Evidence of the Efficacy and the Effectiveness of First Generation COVID-19 Vaccines in Clinical Trials and Real-world Studies

More than 300 COVID-19 vaccine candidates have been developed or are currently in development. COVID-19 vaccines on the World Health Organization’s Emergency Use Listing and other COVID-19 vaccine products conditionally approved by national regulatory authorities are already in large-scale use, thus preventing severe illness or death and inducing herd immunity at the population level in the SARS-CoV-2 pandemic. In this review, we systemically assess the efficacy and effectiveness of COVID-19 vaccines in clinical trials or real-world studies, in various populations, including healthy adults, children, older people, pregnant people, people with cancer, and people receiving long-term hemodialysis or solid organ transplantation. In addition, we review available evidence regarding the effectiveness of COVID-19 vaccine immunization strategies in people with a history of SARS-CoV-2 infection, and the enhanced effectiveness conferred by various booster immunizations. We also discuss knowledge gaps in the persistence and spectrum of vaccine protection of currently available COVID-19 vaccines.

All populations are susceptible to SARS-CoV-2 infection, including children, adults, older people, males and females, and people with underlying medical conditions. Some populations have relatively higher risk of severe COVID-19 or severe outcomes of SARS-CoV-2 infection [5]. The large-scale vaccination campaigns worldwide have inevitably led to increasing studies on the use of COVID-19 vaccines in special populations with underlying medical conditions, such as people with cancer, pregnancy, rheumatic and/or musculoskeletal diseases, long-term hemodialysis, or solid organ transplantation [6,7]. Vaccine protection against COVID-19 may differ in these populations.
In this review, we systematically summarize the efficacy and/or effectiveness of first generation COVID-19 vaccines in clinical trials or real-world studies against the prototype strain or various SARS-CoV-2 variants, in both generally healthy populations and populations with underlying conditions or diseases. In addition, we compare the enhanced efficacy and/or effectiveness associated with various boosting immunization strategies with COVID-19 vaccines. The gaps in understanding of the persistence and spectrum of vaccine protection conferred by currently available COVID-19 vaccines are also discussed. ," with article types restricted to "clinical study," "clinical trial," or "observational study." A total of 319 and 161 articles were found with these searches, respectively. Duplicated studies and meta-analyses were excluded. Additional publications were identified through manual searching of the reference sections of each article identified with the above keywords. We identified a total of 99 articles reporting phase 3 trials or real-world studies determining the efficacy or effectiveness of COVID-19 vaccines, published before July 20, 2022, by reading the titles and abstracts.
From January 2021 to February 2022, five retrospective or prospective cohort studies or test-negative case-control studies on CoronaVac reported moderate or high vaccine effectiveness against SARS-CoV-2 variant associated symptomatic infection, hospitalization, or death (Table 2). A countrywide mass vaccination campaign with CoronaVac was conducted in Chile from February to May 2021, with the predominant strain of Gamma (P.1). The vaccine showed an effectiveness of 65.9% (95% CI, 65.2-66.6) against COVID-19, 87.5% (95% CI, 86.7-88.2) against hospitalization, and 86.3% (95% CI, 84.5-87.9) against COVID-19-associated death [36]. However, the effectiveness of CoronaVac in later studies was comparable to or slightly lower than those values in settings involving new epidemic variant transmission or older populations. A retrospective analysis involving all confirmed cases of COVID-19 in mainland China between May 21, 2021 and February 28, 2022 was conducted. In that period, the epidemic variants shifted from Delta (B.1.617.2) to Omicron (B.1.1.529) [75], thus demonstrating that full vaccination decreased the risk of severe COVID-19 disease by 83% and 69%, and booster vaccination decreased the risk of pneumonia by 86% and 69%, and the risk of severe disease by 98% and 91%, among people 18-59 and ≥60 years of age, respectively. Another study in Hong Kong reported that primary two-dose immunization of CoronaVac conferred high protection (approximately 91.7% -93.3%) against severe, critical disease, and death in adults ≤59 years of age, but the protection was lower (approximately 58.2% -63.0%) in adults 60 years or older, particularly those older than 80 years of age [76].
Generally, CoronaVac has been reported to confer high protection against severe COVID-19, hospitalization,    [13]. Vaccine effectiveness of BBIBP-CorV has been evaluated in China, Argentina, Hungary, and the United Arab Emirates (Table 2). In Argentina, a significantly lower risk of SARS-CoV-2 infection and COVID-19 death in people older than 60 years was reported with BBIBP-CorV vaccination, with a vaccine effectiveness of 44% (95% CI, 42-45) and 85.0% (95% CI, 84.0-86.0), respectively [41]. A real-world effectiveness study conducted in Singapore suggested that BBIBP-CorV is better than CoronaVac in preventing infection and severe disease, but both BBIBP-CorV and CoronaVac confer significantly weaker protection than the mRNA vaccine. On the basis of this evidence, Singapore requires vaccination with three doses of inactivated vaccine as the primary immunization series [78].
In another study, the efficacy and effectiveness of BBV152 were evaluated in India. The efficacy study, involving 25 Indian hospitals or medical clinics, recruited adults (≥18 years of age) who were healthy or had stable chronic medical conditions between November 16, 2020, and January 7, 2021, when the Delta (B.1.617.2) was the predominant pandemic variant [14]. The overall estimated BBV152 vaccine efficacy was 77 [23].
Another phase 3 trial evaluating the efficacy of NVX-CoV2373 in adults (≥18 years of age) was performed in Real-world vaccine effectiveness, as assessed by case-control and observational studies of authorized two-dose regimens for CoronaVac, BBIBP-CorV, BBV152, AZD1222, Sputnik V, BNT162b2, and mRNA-1273, and a one-dose regimen for Ad26.COV2.S and Ad5-nCoV. The point estimates and their 95% confidence intervals reported in studies of different vaccines are shown on the right, with circles representing vaccine effectiveness against infection/symptomatic infection and triangles representing severe disease, including hospitalization or death. Some studies reported vaccine effectiveness only in older adults or children, as indicated. *Older adults ≥70 years of age. † Children 3-5 years of age. ‡ Older adults ≥60 years of age. § Older adults 60-79 years of age and after the first component of Sputnik V. || Older adults ≥80 years of age. ¶ Children 5-11 years of age. **One-dose mRNA-1273 effectiveness.  [24]. Two doses of NVX-CoV2373 had an efficacy of 90.4% (95% CI, 82.9-94.6) against COVID-19 and an efficacy of 100% (95% CI, 87.0-100) against moderateto-severe disease (Table 1).

mRNA vaccines
BNT162b2 and mRNA-1273 are the only two mRNA vaccines listed on the WHO EUL, and are the most widely used COVID-19 vaccines against SARS-CoV-2 infection worldwide [79].
A randomized, double-blind study of the BNT162b2, an mRNA vaccine, performed in a healthy population 16 years of age or older, reported early protection 12 days after the first dose and 95% (95% CI, 90.3-97.6) efficacy 7 days after the second dose (Table 1). Similar vaccine efficacy was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions [25]. During 6 months of follow-up, the vaccine efficacy against COVID-19 was 91.3% (95% CI, 89.0-93.2) and that against severe disease was 96.7% (95% CI, 80.3-99.9) among the participants. In South Africa, where the SARS-CoV-2 variant of concern Beta (B.1.351) was predominant, a vaccine efficacy of 100% (95% CI, 53.5-100) was observed [26]. In a study in participants 12-15 years of age without evidence of previous SARS-CoV-2 infection, no COVID-19 cases with an onset of 7 or more days after dose 2 were observed among BNT162b2 recipients, whereas 16 cases occurred among placebo recipients, thus indicating a vaccine efficacy of 100% (95% CI, 75.3-100).
Injections of two-dose mRNA-1273 28 days apart, as evaluated in a clinical trial at 99 centers across the United States, had a vaccine efficacy in preventing COVID-19 illness of 94.1% (95% CI, 89.3-96.8) for adults ≥18 years of age and 86.4 (61.4-95.2) for people ≥65 years of age [27]. The efficacy in preventing severe disease was 98.2% (95% CI, 92.8-99.6), on the basis of 2 cases in the mRNA-1273 group and 106 in the placebo group; the efficacy in preventing asymptomatic infection starting 14 days after the second injection was 63.0% (95% CI, 56.6-68.5) [28].
The effectiveness of the widely used BNT162b2 vaccine has been reported worldwide, in studies from the United States, United Kingdom, Israel, Italy, Qatar, Canada, France, Hungary, Scotland, South Africa, and others ( Table  2). Most of the studies found that the effectiveness of two-dose BNT162b2 vaccination against COVID-19 was high against various variants in adults, including the Delta BA.1 and BA.2 variants within 1 or 2 months, respectively, but greater than 95% protection against severe, critical, or fatal COVID-19 [80]. mRNA-1273 showed high vaccine effectiveness, similar to that of BNT162b2, against symptomatic, severe, critical, or fatal infections caused by various SARS-CoV-2 variants, but mRNA-1273 also showed consistently high protection against the Omicron (B.1.1.529) BA.1 and BA.2 variants (Table 2).
A real-world surveillance study in Slovenia based on data collected from February, 2022 to March, 2022 reported an overall COVID-19 incidence of 98/100,000 in adults 18 years of age or older [81]. The incidence of COVID-19 varied according to vaccination status: 343/100,000 in the unvaccinated population, 132/100,000 in the two-dose mRNA vaccinated population, and 74/100,000 in the three-dose mRNA vaccinated population. In the most vulnerable population, 65 years of age or older, the protection conferred by mRNA vaccines against hospitalization associated with SARS-CoV-2 infection caused by Omicron (B.1.1.529) was 95% (95% CI, 95-96) in three-dose recipients and 82% (95% CI, 79-84) in two-dose recipients. The level of vaccine protection was maintained for at least 6 months.

COVID-19 VACCINES NOT YET ON THE WHO EUL
Some COVID-19 vaccines have not yet been included on the WHO EUL but vaccine efficacy or effectiveness data from trials or observational studies have been reported.

Third dose
During the Omicron (B.1.1.529) epidemic, a substantial decrease in vaccine protection occurred. The primary two-dose immunization schedule with BNT162b2, mRNA1273, or ChAdOx1 induced only approximately 50% protection against symptomatic COVID-19 between 14 days and 3 months, whereas the protection against infections was somewhat lower, at approximately 37%. Furthermore, the effectiveness of all three vaccines was below 50% for both symptomatic disease and infections 3 months after the primary series. Similarly, the two-dose regimen of inactivated COVID-19 vaccines also did not protect recipients, regardless of age, against symptomatic COVID-19 [76]. Boosting with a third dose of COVID-19 vaccine, with an mRNA, vector-based vaccine, or inactivated vaccine, provided more than 79% protection against all clinically symptomatic infections within 3 months after booster vaccination [87].
Together, this evidence supports the massive boosting vaccination campaign in the previously immunized population to increase protection against COVID-19 diseases associated with Omicron (B.1.1.529) infection.

Fourth dose
Because the protection against Omicron (B.1.1.529) wanes rapidly after the third dose, a fourth dose of COVID-19 vaccine appears necessary to defeat the circulating SARS-CoV-2 variants.
In Israel, one of the first countries to implement national immunization with three doses of COVID-19 vaccines, a study investigating the boosting effects of a fourth dose of COVID-19 vaccine was conducted [92]. The fourth dose, compared with only three doses, decreased the SARS-CoV-2 infection by twofold, and decreased severe disease by 4.3 fold in the older population. Although a fourth dose of BNT162b2 and mRNA-1273 elicited 9-10 fold higher titers of neutralizing antibodies versus baseline before boosting, no significant increases were observed with respect to the peak levels of neutralizing antibodies after the third dose [93]. In addition, a fourth dose had an effectiveness of 30% (95% CI, -8.8-50) with BNT162b2, and 10.8% (95% CI, -43-44) with mRNA-1273 against SARS-CoV-2 infection, with respect to 43.1% (95% CI, 6.6-65.4) with BNT162b2, and 31.4% (95% CI, -18.4-64.2) with mRNA-1273, against symptomatic diseases.
Although a fourth dose of COVID-19 vaccine provides limited additional protection against symptomatic disease associated with SARS-CoV-2 infection, the potential benefits in preventing severe cases or death might be greater in high-risk populations. In Ontario, Canada, a test-negative control database study estimated the relative effectiveness of a fourth dose of vaccination versus three doses among the population 60 years and older living in long-term care centers between December 30, 2021 and March 2, 2022 [94]. The fourth dose of COVID-19 mRNA vaccine enhanced the protection against COVID-19-associated morbidity and mortality caused by the Omicron (B.1.1.529) variant strain in older people in long-term care centers, at an interval more than 84 days after vaccination of the third dose.

Heterologous versus homologous prime-boost vaccination
Various COVID-19 vaccines with different antigens or vaccine vectors have been administered in populations for massive immunization, thus providing a unique opportunity to study heterologous and homologous boost vaccination with the COVID-19 vaccines.
A series of trials or studies have reported that heterologous prime-boost immunization with two different COVID-19 vaccines, particularly a heterologous mRNA vaccine or viral vectored vaccine, as compared with homologous immunization with a single COVID-19 vaccine, elicited greater B cell responses to the prefusion sub-structural domains such as RBD, NTD, and greater affinity of the neutralizing antibodies and broader reactivity [95][96][97].
A nationwide test-negative study in Brazil involving the population of people 18 years of age or older who have received two doses of CoronaVac as a primary immunization followed by a booster dose of CoronaVac or BNT162b2, investigated vaccine protection during the Omicron (B.1.1.529) predominated period [98]. A homologous booster of CoronaVac increased vaccine protection against hospitalization or death, with a relative vaccine effectiveness of 42%, but conferred little or no increase in protection against symptomatic infections. In contrast, a heterologous booster of BNT162b2 significantly increased protection against hospitalization or death, with a relative vaccine effectiveness of 66.9%, which was maintained for at least 3 months. CoronaVac homologous boosting had lower effectiveness against hospitalization or death in people aged 75 years or older (46-54%) than in younger adults, whereas BNT162b2 heterologous boosting elicited high protection in all age groups. These results support heterologous booster vaccination to decrease severe illness and death associated with COVID- 19 [99].
In a population immunized with one dose of adenovirus vaccine, a single dose of an mRNA vaccine heterologous booster provided nearly the same protection as three doses of mRNA vaccine.
A large prospective observational, nationwide cohort study in Chile evaluated the vaccine effectiveness of a booster injection with CoronaVac, AZD1222 or BNT162b2 vaccine in people 16 years of age or older who had completed primary immunization with two doses of CoronaVac [90]. Heterologous boost immunization with BNT162b2 increased the effectiveness to 96

COVID-19 VACCINES IN POPULATIONS WITH UNDERLYING MEDICAL CONDITIONS Cancer
A retrospective cohort study based on electronic health records of patients with cancer from a multicenter, national database in the United States between December 2020 and November 2021 found a significantly higher risk of breakthrough infection in people with than without cancer after receiving two doses of BNT162b2, or mRNA-1273, or one dose of AZD1222 [100]. Among [102]. Lower vaccine effectiveness within the prior 12 months was found in patients with cancer, or those who were treated with radiotherapy or systemic anticancer therapy, than in the general healthy population. Furthermore, vaccine effectiveness declined more rapidly in patients with hematologic tumors, such as lymphoma or leukemia, than in patients with solid tumors.

Long-term hemodialysis
In 6,076 patients with long-term hemodialysis, the vaccine effectiveness was 68.9% (95% CI, 61.9-74.7) for two-dose BNT162b2 and 66.7% (95% CI, 58.9-73.0) for two-dose mRNA-1273-values lower than those observed in healthy adults [104]. A systematic review reported that 396,062 patients receiving hemodialysis had an elevated risk of COVID-19, with 15-fold greater COVID-19 incidence and associated death risk than that in the general population [105].

Solid organ transplantation
The COVID-19 mRNA vaccines' effectiveness against COVID-19-associated hospitalizations is diminished in recipients of solid organ transplantation. However, three doses of mRNA vaccine have been found to confer higher protection than two doses of mRNA vaccine among solid organ transplantation recipients. The effectiveness of mRNA vaccines against hospitalization associated with COVID-19 among 440 recipients of solid organ transplantation was 29% (95% CI, -19-58) for a two-dose regimen and 77% (95% CI, 48-90) for a three-dose regimen [106].
In liver transplant patients, the immune response to two doses of BNT162b2 was low, but the third dose significantly improved the humoral and cellular immune response [107]. Further studies are needed to evaluate the persistence of the immune response to three doses in liver transplant patients to determine the optimal number of doses and the interval between the booster dose and the primary doses.

REMAINING KNOWLEDGE GAPS
The ranking of vaccine regimens' effectiveness has been reported in a living systematic review with network meta-analysis involving a total of 53 studies and 24 combinations of COVID-19 vaccine regimens, with or without boosting, in preventing COVID-19 related symptomatic infection, hospital admission, and death [108]. In this review, a three-dose mRNA COVID-19 vaccine regimen was reported to be the most effective regimen against asymptomatic and symptomatic SARS-CoV-2 infections, with a vaccine effectiveness of 96% (95% CI, 72-99), and against COVID-19 related hospital admission, with an effectiveness of 95% (95% CI, [90][91][92][93][94][95][96][97]. Heterologous boosting with two-dose adenovirus vector COVID-19 vaccines plus one booster of mRNA vaccine also showed a satisfactory vaccine effectiveness of 88% (95% CI, 59-97). Lower vaccine effectiveness was noted with two-dose mRNA vaccines, two-dose adenovirus vectored vaccines, one-dose adenovirus vectored vaccines, one-dose mRNA vaccines, and two-dose inactivated vaccines. These data also support that higher protection may be associated with more doses of vaccination and heterologous boosting with COVID-19 vaccines.
However, we should be aware that vaccine effectiveness, particularly the protective effects of COVID-19 vaccines against severe clinical outcomes including severe or critical disease, and death, may be somewhat overestimated because of the "healthy vaccinee bias": that is, the vaccinated populations in observational studies may potentially be healthier than the unvaccinated population. The vaccinated population's protection by vaccination, as well as their good health condition, may bias results toward higher vaccine effectiveness. The mRNA vaccine BNT162b2 is used worldwide, with application in immunocompromised populations, and data on vaccine protection in various populations have been collected; however, evidence of the effectiveness of most COVID-19 vaccines in the presence of underlying medical conditions remains limited.
In addition, most reported vaccine efficacy and/or effectiveness findings have been obtained shortly after vaccination. Even with highly effective COVID-19 vaccines, the waning of antibodies over time, as well as the vaccineinduced protection against infection of SARS-CoV-2, may be substantial. In addition, breakthrough infections associated with new emerging variants of SARS-CoV-2 are continually being reported. These emerging strains of the Omicron (B.1.1.529) subtypes, such as BA.4/5, pose a major challenge to the first generation of vaccines based on the antigen of the prototype SARS-CoV-2, as well as the herd immunity against infection with previous SARS-CoV-2 variants [109].
Although receiving a fourth dose of the prototype COVID-19 vaccines may be feasible to restore vaccine protection against SARS-CoV-2, a variant-specific vaccine could theoretically generate more optimal immune memory to both conserved and new epitopes. However, the phenomenon of "original antigenic sin" may inhibit the ability of the vaccine to elicit responses to the new variants [110]. A more ideal solution would be next generation COVID-19 vaccines with a wide epitope coverage to provide cross-immunity against SARS-CoV-2 variants and confer a longer duration of protection.
Efficacy and safety are two core characteristics for vaccines, but in massive administration of vaccines in routine programs, the ease of schedules, vaccine effectiveness, booster need and frequency, cost, factors regarding cold-chain logistics, manufacturing scalability, acceptance by communities, and scope for local or regional production are additional important characteristics. Dr Hanna Nohynek, chair of the COVID-19 Vaccine Working Group of the WHO Strategic Advisory Group of Experts, and Dr Annelies Wilder-Smith, coordinator of the COVID-19 Vaccine Working Group, believe that countries worldwide need multiple vaccines tailored to their national conditions, owing to differences in population structure, clinical practice, and levels of economic development [5]. With more vaccine platforms available, decision-making regarding vaccine selection might be improved, because certain vaccine platforms may be more suitable for specific age groups, subpopulations (e.g., those with underlying immune-compromising or other medical conditions), or pregnant people. Mixing and matching vaccines may increasingly be required to leverage the benefits of each of these platforms.
Although more than 4.6 billion people worldwide have been vaccinated with at least one dose of COVID-19 vaccine approved for use, according to the WHO's database collected by 200 of 222 countries [111], the remaining knowledge gaps regarding the persistence and spectrum of vaccine protection provided by the currently available COVID-19 vaccines must be investigated in the future. Pancoronavirus COVID-19 vaccines or polyvalent COVID-19 vaccines with broader antigenic composition, improvement of adjuvants, and heterologous prime-boost regimens might provide efficient strategies to confer longer term protection and strengthen the immune response to new SARS-CoV-2 variants.

CONCLUSION
The efficacy or effectiveness of the first generation COVID-19 vaccines observed in clinical trials or realworld studies supports the massive administration of these vaccines in various populations. However, better vaccine protection has been reported in healthy adults than in in older people or those with underlying medical conditions, such as cancer, long-term hemodialysis, or solid organ transplantation. Booster immunization with COVID-19 vaccines is necessary to enhance their effectiveness against SARS-CoV-2, particularly for heterologous prime-boost vaccination.