there are currently >270 COVID-19 vaccines/vaccine candidates, including protein subunit vaccines, viral vector vaccines, inactivated vaccines, DNA or RNA vaccines, virus-like particles vaccines, and live-attenuated vaccines; of which, approximately 90 have been approved for the use in clinical trials. [2] Till date, 14 COVID-19 vaccines have been approved for marketing or emergency use authorization. [3] In China, five COVID-19 vaccines have been conditionally approved for marketing or emergency authorization for use by the government, including vaccines based on inactivated SARS-CoV-2 (produced by National Vaccine & Serum Institute (Beijing Institute of Biological Products [CNVSI Beijing] and Wuhan Institute of Biological Products [CNVSI Wuhan]), and SINOVAC Biotech, Co., Ltd., China), recombinant SARS-CoV-2 using an Ad5 adenoviral vector (produced by CanSino Biologics, Inc., Tianjin, China), and recombinant SARS-CoV-2 using Chinese hamster ovary (CHO) cells (produced by Anhui Zhifei Longcom Biopharmaceutical, Anhui, China). [4] [5] [6] [7] [8] With the approval of a variety of COVID-19 vaccines for marketing or emergency use, concern has shifted to the safety of their use in large-scale vaccination. [9] Here, we aimed to review the research progress regarding the main currently available COVID-19 vaccines [ Table 1 ] and to analyze the safety events that have occurred after large-scale vaccination to provide a scientific basis for the subsequent development and use of COVID-19 vaccines.

The main component of COVID-19 nucleic acid vaccines is a nucleic acid (RNA or DNA) expressing the target antigen component of SARS-CoV-2 in a vector, such that the effective antigen (eg, S protein) of the virus is manufactured in vivo instead of being manufactured in vitro before its injection into the body. Two major advantages of nucleic acid vaccines are that they are easy and fast to prepare and they can induce high levels of specific antibodies. However, mRNA can cause acute adverse reactions, and these types of vaccines require colder temperatures for preservation, usually below À70°C. Before the research and development of COVID-19 vaccines, no nucleic acid vaccines had been approved for marketing in China or elsewhere.

Three main available nucleic acid COVID-19 vaccines are as follows: BNT162b2 developed by Pfizer, Inc. (New York, USA), and BioNTech SE (Mainz, Germany), the mRNA-1273 vaccine developed by Moderna, Inc. (Cambridge, USA), and the INO-4800 DNA vaccine developed by Inovio Pharmaceuticals (Plymouth Meeting, USA). The interim data from phase 3 clinical trials have been announced for both the mRNA vaccines, and the efficacy of them were >90%. Their immunization schedules both require two injections, administered at intervals of 21 days (BNT162b2) or 28 days (mRNA-1273). Regarding BNT162b2, the results of a phase 3 clinical study conducted in over 40,000 people in 152 regions worldwide showed that the most common local adverse reaction in vaccinated subjects was pain at the injection site, and the most common systemic adverse reactions were headache and fatigue. Most of the adverse reactions were mild to moderate in severity, and the vaccine was 95.0% effective for preventing COVID-19 in people aged >16 years old. [10] Similar to BNT162b2, the mRNA-1273 vaccine was also found in a phase 3 clinical trial, conducted in approximately 30,000 people in 99 regions of the United States, to cause pain at the injection site as the most common adverse reaction to vaccination and have an Compared with the humoral and cellular immunity formed by the intramuscular injection of COVID-19 vaccines, a vaccine administered by inhale injection can also form mucosal immunity, which will be the most ideal state of this triple immunity.

Preliminary efficacy studies of the AZD1222 vaccine in the United Kingdom and Brazil showed that the protective efficacy of two standard doses was 62.1%, whereas the efficacy achieved by administering an initial injection of low-dose vaccine followed by a second injection of standard-dose vaccine could reach 90.0%. Importantly, the overall safety of this vaccine, regardless of the dosing regimen, was good. However, the transverse myelitis was observed in one participant at 14 days after the booster vaccination which was considered to be related to the vaccination by the study investigators. [12] A randomized, double-blind, placebo-controlled phase 3 clinical trial of the Ad26/Ad5 adenovirus-vectored vaccine in Russia (Gamaleya Research Institute) found that its protective efficacy against COVID-19 was 91.4% and that most of the reported adverse reactions were mild, with any serious treatment-emergent adverse events unrelated to vaccination. [13] The interim analysis of a phase 3 clinical trial of Johnson & Johnson's Ad26.COV2.S vaccine revealed that a singledose vaccination was well tolerated in adults aged ≥18 years and that its overall efficacy was 66%. At 28 days post-vaccination, the protective efficacy of Ad26.COV2.S for preventing severe cases of COVID-19 was 85%. [14] The CanSino Ad5-vectored vaccine is the only COVID-19 vaccine approved for use in China that uses a single-dose immunization schedule. The data from an interim analysis of its phase 3 clinical trial show that the overall efficacy of the Ad5-nCoV vaccine for preventing COVID-19 at 28 days post-vaccination was 68.8%, but its protective efficacy for preventing serious disease was 90.1%, and that no serious adverse events related to the vaccine were observed during the study period. [15] Inactivated virus vaccines Inactivated virus vaccines are made from viruses that have lost their infectivity and pathogenicity following the application of physical or chemical processes but have retained the complete viral structure and consequently have antigenicity recognizable by the immune system. Because inactivated vaccines have been used for a long time, the research and development technologies for making this type of vaccine are well-established, and these vaccines have the advantages of a mature industrial technology platform, good stability, and high safety. However, the major disadvantage of inactivated vaccines is their weak immunogenicity; they generally either fail to induce a cellular immune response or induce a very weak one. Consequently, an immunization schedule of two or even three injections is usually required, or adjuvants are added to the vaccine components to enhance the vaccine immunogenicity. [5, 16] Additionally, in a serum cross-neutralization test of 12 prevalent SARS-CoV-2 strains conducted in 80 subjects before and after immunization in China and elsewhere, the neutralizing antibodies induced after vaccination could effectively neutralize different SARS-CoV-2 strains (including the D614G mutant strain), and the positive antibody conversion rate was ≥80.0%. In contrast, a phase 1/2 clinical study of CoronaVac conducted in 550 children aged 3 to 17 years who were vaccinated on the immunization schedule of days 0 and 28 found that at 28 days after the second vaccine dose, the adverse reaction rates in the low-dose, middle-dose, and placebo groups were 25.6%, 29.0%, and 23.7%, respectively, while the positive SARS-CoV-2 neutralizing antibody conversion rates in the low-dose and middle-dose groups were 96.8% and 100.0%, respectively. The induced levels of SARS-CoV-2 neutralizing antibodies were significantly higher in juveniles than in adults or the older adults, suggesting the strong immunogenicity of this vaccine in children and adolescents. [16] Since the safety and immunogenicity of CoronaVac in children 3 to 17 years of age and adults ≥18 years of age are comparable, NMPA has recently approved the emergency use of CoronaVac in individuals ≥3 years of age. Besides, because the benefits of using SINOVAC's inactivated COVID-19 vaccine are greater than the known risks, CoronaVac was approved for emergency use under the WHO Emergency Use Listing procedure on June 2, 2021. [17] The phase 3 clinical trial of the COVID-19 inactivated virus vaccine developed by CNVSI Beijing, conducted in United Arab Emirates, revealed that high levels of SARS-CoV-2 neutralizing antibodies were produced after the administration of two vaccine doses, with a positive antibody conversion rate of up to 99.5%, and that the efficacy of preventing COVID-19 infection was 78.1%, with good safety. [6] Similarly, the mid-term analysis data of the phase 3 clinical study of the COVID-19 inactivated virus vaccine produced by CNVSI Wuhan found that the positive SARS-CoV-2 neutralizing antibody conversion rate after two-dose vaccination was 99.1%, and the overall protective efficacy of the candidate vaccine was 72.5%. [18] In the phase 3 clinical trial of the COVID-19 inactivated virus vaccine COVAXIN independently developed by Bharat Biotech Ltd. (Andhra Pradesh, India), about 25,800 subjects were vaccinated on the immunization schedule of days 0 and 28; the results indicate that the protective efficacy of a two-dose vaccination with COVAXIN is 81.0% in people aged ≥18 years. [19] Subunit protein vaccines Subunit protein vaccines are prepared by culturing an antigenic protein (eg, SARS-CoV-2 S protein) from a pathogen, which can be achieved in various ways, and then purifying it. Protein vaccines have the advantages of high purity and ease of large-scale production. Because this type of vaccine contains only the target antigenic protein of the pathogen, rather than the entire pathogen, it is safer than those that contain the entire pathogen. However, adjuvants are generally required to produce a good immune effect, and the immune memory effect can be weak. Therefore, their immunizations schedules usually required two or three doses. . [21] The phase 3 clinical study of the NVX-CoV2373 vaccine conducted in the United Kingdom with over 15,000 subjects aged 18 to 84 years revealed that the vaccine had a protective efficacy of 89.3%. A post-mortem analysis found that the NVX-CoV2373 vaccine had an efficacy of 95.6% against the original COVID-19 strains, whereas its efficacy against the British variant strain was 85.6%. Additionally, the incidence of adverse reactions after the subjects were vaccinated with two doses of NVX-CoV2373 vaccine was low, and there was no significant difference in adverse reactions between the vaccine and placebo groups. [22] The ZF2001 vaccine has obtained emergency use authorization in China. This recombinant protein vaccine is made in CHO cells and encodes the SARS-CoV-2 S protein receptor-binding domain (RBD) antigen; the RBD encoded by the vaccine is designed to form a dimer joined by tandem repeats. Its immunization schedule is three Chinese Medical Journal 2021;134 (17) www.cmj.org doses, administered at 30-day intervals. The phase 1 and phase 2 clinical trials of ZF2001 were completed in China.

In the phase 2 clinical trial, at 14 days after subjects had received three 25-mg doses of the ZF2001 vaccine, the GMT of SARS-CoV-2 neutralizing antibody was 102.5, and the positive neutralizing antibody conversion rate reached 97%, values which both exceeded those in the group that received 50-mg doses of vaccine. The incidence of adverse reactions was similar in the vaccine and placebo groups, and most reported adverse reactions were mild to moderate in severity. [23] Live-attenuated vaccines

Live-attenuated vaccines are composed of variant strain pathogens with weakened or even non-toxic effects that still retain their immunogenicity. These variant strains are obtained by subjecting the pathogen to one or more of various mutation-inducing treatments and then cultivating the resulting strains. Vaccination conducted with a live virus variant strain does not cause the vaccine recipient to develop disease, but it can induce the development of an immune response. The advantages of live-attenuated vaccines are that they can induce a strong immune response, they generally do not require adjuvants, and they typically require only one or two doses to induce protection. Their biggest drawback is the associated safety concerns. The residual virulence of live viruses may induce disease for some individuals, and the phenomenon of "virulence reversion" can occur. Therefore, people who suffer from autoimmune diseases or have low immunity generally cannot be vaccinated with live-attenuated vaccines. At present, the COVID-19 vaccine candidates that have been developed using a live-attenuated vaccine as a technological platform are still in the preclinical stage or phase 1 clinical study stage.

Most first-generation COVID-19 vaccines were designed using the SARS-CoV-2 S protein or a fragment of S protein (ie, RBD) as the target antigen. immune thrombotic thrombocytopenia, which is a rare adverse event described following immunizations with other vaccines [26] . Although the specific mechanism is not clear yet, this adverse event has been determined to be related to the immune response induced by some COVID-19 vaccines.

Bell palsy was once suspected to be related to vaccination with BNT162b2. In a phase 3 clinical trial of the BNT162b2 vaccine in the United States, four participants developed Bell palsy after vaccination with the BNT162b2 vaccine. [27] However, the US FDA stated that the incidence of this adverse event is equivalent to its expected background incidence in the general population; therefore, a causal relationship between the BNT162b2 vaccine and the occurrence of Bell palsy cannot be confirmed. However, prior studies have shown that the incidence of Bell palsy is 15 to 30 cases per 100,000 person-years. According to a follow-up study on the person-years of the populations who were vaccinated with the BNT162b2 vaccine, the expected number of Bell palsy cases is only one or two, which is lower than the actual number of cases with Bell palsy. [28] However, because the symptoms of Bell palsy are usually mild and can subside spontaneously, and the benefits of vaccination with the BNT162b2 vaccine are much higher than the associated risks, it is still recommended that people aged ≥16 years continue to receive the BNT162b2 vaccine. The possible risk of Bell palsy following administration of the BNT162b2 vaccine should be further monitored.

Currently, 14 COVID-19 vaccines have been approved for marketing in some countries or regions around the world. [3] Because of the vigorous promotion of immunization with COVID-19 vaccines, as of April 18, 2021, about 790 million COVID-19 vaccine doses have been administered to people in countries and regions worldwide. [29] Currently, Israel has the highest COVID-19 vaccination rate. In that country, approximately 90% of people aged ≥60 years have received one or two doses of the BNT162b2 vaccine, which has reduced the incidence of COVID-19 by 40%. [30] Thus, immunization with COVID-19 vaccines plays a significant role in public health. However, with the gradual increase in the number of vaccinated people, a series of unpredictable, rare, and serious adverse events have gradually emerged, including the thromboembolism caused by the AstraZeneca AZD1222 vaccine and the Johnson & Johnson COVID-19 vaccine, which are worrying. Therefore, we should monitor the serious adverse events occurring in the vaccinated populations to ensure the safety of COVID-19 vaccine recipients.

Although the protective efficacy of many COVID-19 vaccines has been confirmed and their efficacy in the prevention of COVID-19 has been proven, the constant mutation of SARS-CoV-2 strains is constantly challenging the protective efficacy of COVID-19 vaccines. Vaccines that use only the SARS-CoV-2 S protein or its RBD as the target protein may not be sufficient to provide effective protection for all people in the future. Especially in the [31] A similar phenomenon was also observed for the Moderna COVID-19 vaccine. [32] Therefore, researchers worldwide still need to closely monitor the mutation and escape of SARS-CoV-2 and to develop more effective next-generation COVID-19 vaccines that can completely control the COVID-19 pandemic. The current mainstream design ideas for COVID-19 vaccine design are still based on the RBD of the SARS-CoV-2 S protein. Recent studies have shown that the heptad repeat 2 (HR2) in the S2 subunit may trigger a metastable state of the S protein and promote conformational changes, thereby achieving immune escape. [33] Animal experiments have also confirmed that an HR2deficient SARS-CoV-2 S protein can induce higher neutralizing antibody titers, which may be useful in the design of next-generation COVID-19 vaccines. [34] At present, most of the immunization programs of COVID-19 vaccine approved globally are based on clinical studies of a single COVID-19 vaccine. It is urgent to carry out studies on sequential vaccination or booster immunization conducted with different types of COVID-19 vaccines because vaccine combinations may improve the level of vaccine-induced immune response and could activate multiple immune response pathways. The first clinical trial to assess a combination of COVID-19 vaccines occurred in Russia, where two COVID-19 vaccines with different viral vectors (rAd26 and rAd5 vectors) were used in a phase 3 clinical trial. For this trial, a two-dose immunization program of basic immunization and booster immunization on days 0 and 21, respectively, was conducted, and the resulting protective efficacy reached 91.6%. [13] An ongoing trial assessing sequential vaccination with an adenovirus-vectored COVID-19 vaccine and the BNT162b2 vaccine, with a 12-week interval between the two vaccine doses, is currently being conducted in the United Kingdom. An interim analysis of this trial showed good safety and slightly strong immunogenicity of the heterologous AZD1222/ BNT162b2 immunization schedule with 10 to 12 week vaccine intervals compared with homologous BNT162b2/ BNT162b2 vaccination with 3-week vaccine intervals. [35] The results of this study are expected to help improve the immunization program using existing COVID-19 vaccines and to enhance the protective efficacy of COVID-19 vaccination. [36] Owing to the extremely high worldwide demand for COVID-19 vaccines, the affordability and accessibility of these vaccines have attracted increasing attention. To ensure that low-and middle-income developing countries can also receive safe and effective COVID-19 vaccines, the Chinese Medical Journal 2021;134 (17) www.cmj.org global alliance for vaccines and immunization (GAVI) has launched a multi-billion-dollar financing plan, known as the advance market commitment (AMC), to provide sufficient COVID-19 vaccines for these countries. [37] AstraZeneca is the world's first vaccine manufacturer to sign an AMC; they are committed to providing 300 million COVID-19 vaccine doses in a non-profit manner. However, there are still countries or regions that are ineligible for GAVI or other assistance for various reasons, where they are unable to independently develop or produce COVID-19 vaccines. For these countries, controlling the price of COVID-19 vaccines may be an effective means of increasing vaccine accessibility. However, if such price control is implemented in only low-and middle-income countries, COVID-19 vaccine manufacturers may choose to supply insufficient doses to or not sell at all in these markets, or they may give priority to high-margin markets. [38] Therefore, other measures, in addition to COVID-19 vaccine price control, must also be taken to ensure the fair distribution of COVID-19 vaccines worldwide.

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