Innovation-driven trend shaping COVID-19 vaccine development in China

Abstract

Confronted with the coronavirus disease 2019 (COVID-19) pandemic, China has become an asset in tackling the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission and mutation, with several innovative platforms, which provides various technical means in this persisting combat. Derived from collaborated researches, vaccines based on the spike protein of SARS-CoV-2 or inactivated whole virus are a cornerstone of the public health response to COVID-19. Herein, we outline representative vaccines in multiple routes, while the merits and plights of the existing vaccine strategies are also summarized. Likewise, new technologies may provide more potent or broader immunity and will contribute to fight against hypermutated SARS-CoV-2 variants. All in all, with the ultimate aim of delivering robust and durable protection that is resilient to emerging infectious disease, alongside the traditional routes, the discovery of innovative approach to developing effective vaccines based on virus properties remains our top priority.

Keywords

SARS-CoV-2 / COVID-19 vaccine / vaccine development

1 Introduction

Coronavirus disease 2019 (COVID-19) is an emerging acute respiratory infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Most of the infected individuals experience fever and respiratory symptoms, such as dyspnoea and cough, while some become critically ill and rapidly develop acute respiratory distress syndrome (ARDS), even resulting in death [1]. The World Health Organization (WHO) declared COVID-19 a public health emergency of international concern (PHEIC) on January 30, 2020 and a global pandemic on March 11, 2020. As shown in WHO COVID-19 dashboard, SARS-CoV-2 has caused more than 762 million confirmed infections, and over 6.8 million deaths in the globe as of April 2023. After severe acute respiratory syndrome coronavirus (SARS) in 2002 and Middle East respiratory syndrome coronavirus (MERS) in 2012, SARS-CoV-2 has become the 3rd zoonotic highly pathogenic coronavirus of the 21st century [2,3]. Experiences accumulated from previous studies on vaccines against SARS and MERS were applied in a timely manner to accelerate the research and development of SARS-CoV-2 vaccines. In the first-wave of COVID-19 in China, public health institutions have successfully isolated pathogen and quickly initiated clinical trials of treatments and vaccines development within 4 months of the outbreak, taking an important step toward understanding the virus virology and managing this pandemic. The progression of vaccine candidates in clinical development is useful for informing future COVID-19 vaccine development efforts, as well as vaccine R&D strategies for future infectious disease emergence. In this review, the technical characteristics and product development status of SARS-CoV-2 vaccines are summarized according to different technical routes, while the development status of next generation modified vaccines against SARS-CoV-2 variant strains are also demonstrated. In addition to the focus on SARS-CoV-2 vaccines, the notable progress made in novel immunization strategies, therapeutics in COVID-19 prevention and control, as well as the establishment of vaccine technology platforms are discussed, which pave the way in achieving universal health coverage in China.

2 Virology and immunology of SARS-CoV-2

SARS-CoV-2 belongs to the beta coronavirus within the family Coronaviridae [4], which are cytoplasmically replicating, positive-sense, single-stranded RNA viruses [5]. As a typical beta coronavirus, SARS-CoV-2 is a spherical shaped virus with genome size of 30 kb, which shares 79% genome sequence identity with SARS-CoV and 50% with MERS-CoV [6]. The major viral proteins include the spike (S) protein, the envelope (E) protein, the membrane (M) protein, and the nucleocapsid (N) protein [7] (Fig.1).

The similarity between SARS-CoV and SARS-CoV-2 contribute to revealing the entry mechanism of virus into the host. Just like SARS-CoV, invasion and infection of SARS-CoV-2 are found to be regulated by the interaction between the angiotensin-converting enzyme 2 (ACE2) receptor on the surface of host cells and the S protein [8,9]. As shown in Fig.1, the S protein comprises two functional subunits, spike 1 (S1) and spike 2 (S2). The S1 subunit, consisting of a N-terminal domain and a C-terminal domain, mediates the receptor-ligand binding through the receptor binding domain (RBD) [10]. Meanwhile, the S2 subunit, which contains a fusion peptide, two heptad repeats, a transmembrane domain, and a cytoplasmic domain, can be anchored to the membrane through the transmembrane region and is responsible for the fusion of the virus with cellular membranes [11,12]. Following S1-mediated attachment and S2-assisted fusion, the genetic material RNA of SARS-CoV-2 is released in the host cell, initiating the replication, transcription, assembly, and release of the virus [10,13].

Upon the infection of SARS-CoV-2, innate immune responses are triggered within hours after the infection, and followingly initiate the adaptive immune responses, including pathogen-specific cellular and humoral immune responses [14]. Immune cells such as monocytes, macrophages, neutrophils, dendritic cells (DCs), and natural killer (NK) cells are rapidly recruited to the infection site, and activated to kill virus-infected cells or viruses directly or indirectly via secretion of pro-inflammatory chemokines, cytokines, or interferons (IFNs) [15]. T cell-based cellular immune responses and antibody-based humoral immune responses, which are crucial for fighting against SARS-CoV-2, are both activated by components of the innated immune system, especially the antigen presenting cells (APCs) [16]. However, cytokine storm, ineffectual type I interferon responses, eosinopenia, lymphopenia, and exhaustion of T cells, B cells, and NK cells have been found in patients with severe COVID-19, and thought to cause associated organ damages and accelerated disease course [15,17]. In studies on convalescent COVID-19 infectors, the S protein, N protein, M protein, and a series of non-structural proteins are found to contribute to over 80% of the total CD4⁺ and CD8⁺ T-lymphocyte responses [18]. Based on analyses on infected/recovered patients as well as animal models, the significant insights into the humoral immune response and antibody immunity following SARS-CoV-2 infection suggest the production of SARS-CoV-2-specific IgM, IgA, IgG and neutralizing antibodies play essential roles in suppressing the viral replication [19]. S protein-specific IgG, IgM, and IgA antibodies as well as N protein-specific IgG antibody exist in infected adults, and anti-RBD antibodies are demonstrated to correlate with the neutralizing potency [20,21]. The understanding of immunity to SARS-CoV-2 can contribute to the selection of target antigens for vaccine design.

3 Current development of the COVID-19 vaccines

Since the outbreak of the COVID-19 pandemic, the public and private sectors and multilateral efforts have launched hundreds of SARS-CoV-2 candidate vaccines. Development was initiated when the genetic sequence of the virus became available in early January 2020, and the first phase I trial was started in March 2020 at an unprecedented speed. According to WHO Coronavirus (COVID-19) Dashboard With Vaccination Data, there are 382 vaccine candidates as of March 30, 2023, among which 183 are in clinical trials.

Current COVID-19 vaccine candidates mainly contain the following five designs: inactivated vaccine, protein subunit vaccine, viral vector vaccine, mRNA vaccine, and DNA vaccine, which covers from the first-generation vaccine platforms (whole virus-based or protein-based vaccines) to the next-generation vaccines (nucleic acid vaccine). Classical vaccine platforms have contributed to major public health breakthroughs, such as the first vaccine which eradicated the infectious smallpox [22]. However, certain limitations are associated with several of these platforms that make them less amenable to fast vaccine production in dreadful COVID-19 pandemic. The main advantage of next-generation vaccines is that they can be developed based on sequence information alone, instead of depending on the ability to culture the virus. This makes these platforms highly adaptable and speeds up vaccine development considerably, thus the majority of current COVID-19 vaccines involve the next-generation platform as shown in Fig.2.

In China, there are a range of COVID-19 vaccines in various designs on the market or in late phases of clinical trials (Tab.1).

3.1 Inactivated vaccine

Among various vaccine platforms, inactivated vaccine is the most traditional one with mature techniques. The common use of inactivated hepatitis B vaccine [38], inactivated polio vaccine [39], inactivated enterovirus 71 (E71) vaccine and diphtheria vaccine [40] suggest the huge role of inactivated vaccine in the prevention and control of infectious diseases. Through physical, chemical, and other methods, such as formaldehyde, glutaraldehyde, β-propiolactone, and ultraviolet (UV), viruses are processed to eliminate infectivity and pathogenicity while preserve immunogenicity [41]. As mentioned above, various proteins including the S protein, E protein, M protein, N protein and non-structural proteins trigger a series of immune responses based on non-specific immune cells, pro-inflammatory chemokines, cytokines, T cells, binding and neutralizing antibodies, etc. [42,43]. Containing all components of SARS-CoV-2, inactivated vaccines present varieties of antigens to the host, and are supposed to induce broad and comprehensive immune responses, with humoral immunity being the most prominent. COVID-19 convalescent plasma (CCP) treatment has been proved to effectively ameliorate the clinical and biological parameters of severe COVID-19 patients [44] without significant ADE induced [45], indicating the potential efficacy of inactivated vaccine-triggered humoral immunity and few safety concerns on heterogeneous antibodies. Adjuvants are usually needed to enhance the immunogenicity of inactivated viruses and promote a strong immune response [46].

Several vaccine products based on inactivated SARS-CoV-2, such as BBIBP-CorV developed by Sinopharm/Beijing Institute of Biological Products (China) [47], CoronaVac developed by Sinovac Biotech (China) [48,49], and BBV152/Covaxin developed by Bharat Biotech (India) [50], have shown good safety and protective efficacy in clinical trials, and been approved for emergency use by WHO.

As the first COVID-19 vaccine approved for application in China, BBIBP-CorV is one of the most widely administered COVID-19 vaccines, and has been included in WHO’s Emergency Use Listing (EUL) and employed in 119 countries and regions. To meet the urgent demand for vaccines early in the pandemic, the inactivated vaccine platform was chosen by Sinopharm based on the understanding of immunological mechanism of COVID-19, the successful experiences in preventing against a series of infectious diseases and the potential for rapid development. In the design of BBIBP-CorV, the HB02 strain with highly efficient proliferation and high genetic stability was inactivated by beta-propiolactone, and aluminum hydroxide was used as the adjuvant [23]. High levels of neutralizing antibody and highly efficient protection against SARS-CoV-2 challenge were induced by BBIBP-CorV in six mammalian species, and no observable ADE or immunopathological exacerbation occurred [23]. In a phase 3 trial conducted in the United Arab Emirates (UAE), the efficacy of BBIBP-CorV in preventing symptomatic infections was 78.1% (95% CI 64.8%–86.3%) through a recommended two-dose administration [25]. In the same study, the total adverse reactions were reported as 41.7% (slightly lower than the 46.5% of alum-only group) within the first 7 days after each injection, and most of the adverse reactions were mild to moderate. No serious adverse events were reported within 28 days after vaccination. In a retrospective cohort study containing 3 147 869 adults in a 1:1 ratio of vaccinated and unvaccinated, the vaccine effectiveness of BBIBP-CorV was summarized to be 79.6%, 86%, and 84.1% against hospitalization, critical care admission, and death due to COVID-19, respectively [51].

Another inactivated vaccine applied on a large scale in China is CoronaVac, with a pooled vaccine efficacy for the prevention of symptomatic COVID-19 estimated to be 67.7% based on three phase 3 trials [24]. Data of the phase 3 clinical trial showed that a two-dose injection of CoronaVac induced robust humoral responses and Th1-biased cellular immune responses [52]. Furthermore, a phase 4 clinal trial confirmed the robust lot-to-lot consistency, immunogenicity, and safety of CoronaVac, indicating the feasibility for large-scale use [53].

In addition, WIBP-CorV/COVILO, an inactivated vaccine based on the WIV04 strain of SARS-CoV-2 developed by Sinopharm/Wuhan Institute of Biological Products, showed a vaccine efficacy of 72.8% and a similar safety level to BBIBP-CorV in the phase 3 study, and has received conditional market approval by Center for Drug Evaluation (CDE) [25]. The SARS-CoV-2 inactivated vaccines named “KCONVAC” and “IMBCAMS, China” were developed by Shenzhen Kangtai Biological Products and Institute of Medical Biology, Chinese Academy of Medical Sciences, respectively, and have both been authorized for emergency use in China.

Inactivated vaccine is thought to be highly safe because of the use of non-infectious antigen. No obvious ADE or immunopathological exacerbation has been reported in the clinical trials of COVID-19 inactivated vaccines. Moreover, strong stability is a feature of inactivated vaccine over live-attenuated vaccine, which facilitated the storage and transportation of COVID-19 inactivated vaccines during the pandemic. Compared to vaccines consisting of certain parts of the pathogen, inactivated vaccine can trigger a broader immune response to provide protection against cross-infection, because of the multiple antigens it contains. Selection of viral strain with high proliferative efficiency and high genetic stability is of vital importance since it is directly related to the immunogenicity [54]. Proper inactivation process is a key point as well. Host humoral immunity would be weakened if the vital epitopes are destroyed, leading to possibly attenuated immune protective efficacy of the vaccine [55]. Generally, multiple doses are needed for inactivated vaccine to achieve optimal protection.

3.2 Protein subunit vaccine

Unlike inactivated vaccines, key immunodominant fragments of the virus are used as antigens in protein subunit vaccines. Generally, adjuvant is needed to enhance the antigen immunogenicity and promote a strong immune response. Similar to inactivated vaccines, multiple immunizations are needed for better performance.

NVX-CoV2373 in WHO’s EUL was developed by Novavax, and manufactured by Novavax with the name of Nuvaxovid. NVX-CoV2373 is the nanoform of modified trimer full-length S protein of the prototype strain in combination with a novel saponin adjuvant Matrix-M [56]. Its protection rate reached 89.3% in a large-scale phase 3 clinical study with 30 000 subjects in the UK [57]. Furthermore, in contrast to the storage requirements of mRNA vaccines at ultra-low temperature, NVX-CoV2373 remain stable in the regular cold-chain facilities (2 °C–8 °C) for up to three months, making them easier to store and transport. In China, a dimeric form of RBD was applied as the antigen of the recombinant protein vaccine ZF2001, which was developed by Zhi Fei Biological and Institute of Microbiology, Chinese Academy of Sciences, and has been approved for emergency use [58]. In a phase 3 clinical trial, ZF2001 showed the protective efficacy against any forms of infection (81.43%), occurrence of death related to COVID-19 (100%), respectively [29]. High safety was shown, with no vaccine-related serious adverse events reported.

Recombinant antigens used for COVID-19 vaccines could be roughly divided into S protein-based and RBD-based. The complete S protein is able to induce stronger immune responses because of its multiple epitopes [59], while the produced non-neutralizing antibodies might be related to ADE or harmful immune responses. Moreover, the acquisition of the correct conformation of full-length S protein places high demands on eukaryotic cell expression systems, resulting in higher costs for vaccine development [59]. RBD, as a key neutralizing epitope in spike, induces 90% neutralizing antibody and T cell immune response, and may be a safer antigen target than S protein [60]. Protein subunit vaccines support for global sharing of safe, effective, and affordable vaccine doses. The rational design of antigen and adjuvant is of vital importance for further accelerating the development of recombinant protein vaccine.

3.3 Viral vector vaccine

Viral vector vaccines use a virus as a vector to deliver antigen genes, and express and release the antigens in the vaccine recipients, thus stimulating host immune responses. Viral vector vaccines can be further divided into non-replicating viral vector vaccines and replicating viral vector vaccines, and the former have been used more widely for safety concerns [61].

Adenoviruses, non-enveloped double-stranded DNA viruses with a packaging capacity of up to 7.5 kb of foreign genetic information, are used in most COVID-19 vaccines as vectors to express S protein or RBD domain [62,63]. At the beginning of the COVID-9 pandemic, vaccines based on the S protein gene sequence of the pandemic strain, including Ad5-nCoV and AZD1222 were developed. As demonstrated in Tab.1, AZD1222 Vaxzevria, Covishield (ChAdOx1_nCoV-19), Ad26.COV2.S and Ad5-nCoV/Convidecia are using various adenoviral vectors to express the full-length S protein, inducing highly effective humoral and cellular immune effects after 1–2 doses [64,65]. A domestically used vaccine in China, Ad5-nCoV, was developed by Military Medical Research Institute and CanSino Biologics. According to the clinical data (NCT04526990), it could generate a vaccine efficacy of 65.7% against symptomatic COVID-19 [66]. However, in an international, multicenter, randomized, double-blinded, placebo-controlled phase 3 trial, after a single dose of Ad5-nCoV, mild adverse events were reported in higher levels than those of placebo group [32].

Vaccinia viruses and influenza viruses are also frequently-used viral vectors for vaccine development. COVID-19 vaccines based on the modified vaccinia virus Ankara (MVA) vectors, such as COH04S1 (MVA-SARS-2-S), MVA vector expressing a stabilized SARS-CoV-2 spike protein, and MVA-SARS-2-ST Vaccine, are in their early clinical phases currently. Constructed of a synthetic attenuated MVA vector co-expressing SARS-CoV-2 S and N proteins, COH04S1 was reported to be safe and induce both antibody and T cell responses in an open-label and randomized, phase 1 trial [67]. H3N2 recombinant attenuated influenza virus vector with modified NS gene coding for the N protein fragment of SARS-CoV-2 is developed by Research Institute of Influenza, and is in phase 1/2 clinical stage (NCT05696067). Encouragingly, influenza virus vector COVID-19 vaccine for intranasal spray developed by WANTAI BioPharm, Xiamen University, and University of Hong Kong has been approved for EUA in China. This vaccine was designed to comprise H1N1 influenza virus vector expressing the SARS-CoV-2 S RBD (DelNS1-nCoV-RBD LAIV), and was proved to be safe and possess mucosal immunogenicity via intranasal administration [68].

Viral vector vaccine has great advantage of inducing both humoral and cellular immune responses, indicating that a single immunization is sufficient. With the similar capability of infecting host cells and amplifying antigens, viral vector vaccine could also induce high protective efficacy as live-attenuated vaccine. Meanwhile, higher safety is observed in viral vector vaccine due to the well-researched vectors with low or no pathogenicity. When it refers to COVID-19 vaccines, viral vector vaccine has demonstrated higher stability and comparable efficacy than mRNA vaccine [62]. The production process of virus vector vaccines is relatively simple and can be easily scaled up, making it a viable option when vaccines are in short supply. However, the immune system might be less reactive to the vaccine if the vaccinator has been infected with the vector virus before, which is attributed to pre-existing immunity and should be of concern, especially in the elderly. Emerging strategies including the use of less-prevalent viruses, nonhuman viruses or chimeric viruses, and higher dosing regiments have been proposed to circumvent the issue [62].

3.4 Nucleic acid vaccine

Different from vaccines employing either whole or parts of the pathogen as antigens, the key component of a nucleic acid vaccine is a section of genetic material encoding specific proteins. Nucleic acid vaccine is divided into mRNA vaccine and DNA vaccine. mRNA vaccine is based on mRNA fragments encoding protein antigens (such as the S protein or RBD of SARS-CoV-2) [69]. DNA vaccine is constructed by inserting the DNA sequence encoding the specific antigen protein into a eukaryotic expression vector [70]. After injection into the body, the target genes are transcribed and then translated by host cells to produce antigens, thereby inducing both humoral and cellular immune responses [71,72].

BNT162b2 and mRNA-1273 are at the head of the development runway, both employing lipid nanoparticle (LNP) delivery systems for encapsuling mRNA fragments encoding the full-length S protein of SARS-CoV-2. A two-dose immunization of BNT162b2 provided 95% protection against COVID-19 with similar safety level to other viral vaccines [73]. mRNA-1273 also showed a high protective efficacy of 94.1% in the phase 3 trial [73]. Developed by CSPC Pharmaceutical Group, SYS6006 became the first domestic COVID-19 mRNA vaccine authorized for emergency use in China in 2023. mRNA fragments designed on the basis of S protein sequence of the prototype SARS-CoV-2 strain and key mutations of some variants were used to form nanoparticles with the aid of lipids [34].

As a novel technology, mRNA vaccine has several advantages: no infection, long-term immunity, and short development and production cycle [74,75]. With lower molecule weight, mRNA vaccine can be delivered directly into the host cells and instruct the antigen production without reduced efficacy due to antivector immunity [76]. However, the instability of RNA itself will seriously affect the effectiveness of vaccine, which also poses a high requirement of storage temperature [77,78]. Furthermore, adverse events and a higher risk of medically attended events than other COVID-19 vaccines have been reported for mRNA vaccine. It is believed that these adverse effects are directly related to mRNA, and optimizing of the dosage may help to improve.

No DNA vaccines are currently on the market, while most of candidates in clinical trials choose the S protein as the antigen [75]. INO-4800 developed by Inovio Pharmaceuticals and Advaccine Biopharmaceuticals (China) and ZyCOV-D developed by Zydus Cadila are DNA vaccines with the target antigen of full-length S protein, and both induce high-titer neutralizing antibodies and Th1-biased cellular immune responses in vaccine recipients [79–81]. ZyCOV-D has received approval in India, representing a historic first for DNA-based COVID-19 vaccines [82].

Distinct from mRNA vaccine, DNA vaccine is more stable at ambient temperature, and is capable of expressing antigens in their native conformation, thus triggering CD8⁺ T cell responses [83], making it possible to transport without cold chain [84]. Besides, good tolerance and safety of DNA vaccine have been proved in a series of animal and human trials [85]. However, inadequate clinical benefits elicited by DNA vaccine still remain a big challenge for practical DNA vaccine use [75].

3.5 Live-attenuated vaccine

By reverse genetics or adaptation to reduce virulence, virus with weakened or no virulence is obtained to construct live-attenuated vaccine [86]. According to the attenuated approaches used in existing and developing live-attenuated vaccines, such as those against the measles virus and rubella virus, the main manufacturing processes include codon pair deoptimization, virulence gene knockout, adaptation to cold culture conditions, and passages in non-human animals [86,87]. Owing to its similarity to naturally infected virus, live-attenuated vaccine usually shows high immunogenicity and elicits both humoral and cellular immunity. The effective protection induced by replication of live-attenuated viruses in the host could last for a long period, even without the need for a booster immunization. Although both live-attenuated vaccine and inactivated vaccine use whole pathogen as antigen, their characteristics differ significantly, mainly due to differences in viral activity. Unfortunately, the potential risk of pathogenicity and mutation has hindered the development of live-attenuated vaccine against virus causing a lethal disease [88]. The high requirements for storage and transportation conditions to keep the viruses alive are also challenges for the application of live-attenuated vaccine. For COVID-19 live-attenuated vaccines, no products have been approved due to likely safety concerns and the long development cycle. Through a live-attenuated codon-pair-deoptimized virus approach, COVI-VAC was developed by Codagenix/Serum Institute of India, and is currently in phase 3 clinical trials [89].

4 Effects of SARS-CoV-2 variants on vaccine efficacy and response strategies

Thanks to the global vaccination of the first-generation vaccines developed in mature platforms, as of April 2023, 65.45% of global population were prime vaccinated. In China, the main shots deployed are inactivated vaccines developed and manufactured domestically, e.g., BBBIP-CorV from Sinopharm. About 90% of the population has received at least two doses of inactivated vaccines, while the impact of mutated VOCs should not be ignored. So far, five major VOCs (Alpha, Beta, Gamma, Delta, and Omicron) have been recognized by the WHO, their epidemiological characteristics are summarized in Tab.2.

The emergence of SARS-CoV-2 VOCs has resulted in corresponding new waves of global infection. In 2020–2021, the increased transmissibility and immunity evasion of Beta and Delta VOC were accompanied with long duration of infectivity and high reinfection rates [90–92], and led to the new wave of infection in the globe [93,94]. By the end of 2021, a new VOC named Omicron variant (B.1.1.529) appeared, which contains 32 amino acid mutations in the spike, leading to increased transmission and reinfection rates [95,96], then replacing Delta as the dominant strain in the world. Omicron VOCs now become the globally predominant lineage. Recent study using an AI model predicts that Omicron BA.1 will be 10 and 2.8-fold more infectious than the wild-type strain and Delta variants respectively [97]. Since then, multiple Omicron subvariants have emerged, in the first months of 2022, an Omicron subvariant called BA.2 (B.1.1.529.2) began to spread even faster than other Omicron subvariants [98], followed by BA.4 and BA.5, only to be outdone by the BQ subvariants. Some of them more adapt than others at evading immunity from vaccination or previous infection [99,100]. In early 2023, a new Omicron subvariant called XBB.1.5, the most transmissible strain of the virus so far [101], was predominant in the globe. Researches are working arduously for a better understanding of XBB.1.5 and other Omicron subvariants, such as BQ 1.1 [102], which continue to circulate.

As an important dominant antigen of the SARS-CoV-2, S protein determines the hosts and specificity of the virus, and is also a vital site for the production of neutralizing antibodies (nAbs) in the hosts [22]. SARS-CoV-2 based on RNA genomes exhibit remarkably high mutation rates [103]. So far, several mutated strains have emerged with increased viral infectivity and transmissibility [104], resulting in immunity evasion against protection induced by prior infection or vaccination [105]. Muik et al. tested serum samples from 40 participants who were vaccinated with the Pfizer/BioNTech mRNA vaccine (BNT162b2) with pseudoviruses of B.1.1.7 and wild-type strain. Even though there was a slight reduction, the immune sera overall preserved neutralizing titers against B.1.1.7 [106]. However, Jangra et al. reported a 3.4-fold reduction when the E484K rSARS CoV-2 virus was used in neutralization assays for sera samples from five individuals who received two doses of the Pfizer/BioNTech vaccine [107]. Nonetheless, in the study by Penny et al., most of the convalescent serum suffered less than a 4-fold reduction in total binding activity, suggesting that a considerable non-neutralizing antibody component is still able to bind the B.1.351 spike, which indicates the prospect of reinfection with antigenically distinct variants [108]. In terms of Omicron and its subtype variants, no effect against the Omicron variant was noted from 20 weeks after two ChAdOx1 nCoV-19 doses, whereas vaccine effectiveness after two BNT162b2 doses was 65.5% (95% CI 63.9 to 67.0) at 2 to 4 weeks, dropping to 8.8% (95% CI 7.0 to 10.5) at 25 or more weeks [109]. Both BA.1 and BA.2 have been shown to evade neutralizing antibodies elicited by a primary series of mRNA (mRNA-1273 or BNT162b2), vector-based (Ad26.COV2, Sputnik V, or ChAdOx1 nCoV-19), subunit (NVX-CoV2373), and inactivated (BBIBP-CorV) vaccines [110].

To date, with the rapid change of epitopes on SARS-CoV-2, the marked loss of neutralization ability and decline in the protective efficacy of current vaccines indicates the potential immune escape of SARS-CoV-2 VOCs, leaving the world less confident that global vaccination routine is sufficient to control SARS-CoV-2 infection [120,121]. Vaccine effectiveness of full vaccine against Alpha, Beta, Gamma, Delta, and Omicron variants was concluded to be 88.0%, 73.0%, 63.0%, 77.8%, and 55.9% by a meta-analysis on 11 COVID-19 vaccines [122]. Neutralizing monoclonal antibodies and bispecific antibodies elicited by the inactivated vaccine BBIBP-CorV were proved to possess broad and potent neutralizing activity against a series of variant strains including XBB.1.5, BQ.1.1, and BN.1, indicating the potential application for the broad spectrum of protection [123]. Overall, the epidemiological characteristics of VOCs have changed considerably, may have a higher transmission capacity or be more pathogenic, hence impair the effectiveness of current drugs and vaccines [124]. To fight against the fluctuating COVID-19 pandemic, developing universal vaccine with enhanced magnitude and breadth of neutralizing capability is imperative [59].

Estimating vaccine effectiveness (VE) against Omicron variant has been challenging by its enhanced transmissibility and escape of vaccine-derived immunity. Compared with the wild-type virus, serum neutralizing antibody titers against Omicron BA.2 were significantly reduced in individuals recently vaccinated with three doses of CoronaVac, with antibody titers was below the protective threshold [125], suggesting that first generation vaccines have limitations in preventing SARS-CoV-2 variants infection and transmission in the long-term. However, a recent VE study of the CoronaVac vaccine during the same BA.2 epidemic in Hong Kong showed strong protection against severe illness and death [126]. As previous study suggested, neutralizing antibody titers may underestimate the protective effect conferred by whole-virus inactivated vaccines, which provides the host immune system with multiple pathways including T cell immunity and antibody-dependent cytotoxicity [127]. In addition, since strong protections against hospitalization and death can be restored through BNT162b2 or CoronaVac [126,128,129], booster vaccination remains a key tool to reduce the burden and mortality of COVID-19 on the healthcare system. The global COVID-19 vaccination during 2020–2021 has been fundamental in providing supplemental protection against COVID-19-related hospitalization, admission to the intensive care unit (ICU), and death—especially among the elderly and those most at-risk and vulnerable to COVID-19, protecting health systems and reducing widescale social disruption.

In the beginning, current mRNA vaccine was reported to reach the “immune ceiling” after the third dose, therefore three doses of the vaccine was proven to provide sufficient protection against Omicron [130]. Recent researches showed the heterologous-boosted strategy could induce higher neutralizing antibody titers against the WT isolate and all Omicron subvariants than groups that had received three doses of the same inactivated vaccine [131]. Meanwhile, the classical protein subunit vaccine (ZF2001) has been proved to be a potential booster, which could induce increased titers of neutralizing antibodies against Omicron variants through the administration of multiple booster doses and immune-maturation methods [132]. However, as the antibodies induced by 3-dose vaccination diminish over time [118,119], some countries have approved the implementation of a fourth dose of vaccine [133,134]. A fourth dose of vaccine is proved to be beneficial in certain groups, such as the elderly and immunocompromised population [135]. In compensation of lower protection against Omicron infection, the components of the currently available COVID-19 vaccines need to be updated to provide additional support for a mix-and-match approach. According to the guidelines of China authorities in 2022, fully vaccinated people can choose to receive a different shot from their original inoculation as a booster in a process called sequential immunization. Compared with a homologous booster vaccination strategy, sequential immunization can improve the breadth, strength, durability and functionality of herd immunity [136].

Currently, Chinese vaccine manufacturers including Sinopharm, Sinovac Biopharm, CanSino, Abogenbio, and Stemirna are developing specific vaccines for Omicron. So far, a few new vaccines manufacturers have been approved for the emergency use authorization (EUA) as described in Tab.3. Since inactivated virus retains stable immune activity, polyvalent vaccines are available to further accelerate the development of safe and effective tools. Results showed that the HB02 + Delta + Omicron trivalent vaccine provided broad-spectrum protection against HB02, β, Delta, and Omicron viruses. In addition, different polyvalent COVID-19 inactivated vaccines could enhance cellular immunity, providing ideas for antigen design for future COVID-19 vaccines [137].

5 Future direction of COVID-19 vaccines

Overall, the emergence of the Omicron and sublineage variants suggest that efforts to end the COVID-19 pandemic may be hampered by trends in viral mutation. It is critical to develop a broad-spectrum preventive vaccine against the highly mutated SARS-CoV-2 variant with safety and efficacy. The novel vaccine research is urgently needed to demonstrate the evolutionary design in a more refined way.

5.1 Optimized pre-fusion antigen

Attachment and entry are critical to the SARS-CoV-2 life cycle, making S protein a primary target for key vaccine antigen development [13]. Stable pre-fusion conformations of fusion proteins are desirable for vaccine development, inspired by previous successful applications of proline replacement in class I fusion proteins including HIV-1 Env [138], influenza HA [139], RSV F [140], Lassa GPC [141], MERS-CoV and SARS-CoV spike [142]. S-2P contains two consecutive proline substitutions in the S2 subunit, alternating between the central helix (CH) and the heptad repeat 1 (HR1), which is particularly pertinent to pre-post spike transition. Importantly, this S-2P design was successfully transplanted into the SARS-CoV-2 spike (SARS-CoV-2 S-2P), high-resolution cryo-EM structures verified that 2P substitutions did not lead to any unintended conformational changes. Based on S-2P, Xie et al. reported S-6P that increased spike expression and/or stability relative to the S-2P base structure. Combining the four proline substitutions into a single construct called HexaPro stabilized the pre-fusion S conformation and increased its expression by 10-fold. The high-resolution cryo-EM structure of this variant confirms that proline substitutions adopt the designed conformation and do not destroy the conformation of the S2 subunit, thus well-preserved its antigenicity [143]. These works focus on pre-fusion antigen stabilization, will continue to facilitate future viral subunit vaccine, and have broad implications for next-generation vaccine design.

5.2 Chimeric antigen strategy

Existing data indicate that RBD protein stimulates the production of a diverse range of neutralizing antibodies in the body, and the neutralizing efficacy is not affected by mutations in the NTD site [144]. Therefore, using RBD as a template for broad-spectrum antigen design has great development potential. Inspired by the research on β-CoV antigen design [58], several chimeric antigen candidate vaccines based on RBD-dimer were developed in use, one chimeric antigen containing Beta-Prototype (PT) or Delta-Omicron RBD dimer was designed [145]. In addition, NVSI-06-08 developed by Sinopharm, contains a mixed immunogen integrated prototype, Beta, and Kappa RBDs trimer. Statistics have shown this recombinant vaccine provide better neutralizing response against Beta and Delta variants compared with homotypic trimer constructed by prototype strain alone [146]. In addition to RBD epitopes, chimeric immunogen design could apply to the whole spike ectodomain. S-Trimer, a native spike-like trimer based on trimer-Tag technology, induces protective immunity [147]. The chimeric antigen design strategy is not only restricted to the S1 region, the partially neutralized region of the S2 region has also been considered as a chimeric antigen composition [148]. He et al. developed a subunit vaccine named RBD-HR/trimer by directly linking the sequence of Delta variant RBD in tandem with HR1 and HR2 in SARS-CoV-2 S2 subunit [149], which provided complete protection against live Omicron and Delta variants.

5.3 Size-up multiple antigen display

RBD, as a sizzling target of SARS-CoV-2 antigen candidate, can minimize the ADE effect and induce neutralizing antibody response. However, RBD is too small in size to elicit durable immune response. Borrowed from study on influenza [150] and HIV-1 [151], nanoparticles were used as scaffold so that antigen can be intensively displayed, which strongly improved antigen captured by immune system. Metal-based nanoparticle is an attractive platform for vaccine production, recent vaccine studies reported improvement in immunogenicity of the RBD/Spike by cross-linking the RBD/S monomer to nanoparticles on ferritin scaffold [152–155]. Via covalent conjugation using the SpyTag-SpyCatcher system, this technology provides a reference for both subunit vaccine and mRNA vaccine. Sun et al. designed a type of mRNA vaccine based on the encoded self-assembled nanoparticle trimeric RBD (TF-RBD), which produced broad-spectrum neutralizing antibodies against the α (B.1.1.7) and β (B.1.351) variants [156]. Apart from these, RBD-Fc fusion protein, produced by fusing a functional protein (e.g., RBD) molecule with the Fc fragment of immunoglobulins (IgG, IgA, etc.), not only retains the immunogenicity, but also has some antibody properties, such as prolonging the half-life by binding to the relevant Fc receptors and triggering antibody-dependent cell-mediated cytotoxic effects. Recent studies have shown antisera induced by SARS-CoV-2 RBD-Fc vaccine via cross-neutralizing activity against SRAS-CoV-2 variants and spectrum B β-coronavirus [157]. To update with Omicron variants, researchers have further designed a self-assembled ferritin nanoparticle (FNP) vaccine against the SARS-CoV-2 Omicron variant. Based on 24 ferritin copies containing an N-terminal protein A tag to form the structural scaffold, the SARS-CoV-2 Omicron RBD with an Fc tag at the C-terminal (Fc-RBD Omicron) served as the immunogen. Results demonstrated FNP-Fc-RBD with Omicron vaccine induced antigen-specific humoral and cellular responses to multiple SARS-CoV-2 VOCs [155].

5.4 Mosaic vaccines

Among all novel antigen modification, mosaic nanoparticle is recognized as the most promising nanoparticle construction form. Bale et al. proposed I53-50 NP, an accurate design of a two-component protein complex consisting of an icosahedral trimer I53-50A and a dodecahedral pentamer I53-50B co-assembled in vitro [158]. To address the SARS-CoV-2 VOCs challenge, the research team innovatively designed a tetravalent mosaic-type recombinant protein nanoparticle vaccine that includes a total of 60 recombinant spike proteins (S-6P, HexaPro) of four SARS-CoV-2 variants. This quadrivalent chimeric nanoparticle vaccine produced a very strong and higher antibody response to immune stimulation after one dose of immunization of mice compared to the prototype HexaPro and monovalent HexaPro nanoparticle vaccines, with only a slight reduction in neutralization titers against the original strain. In addition, this vaccine could induce higher neutralizing antibody titers against the other variants (Alpha, Beta, Gamma, Delta, and Eta), providing broad-spectrum immune response against SARS-CoV-2 variants [159]. The mosaic NP platform was further designed against sarbecovirus challenge [160].

5.5 Discovery consensus sequence of virus evolution

Even when vaccine companies can update vaccines based on changes in virus variants, they tend to lag behind the emergence of variant viruses. Manufacturers should not only timely update and design vaccines against mutant strains of viruses with severe immune escape, but also consider the importance and feasibility of a universal vaccine to fight both the current circulating strains and the possible variants of the future. It is speculated that such mutations found in the RBD and NTD of the SARS-CoV-2 VOCs are responsible for increased resistance to serum and monoclonal antibodies (mAbs) [161]. Assisted by reverse vaccinology and immune-informatics approaches, multiple conserved epitopes were discovered from COVID-19 subjects. CV3-25, an anti-S2 mAb, displayed cross-neutralization against Beta/Delta/Omicron variants, along with several mAbs binding to the stem helix at the base of S2 spike, all showing a certain degree of cross-neutralizing activity of CoV [162]. CV3-25 also possessed cross-reactivity against some β-CoVs (OC43 and HKU1) [163]. S2 subunit was determined to be a highly-conserved epitopes among all variants, which could direct to SARS-CoV-2/sarbecovirus universal vaccine design.

5.6 Other strategy

Existing vaccines use at least one of four approaches: nucleic acid vaccines with primarily mRNA, inactivated vaccines using the whole virus itself, protein vaccines consisting of the spike protein or RBD, and viral vector vaccines. The next generation of vaccines may involve tweaks to these designs or changes to delivery mechanisms that may improve performance. Self-amplifying RNA vaccines (saRNA vaccines) may make vaccines cheaper and more effective while minimizing side effects, in that smaller and potentially less doses of saRNA vaccines can achieve the same or even stronger immune response than traditional mRNA vaccines [164]. The marked improvement in administration route is favorable to treatment and control of COVID-19. Several vaccine candidates in development can be orally administered, aerosolized or administered nasally, which may not require to be administered by a health care professional, with the potential to induce mucosal protection in the respiratory system [165]. Some research teams are also developing “swallowable” and pill formulations of the vaccine, which would also make it easier for the public to self-administer the vaccine. Data from animal studies suggest this may be possible [166], and at least five nasal vaccines have been approved for use—two in China and one each in India, Iran, and Russia. However, no data are available on whether these vaccines are superior to injections in reducing viral infection or transmission. Moreover, the role of immunoinformatics in identifying immunogenic peptides as potential vaccine targets involves databases and the prediction and characterization of epitopes that can be used to design future coronavirus vaccines [167].

6 Conclusions

In the global combat against SARS-CoV-2 and VOCs, promising vaccines and optimized vaccination strategies in many countries, including China have done remarkably well with national vaccination efforts. With comprehensive advantage in R&D, production capacity and industrial development, Chinese COVID-19 vaccine candidate based on the inactivated whole SARS-CoV-2 virus is safe and elicits sufficient antibody response to protect people from the SARS-CoV-2 pandemic. Moreover, the heterologous booster strategy was proposed by Chinese health agencies as a significant method for individuals previously primed with two doses of an inactivated COVID-19 vaccine. Among diverse vaccine platforms, the next-generation vaccine, including advanced mRNA and novel vectored vaccine, has been used on a large scale in healthy people for the first time, which demonstrated exhilarating effectiveness in both responsiveness and immunogenicity. Compared with traditional vaccine products, the outstanding advantage of these next-generation vaccines is the ability of antigen-modification for controlling prototype and mutated variants epidemic, the development period for the novel vaccines has been obviously reduced by 12 months relative to the cycle of conventional vaccines, and is capable to keep up with circulating antigen mutation. The intractable Omicron variants have been a real push for the novel vaccine platform development, which has attracted extensive attention worldwide as a complicated task.

For a more rapid public health response to a disease like COVID-19 in the future, there are more aspects of vaccine development that are worth continuous investigating. One is the innovative enrichment of existing technology platform, the breakthrough in traditional inactivated vaccine platform provides huge support in meeting global demand of COVID-19 vaccines. Meanwhile, other vaccine products in different routes are also helpful in combating SARS-CoV-2 VOCs as prime or booster candidates. These collaborative planning are critical for fully-vaccination covering developed countries and the rest of the world likewise.

Owing to the limited application scope of the licensed vaccine against SARS-CoV-2, a case in point is elderly and immunodeficient population. The emergence of SARS-CoV-2 VOCs has raised questions about what can offset for the weakness of vaccination alone. In 2022, Ambavir monoclonal antibody and Remdesivir monoclonal antibody combination therapy was proposed in China. With only one injection, it not only reduced the risk of hospitalization and death by 80% for COVID-19 patients, but also promoted immune response in both early and late stages of the disease. The advantages of neutralizing antibody drugs are intuitive with stability and direct Spike-targeted capability, while the virus mutation would inevitably diminish its efficacy. On the path of COVID-19 drugs, small molecule drugs seem to distinguish themselves in the competition, as represented by Pfizer’s Paxlovid (nirmatrelvir + ritonavir), since the targets of small molecule drugs are more conservative and less prone to mutation. A study published earlier this year showed that the efficacy of antiviral drugs was largely ineffective against the Omicron variants, while Molnupiravir developed by Merck Sharp & Dohme and Remdesivir of Gilead were largely effective against the mutated strains [168]. Apart from monoclonal antibodies and convalescent plasma from convalescent patients, AI-aided drug design is a new strategy for COVID-19 drug research, while many small molecules and peptides against viral targets have now been predicted, since these platforms are believed to be used as potential techniques against future epidemic or pandemic [169].

Supplemented by a combination of broad-spectrum antibiotics, antivirals, convalescent plasma, and traditional Chinese medicine (TCM) [170], the mainstream strategy in China for COVID-19 control and prevention is vaccination. To cope with the pathogen yet to emerge, despite those advanced technologies that are demanded for protecting individuals from the epidemic or pandemic, mature strategies including inactivated vaccine platform are still in need for quick reaction to unknown infectious diseases. We expect that with these collaborated efforts, more “weapons” could be put on the market on a large scale, and make contributions to ensuring human public health safety.

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