Understanding the mechanisms for COVID-19 vaccine’s protection against infection and severe disease

ABSTRACT

Introduction

Multiple COVID-19 vaccines have been approved and employed in the fight against the pandemic. However, these vaccines have limited long-term effectiveness against severe cases and a decreased ability to prevent mild disease.

Areas covered

This review discusses the relevant factors influencing the efficacy of the vaccines against mild and severe infection, analyzes the possible underlying mechanisms contributing to the different outcomes in terms of vaccine function and disease progression, and proposes improvements for the next generation of vaccines.

Expert Opinion

The reduced efficacy of the COVID-19 vaccine in the prevention of viral infection is closely related to the emergence of novel SARS-CoV-2 variants and their rapid transmission ability. Fundamentally, the immune responses induced by COVID-19 vaccines cannot effectively halt virus replication in the upper respiratory tract because only a limited number of specific antibodies reach these areas and decrease in concentration over time. However, the established immune response can provide sufficient protection against severe diseases by blocking viral infection of the lower respiratory tract or lung owing to sufficient antibody repertoires and memory responses. Considering this situation, future COVID-19 vaccines should have the potential to replenish the mucosal immune response in the respiratory tract to prevent viral infection.

KEYWORDS:

• COVID-19 vaccine
• mechanisms
• mild disease
• severe disease
• viremia
• virus variants

1. Introduction

Severe acute respiratory syndrome type 2 virus (SARS-CoV-2) has infected over 600 million individuals and has caused more than 6 million deaths globally over the past few years[1]. To fight against the coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, a COVID-19 vaccine was developed and approved for emergency use almost a year after the emergence of the pandemic, breaking the record for vaccine research and development. Multiple COVID-19 vaccines developed by global scientists using a variety of techniques have been approved for mass immunizations. The ability of vaccines in preventing severe disease was widely recognized by the public and health communities; however, real-world use of the currently available vaccines has proven their inability to prevent symptomatic infection and transmission in communities, lowering the prospects of the vaccines in curtailing the pandemic.

Although there are many challenges in the application of COVID-19 vaccines, their effectiveness in preventing severe diseases is still very relevant. Therefore, it is necessary to summarize the current situation and elucidate the possible mechanisms of function of the vaccines against COVID-19. This will facilitate improvement in the next generation of vaccines and will enable the development of vaccines against other possible respiratory viruses. To concisely explain the two distinct prevention mechanisms of vaccines, in this review, ‘infection’ mainly refers to the virus attack on the upper respiratory tract (nasal passages, throat, and trachea), which mostly leads to milder disease; ‘severe disease’ refers to the outcomes of virus attack on the lower respiratory tracts/lung or other organs, which usually require hospitalization or lead to death.

2. Current situations in the application of COVID-19 vaccine – a paradoxical manifestation for the prevention of infection and severe disease

To date, 172 vaccines are being clinically developed globally. Some of these vaccines have been granted emergency use license (EUL) by the World Health Organization or conditional marketing authorizations, with a cumulative total of 7.9 billion doses of vaccination administered globally [2]. The COVID-19 vaccines have been estimated to have prevented death in approximately 20 million people in the first year of use since its launch on 8 December 2020 [3]. However, with the prolonged time after vaccination and the emergence of SARS-CoV-2 variants, the application of the COVID-19 vaccine has encountered some unprecedented circumstances including the reduced ability to prevent infection and interrupt transmission, while maintaining an ability to prevent severe disease or hospitalization. Further research on this contradictory phenomenon could provide information on the protective mechanism of COVID-19 vaccines and facilitate further improvements.

2.1. Rapid decline in capacity to prevent infection – unexpected facts and justifications

The efficacy of various vaccines against viral infections in phase III clinical trials was > 80% for ancestral strains [4]. However, the protective efficacy of this vaccine against infections caused by the variants has decreased significantly. For example, the efficacy of two doses of inactivated vaccine (CoronaVac) to prevent symptomatic infection of Omicron after 180 days was only 8.1% [5]. The two doses of the ChAdOx1 nCoV-19 vaccine (AZD1222) had an even less effect on the prevention of Omicron infection at week 20 after vaccination. The effectiveness of the two doses of BNT162b2 vaccine (Comirnaty) was 65.5% at 2–4 weeks after vaccination and decreased to 8.8% at week 25. This trend was also observed even after the third booster dose with homogenous or heterologous vaccines [6]. In this review, we propose several factors responsible for this phenomenon.

The first factor is the decrease in IgG antibody levels in the upper respiratory tract. SARS-CoV-2 usually first infects the lumen epithelial cells of the upper respiratory tract including the nasal cavity, pharynx, and trachea [7]; therefore, the antibodies or local memory immune responses will determine the outcome of infection. It is well known that nasal infection or vaccination elicits a mucosal immune response, and secretory immunoglobulin A (IgA) is the main functional indicator. However, the current intramuscularly injected vaccines mainly elicit a systemic immune response and circulating immunoglobulin G (IgG) in serum and body fluid are the main functional components [8]. To prevent viral infection, vaccine-induced serum IgG antibodies must gain access to the lumen of the respiratory tract. Although the detailed mechanism of IgG transduction across epithelial cells of the respiratory tract is not clear, some studies suggest that the human neonatal Fc receptor (FcRn) may be involved in this process. For example, Yoshida et al. reported that FcRn, which is expressed in intestinal epithelial monolayers in the mucosa, mediates the transport of IgG across the epithelial barrier into the lumen. The IgG/antigen complex can be recycled by FcRn across the intestinal barrier into the lamina propria for later presentation to CD4⁺ T cells [9]. Li et al. also found that FcRn could mediate bidirectional IgG transport across primary human genital epithelial cells in vitro. Following passive immunization with herpes simplex virus-2 (HSV-2), polyclonal serum WT mice showed higher protection against intravaginal HSV-2 challenge in comparison to FcRn knockout mice [10]. Recently, by mimicking this natural IgG transfer, Ochsner et al. fused the IgG Fc region to the influenza viral hemagglutinin (HA) protein for mucosal immunization. Intranasal immunization with HA-Fc conferred significant protection against lethal challenge with the influenza virus in wild-type mice but not in FcRn-knockout mice. Although current COVID-19 vaccines are designed for delivery via parenteral routes, specific IgG antibodies can gain access to the respiratory tract. Mades et al. detected IgG antibodies in oral and nasal mucosal specimens from all participants following vaccination with a COVID-19 mRNA vaccine [11].

IgG antibodies in the mucosa of the respiratory tract and the alveolar epithelial surface can prevent viral infection by blocking virus attachment or function as opsonin/agglutinins as part of the local host defense in the airways [12]. However, studies on human respiratory syncytial virus (HRSV) in humans have suggested an antibody concentration gradient of approximately 350:1 between sera and nasal washes [13]. Furthermore, the therapeutic effect of passive antibodies in reducing HRSV replication in cotton rats was 160-fold greater when administered directly to the respiratory tract than when administered systemically [14]. Consequently, high serum antibody titers are necessary to protect the respiratory tract. However, the circulating IgG repertoires in the body declined over time after vaccination until a further booster dose or contact with the pathogens. Therefore, the passive transport of IgG antibodies to the lumen of the respiratory tract will decrease accordingly, leading to reduced efficiency against viral infection.

The second factor is the emergence and prevalence of mutant viral strains. An increasing number of mutation sites have been observed between the variants and ancestral strains, leading to the evolution of mutant virus strains. The currently circulating Omicron variant, has 18,261 nucleotide mutation sites, and more than 97% of the mutations are located in the coding region, and 31 mutations are located in the S protein receptor binding domain (RBD) [15], resulting in less cross-protection against variant viruses from the prototype vaccine. Preliminary studies have shown that the neutralizing titers of three doses of the BNT162b2 vaccine against the Omicron mutant virus decreased approximately 40-fold compared to the titers tested against the prototype virus [16].

The third possible factor is the stronger contagious Omicron strain, owing to its altered mechanism of entry into host cells. Previous SARS-CoV-2 variants rely on the receptor of angiotensin-converting enzyme 2 (ACE2) to bind to host cells, and transmembrane serine protease 2 (TMPRSS2) is highly expressed on lung epithelial cells to cleave the spike proteins and facilitate viral entry. However, Omicron variants infect cells mainly through endocytosis mediated by nucleosomes without the need for TMPRSS2 [17]. Once they enter the epithelial cells, the virus rapidly replicates in the upper respiratory system compared to the previous variant and causes milder symptoms in the lung [18]. This unique mechanism of viral entry resulted in a decrease in the latent period from 4–12 days to an average of 3.4 days [19,20], leaving insufficient time for the activation of protective memory immune cells against infection.

Immune memory has been shown to provide long-lasting protection against viral infection in previous vaccines. For upper respiratory tract infections, tissue-resident memory (T_RM) T cells in the respiratory tract are considered a vital memory T cell subset that can confer optimal protection against encountered pathogens [21]. However, it remains to be investigated whether current vaccines given by intramuscular routes can effectively activate T_RM in the human upper respiratory tract. Minne et al. reported that the currently injected influenza vaccine can only elicit relatively poor mucosal immune responses and T_RM cells in the mouse respiratory tract and lung tissue [22]. Nevertheless, the COVID-19 vaccine proved to be effective against viral infection initially but confers less protection against mild-to-moderate symptomatic diseases over time. This trend seems to be associated with the waning titers of circulating antibodies in the body.

2.2. Prophylaxis of severe disease is durable – bottom line, but comparable to other successful vaccines

COVID-19 vaccines offer stable protection against severe disease, in contrast to their decreased protection ability against mild disease. For example, mRNA-1273, BNT162b2, and AZD-1222 vaccines showed efficacies of 92%, 77–93%, and 70.3%, respectively, against severe COVID-19 infection, such as hospitalization and death, up to 6 months after the complete vaccination [23,24]. During the Omicron epidemics in the UK and Hong Kong, all COVID-19 vaccines offered more than 80% protection against severe diseases [25]. Indeed, both health scientists and the public have now recognized that reducing the rate of severe disease is feasible, although it is not the sole expectation for the massive usage of the vaccine during the COVID-19 epidemic. However, addressing this issue, especially by combining it with the prevention of virus infection, remains a challenge. The following section will analyze the relevant aspects of severe COVID-19 disease and possible mechanisms for vaccine function.

Upon direct binding to epithelial cells in the upper and lower respiratory tract, SARS-CoV-2 starts replicating and migrates down to alveolar epithelial cells in the lungs or directly binds to the alveolar epithelium and capillary endothelium. This triggers a cytokine storm syndrome, leading to pathological changes in the lungs, such as infiltration of inflammatory cells and increased secretion of mucus that impedes gas exchange [26–28]. Respiratory failure due to acute respiratory distress syndrome (ARDS) is the leading cause of mortality in patients with COVID-19 [29]. Therefore, the prevention of pulmonary alveoli from viral attack and subsequent damage is a crucial determinant of the vaccine’s functioning mechanism.

The pulmonary alveolus is a specialized structure in the lung and is responsible for most of its functions, including a gas exchange between the lung and the blood. Pulmonary arteries, airways, and veins constitute the largest vascular bed in the body [30,31]. Circulating blood in the lung accounts for approximately 9% of the whole body, which is meaningful for gas exchange, and indicates the vast antibody repertoire in this area. In addition, the proximity of the vasculature to the epithelium in the terminal airways and alveoli sets the stage for potential crosstalk, facilitating the transport of antibodies to the lumen of pulmonary airways and its subsequent detection in bronchoalveolar lavage fluid [12]. Therefore, after immunization with vaccines, the epithelial cells of alveoli can be readily protected by specific neutralizing IgG antibodies on the cell surface; the latter can be continuously supplied by tightly adjacent capillaries.

Besides epithelial cells, endothelial cells of alveoli are known to suffer damage in severe COVID-19 disease as a result of immune cell infiltration. Damaged endothelial cells lose their ability to maintain physiological functions, especially antithrombotic activity at the luminal surface [32]. Viral particles have been detected in endothelial cells, in line with previous reports showing endothelial expression of ACE2 [33], suggesting that direct viral infection of endothelial cells in the lung microvasculature is another important contributor to severe disease. However, after vaccination, IgG antibodies persist in the serum and directly contact the endothelial cell surface, thus neutralizing the infectivity of viruses, and eventually preventing damage to other tissues or organs through viremia.

The second consideration is immune memory lymphocytes, which are the key immune players established by routine vaccination. Following an encounter with a viral infection, immune memory B cells can be quickly activated and secrete a large number of specific antibodies, inhibiting the proliferation and dissemination of the virus. In addition, a study has demonstrated the role of memory B cells in response to diverse SARS-CoV-2 variants. Among 323 monoclonal antibodies (mAb) isolated from human memory B cells following immunization with prototype vaccines, half (163) recognized receptor binding regions of Spike protein, and 24 were able to effectively neutralize all SARS-CoV-2 variants of concern (VOCs), including Omicron [34].

In a previous study of SARS infection, the T-cell memory response against conserved proteins was maintained for 6–17 years [35]. Long-lasting T-cell memory can facilitate a response when faced with a virus attack. In a study of SARS-CoV-2 vaccines (mRNA-1273, BNT162b2, Ad26.COV2.S, and NVX-CoV2373), 90% and 87% of CD4⁺ and CD8⁺ memory T cells responded to other variants, with 84% and 85% of them responding to Omicron 6 months post-vaccination, respectively. In addition, among 11 and 10 spike epitopes recognized by CD4⁺ and CD8⁺ T cells, respectively, over 80% responded to Omicron [36]. CD8⁺ T cells, also called cytotoxic T cells, can bind to major histocompatibility complex (MHC) class I molecules through their TCR and promote the production and release of perforin and granzymes stored in cytosols, initiating the direct killing of target cells. CD4⁺ T cells recognize foreign antigens presented by MHC class II molecules on the surface of antigen-presenting cells including dendritic cells, B cells, and macrophages, through their T-cell receptors (TCRs) and produce cytokines to recruit other immune cells to the site of infection to fight invading pathogens. In addition, studies have shown that CD8⁺ T cells in patients with COVID-19 share a broad spectrum of epitopes, including those from N-proteins [37], suggesting that vaccines containing the conserved components of the virus may have some advantages against various variants.

The third contributor to preventing severe disease is inhibiting virus dissemination within the body, especially from the respiratory system to other organs. Many reports have demonstrated that SARS-CoV-2 viremia in hospitalized patients is associated with severe disease and death [38–40], and viral RNAs have been detected in the kidneys, liver, brain, heart, and vascular tissues in cases with severe SARS-CoV-2 infection [41,42]. It is reasonable to speculate that viremia may occur during severe systemic infections. In this scenario, specific antibodies within the blood or lymph can effectively block virus transmission within the body, similar to the performance of other vaccines. Most vaccine-preventable infectious diseases undergo viremia from the initial infection site to the targeted organs. For example, poliovirus reaches motor neurons of the spinal cord from the intestines [43], and measles virus enters bronchial-associated lymphoid tissue or draining lymph nodes from respiratory epithelial cells and spreads systemically due to viremia [44,45]. It is plausible that neutralizing antibodies induced by vaccination effectively block this process. Taking the poliovirus vaccine as an example, neutralizing antibody titers of 1:8 in sera can prevent poliomyelitis [46,47]. In other words, if calculated by 100 CCID₅₀/50 μL of challenging virus in conventional neutralizing antibody testing methods, 1.6 × 10⁷ CCID₅₀ of viruses can be blocked per liter of serum at the lowest 1:8 titer. In addition, owing to breakthrough infections, memory B cells can be activated to release more antibodies into the blood circulation, thereby preventing the development of severe diseases. This is extremely meaningful for infections with VOCs because higher titers of antibodies are desirable, as mentioned earlier.

Taken together, a thorough understanding of the protection mechanism of the vaccine, including the precise immune response established by the immunization and the pathogenic process of the respiratory viruses, as demonstrated in Figure 1, will enable an elaboration of the performance characteristics of the COVID-19 vaccine. The current COVID-19 vaccine is one of the few available vaccines, besides the influenza vaccine, that is specific for respiratory viruses, which infect and cause mild disease in the upper respiratory before spreading to the lower respiratory tracts or other organs, although rarely, to cause severe diseases.

Figure 1. The mechanism of infection of SARS-CoV-2 and protection offered by COVID-19 vaccine immunization.

Following binding to host cells, the SARS-CoV-2 virus initially infects the upper respiratory tract and causes flu-like symptoms, including dry cough, fatigue, and fever. Upon viral expansion to the lungs, patients develop viral pneumonia, characterized by pulmonary inflammation and coagulopathy. Cytokine storm can also occur to leading to alveolar epithelial damage, lung mucin secretion, and ventilatory dysfunction. Severe pneumonia is characterized by acute respiratory distress syndrome (ARDS) and an unfavorable clinical course (left).Following vaccination via the intramuscular route, neutralizing IgG antibodies are mainly induced in the circulation within the blood or lymph. An antibody gradient exists between the serum and the terminal of the upper respiratory tract (URT), as shown by the blue arrow. Only a small number of antibodies enter the airway lumen of the URT by physical exudation or active transport. This decrease in antibodies is in accordance with the decline in systemic antibodies, resulting in waning protection against virus infection of the URT. However, the antibody repertoire in the lung can efficiently inhibit viral attacks on the alveolar epithelium and capillary endothelium, limiting the occurrence of severe diseases. Systemic antibodies can also inhibit viremia and consequently prevent viral dissemination to other organs (right).

3. Possible improvement strategies for COVID-19 vaccines in the future

Given the continuous emergence of VOCs and variants of interest, there is an increasing demand to develop novel vaccines or improve the immune responses to currently available vaccines. The following recommendations are made:

The first is to develop updated vaccines based on antigens of viral variants or multivalent vaccines. However, the rapid and continuous evolution of SARS-CoV-2 variants including the Alpha, Beta, and Delta strains posed difficulties in updating vaccines until the Omicrons appeared. The European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) approved COVID-19 bivalent vaccines containing the specific antigen of Omicron variants [48] produced by Pfizer-Biotech on 15 August 2022 and 31 August 2022 respectively. Clinical data suggest that booster vaccination with the variant-modified COVID-19 vaccine can increase the protective efficacy against both infection and severe disease caused by SARS-CoVs [49].

The second is to improve the mucosal immune response of vaccines. SARS-CoV-2 colonizes the nasal cavity and causes upper respiratory tract infection. The virus spreads mainly by the emission of droplets and aerosols containing the virus through coughing and vigorous breathing. Therefore, the induction of an antiviral immune response in the upper respiratory tract, especially in the nasal tract, would be an effective strategy to prevent viral infection and transmission.

A study by Renegar et al. compared the effects of anti-influenza virus IgG antibody and anti-influenza virus polymeric IgA (pIgA) monoclonal antibody by intravenous injection (i.v.) in the same amounts as murine convalescent serum or nasal antibody, respectively. It was reported that only pIgA can eliminate nasal viral shedding and prevent virus-induced pathology in the upper respiratory tract, and IgG did not prevent viral infection of the nasal cavity but prevented viral pathology in the murine lung [50]. Intranasal inoculation of the vaccine may provide effective mucosal IgA, which is advantageous for preventing the entry of the virus into the nasal cavity. For example, the mRNA or adenovirus COVID-19 vaccine induces neutralizing S-specific IgA and IgG responses following intranasal vaccination [27,51]. Primary vaccination with an mRNA vaccine and mucosal booster vaccination with an adenovirus-S vaccine could induce strong neutralizing antibodies, not only against the ancestral virus but also against the Omicron BA.1.1 variant [52]. Wantai BioPharm recently reported the phase III clinical trial results of the nasal spray vaccine constructed by inserting the RBD gene sequence into the attenuated seasonal influenza virus (CA4-dNS1), which demonstrated 55% and 82% protective efficacy against Omicron strains, including BA.2, BA.4 and BA.5, in populations without a history of immunization or booster immunization, respectively (Data reported in news by Wantai BioPharm). Thus, intranasal immunization can establish a strong mucosal immune defense and increase the ability of vaccines to prevent viral infections in the respiratory tract.

It is also worth noting that the current successful intranasal vaccines including FluMist, live attenuated or vector-virus-based vaccines, can enter the human body through specific receptors on the host. Other types of vaccines have low effectiveness in humans due to their short residence time in the nasal cavity and poor antigen absorption resulting from mechanical mucosal barriers, thick mucus layers, and mucociliary clearance. The possible approaches to enhance mucosal immunity include screening proper adjuvant/formulation to facilitate the adsorption and prolong the retention time on nasal epithelial cells, employing ligands to facilitate the delivery of antigens to target cells such as M-cells, DCs and macrophages in the nasal cavity, and vaccines into the posterior region of the nose [53,54].

4. Conclusions

The SARS-CoV-2 pandemic has been controlled by the development and use of vaccines. However, the currently available vaccines show weakened protection against infection and mild diseases of the upper respiratory tract, while maintaining robust protection against severe disease resulting from the lower respiratory tract and systematic infections. This differs from the notion that milder symptoms can be easily prevented by vaccines. Several factors contribute to these seemingly contradictory outcomes, including the systemic immune response stimulated by intramuscular injection of current vaccines, constantly emerging VOCs, and the pathogenesis and pathological process of SARS-CoV-2. The possible immune mechanisms triggered by the vaccine, along with its ‘interaction’ with or ‘blocking’ of the viral infection process, are discussed.

5. Expert opinion

The successful development of the COVID-19 vaccine is a landmark in the history of human vaccines. However, the COVID-19 vaccine differs from other conventional vaccines and offers contrasting protection against milder infections and severe diseases. Knowledge of the immune protection mechanism of the vaccine, as well as the infection characteristics, and the pathogenic process of the virus, will improve the understanding of its contradictory function.

SARS-CoV-2 is a typical respiratory virus, in terms of transmission and infection, with cell receptors found mainly in the oral and nasal mucosa, nasopharynx and lung alveolar epithelial cells as well as enterocytes of the small intestine. Infection with the virus leads to disease symptoms in these areas initially; in particular, the infection and disease caused by its variants are confined to the upper respiratory tract. However, vaccine-induced neutralizing antibodies are mainly present in circulation, with a minor portion exudating to the lumen and surface of epithelial cells in the upper respiratory tract. As observed in real-world studies, the protection against infection may decline as circulating antibodies decrease.

However, in severe pneumonia, the terminal airway and alveolar endothelium are closely adjacent to blood vessels and capillaries facilitating the exudation or transport of the specific neutralizing antibody IgG to the surface of alveolar endothelial cells, or direct contact with circulation IgG preventing virus replication and progression to severe disease. Moreover, considering the effects of viremia in causing severe infections of other systemic organs, memory immune cells and circulating antibodies can prevent this process from occurring. In addition to measles and poliovirus, varicella-zoster virus, rabies virus, and smallpox virus cause disease through viral transmission in the blood, and vaccines against these viruses can provide effective IgG antibodies in circulation and sustained protection. As a result, the protection conferred by the COVID-19 vaccines against severe diseases will last for a long time.

A vaccine strategy based on the mucosal immune response and the characteristics of the virus will be more suitable in combating the current epidemic situation. Mucosal immunization provides more abundant IgA antibodies in the mucosal epithelium of the respiratory tract and increases lung T_RM immune memory T cells, improving vaccine protection against infection in the upper respiratory tract.

Indeed, current vaccines are very effective in preventing severe diseases, but less effective in halting transmission. Effective prevention of infection may require a better understanding of mucosal immunity through the use of mucosal adjuvants and nasal administration, along with other strategies aimed at suppressing viral replication in the upper respiratory tract. These types of vaccines are being vigorously investigated by scientists worldwide, and more clinical data are required to establish the safety and efficacy of these vaccines. Nevertheless, it is of critical importance to ensure that currently approved vaccines are deployed worldwide. These vaccines have proven to be safe and effective in reducing hospitalizations and deaths. While the development of efficacious mucosal vaccines would require some time, it is highly possible, as COVID-19 has taught us a lot about vaccines against emerging respiratory viruses in just three years.

Article highlights

• Two significant aspects were identified during the application of the COVID-19 vaccine: the decline in efficacy of protection against mild infections and limited long-term efficacy in preventing severe diseases.

• The decline in the protective function of the vaccine against infection is consistent with the decrease in circulating antibodies in the body, which may be due to the limited exudation of antibodies into the lumen of the respiratory tract. This becomes more evident with the occurrence of virus variants, especially Omicrons, whose infection is more limited to the upper respiratory tract with a short incubation period.

• Severe disease caused by SARS-CoV-2 involves the virus transmission from the upper respiratory tract to the lower respiratory tract, lung, or other organs. The physiological structure of the lungs, especially the contact between the alveolar epithelium and capillary endothelium, provides a pathway for IgG antibody transport or exudation into the bronchial cavity and the surface of the alveoli, effectively preventing viral replication and the occurrence of severe pneumonia.

• For severe systemic disease, both memory B cells and T cells containing broad-spectrum elements against SARS-CoV-2 conserved proteins or epitopes are vital sources to stop disease progression. In addition, the neutralizing antibodies present in circulation can effectively halt viremia and consequently inhibit the spread of the virus.

• Multivalent vaccines for different variants and/or vaccines that induce mucosal immune responses are of scientific interest for improving the efficacy of the COVID-19 vaccines in the prevention of virus infection and transmission.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or mending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have received research grants from Moderna, Pfizer, GSK, and Astra Zeneca, and received personal fee for board participation from GSK. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Author contributions

Huijie Yang conceived and drafted the manuscript; Ying Xie offered valuable discussions and partial content; Changgui Li provided specialized guidance and revised the manuscript. All authors have read and approved this article.

Additional information

Funding

This paper was not funded.