A Review of COVID-19 Vaccines, Immunogenicity, Safety, and Efficacy toward Addressing Vaccine Hesitancy, Inequity, and Future Epidemic Preparedness

Abstract

This chapter provides an update on COVID-19 vaccines, emphasizing their immunogenicity, safety, efficacy, and potential impact on vaccine hesitancy, inequity, and future epidemic preparedness. Various vaccine types, such as mRNA-based, DNA-based, viral vector, inactivated, and protein subunit vaccines, are explored, evaluating their mechanisms and advantages in eliciting robust immune responses. Safety is thoroughly assessed using clinical trials and real-world data to address hesitancy concerns. Strategies for equitable distribution are discussed to achieve widespread coverage and overcome barriers. Lessons drawn from the pandemic serve as a roadmap for proactive measures aimed at bolstering epidemic preparedness, highlighting the critical role of global cooperation and equitable vaccine distribution in safeguarding public health worldwide.

1. Introduction

On January 30, 2020, the World Health Organization (WHO) officially declared the outbreak of novel coronavirus disease 2019 (COVID-19) as a global pandemic. This declaration was made in response to the highly transmittable and pathogenic nature of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an RNA virus [1]. Since then, COVID-19 has caused more than 6 million deaths worldwide [2], resulting in significant economic losses globally [3]. Despite efforts to control the pandemic, it is still ongoing as China continues to report high numbers of cases. Concerns are rising that the “Zero COVID” policies implemented in China may not effectively contain the spread of COVID-19 [4]. Furthermore, scientific evidence suggests that climate changes, such as global warming, rapid population growth, urban expansion, and deforestation, are bringing human habitation closer to livestock and wildlife, potentially serving as hosts for future pandemic pathogens [5].

Since the onset of the disease, vaccines and vaccination strategies have continuously evolved, gaining particular attention in the wake of the COVID-19 outbreak. Notable advancements have been made in the development of novel vaccine technologies, resulting in the creation of effective vaccines against various diseases [6, 7]. Specifically addressing the ongoing global pandemic caused by the SARS-CoV-2 virus, COVID-19 vaccines have been swiftly developed and distributed, serving as a crucial tool in the fight against the pandemic [8, 9, 10]. Clinical trials have demonstrated that these vaccines effectively prevent severe illness, hospitalization, and death. Furthermore, they possess the potential to slow down virus transmission and reduce the emergence of new variants (Tables 1–3). The widespread administration of vaccines is vital in safeguarding vulnerable populations, including the elderly and individuals with underlying health conditions [10]. Compared to natural infection, vaccination plays a prominent role in saving humanity from various COVID-19 variants, including the recent surge of the Omicron variant and aiding in the recovery from the global economic crisis (Tables 1–3).

Approved vaccines	Developers (Companies or Institutions)	Vaccines’ immunogenicity
Sinovac - inactivated (CoronaVac)	Developed by Sinovac Biotech, a Chinese biopharmaceutical company	After receiving two doses of the Sinovac (CoronaVac) vaccine, individuals aged 18 to 59 [11] or children/adolescents aged 3 to 17 [12] exhibited a robust immune response to SARS-CoV-2. This immune response effectively neutralized the alpha, beta, gamma, delta, and omicron variants, although there may be some reduced efficacy against certain variants [13]. Furthermore, when individuals were given a booster dose of the same vaccine between twenty-four and thirty weeks after the second dose, the levels of neutralizing antibodies and T-cell responses significantly increased against the Delta and Omicron variants of concern [14].
Bharat Biotech (BBV152) - inactivated (Covaxin)	Developed by Bharat Biotech, an Indian biotechnology company	The BBV152 vaccine induced strong immune responses, both in the form of neutralizing antibodies and cell-mediated immune responses, which remained at high levels for 3 months after the second vaccination in healthy adults and adolescents (aged 12–65 years) [15]. Furthermore, the effectiveness of Covaxin against various variant lineages, including B.1.617.2 (Delta, India), B.1.617.2.1 (Delta Plus, India), B.1.351 (Beta, South Africa), B.1.1.7 (Alpha, UK), and B.1.1.529 (Omicron), was also investigated [16]. The findings of the study demonstrated the persistence of these immune responses for up to 12 months following vaccination.
Sinopharm (BBIBP-CorV)	Developed by the Beijing Institute of Biological Products, a subsidiary of Sinopharm, a Chinese state-owned company	The Sinopharm vaccine exhibits the ability to trigger the production of neutralizing antibodies upon completion of the two-dose regimen of individuals between the ages of 18 to 59 [17, 18]. Furthermore, a booster dose has been shown to reverse the decline of antibodies, thereby enhancing cellular immune responses, including T-cell responses [19].
Wuhan Institute of Biological Products (Sinopharm)	Another inactivated vaccine developed by the Wuhan Institute of Biological Products, another subsidiary of Sinopharm	Refer to Sinopharm produced by BBIBP-CorV
Covovax	Developed by Novavax, an American vaccine development company, in collaboration with the Serum Institute of India	A study [20] identified Covovax as a promising candidate for a booster dose after various priming dose regimens. The study observed that administering a third dose of Covovax after the second dose of BBIBP-CorV, AZD1222, BNT162b2, or CoronaVac/AZD1222, within a time interval of 3–10 months, resulted in strong immunogenicity and exhibited a good safety profile. The Covovax vaccine stimulated the production of antibodies and triggered cellular immune responses, including the activation of T cells. Overall, these findings suggest that Covovax has the potential to be an effective booster dose, providing enhanced immune protection to individuals who have previously received different priming dose regimens.
Soberana 02	Developed by the Finlay Vaccine Institute in Cuba	In a Phase 3 study [21], involving 100 volunteers aged 19–80 years, it was reported that two doses of Soberana 02 (SOBERANA 02–25 μg) were administered. Half of the volunteers received a third dose of the corresponding SOBERANA 02, while the other half received a heterologous dose of SOBERANA Plus. The study found that SOBERANA 02 was safe and immunogenic in individuals aged 19–80 years, leading to the production of neutralizing antibodies and specific T-cell responses. The highest immune responses were observed in the group that received the heterologous three-dose protocol. These immune responses are crucial for protecting against COVID-19 and reducing the severity of symptoms.
Abdala	Developed by the Center for Genetic Engineering and Biotechnology in Cuba	The Abdala vaccine is found to induce substantial humoral immune responses against SARS-CoV-2 among adults 19–80 years of age after third dose of vaccination [22]. In addition, Abdala vaccine also stimulated the production of specific IgG antibodies against the RBD of SARS-CoV-2, as well as ACE2 inhibition titers and neutralizing antibodies in healthy children and adolescents with age (3–11 years, or 12–18 years old) [23].
Oxford-AstraZeneca (Vaxzevria, Covishield)	Developed by the University of Oxford and AstraZeneca	Extensive data and studies have been conducted on the immunogenicity of the Oxford-AstraZeneca vaccine [24, 25, 26, 27, 28]. Clinical trials and real-world data have shown that the vaccine elicits a robust immune response, including producing antibodies and activating cellular immune responses [25, 26]. The vaccine stimulates the production of neutralizing antibodies that target the spike protein of the SARS-CoV-2 virus [24, 25, 26, 27, 28]. These antibodies are crucial for preventing infection and reducing the severity of COVID-19 symptoms. Additionally, the vaccine activates T-cell responses, which play a role in recognizing and destroying virus-infected cells. Studies have demonstrated that the Oxford-AstraZeneca vaccine induces strong responses after the completion of the two-dose regimen. It is effective in reducing the risk of severe disease, hospitalization, and death due to COVID-19 [29].
Johnson & Johnson (Janssen)	Developed by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson	Similar to Oxford-AstraZeneca mentioned above. The vaccine stimulates the production of neutralizing antibodies and activates cellular immune responses, including T-cell responses [30, 31]. Clinical trial has shown that the Johnson & Johnson vaccine induces strong immune responses after a single dose [32]. It has effectively reduced severe disease, hospitalization, and death due to COVID-19. Additionally, the vaccine has shown effectiveness against multiple virus variants, including the Alpha and Beta variants [33, 34].
Sputnik Light, the first component of Sputnik V	Developed by the Gamaleya Research Institute of Epidemiology and Microbiology in Russia	Sputnik Light vaccine induces strong humoral and cellular immune responses after the completion of the single-dose regimen [35]. Sputnik Light is also a leading booster shot that has demonstrated efficacy in preventing COVID-19 and reducing the risk of severe disease, hospitalization, and death. The vaccine has also shown effectiveness against different variants of the SARS-CoV-2 virus, including the Alpha, Gamma, and Omicron variants [36].
CanSinoBIO (Convidecia)	Developed by CanSino Biologics in China	CanSinoBIO vaccine induces strong immune responses after a single dose [37]. In addition, a booster shot is recommended for the highest and high-priority-use groups at 4–6 months after completion of the primary dose [38]. It has demonstrated efficacy in preventing COVID-19 and reducing the risk of severe disease and hospitalization [38].
Covishield	The name given Oxford-AstraZeneca vaccine when manufactured by the Serum Institute of India	Like the AstraZeneca vaccine [24, 25, 26, 27, 28], Covishield induces strong antibody responses upon completing the two-dose regimen. Furthermore, a recent study demonstrated that individuals who received either homologous or heterologous boosting with COVISHIELD™ or COVAXIN® after being initially primed with COVISHIELD™ or COVAXIN® exhibited immunogenic and safe responses. Among the four combinations assessed, the most potent immune response was observed in those who received a heterologous boost with COVISHIELD™ following a COVAXIN® prime [39].
Pfizer-BioNTech COVID-19 Vaccine (Comirnaty)	Developed by Pfizer and BioNTech	Pfizer-BioNTech vaccine generates high levels of neutralizing antibodies after the completion of the two-dose regimen [40]. These antibodies specifically target the spike protein of the SARS-CoV-2 virus. The vaccine has also been shown to activate strong T-cell responses, contributing to the overall immune response against the virus [41]. Clinical trials and real-world data have shown that the Pfizer-BioNTech vaccine has high efficacy in preventing COVID-19 infection, severe disease, hospitalization, and death [42]. The vaccine has also demonstrated effectiveness against Omicron variant of the SARS-CoV-2 virus and the immunogenicity of the Pfizer-BioNTech vaccine has been studied across various populations, including different age groups [43].
Moderna COVID-19 Vaccine (mRNA-1273)	Developed by Moderna	According to Ref. [44, 45], the Moderna COVID-19 vaccine (mRNA-1273) exhibits high immunogenicity as an mRNA-based vaccine encoding the spike protein of SARS-CoV-2. It generates a robust immune response with neutralizing antibodies that block the spike protein, preventing viral entry into human cells. The vaccine also induces a strong cellular immune response involving T-cells, contributing to its effectiveness against COVID-19 and its variants. Its immunogenicity has been critical in preventing severe illness, hospitalization, and fatalities, playing a crucial role in mitigating the global pandemic impact.
Zydus Cadila (ZyCoV-D)	Zydus Cadila	The Zydus Cadila COVID-19 vaccine, ZyCoV-D, had received emergency use authorization in India [46]. It is a DNA-based vaccine using a plasmid DNA platform to deliver the spike protein’s genetic code from the SARS-CoV-2 virus. ZyCoV-D vaccine was reported to induce strong humoral and cellular immune responses in animal models [47].
Novavax (NVX-CoV2373)	Novavax	Novavax vaccine induces a strong immune response, including the production of neutralizing antibodies and the activation of cellular immune responses [48].; Clinical trials have demonstrated that the Novavax vaccine generates robust antibody responses after the completion of the two-dose regimen. The vaccine has shown efficacy in preventing COVID-19 infection, reducing the severity of the disease, and preventing hospitalization [49]. Additionally, the Novavax vaccine has shown effectiveness against different variants of the SARS-CoV-2 virus, including the Omicron variant, and after booster shots (3rd or 4th doses) resulted in enhanced cross-reactive immunity to SARS-CoV-2 variants [50].
Medicaga	Medicaga & GSK	Medicago vaccine induces a strong immune response, including the production of neutralizing antibodies and the activation of cellular immune responses after the completion of the two-dose regimen [51]. The vaccine has shown efficacy in preventing COVID-19 infection, reducing the severity of disease caused by the Delta variant [52].

Table 1.

A comprehensive review of the immunogenic characteristics exhibited by approved COVID-19 vaccines.

Approved vaccines	Developers (Companies or Institutions)	Vaccines’ safety and side-effect profile
Sinovac - inactivated (CoronaVac)	Developed by Sinovac Biotech, a Chinese biopharmaceutical company	Overall, Sinovac vaccine has been found to have a good safety profile [53]. Frequently reported side effects of the CoronaVac vaccine include mild to moderate pain or tenderness at the injection site, fatigue, headache, muscle pain, and fever. These side effects are typically temporary and tend to subside within a few days. The majority of adverse reactions or events were observed in less than 10% of individuals who received the CoronaVac vaccine.
Bharat Biotech (BBV152) - inactivated (Covaxin)	Developed by Bharat Biotech, an Indian biotechnology company	Comprehensive safety evaluations have been conducted, and the vaccine has been found to be safe for people aged 18 and above. There are no serious adverse events were reported [15], and there are no safety concerns raised in an interim analysis [54].
Sinopharm (BBIBP-CorV)	Developed by the Beijing Institute of Biological Products, a subsidiary of Sinopharm, a Chinese state-owned company	WHO has recommended its use for people aged 18 and above [17]. The most common side effects experienced after the first dose of the vaccine were injection site pain and fatigue. Similarly, injection site pain and fatigue were also the most common side effects reported after the second dose. These side effects were more commonly observed in individuals aged 49 years or younger compared to those over the age of 49. Additionally, females were more likely to experience these side effects than males [55].
Wuhan Institute of Biological Products (Sinopharm)	Another inactivated vaccine developed by the Wuhan Institute of Biological Products, another subsidiary of Sinopharm	Refer to Sinopharm produced by BBIBP-CorV
Covovax	Developed by Novavax, an American vaccine development company, in collaboration with the Serum Institute of India	Based on the WHO’s report [56], the Covovax vaccine has been proven to be both safe and effective for individuals aged 12 and above, but it is not recommended for those younger than 12 years of age. Although very rare, some serious adverse events of myocarditis and pericarditis have been observed after vaccination, typically occurring within a few days. However, it is essential to note that these cases were generally mild.
Soberana 02	Developed by the Finlay Vaccine Institute in Cuba	A phase 3 study [21] showed that this vaccine exhibits a favorable safety profile and could serve as an appealing choice for incorporation into COVID-19 vaccination programs. The incidence of serious and severe adverse events (AE) was exceedingly rare and occurred at comparable rates between the placebo and vaccine recipients. Although there were slightly more solicited AEs in the vaccine group, they were primarily localized reactions and mostly mild and temporary in nature.
Abdala	Developed by the Center for Genetic Engineering and Biotechnology in Cuba	Abdala vaccine was safe, encompassing a diverse range of participants spanning from 3 to 80 years old [22, 23]. Most adverse reactions to the vaccine were mild and localized to the injection site, resolving within 24–48 hours. No severe adverse events directly linked to the vaccine were reported.
Oxford-AstraZeneca (Vaxzevria, Covishield)	Developed by the University of Oxford and AstraZeneca	Overall, the Oxford-AstraZeneca vaccine has been found to have a good safety profile. Common side effects include pain or tenderness at the injection site, fatigue, headache, muscle pain, fever, and flu-like symptoms [24, 25]. These side effects are generally mild to moderate in severity and resolve on their own within a few days. Through phase 1/2 and 3 trials, no serious adverse events or deaths that were treatment-associated occurred in ChAdOx1 nCoV-19 recipients [24, 25, 26]. However, following the administration of this vaccine, there have been reports of an exceptionally uncommon and unfavorable occurrence known as Thrombosis with Thrombocytopenia Syndrome (TTS) [29]. This syndrome is characterized by atypical and severe instances of blood clotting, coupled with reduced platelet levels. The occurrence of TTS is infrequent.
Johnson & Johnson (Janssen)	Developed by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson	Similar to Oxford-AstraZeneca mentioned above. There was found to have a good safety profile and common side effects include fatigue, headache, myalgia, and injection-site pain [30]. A rare serious adverse event is the “thrombosis with thrombocytopenia syndrome” and “Guillain-Barre Syndrome” reported [34].
Sputnik Light, the first component of Sputnik V	Developed by the Gamaleya Research Institute of Epidemiology and Microbiology in Russia	Safety was confirmed by real-world data and clinical trials; Sputnik Light demonstrates a favorable safety profile [36]. The majority of reported adverse reactions were mild (66.4% of all vaccines), with only a small percentage classified as moderate (5.5%) [35]. Notably, no serious adverse events were recorded following vaccination with Sputnik Light [36].
CanSinoBIO (Convidecia)	Developed by CanSino Biologics in China	The CanSinoBIO vaccine has been found to be safe and effective, with common side effects primarily related to solicited systemic or injection-site reactions, which were reported as mild or moderate. Redness and swelling at the injection site were observed in less than 10% of Ad5-nCoV recipients and less than 2% of placebo recipients [37]. However, there have been rare reports of Thrombosis with Thrombocytopenia Syndrome (TTS) occurring approximately 3–30 days after receiving the Ad5-nCoV vaccine. While a plausible link between the vaccine and TTS is suspected, further evidence is necessary to confirm this association [38]. The vaccine is recommended for individuals aged 18 and above [38].
Covishield	The name given Oxford-AstraZeneca vaccine when manufactured by the Serum Institute of India	Refer to Oxford-AstraZeneca developed by University of Oxford mentioned above.
Pfizer-BioNTech COVID-19 Vaccine (Comirnaty)	Developed by Pfizer and BioNTech	Overall, the Pfizer-BioNTech vaccine has demonstrated a favorable safety and side-effect profile [40, 57]. Common side effects include pain at the injection site, fatigue, and headache [40]. These side effects are usually mild to moderate in severity and resolve within a few days. Serious adverse events following vaccination with the Pfizer-BioNTech vaccine are very rare. A very rare serious adverse event is myocarditis, which is mainly observed in young males aged 18–35 after the second dose [57]. Typically, these cases of myocarditis occur within a few days after vaccination, and they are generally mild in nature, responding well to conservative treatment. Moreover, they tend to be less severe with more favorable outcomes compared to classical myocarditis or myocarditis related to COVID-19 [57].
Moderna COVID-19 Vaccine (mRNA-1273)	Developed by Moderna	The Moderna vaccine has shown a good safety profile, with common side effects including pain or swelling at the injection site, fatigue, headache, and myalgia [45]. These side effects are generally mild to moderate in severity and resolve within a few days. Like Pfizer-BioNTech, myocarditis, an extremely infrequent and serious adverse event, is primarily observed in young males aged 18–35 after receiving the second dose [58].
Zydus Cadila (ZyCoV-D)	Zydus Cadila	The DNA vaccine, ZyCoV-D, was safely administered intradermally using a needle-free injection system with a 28-day interval between each of the three doses. It has demonstrated safety in both phases I/II [46] and phase III trials [59].
Novavax (NVX-CoV2373)	Novavax	Novavax vaccine demonstrated a generally favorable safety profile [49, 50]. Although very rare, serious adverse events of myocarditis and pericarditis have been observed. Typically, these cases occurred within a few days after vaccination and were generally mild in severity [56].
Medicaga	Medicaga & GSK	Regarding the Medicaga vaccine, no reports of related severe adverse events were recorded, and the reactogenicity was generally mild to moderate and of short duration [51].

Table 2.

A comprehensive review of the safety profiles demonstrated by approved COVID-19 vaccines.

Approved vaccines	Developers (Companies or Institutions)	Vaccines’ efficacy against symptomatic COVID-19
Sinovac - inactivated (CoronaVac)	Developed by Sinovac Biotech, a Chinese biopharmaceutical company	The efficacy of the Sinovac vaccine has been reported to vary across different studies and settings. Overall, the vaccine has shown efficacy in reducing the risk of symptomatic COVID-19, hospitalization, and severe disease. The effectiveness of the Sinovac vaccine in preventing symptomatic COVID-19 has been reported to range from around 50.7% to 83.5% in different studies [53].
Bharat Biotech (BBV152) - inactivated (Covaxin)	Developed by Bharat Biotech, an Indian biotechnology company	The Bharat Biotech vaccine has shown efficacy in preventing symptomatic COVID-19 and its associated complications. The Bharat Biotech vaccine has reported an efficacy rate of 77·8% in preventing symptomatic COVID-19 [60].
Sinopharm (BBIBP-CorV)	Developed by the Beijing Institute of Biological Products, a subsidiary of Sinopharm, a Chinese state-owned company	Based on a substantial multi-country Phase 3 trial, it has been demonstrated that administering two doses of the vaccine at an interval of 21 days results in an efficacy of 79% against symptomatic COVID-19, starting from 14 days after the second dose [17].
Wuhan Institute of Biological Products (Sinopharm)	Another inactivated vaccine developed by the Wuhan Institute of Biological Products, another subsidiary of Sinopharm	Refer to Sinopharm produced by BBIBP-CorV
Covovax	Developed by Novavax, an American vaccine development company, in collaboration with the Serum Institute of India	The NVX-CoV2373 vaccine, at least 7 days after administered in a two-dose regimen to adult participants, provided 89.7% protection against symptomatic COVID-19 and demonstrated high efficacy against the B.1.1.7 variant [49].
Soberana 02	Developed by the Finlay Vaccine Institute in Cuba	Two doses of the Soberana 02 vaccine demonstrated an efficacy rate of 69.7% in preventing symptomatic COVID-19 [21].
Abdala	Developed by the Center for Genetic Engineering and Biotechnology in Cuba	According to the preliminary data from the phase 3 trials, the Abdala vaccine demonstrated an efficacy rate of around 92.28% in preventing symptomatic COVID-19 [22].
Oxford-AstraZeneca (Vaxzevria, Covishield)	Developed by the University of Oxford and AstraZeneca	Based on the primary analysis of data from trial participants who received two standard doses of the AstraZeneca vaccine, the efficacy against symptomatic SARS-CoV-2 infection was found to be 72% [29]. The inter-dose interval varied from about 4–12 weeks. Notably, vaccine efficacy tended to be higher when the interval between doses was longer.
Johnson & Johnson (Janssen)	Developed by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson	According to data gathered from the United States, the two-dose vaccine regimen, administered at a 2-month interval, exhibited a remarkable efficacy of 94% in preventing symptomatic infections. On the other hand, the single-dose vaccine showed a lower efficacy rate of 72% [34].
Sputnik Light, the first component of Sputnik V	Developed by the Gamaleya Research Institute of Epidemiology and Microbiology in Russia	The Sputnik Light vaccine has demonstrated a noteworthy efficacy of 80% against symptomatic COVID-19 infections [36].
CanSinoBIO (Convidecia)	Developed by CanSino Biologics in China	The CanSinoBIO vaccine has shown an overall efficacy rate of 64% in preventing symptomatic COVID-19 [37].
Covishield	The name given Oxford-AstraZeneca vaccine when manufactured by the Serum Institute of India	Refer to Oxford-AstraZeneca developed by University of Oxford mentioned above.
Pfizer-BioNTech COVID-19 Vaccine (Comirnaty)	Developed by Pfizer and BioNTech	Real-world studies have shown that the Pfizer-BioNTech vaccine boasts an efficacy rate of approximately 91.2% in preventing symptomatic COVID-19 after completing the full vaccination regimen [42]. This effectiveness has been observed across various age groups and has exhibited promising results against different COVID-19 variants, including the Omicron variant [43].
Moderna COVID-19 Vaccine (mRNA-1273)	Developed by Moderna	After the recommended two-dose regimen, the Moderna vaccine has demonstrated an impressive efficacy rate of 98.1% in preventing symptomatic COVID-19 [42].
Zydus Cadila (ZyCoV-D)	Zydus Cadila	Following the administrating of the third dose at 28 days, the ZyCoV-D vaccine has exhibited an efficacy rate of 66.6% in preventing symptomatic COVID-19 [59].
Novavax (NVX-CoV2373)	Novavax	The Novavax vaccine has displayed an efficacy rate of 89.7% in preventing symptomatic COVID-19 at least 7 days after the second dose [49].
Medicago	Medicago & GSK	As per the joint announcement from Medicago and GSK regarding phase 3 results, the Medicago vaccine showcased an efficacy rate of 75.3% in preventing symptomatic COVID-19 [52].

Table 3.

A comprehensive review of the effectiveness of approved COVID-19 vaccines in preventing symptomatic COVID-19.

While COVID-19 vaccines offer numerous benefits, they also have limitations regarding their immunogenicity, safety, and effectiveness. Vaccine hesitancy is a concern, as individuals may refuse vaccination due to apprehensions about the immunogenicity, safety, and efficacy of the vaccines [61, 62, 63, 64, 65]. The efficacy rates of COVID-19 vaccines vary among different types, and emerging virus variants can impact their effectiveness. For instance, mRNA vaccines have demonstrated higher efficacy rates compared to viral vector and inactivated virus vaccines (Table 3). Extensive research and monitoring have been conducted to ensure the safety of COVID-19 vaccines with most reported adverse events being mild and temporary (Table 2). However, rare cases of severe adverse events, such as blood clots, have been associated with some vaccines, leading to temporary suspensions in vaccine distribution and increased surveillance [65, 66].

Overall, COVID-19 vaccines induce immunogenicity by stimulating the production of neutralizing antibodies and cellular immune responses (Table 1). While the inactivated COVID-19 vaccines may exhibit slightly lower immunogenicity compared to certain other formed vaccines, they still prove effective in reducing the severity of COVID-19 and providing protection against severe outcomes (Table 3). Despite the development and approval of multiple vaccines, there remains a significant challenge of inequitable access to vaccines, particularly in low- and middle-income countries (LMICs) [67]. Additionally, logistical obstacles such as cold chain storage and vaccine distribution have hindered efficient delivery in certain regions [68].

At this juncture, it is crucial for us to reflect upon the valuable lessons learned during the COVID-19 pandemic spanning the past 3 years. It is imperative that we contemplate how to prepare better and effectively respond to future challenges. In addition to implementing measures like social distancing, it is essential to have a comprehensive understanding of vaccine technologies and the immunogenicity, safety, and efficacy of vaccines. The objective of this chapter is threefold: (1) To examine and reflect upon recent advancements in vaccine technologies, focusing on the immunogenicity, safety, and efficacy of approved COVID-19 vaccines; (2) To provide critical insights aimed at addressing gaps in vaccine inequity, ensuring that access to vaccines is fair and equitable for all; (3) To provide critical insights and recommendations for preparedness and control measures in response to potential future pandemics. By addressing these aspects, we aim to enhance our preparedness and response capabilities, ultimately striving for more effective control and management of future health crises.

2. Overview of SARS-CoV-2 and its biology

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), belonging to the coronavirus family, has led to outbreaks of various diseases. This family of viruses includes common viruses responsible for ailments ranging from common colds to more severe conditions like severe acute respiratory syndrome (SARS), which caused an outbreak in 2003 [69], as well as middle east respiratory syndrome (MERS), which caused an outbreak in 2012 [70]. The most recent outbreak occurred in 2019 with the emergence of SARS-CoV-2 [1], resulting in significant global health impacts [2] and economic consequences [3].

SARS-CoV-2 is an enveloped virus characterized by its positive-sense single-stranded RNA genome. The genome of SARS-CoV-2 contains instructions for the production of four primary structural proteins: spike glycoprotein (S), envelope protein (E), membrane protein (M), and nucleoprotein (N) [71]. These four structural proteins come together to encapsulate the viral genetic material (RNA), forming a complete virus capable of replication, transmission, and disease onset (Figures 1 and 2).

Figure 1.

The structural representation of SARS-CoV-2. This visual depiction was obtained from biorender (https://www.biorender.com).

Figure 2.

The portrayal of SARS-CoV-2’s entry into host cells via the ACE2 receptor. This visual representation illustrates the simulated steps and mechanisms involved in the recognition and entry of host cells through ACE2-mediated pathways by the prefusion spike glycosylation (S1). This visual depiction was obtained from biorender (https://www.biorender.com).

The virus exhibits a spherical shape and displays spike-like projections on its surface, which gives it a crown-like appearance (Figure 1). These projections are composed of the glycoprotein spike (S protein), consisting of two subunits, S1 and S2, and play a crucial role in receptor recognition and fusion with the host cell membrane [72, 73]. Specifically, SARS-CoV-2 attaches to host cells by utilizing its spike protein to bind to the angiotensin-converting enzyme 2 (ACE2) receptor located on the surface of human cells. Upon entering the host cell, the viral RNA genome is released and serves as a template for the synthesis of viral proteins. The viral RNA is then replicated, packaged into new virus particles, and subsequently released from the host cell to infect other cells, leading to the development of novel coronavirus disease 2019 (COVID-19) (Figure 2). In the absence of prevention or treatment, SARS-CoV-2 primarily targets the respiratory tract and can cause symptoms ranging from mild to severe respiratory illness [74]. It is worth noting that the virus can also infect other organs, including the skin, kidneys, endocrine organs, and eyes [75]. The severity of COVID-19 disease can vary widely and is influenced by factors such as age, underlying health conditions, and viral load [76].

Mounting an effective immune response to SARS-CoV-2 infection plays a crucial role in controlling the virus and mitigating the development of severe disease [77, 78, 79, 80]. Vaccination, in particular, elicits the production of antibodies targeting the S proteins, which have been shown to generate neutralizing antibodies capable of impeding the virus from infecting host cells. Additionally, T cells are activated, enabling them to identify and eliminate infected cells (Table 1).

Like all viruses, including SARS-CoV-2, there are numerous mutations that can give rise to new variants with distinct characteristics. These characteristics can include rapid transmission, increased disease severity, or resistance to vaccines and treatments [81, 82]. These altered versions of the virus are commonly referred to as “variants”. Some variants have shown higher transmissibility and may be linked to an elevated risk of severe illness [83, 84, 85]. The emergence of these variants highlights the critical need for ongoing surveillance and research to comprehend the evolution and dissemination of the virus [81]. The Omicron variant of SARS-CoV-2, initially identified in South Africa, was reported to the WHO on November 24, 2021, as a novel variant [84].

3. An update of COVID-19 vaccines

Recent advancements in vaccine technology have led to the development of various vaccines available in the market (Figure 3) [6, 7]. These vaccines consist of several crucial components. First, they contain an antigen, which can be in the form of a live-attenuated or killed virus, or a specific protein derived from the virus. The presence of the antigen enables our bodies to recognize and combat the disease if we come into contact with it in the future. Second, vaccines include an adjuvant, which assists in enhancing our immune response and improving the effectiveness of the vaccine. Additionally, vaccines are formulated with preservatives to maintain their efficacy over time, and stabilizers to prevent mechanical failures during storage and transportation. It is important to note that all the ingredients used in vaccines, as well as the vaccines themselves, undergo thorough testing and monitoring to ensure their safety and efficacy [7].

Figure 3.

An overview of the approved COVID-19 vaccines. Fifty approved COVID-19 vaccines were obtained from the COVID-19 vaccine tracker (https://covid19.trackvaccines.org/), with data updated until December 2, 2022, and accessed on June 19, 2023. The vaccine platforms are classified into four main categories, based on their vaccine technologies. Each vaccine platform as a representative example was illustrated for its immunogenic mechanisms. (A) inactivated vaccines (11 vaccines), (B) protein-based vaccines (19 protein vaccines & 1 VLP vaccine), (C) viral vector vaccines (9 vaccines), and (D) nucleic acid vaccines (9 mRNA vaccines & 1 DNA vaccine). This visual depiction was produced using a biorender (https://www.biorender.com).

Up until December 2, 2022, a significant milestone has been reached with the approval of 50 vaccines by at least one country. Additionally, the WHO has granted Emergency Use Listing (EUL) to 11 vaccines, benefiting a total of 201 countries [86]. This remarkable progress showcases the global efforts in combating the COVID-19 pandemic. The extensive pursuit of vaccine development is evident in the reported 821 vaccine trials. Currently, there are 242 vaccine candidates undergoing clinical trials at various stages of progress. Among them, 66 vaccines are in Phase 1 trials, indicating their initial safety and dosage assessments. Phase 2 trials involve 72 vaccines, evaluating their effectiveness in larger populations. Furthermore, 92 vaccines are in Phase 3 trials, which involve large-scale testing to determine their overall efficacy. Notably, 50 vaccines have already received authorization, indicating their successful completion of clinical trials and regulatory approval. These crucial vaccine trials are being conducted in 80 countries worldwide, highlighting the widespread collaboration and dedication in the pursuit of effective COVID-19 vaccines (Figure 4).

Figure 4.

An overview of the present scenario concerning COVID-19 vaccines available in the market. The figure was adopted from the COVID-19 vaccine tracker (https://covid19.trackvaccines.org/), with data updated until December 2, 2022, and accessed on June 19, 2023. This visual depiction was produced using a biorender (https://www.biorender.com).

Furthermore, the authorized COVID-19 vaccines encompass a diverse array of types, showcasing advancements in medical technology. These include mRNA, DNA, viral vectors, inactivated or killed viruses, and protein-based subunit vaccines (Figure 3). mRNA vaccines, such as the notable ones developed by Pfizer-BioNTech and Moderna, harness the power of genetic material to initiate an immune response within the body. Similarly, DNA vaccines like Zydus Cadila utilize genetic material to stimulate the immune system’s defenses. Viral vector vaccines, such as the well-known ones manufactured by AstraZeneca and Johnson & Johnson, take advantage of a modified virus as a delivery system to transport genetic material and activate the immune response. By utilizing this approach, these vaccines can effectively trigger the body’s defense mechanisms against the virus. Inactivated or killed virus vaccines, exemplified by the commendable efforts of Sinovac or Sinopharm, employ viruses that have been rendered inactive or killed to provoke an immune response. Through this method, the immune system becomes primed to recognize and combat the virus should an actual infection occur. Protein subunit vaccines, including the notable ones produced by Novavax or Medicago, employ specific proteins derived from the virus itself. By introducing these viral proteins into the body, an immune response is triggered, enabling the immune system to develop defenses against the virus. Collectively, these various COVID-19 vaccine platforms have demonstrated their efficacy in generating neutralizing antibodies and stimulating cell-mediated responses, as depicted in Figure 3 and referenced in Tables 1–3.

4. The immunogenicity of COVID-19 vaccines

Vaccine immunogenicity refers to the capacity of a vaccine to stimulate an immune response within the body. The primary objective of vaccination is to activate the immune system, prompting it to recognize and counter specific components of a pathogen, such as a virus, while avoiding the onset of the actual disease [87]. Upon administration of the vaccine, the immune response is triggered, leading to the activation of various immune cells, including B cells. The immune system identifies the foreign components within the vaccine as antigens and initiates an immune response against them. B cells are responsible for producing antibodies that can neutralize the pathogen or mark it for elimination by other immune cells. T cells, comprising helper T cells and killer T cells, play a crucial role in coordinating and executing the immune response [88].

Vaccine immunogenicity is evaluated through clinical trials, wherein researchers measure the production of specific antibodies, such as neutralizing antibodies, in the blood of vaccinated individuals (Table 1). These antibodies are designed to recognize and bind to the specific components of the targeted pathogen that the vaccine aims to address. The presence of these antibodies indicates that the vaccine has successfully stimulated an immune response. The level and quality of the immune response induced by a vaccine can vary based on several factors, including the vaccine type, the antigens it contains, the dosage, and the vaccination schedule [89]. High immunogenicity is desirable as it suggests that the vaccine effectively triggers a robust immune response and provides protection against the specific pathogen being targeted [90].

Table 1 provides a comprehensive analysis of the immunogenicity of approved COVID-19 vaccines. Overall, these vaccines have been shown to elicit strong immune responses, including the generation of neutralizing antibodies and virus-specific T cells which are effective in reducing the risk of severe disease, hospitalization, and death due to COVID-19.

5. The safety of COVID-19 vaccines

Vaccine safety encompasses the comprehensive evaluation of potential risks and adverse effects associated with the administration of a vaccine. This evaluation involves rigorous testing throughout clinical trials and ongoing monitoring following its approval and widespread use [2]. Before entering clinical trials, vaccines typically undergo preclinical testing, including laboratory studies and animal testing to assess their safety and effectiveness. This initial evaluation helps identify any potential safety concerns and informs the decision to proceed with human trials. Subsequently, vaccines progress through various phases of clinical trials involving human participants. These trials thoroughly examine the vaccine’s safety, immunogenicity, and efficacy. Throughout these trials, vaccine safety is closely monitored, and participants are carefully observed for any adverse reactions or side effects [91, 92, 93].

Table 2 provides a comprehensive analysis of the safety profile of approved COVID-19 vaccines, which has been extensively studied in both clinical trials and real-world settings. Most of the reported adverse events have been mild and temporary, such as localized pain at the injection site and low-grade fever [92]. Although rare, there have been reports of more severe adverse events, including anaphylaxis [93]. However, it is important to note that the occurrence of such serious adverse events is very low [93]. Overall, the risk of experiencing severe adverse events from the vaccines is significantly lower compared to the risk of severe illness resulting from COVID-19 (Table 2).

6. The efficacy of COVID-19 vaccines

Vaccine efficacy is a measurement of the effectiveness of a vaccine in disease or infection prevention, determined through controlled clinical trials under controlled conditions. This measure quantifies the reduction in disease incidence among vaccinated individuals in comparison to their unvaccinated counterparts, offering insights into the vaccine’s capacity to protect against a specific pathogen. Clinical trials randomly assign participants to receive either the vaccine or a placebo, monitoring the occurrence of the targeted disease or infection in both groups [94]. By comparing the incidence rates, researchers can calculate the vaccine’s efficacy, expressed as a percentage that represents the reduced risk of developing the disease among vaccinated individuals.

Table 3 provides an efficacy review analysis of approved COVID-19 vaccines in preventing symptomatic COVID-19. Clinical trials and real-world data have demonstrated that all COVID-19 vaccines effectively protect against severe illness, hospitalization, and mortality. When it comes to preventing symptomatic COVID-19, mRNA vaccines have demonstrated notably higher efficacy rates compared to other types of vaccines (Table 3) [94].

7. Opinions on immunogenicity, safety, and efficacy toward filling gaps of vaccine hesitancy

The evaluation of COVID-19 vaccines takes into account important factors such as immunogenicity, safety, and efficacy. A thorough review of these factors for authorized COVID-19 vaccines reveals that various vaccine platforms, including inactivated vaccines, viral vector vaccines, mRNA vaccines, DNA vaccines, and protein-based vaccines, demonstrate strong immunogenicity by eliciting neutralizing antibodies and cellular immune responses (Table 1). Moreover, studies have demonstrated that these vaccines are both safe and effective in preventing symptomatic cases of COVID-19 (Tables 2 and 3).

In terms of immunogenicity, both the recommended two-dose regimen and a single dose of the Johnson & Johnson vaccine have been shown to elicit strong immune responses in clinical trials and real-world data (Table 1). These responses include the production of neutralizing antibodies and the activation of T-cell responses, which are important for combating the SARS-CoV-2 virus. While the level of immunogenicity may vary among different vaccine platforms, overall, vaccines have proven effective in reducing the severity of COVID-19 symptoms and preventing hospitalization and mortality (Table 3).

When it comes to safety, robust monitoring systems have been implemented to continuously evaluate the side effects of vaccines [53, 92, 93]. Most adverse events have been mild and temporary, including symptoms like pain at the injection site, fatigue, or low-grade fever (Table 2). These mild to moderate side effects have been observed across various vaccine platforms and generally resolve on their own within a few days. Serious adverse events are exceedingly rare [53], and the benefits of vaccination in preventing severe COVID-19 far outweigh the potential risks. However, ensuring vaccine safety remains a top priority, and ongoing surveillance plays a critical role in promptly addressing any emerging safety concerns [53].

In terms of efficacy, COVID-19 vaccines have shown remarkable effectiveness in preventing both the incidence and severity of COVID-19 [94] (Table 3). Vaccination has proven to be highly successful in reducing hospitalizations and fatalities, even in the presence of emerging variants of concern. However, breakthrough infections can still occur, particularly with new variants like “Omicron,” underscoring the need for ongoing surveillance, booster doses, and the development of updated vaccines to address viral mutations. Continued vigilance and adaptation are crucial to ensure the continued effectiveness of COVID-19 vaccination efforts according to a report [95].

Furthermore, the prime-boost vaccination strategy has demonstrated its potency, safety, and effectiveness in combating COVID-19 (Tables 2 and 3). In addition, studies have shown that heterologous prime-boost vaccination using combinations of an inactivated vaccine, AstraZeneca, Pfizer, and Moderna vaccines can be even more potent compared to homologous prime-boost vaccination using any single vaccine alone [96, 97]. The implementation of homologous or heterologous prime-boost vaccination strategies has been observed. In Cambodia, for instance, a homologous or heterologous prime-boost vaccination approach has been implemented, with inactivated vaccines used as the priming vaccine and viral vector or mRNA vaccines as the boosting vaccine. Encouragingly, no adverse events have been reported, and the vaccinated population in Cambodia has experienced a significant reduction in mortality [98]. These findings further emphasize the overall convenience and benefits of COVID-19 vaccination strategies.

8. Opinions on immunogenicity, safety, and efficacy toward filling gaps of vaccine inequity

In the global context, the impact of COVID-19 vaccines is influenced by the administration of numerous approved vaccines worldwide, as illustrated in Figures 4 and 3. A staggering 13.47 billion vaccine doses have been administered globally, with an average of 70.3% of the world population having received at least one dose and 93,683 doses being administered daily [8]. However, it is concerning that only 32.2% of individuals in low and middle-income countries (LMICs) have received at least one vaccine dose, primarily utilizing vaccines with lower prominence [8]. These statistics highlight the existence of a “vaccine inequity” gap between LMICs and developed nations.

The “vaccine inequity” observed among LMICs can be attributed to several crucial factors. These include the inability of these countries to manufacture their own vaccines, limited budgets to purchase advanced vaccines like Pfizer or Moderna [7], and concerns regarding the immunogenicity, safety, and efficacy of lower-profile vaccines, which may lead to vaccine hesitancy [61, 62, 63, 64, 65]. In light of these challenges, it is important to emphasize that the available vaccines, as outlined in Tables 2 and 3, have demonstrated overall safety and effectiveness, particularly in reducing hospitalizations and deaths. Therefore, individuals are encouraged to receive any vaccines that are accessible and affordable to help mitigate the impact of COVID-19.

COVAX and vaccine diplomacy are crucial strategies that have significant impacts on achieving equitable distribution of vaccines. By pooling resources and coordinating with vaccine manufacturers, COVAX aims to provide vaccines to LMICs that may otherwise struggle to secure sufficient doses. This initiative helps bridge the gap between nations with ample resources and those facing financial and logistical challenges. In addition, to effectively address vaccine inequity, it is also crucial to establish comprehensive vaccine surveillance systems that monitor the immunogenicity, safety profile, and efficacy of vaccines in regional countries. Taking inspiration from the UK report released by the UK Health Security Agency on October 21, 2021 [95], implementing such surveillance systems can provide valuable insights and help ensure that vaccines are being administered effectively and safely in different regions. This approach would significantly enhance trust in vaccine uptake within these countries and serve as essential documentation for future vaccine research and development. In Cambodia, for instance, a range of vaccines, including inactivated vaccines (Sinovax & Sinopharm), mRNA vaccines (Pfizer & Moderna), and viral vector vaccines (Astrazeneca & Janssen), are being used [7, 98]. It would be highly beneficial if Cambodia also conducts evaluation reports similar to the UK case [95]. These reports will be invaluable for future vaccine research and development in Cambodia, providing insights into which vaccine-based platforms offer long-lasting protective and therapeutic efficacy for the country’s geographic and regional populations. Additionally, the reports will bolster efforts to enhance vaccine production capabilities, enabling better preparedness for future pandemics and ensuring the availability, safety, effectiveness, and affordability of vaccines in Cambodia.

In the global context, furthermore, as the UK holds the presidency of the G7, it should also consider conducting a comprehensive study in line with the research conducted by Edward J Mills and Gilmar Reis [99]. This study would involve head-to-head clinical trials comparing vaccines such as Pfizer, Moderna, Astrazeneca, Sputnik V, and Sinopharm, among others. The aim of this study would be to accumulate data and establish trust in the immunogenicity, safety, and efficacy of these vaccines. Including lower-profile vaccines in the study would have a significant impact on many LMICs, maximizing vaccine uptake in those regions. Importantly, such a study would contribute to shaping a better global solution regarding the prioritization of vaccine production, determining who should be offered the vaccine and establishing guidelines for booster shots, both in LMICs and developed nations. Moreover, it would enhance preparedness and control measures for future pandemic threats, ensuring a more effective response.

In cases where certain lower-profile vaccines are not approved for use in the UK, conducting a head-to-head study becomes limited. However, it is crucial to consider alternative approaches such as a collective report from G7 and G20 countries, along with data from LMICs. This would provide a more comprehensive analysis of vaccines’ immunogenicity, safety, and efficacy. Additionally, the inclusion of vaccines like the DNA vaccine (Zydus Candila) from India, VLP (Medicago) from Canada, and Novavax (USA) (Figure 3) should be considered. Another valuable approach would be to develop a methodology that combines data from separate studies to estimate the immunogenicity, safety, and efficacy of different vaccines. This approach would enhance the credibility and reliability of the findings.

9. Opinions on immunogenicity, safety and efficacy toward future epidemic preparedness and control

This report presents an update on the current landscape of COVID-19 vaccines, emphasizing their immunogenicity, safety, and efficacy in the context of filling gaps of vaccine hesitancy, vaccine inequity, and future epidemic preparedness and control. The development and widespread administration of vaccines have played a crucial role in mitigating the impact of the ongoing COVID-19 pandemic [9, 10]. With numerous vaccines receiving emergency use authorization, the knowledge gained from their development and deployment can significantly contribute to future epidemic preparedness and control efforts [100]. The remarkable speed at which vaccines were developed and distributed globally highlights the potential for expediting vaccine development in response to emerging infectious diseases. Through collaborative endeavors involving governments, researchers, and pharmaceutical companies, we can further enhance vaccine production, distribution, and ensure equitable access, thus strengthening global preparedness against future epidemics [7].

Furthermore, it is crucial for LMICs to prioritize the enhancement of laboratory capacities to enable prompt and accurate diagnosis of infectious diseases [101]. This can be achieved by investing in infrastructure, equipment, and training for laboratory personnel. By strengthening laboratory capabilities, LMICs can effectively contribute to epidemic prevention, detection, and control. It is also important for LMICs to allocate resources to support research and development initiatives focused on combating epidemics [7]. This entails providing financial support to local research institutions, fostering collaborations with international partners, and conducting studies on the local epidemiology of infectious diseases, actively practice in non-pandemic times through one health concept [101]. To ensure reliable and standardized testing, it is imperative to establish well-equipped laboratories, provide comprehensive training to laboratory staff, and implement robust quality control measures [7]. Additionally, addressing vaccine hesitancy is paramount. This can be accomplished through transparent communication, accessible education, and community engagement. Public health campaigns should prioritize disseminating accurate information, dispel myths and misinformation, and address concerns in order to enhance vaccine acceptance among the population.

10. Conclusion

In summary, the utilization of COVID-19 vaccines has demonstrated their effectiveness in mitigating the impact of the pandemic, showcasing favorable immunogenicity, safety, and efficacy against the virus. These valuable insights gained from developing and deploying vaccines can be invaluable for future epidemic preparedness and control. To ensure successful vaccination strategies in future outbreaks and epidemics, it is imperative to prioritize factors such as maintaining public trust, promoting equitable access to vaccines, and continuing research and development efforts. By applying these lessons, we can strengthen our readiness to effectively address and control potential future epidemics.

Conflict of interest

The authors declare no competing financial interests or personal relationships that could have appeared to influence the work reported in this chapter.