+1 Recommend
3 collections

      Zoonoses now indexed by SCOPUS from December 2023. Interested in becoming a Zoonoses published author?

      • Platinum Open Access with no APCs.
      • Fast peer review/Fast publication online after article acceptance.

      Check out the call for papers on our website https://zoonoses-journal.org/index.php/2023/04/26/zoonoses-call-for-papers-2/

      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      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.

            Main article text


            The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has led to more than 575 million confirmed cases and 6 million deaths worldwide through August 2, 2022 [1]. Efficacious vaccines are important preventive measures against COVID-19. According to World Health Organization (WHO) data released on June 1, 2022, more than 300 COVID-19 vaccine candidates have been developed or are in development. Of these, 153 COVID-19 vaccine candidates have been evaluated in clinical trials. These vaccines mainly include inactivated vaccines (accounting for 14% of the total), live attenuated vaccines (1%), viral vector vaccines (replication and non-replication; 17% of the total), RNA vaccines (18%), DNA vaccines (11%), protein subunit vaccines (34%), and VLP vaccines (4%) [2].

            The first generation COVID-19 vaccines were designed on the basis of the receptor-binding domain (RBD) or spike protein of the prototype SARS-CoV-2 or the whole prototype virus. The WHO Emergency Use Listing (EUL) has authorized 11 vaccines for emergency use through June 13, 2022, including Ad26.COV2.S developed by Janssen, COVAXIN developed by Bharat Biotech, BNT162b2 developed by Pfizer-BioNTech, AZD1222 Vaxzevria developed by Oxford-AstraZeneca, mRNA-1273 developed by Moderna, inactivated SARS-CoV-2 Vaccine BBIBP-CorV developed by Sinopharm, CoronaVac developed by Sinovac, NVX-CoV2373/Nuvaxovid developed by Novavax, ChAdOx1 nCoV-19 and NVX-CoV2373/Covovax developed by the Serum Institute of India, and Ad5-nCoV developed by CanSino Biologics [3]. These vaccines on the WHO EUL, along with seven other vaccine products conditionally approved by national regulatory authorities, are already in large-scale use [3,4] to mitigate the SARS-CoV-2 pandemic by preventing severe illness or death, and inducing herd immunity in populations.

            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.


            We searched PubMed with the key terms “(COVID-19[Title/Abstract] OR SARS-CoV-2[Title/Abstract]) AND (vaccine[Title/Abstract] OR vaccination[Title/Abstract]) AND (efficacy[Title] OR effectiveness[Title/Abstract] OR protection[Title/Abstract] OR effect[title/Abstract])” and “(protection [Title/Abstract]) AND ((SARS-CoV-2 [Title/Abstract]) OR (COVID-19 vaccination[Title/Abstract]) OR (breakthrough infection[Title/Abstract])),” 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.


            Inactivated vaccines

            Three inactivated COVID-19 vaccines are included on the WHO EUL: BBIBP-CorV and CoronaVac developed in China, which are β-propiolactone inactivated prototype vaccines adjuvanted with aluminum hydroxide [8], and BBV152 developed in India, which is also a β-propiolactone-inactivated whole-virion SARS-CoV-2 vaccine but is adjuvanted with Algel-IMDG, an imidazoquinoline class molecule (TLR7 and TLR8 agonist) adsorbed onto Algel [9].

            The first phase 3 efficacy trial of CoronaVac, performed between July 2020 and January 2021 in Turkey, Brazil and Indonesia, reported an efficacy of 83.5% (95% CI 65.4–92.1), 50.7% (95% CI, 36.0–62.0), and 65.3% (not available for 95% CI) in preventing PCR-confirmed symptomatic COVID-19 at 14 or more days after the second dose, respectively (Table 1) [1012].

            TABLE 1 |

            Efficacy of COVID-19 vaccines in phase 3 randomized controlled clinical trials.

            Sponsor/countryVaccineDose/regimenRegion/countryStudy periodVE (any variant)VE against COVID-19 of any severity (any variant)
            VE in the older populationVE against VOC
            Mild/moderateSevere/criticalAlpha (B.1.1.7)Beta (B.1.351)Gamma (P.1)Delta (B.1.617.2)
            Sinovac/ChinaCoronaVac2 doses/14 days apartTurkey [10]September 2020 to January 202183.5% (65.4–92.1)-------
            Brazil [11]July to December 202050.7% (36.0–62.0)100% (56.4–100.0)* 100% (16.9–100.0)51.1% (−166.9–91.0)
            Indonesia [12]August to October 202065.30%--
            Beijing CNBG/ChinaBBIBP-CorV2 doses/21 days apartUnited Arab Emirates and Bahrain [13]July to December 202078.1% (64.8–86.3)-100%-----
            Bharat Biotech/IndiaBBV1522 doses/28 days apartIndia [14]November 2020 to January 202177.8% (65.2–86.4)-93.4% (57.1–99.8)67.8% (8.0–90.0) ---65.2% (33.1–83.0)
            AstraZeneca/United KingdomAZD12222 doses/21–35 days apartUnited Kingdom and Brazil [15]April to November 202062.1% (41.0–75.7)-------
            United States, Chile, and Peru [16]-74.0% (65.3–80.5)-100%83.5% (54.2–94.1) ---
            South Africa [17]June to December 2020-21.9% (−49.9–59.8)---10.4% (−76.8–54.8)-
            United Kingdom [18]May to November 2020----70.4% (43.6–84.5)--
            Brazil [19]June to December 2020------64% (−2.1–87.0)
            Janssen/United StatesAd26.COV2.S1 doseArgentina, Brazil, Chile, Colombia, Mexico, Peru, South Africa, and United StatesSeptember 2020 to January 2021 [20]66.9% (59.1–73.4)64.8% (55.8–72.2)76.7% (54.6–89.1)76.3% (61.6–86.0) ----
            September 2020 to July 2021 [21]55.9% (51.0–60.5)29.4% (−64.6–70.7)
            52.1% (46.1–57.4)
            73.3% (63.9–80.5)55.0% (42.9–64.7) 70.1% (35.1–87.6)38.1% (4.2–60.4)36.4% (13.9–53.2)−6.0% (−178.3–59.2)
            CanSino/ChinaConvidecia1 doseArgentina, Chile, Mexico, Pakistan, and Russia [22]September 2020 to January 202157.5% (39.7–70.0)--17.5% (−127.6–70.1) ----
            Novavax/United StatesNVX-CoV23732 doses/21 days apartUnited Kingdom [23]September to November 202089.7% (80.2–94.6)--88.9% (20.2–99.7) 86.3% (71.3–93.5)---
            United States and Mexico [24]December 2020 to February 202190.4% (82.9–94.6)-100% (87.0–100)-92.6% (83.6–96.7)
            Pfizer/BioNTech/United States/GermanyBNT162b22 doses/21 days apartUnited States, Argentina, Brazil, South Africa, Germany, and TurkeyJuly to November 2020 [25]95.0% (90.3–97.6)-75.0% (−152.6–99.5)94.7% (66.7–99.9) ----
            July to October 2020 [26]91.3% (89.0–93.2)96.7% (80.3–99.9)94.5% (88.3–97.8)
            96.2% (76.9–99.9)||
            100% (53.5–100)
            Moderna/United StatesmRNA-12732 doses/28 days apartUnited States [27]July to October 202094.1% (89.3–96.8)-100%86.4% (61.4–95.2) ----
            United States [28]July to October 202093.2% (91.0–94.8)98.2% (92.8–99.6)91.5% (83.2–95.7) -
            United States and Canada [29]March to August 2021---88.0% (70.0–95.8)‡‡
            Gamaleya/RussiaSputnik V2 doses/21 days apartRussia [30]September to November 202091.6% (85.6–95.2)-100% (94.4–100.0)91.8% (67.1–98.3)§ ----
            Wuhan CNBG/ChinaWIBP-CorV2 doses/21 days apartUnited Arab Emirates and Bahrain [13]July to December 202072.8% (58.1–82.4)-100%-----
            Zhifei Longcom/ChinaZF20013 doses/30 days apartUzbekistan, Indonesia, Pakistan and Ecuador [31]December 2020 to December 202175.7% (71.0–79.8)-87.6% (70.6–95.7)67.6% (21.9–87.8) 88.3% (66.8–97.0)--76.1% (70.0–81.2)
            Clover Biopharmaceuticals/Hong Kong, ChinaSCB-20192 doses/21 days apartBelgium, Brazil, Colombia, Philippines and South Africa [32]March to August 202167.2% (54.3–76.8) 83.7% (55.9–95.4)* 100% (25.3–100.0)** 58.4% (−73.4–92.9) --91.8% (44.9–99.8)78.7% (57.3–90.4)
            GSK+Medicago/United States and CanadaCoVLP+AS032 doses/21 days apartArgentina, Brazil, Canada, Mexico, United Kingdom, and United States [33]March to September 202169.5% (56.7–78.8)76.9% (51.5–90.0)
            78.8% (55.8–90.8)*
            100.0% (−63.7−NA)12.9% (−3295.5–97.8) 100% (38.2–NA)-87.8% (73.0–95.3)74.05% (51.7–86.8)
            Cadila Healthcare/IndiaZyCoV-D3 doses/28 days apartIndia [34]January to June 202166.6% (47.6–80.7)64.9% (44.9–79.8)100%-
            CureVac/GermanyCVnCoV2 doses/28 days apartEurope and Latin America [35]December 2020 to April 202148.2% (31.0–61.4)†† 70.7% (42.5–86.1)* --55.1% (23.5–73.6)-67.1% (29.8–84.6)-

            VE (vaccine efficacy) is represented with point estimates and their 95% confidence intervals.

            *Represents moderate to severe disease.

            Represents the older population ≥60 years of age.

            Represents the older population ≥65 years of age.

            §Represents the older population >60 years of age.

            ||Represents the older population ≥75 years of age.

            Represents 95.72% CI.

            **Represents 97.86% CI.

            ††Represents 95.826% CI.

            ‡‡Represents children 6–11 years of age receiving one dose of mRNA-1273.

            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].

            TABLE 2 |

            Effectiveness of COVID-19 vaccines against SARS-CoV-2 variants in real-world studies.

            Sponsor/countryName of vaccineStudy designCountry/countriesStudy periodEffectiveness against SARS-CoV-2 variants
            Sinovac/ChinaCoronaVac [3640]2 retrospective cohort studies;
            2 prospective cohort studies;
            1 test-negative case-control study
            Chile, China, Turkey, and BrazilJanuary 2021 to February 2022
            Beijing Institute of Biological/ChinaBBIBP-CorV [4043]2 retrospective cohort studies;
            1 test-negative, case-control study;
            1 retrospective, observational study
            China, Argentina, Hungary, and the United Arab EmiratesSeptember 2020 to September 2021
            Bharat Biotech/IndiaBBV152 [44]1 test-negative, case-control studyIndiaApril 2021 to May 2021
            AZD1222/United KingdomAZD1222 Vaxzevria [41,43,4550]6 test-negative case-control studies;
            1 large community-based survey;
            1 retrospective, observational study
            United Kingdom, Scotland, Canada, Brazil, Argentina, and HungaryDecember 2020 to January 2022
            Janssen/United StatesAd26.COV2.S [51,52]1 test-negative design study;
            1 matched cohort design study
            South AfricaNovember 2021 to January 2022
            CanSino/ChinaConvidecia [53]1 retrospective cohort studyChinaIn July 2021
            Gamaleya/RussiaSputnik V [41,43]1 test-negative, case-control study;
            1 retrospective, observational study;
            1 retrospective cohort study
            Argentina and HungaryDecember 2020 to September 2021
            Pfizer/BioNTech/United States/GermanBNT162b2 [43,45,46,48,49,50,52,5472]11 test-negative case-control studies;
            6 retrospective cohort studies;
            5 prospective cohort studies;
            3 observational studies
            United States, United Kingdom., Israel, Italy, Qatar, Canada, France, Hungary, Scotland, South Africa, and GermanyFebruary 2020 to February 2022
            Moderna/United StatesmRNA-1273 [43,46,48,56,64,65,68,70,7274]6 test-negative case-control studies;
            2 retrospective cohort studies;
            2 prospective cohort studies;
            1 observational study
            United States, Qatar, Canada, France, Hungary, and United KingdomDecember 2020 to January 2022

            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.

            Generally, CoronaVac has been reported to confer high protection against severe COVID-19, hospitalization, and intensive care unit (ICU) admission among children and adolescents [77]. In children 6–16 years of age, the effectiveness of CoronaVac against infection was 74.5% (95% CI, 73.8–75.2), that against hospitalization was 91.0% (95% CI, 87.8–93.4), and that against ICU admission was 93.8% (95% CI, 87.8–93.4). However, a population-based cohort study of 490,694 children 3–5 years of age, who were observed to evaluate the effectiveness of CoronaVac during the Omicron (B.1.1.529) outbreak in Chile, reported a clear decrease in vaccine protection against Omicron (B.1.1.529) variant infection [38]. The estimated vaccine effectiveness was 38.2% (95% CI, 36.5–39.9) against symptomatic COVID-19, 64.6% (95% CI, 49.6–75.2) against hospitalization, and 69.0% (95% CI, 18.6–88.2) against ICU admission.

            Another inactivated COVID-19 vaccine, BBIBP-CorV, manufactured by Beijing Institute of Sinopharm, was developed on the basis of the prototype SARS-CoV-2 HB02 strain. An efficacy study of BBIBP-CorV conducted in the United Arab Emirates and Bahrain among adults 18 years and older without a known history of COVID-19, from July 2020 to December 2020, indicated an efficacy of 78.1% (95% CI, 64.8–86.3) against symptomatic COVID-19 during a median follow-up of 77 days (range: 1–121), starting 14 days after the second dose (Table 1) [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 77.8% (95% CI, 65.2–86.4) for symptomatic cases and 93.4% (95% CI, 57.1–99.8) for severe cases (Table 1). The efficacy was 67.8% (95% CI, 8.0–90.0) for older people (≥60 years) and 79.4% (95% CI, 66.0–88.2) for people younger than 60 years. However, the effectiveness data indicated that the protection conferred by BBV152 against symptomatic COVID-19 diseases decreased when Delta (B.1.617.2) became predominant in the pandemic [44].

            Viral vector vaccines

            The ChAdOx1 nCoV-19 vaccine (AZD1222), developed by Oxford University, consists of a replication-deficient chimpanzee adenoviral vector, ChAdOx1, containing the SARS-CoV-2 structural spike protein gene. In phase 3 trials conducted in the United Kingdom and Brazil, two doses of ChAdOx1 nCoV-19 showed an overall vaccine efficacy of 62.1% (95% CI, 41.0–75.7) in adults 18 years of age and older (Table 1) [15]. Another phase 3 trial in the United States, Chile, and Peru, estimated that two doses of ChAdOx1 nCoV-19 vaccines conferred an overall vaccine efficacy of 74.0% (95% CI, 65.3–80.5) in participants 18 years of age or older and 83.5% (95% CI, 54.2–94.1) in participants 65 years of age or older [16]. However, in a multicenter, double-blind, randomized, controlled trial in South Africa, the two-dose regimen of ChAdOx1 nCoV-19 vaccine demonstrated nearly no protection 10.4% (95% CI, –76.8–54.8) against mild-to-moderate COVID-19 due to the Beta (B.1.351) variant [17]. With the massive administration of the ChAdOx1 nCoV-19 vaccine in populations, the effectiveness of this vaccine has been assessed in the United Kingdom, Scotland, Canada, Brazil, Argentina, and Hungary (Table 2). Surveillance data on symptomatic cases of COVID-19 in England revealed an effectiveness of two doses of the ChAdOx1 nCoV-19 vaccine of 74.5% (95% CI, 68.4–79.4) among people exposed to the Alpha (B.1.1.7) variant and 67.0% (95% CI, 61.3–71.8) among those exposed to the Delta (B.1.617.2) variant [45]. During the Omicron (B.1.1.529) epidemic, two-dose immunization with the ChAdOx1 vaccine induced a protection of approximately 48.9% (95% CI, 39.2–57.1) against symptomatic infections 2–4 weeks after second dose, which subsequently waned over time. Two doses of the ChAdOx1 vaccine conferred little to no protection against Omicron (B.1.1.529)-associated infection 6 months after the second vaccination [46].

            The Ad26.COV2.S (Johnson & Johnson) vaccine, developed by Janssen, is a recombinant, replication-incompetent human adenovirus type 26 vector encoding full-length SARS-CoV-2 spike protein in a prefusion-stabilized conformation. In phase 3 trials, a single dose of Ad26.COV2.S conferred protection of 66.9% (95% CI, 59.1–73.4) and 55.9% (95% CI, 51.0–60.5) against symptomatic COVID-19 of any severity, and 76.7% (95% CI, 54.6–89.1) and 73.7% (95% CI, 63.9–80.5) against severe to critical COVID-19 disease, with an onset of protection at least 14 days after vaccination (Table 1) [20,21]. Ad26.COV2.S conferred significant protection against the Alpha (B.1.1.7), Beta (B.1.351), and Gamma (P.1) variants, but not the Delta (B.1.617.2) variant [21]. The effectiveness of a single dose of the Ad26.COV2.S vaccine, evaluated in South Africa from November 2021 to January 2022 (Table 2), was 75% (95% CI, 69–82) in preventing COVID-19-associated hospital admissions requiring critical or intensive care, and 62% (95% CI, 42–76) and 67% (95% CI, 62–71) in preventing COVID-19-associated hospitalizations [51] during epidemics dominated by the Beta (B.1.351) and Delta (B.1.617.2) variants.

            Convidecia is a single-dose Ad5 vectored vaccine expressing the SARS-CoV-2 spike protein (Ad5-nCoV vaccine), manufactured by CanSino Biologics, China. A phase 3 clinical trial enrolling adults 18 years of age and older, performed in Argentina, Chile, Mexico, Pakistan and Russia, found that one dose of Convidecia had a 57.5% (95% CI, 39.7–70.0) efficacy against symptomatic, PCR-confirmed SARS-CoV-2 infection at 28 days or more after vaccination (Table 1) [22]. Only one observational study, in Yunnan province in China, has reported the effectiveness of the Ad5-nCoV vaccine Convidecia [53]; the study indicated a protection of 61.5% (95% CI, 9.5–83.6) against symptomatic COVID-19, 67.9% (95% CI, 1.7–89.9) against COVID-19 pneumonia, and 100% (95% CI, 36.6–100) against severe/critical COVID-19 caused by the Delta (B.1.617.2) variant.

            Protein subunit vaccine

            NVX-CoV2373 is the only recombinant protein vaccine currently on the WHO EUL. It contains a recombinant nanoparticle prefusion spike protein of the prototype strain plus Matrix-M adjuvant. In a phase 3 trial conducted at 33 sites in the United Kingdom, in adults 18–84 years of age, two doses of NVX-CoV2373 showed an overall vaccine efficacy of 89.7% (95% CI, 80.2–94.6) against symptomatic disease largely caused by the Alpha (B.1.1.7) variant [23].

            Another phase 3 trial evaluating the efficacy of NVX-CoV2373 in adults (≥18 years of age) was performed in the United States and Mexico during the first half of 2021 [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 moderate-to-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 (B.1.617.2) variant, but decreased over time. However, the two-dose BNT162b2 regimen was found to be less effective against the Omicron (B.1.1.529) variant: for both Omicron (B.1.1.529) BA.1 and BA.2, two doses of BNT162b2 vaccine in the population without previous SARS-CoV-2 infection history showed no protection against symptomatic infections for 200 days post-vaccination. Three doses of the BNT162b2 vaccine conferred 59.6% (95% CI, 52.9–65.3) and 52.2% (95% CI, 48.1–55.9) protection against symptomatic infections caused by the Omicron (B.1.1.529) 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.

            A case-control study in adolescents aged 12–18 years, performed during the Delta (B.1.617.2) and Omicron (B.1.1.529) epidemics, showed that two-dose BNT162b2 vaccines provided similar protection in the 12- to 15-year-old and 16- to 18-year-old groups (83% versus 82%). The vaccine efficacy during the Delta (B.1.617.2) epidemic was 96% (95% CI, 90–98) and 91% (95% CI, 86–94) among these adolescents for critical cases and non-critical hospitalizations, respectively [82]. The vaccine efficacy during the Omicron (B.1.1.529) epidemic declined to 79% (95% CI, 51–91) for critical cases and to 20% (95% CI, −25–49) for non-critical illness. Although the protection conferred by two doses of BNT162b2 was lower against Omicron (B.1.1.529) than Delta (B.1.617.2) COVID-19 in adolescents, the vaccine protection against critical illness was sustained. In Denmark, a large observational study in adolescents also reported a vaccine effectiveness of 93% (95% CI, 92–94) 60 days post-vaccination with BNT162b2 during the Delta (B.1.617.2) epidemic [83]. Nonetheless, a 3.7-fold (95% CI, 2.7–5.2) lower rate of confirmed infection risk was observed after boosting than after two doses, at time points as long as 60 days post-vaccination in adolescents [84]. All SARS-CoV-2 infections pose a risk of long COVID, but a study has reported that vaccination with mRNA vaccines or Ad26.COV2.S before infection confers only 15% protection against post-acute sequelae, with respect to that in people with SARS-CoV-2 infection without prior vaccination [85].


            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.

            Gam-COVID-Vac (Sputnik V) is a heterologous two-dose regimen against COVID-19 approved for emergency use in Russia, with a recombinant of adenovirus type 26 (rAd26) vector-based vaccine as the first dose, and an rAd5 vector-based vaccine as the second dose; both vectors carry the gene for the full-length SARS-CoV-2 S glycoprotein. Sputnik V provided an overall efficacy of 91.6% (95% CI, 85.6–95.2) and 100% (95% CI, 94.4–100.0) against severe disease in a phase 3 trial in Russia [30]. A vaccination campaign against COVID-19 with the rAd26-rAd5 Sputnik V vaccine, undertaken in Argentina for people older than 60 years, demonstrated an effectiveness of 64% (95% CI, 63–65) against infection, and 93.1% (95% CI, 92.6–93.5) against death during epidemics associated with the Gamma (P.1), Lambda (C.37), and Alpha (B.1.1.7) variants [41] (Table 2). Another retrospective cohort study in Argentina reported an effectiveness of the first component of Sputnik V of 78.6% (95% CI, 74.8–81.7), 87.6% (95% CI, 80.3–92.2) and 84.8% (95% CI, 75.0–90.7) in decreasing SARS-CoV-2 laboratory-confirmed infections, hospitalizations, and mortality, respectively, in an older population 60–79 years of age in a Gamma (P.1) variant dominated period [86].

            WIBP-CorV (developed by Wuhan Institute of Sinopharm, China), is a similar β-propionolactone inactivated prototype vaccine to BBIBP-CorV (developed by Beijing Institute of Sinopharm, China) adjuvanted with aluminum hydroxide. The efficacy of WIBP-CorV, as evaluated in the United Arab Emirates and Bahrain among adults 18 years of age or older, demonstrated 72.8% (95% CI, 58.1–82.4) protection against symptomatic COVID-19 at a time when variants were not common [13].

            ZF2001, a protein subunit COVID-19 vaccine using the tandem-repeat dimeric RBD of the SARS-CoV-2 spike protein (from the original Wuhan-Hu-1 strain) as an antigen, manufactured by Anhui Zhifei Longcom Biopharmaceutical, has been authorized for emergency use in China. In the recently reported phase 3 trial, a total of 12625 ZF2001 recipients had 158 cases of symptomatic COVID-19, whereas 12568 placebo recipients had 580 cases, thus indicating an efficacy of 75.7% (95% CI, 71.0–79.8) during the Delta (B.1.617.2) predominant period. Three doses of ZF2001 provided 76.0% (95% CI, 71.2–80.1) protection in younger adults 18–59 years of age and 67.6% (95% CI, 21.9–87.8) protection in people over 60 years of age [31]. Three doses of ZF2001 provided 87.6% (70.6–95.7) protection against severe or critical COVID-19.

            SCB-2019 is an S protein subunit vaccine against SARS-CoV-2 consisting of the trimeric structure of the S protein adjuvanted with CpG-1018 and alum, developed by Clover Biopharmaceuticals. An efficacy trial was conducted in adults 18 years of age and older in Belgium, Brazil, Colombia, the Philippines, and South Africa from March 24, 2021 to August 10, 2021 [32]. Two doses of SCB-2019 provided 67.2% (95.72% CI, 54.3–76.8) protection against COVID-19 of any severity, 83.7% (97.86% CI, 55.9–95.4) protection against moderate-to-severe COVID-19, and 100% (97.86% CI, 25.3–100.0) against severe COVID-19.

            The CoVLP+AS03 vaccine consists of coronavirus-like particles (CoVLP), which are produced in plants and display the prefusion spike glycoprotein of the original strain of SARS-CoV-2, which is combined with an AS03 adjuvant (Adjuvant System 03). In a phase 3 trial, the vaccine efficacy was 69.5% (95% CI, 56.7–78.8) against any symptomatic COVID-19 caused by five variants (Alpha, Gamma, Delta, Lambda, or Mu), 76.9% (95% CI, 51.5–90.0) against moderate disease, and 100.0% (95% CI, -63.7-NA) against severe disease [33].

            ZyCoV-D comprises a DNA plasmid vector pVAX1 carrying a gene expressing the spike protein of SARS-CoV-2 and an IgE signal peptide, and is administered intradermally via a needle-free injection system (Table 1). In a multicenter, double-blind, randomized, controlled trial at 49 hospitals in India, ZyCoV-D showed a vaccine efficacy of 66.6% (95% CI, 47.6–80.7) for all COVID-19 cases, 64.9% (95% CI, 44.9–79.8) for mild cases, and 100% for severe cases [34].

            CVnCoV is formulated with the RNActive mRNA vaccine platform, containing 12 μg mRNA per dose, which was evaluated in a phase 2b/3 clinical trial in 47 public and private hospitals and clinics across four countries in Europe (Belgium, Germany, the Netherlands, and Spain) and six countries in Latin America (Argentina, Colombia, the Dominican Republic, Mexico, Panama, and Peru) (Table 1). CVnCoV conferred 48.2% (95.826% CI, 31.0–61.4) protection against COVID-19 of any severity and 70.7% (95% CI, 42.5–86.1) protection against moderate-to-severe COVID-19 [35].


            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].

            In an observational cohort study in more than 3000 health care workers in the United States, three doses of mRNA vaccines showed an effectiveness of 91% (95% CI, 84–95) in preventing Delta (B.1.617.2) infection, with a relative vaccine effectiveness of 86% (95% CI, 69–94) with respect to the effectiveness of two doses of mRNA vaccine. The effectiveness of two doses of mRNA vaccine was 46% (95% CI, 25–61) in preventing Omicron (B.1.1.529) infection, and the relative vaccine effectiveness was 60% (95% CI, 40–73) [88]. Two- or three-dose vaccination with mRNA vaccines was less effective against mild or asymptomatic infections caused by Omicron (B.1.1.529) than Delta (B.1.617.2). From November 27, 2021 to January 12, 2022, a test-negative design study in England found that booster vaccination with BNT162b2 or mRNA1273 increased vaccine effectiveness against severe disease to more than 75%, and this effect was maintained until approximately 6 months, whereas the effectiveness against symptomatic infections increased to 55–78% within first 3 months after the third dose, then decreased to 29–64% by 3–6 months [46]. Among adolescents 12–15 years of age, a protection of 71.1% (95% CI, 65.5–75.7) was observed 2–6.5 weeks after booster injection of BNT162b2 [89]. Although a BNT162b2 or mRNA-1273 booster dose conferred significantly higher protection against Omicron (B.1.1.529), protection still waned shortly thereafter.

            A large-scale prospective cohort study in Chile found that a third dose of the CoronaVac enhanced the vaccine protection against Omicron (B.1.1.529). Compared with only two doses of CoronaVac, the effectiveness of booster vaccination with CoronaVac was 63.8% (95% CI, 60.4–67.0) in preventing laboratory-confirmed SARS-CoV-2 infection, 59.3% (95% CI, 51.5–65.9) in preventing hospitalization, and 62.7% (95% CI, 44.9–74.7) in preventing death [90]. In Tianjin, China, a retrospective study also found that three doses of inactivated vaccines was associated with a significantly lower risk of ICU hospitalization [OR 0.023 (95% CI, 0.002–0.214)], positive nucleic acid re-tests [OR 0.240 (95% CI, 0.098–0.587)], and shorter hospitalization and recovery time [OR 0.233 (95% CI, 0.091–0.596)] in adults with breakthrough infection [91].

            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 pre-fusion sub-structural domains such as RBD, NTD, and greater affinity of the neutralizing antibodies and broader reactivity [9597].

            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 during the Omicron (B.1.1.529) epidemic.

            A test-negative study conducted in the United States between January 2 and March 23, 2022 reported that one dose of Ad26.COV2.S had an effectiveness of 17.8% (95% CI, 4.3–29.5) between 14 days and 1 month, which then decreased to 8.4% (95% CI, 1.5–14.8) at 2–4 months, whereas two-dose Ad26.COV2.S enhanced the protection to 27.9% (95% CI, 18.3–36.5) and 29.2% (95% CI, 23.1–34.8), respectively. One-dose Ad26.COV2.S plus a heterologous booster of mRNA enhanced the vaccine protection to 61.3% (95% CI, 58.4–64.0) and 54.3% (95% CI, 52.2–56.3), respectively, values similar to those induced by three-dose mRNA vaccination [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 96.5% (95% CI, 96.2–96.7), and AZD1222 increased the effectiveness to 93.2% (95% CI, 92.9–93.6), as compared with 78.8% (95% CI, 76.8–80.6) after homologous boosting with CoronaVac.



            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 45,253 vaccinated patients with 12 specific cancer types, the highest risk was associated with liver cancer [hazard ratio 1.78 (95% CI, 1.38–2.29)], followed by lung cancer [hazard ratio 1.73 (95% CI, 1.50–1.99)], pancreatic cancer [hazard ratio 1.64 (95% CI, 1.24–2.18)], and colorectal cancer [hazard ratio 1.53 (95% CI, 1.32–1.77)]; the lowest risk was for thyroid cancer [hazard ratio 1.07 (95% CI, 0.88–1.30)], skin cancer [hazard ratio 1.17 (95% CI, 0.99–1.38)], breast cancer [hazard ratio 1.16 (95% CI, 1.07–1.25)], and prostate cancer [hazard ratio 1.19 (95% CI, 1.10–1.29)]. Breakthrough infections with SARS-CoV-2 in people with cancer are also associated with a significant and substantial risk of hospitalization and death.

            A retrospective, cross-sectional study involving 2,578 patients with cancer from March 2020 to December 2021 was performed to assess the effectiveness of vaccination with BNT162b2 or CoronaVac against COVID-19 [101]. No significant difference in COVID-19 risk between recipients of two doses of BNT162b2 and three doses of CoronaVac vaccine was observed. Two doses of CoronaVac with one boost dose of BNT162b2 was more effective than two doses of BNT162b2 or three doses of CoronaVac; and two doses of BNT162b2 or three doses of CoronaVac provided significantly higher protection than two doses of CoronaVac in these people with cancer.

            A population-based test-negative case-control study in 377,194 patients with cancer has indicated that BNT162b2 vaccines had 72.1% effectiveness (95% CI, 71.6–72.7) against COVID-19, whereas the ChAdOx1 nCov-19 vaccine had 59.0% effectiveness (95% CI, 58.5–59.6) [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.


            An observational cohort of 10,861 vaccinated pregnant women 16 years of age or older was matched to 10,861 unvaccinated pregnant controls; the estimated vaccine effectiveness was 96% (95% CI, 89–100) for any documented symptomatic infection, 97% (95% CI, 91–100) for infections with documented symptoms, and 89% (95% CI, 43–100) for COVID-19-associated hospitalization [103]. In addition, vaccination of pregnant people may provide protection against SARS-CoV-2 for newborn children.

            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.


            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, 90–97). 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 vaccine-induced 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.


            The efficacy or effectiveness of the first generation COVID-19 vaccines observed in clinical trials or real-world 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.


            The authors declare no competing interests.


            1. WHO. Coronavirus (COVID-19) Dashboard. https://covid19.who.int/Accessed on 13 June 2022

            2. WHO. COVID-19 vaccine tracker and landscape. https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccinesAccessed on 5 June 2022

            3. WHO. Regulation and Prequalification. https://www.who.int/teams/regulation-prequalification/eul/covid-19Accessed on 13 June 2022

            4. London School of Hygiene & Tropical Medicine. COVID-19 vaccine tracker. https://vac-lshtm.shinyapps.io/ncov_vaccine_landscape/Accessed on 8 June 2022

            5. Nohynek H, Wilder-Smith A. Does the world still need new covid-19 vaccines? N Engl J Med. 2022. Vol. 386:2140–2142

            6. Wang Z, Liu H, Li Y, Luo X, Yang N, Lv M, et al.. COVID-19 vaccine guidelines was numerous in quantity but many lack transparent reporting of methodological practices. J Clin Epidemiol. 2022. Vol. 144:163–172

            7. Amraotkar AR, Bushau-Sprinkle AM, Keith RJ, Hamorsky KT, Palmer KE, Gao H, et al.. Pre-existing comorbidities diminish the likelihood of seropositivity after SARS-CoV-2 vaccination. Vaccines (Basel). 2022. Vol. 10:8[Cross Ref]

            8. Xia S, Zhang Y, Wang Y, Wang H, Yang Y, Gao GF, et al.. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial. Lancet Infect Dis. 2021. Vol. 21:39–51

            9. Ella R, Vadrevu KM, Jogdand H, Prasad S, Reddy S, Sarangi V, et al.. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: a double-blind, randomised, phase 1 trial. Lancet Infect Dis. 2021. Vol. 21:637–646

            10. Tanriover MD, Dog˘anay HL, Akova M, Güner HR, Azap A, Akhan S, et al.. Efficacy and safety of an inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac): interim results of a double-blind, randomised, placebo-controlled, phase 3 trial in Turkey. Lancet. 2021. Vol. 398:213–222

            11. Palacios R, Batista AP, Albuquerque CSN, Patiño EG, Santos JdP, Conde MTRP, et al.. Efficacy and safety of a COVID-19 inactivated vaccine in healthcare professionals in Brazil: the PROFISCOV Study. SSRN Electron J. 2021.

            12. Fadlyana E, Rusmil K, Tarigan R, Rahmadi AR, Prodjosoewojo S, Sofiatin Y, et al.. A phase III, observer-blind, randomized, placebo-controlled study of the efficacy, safety, and immunogenicity of SARS-CoV-2 inactivated vaccine in healthy adults aged 18-59 years: an interim analysis in Indonesia. Vaccine. 2021. Vol. 39:6520–6528

            13. Al Kaabi N, Zhang Y, Xia S, Yang Y, Al Qahtani MM, Abdulrazzaq N, et al.. Effect of 2 inactivated SARS-CoV-2 vaccines on symptomatic COVID-19 infection in adults: a randomized clinical trial. Jama. 2021. Vol. 326:35–45. [Cross Ref]

            14. Ella R, Reddy S, Blackwelder W, Potdar V, Yadav P, Sarangi V, et al.. Efficacy, safety, and lot-to-lot immunogenicity of an inactivated SARS-CoV-2 vaccine (BBV152): interim results of a randomised, double-blind, controlled, phase 3 trial. Lancet. 2021. Vol. 398:2173–2184

            15. Voysey M, Clemens SAC, Madhi SA, Weckx LY, Folegatti PM, Aley PK, et al.. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet. 2021. Vol. 397:99–111

            16. Falsey AR, Sobieszczyk ME, Hirsch I, Sproule S, Robb ML, Corey L, et al.. Phase 3 safety and efficacy of AZD1222 (ChAdOx1 nCoV-19) covid-19 vaccine. N Engl J Med. 2021. Vol. 385:2348–2360

            17. Madhi SA, Baillie V, Cutland CL, Voysey M, Koen AL, Fairlie L, et al.. Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant. N Engl J Med. 2021. Vol. 384:1885–1898

            18. Emary KRW, Golubchik T, Aley PK, Ariani CV, Angus B, Bibi S, et al.. Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): an exploratory analysis of a randomised controlled trial. Lancet. 2021. Vol. 397:1351–1362

            19. Clemens SAC, Folegatti PM, Emary KRW, Weckx LY, Ratcliff J, Bibi S, et al.. Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 lineages circulating in Brazil. Nat Commun. 2021. Vol. 12:5861

            20. Sadoff J, Gray G, Vandebosch A, Cárdenas V, Shukarev G, Grinsztejn B, et al.. Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19. N Engl J Med. 2021. Vol. 384:2187–2201

            21. Sadoff J, Gray G, Vandebosch A, Cárdenas V, Shukarev G, Grinsztejn B, et al.. Final analysis of efficacy and safety of single-dose Ad26.COV2.S. N Engl J Med. 2022. Vol. 386:847–860

            22. Halperin SA, Ye L, MacKinnon-Cameron D, Smith B, Cahn PE, Ruiz-Palacios GM, et al.. Final efficacy analysis, interim safety analysis, and immunogenicity of a single dose of recombinant novel coronavirus vaccine (adenovirus type 5 vector) in adults 18 years and older: an international, multicentre, randomised, double-blinded, placebo-controlled phase 3 trial. Lancet. 2022. Vol. 399:237–248

            23. Heath PT, Galiza EP, Baxter DN, Boffito M, Browne D, Burns F, et al.. Safety and efficacy of NVX-CoV2373 Covid-19 vaccine. N Engl J Med. 2021. Vol. 385:1172–1183

            24. Dunkle LM, Kotloff KL, Gay CL, Áñez G, Adelglass JM, Barrat Hernández AQ, et al.. Efficacy and safety of NVX-CoV2373 in adults in the United States and Mexico. N Engl J Med. 2022. Vol. 386:531–543

            25. Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al.. Safety and efficacy of the BNT162b2 mRNA covid-19 vaccine. N Engl J Med. 2020. Vol. 383:2603–2615

            26. Thomas SJ, Moreira ED Jr, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al.. Safety and efficacy of the BNT162b2 mRNA covid-19 vaccine through 6 Months. N Engl J Med. 2021. Vol. 385:1761–1773

            27. Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, et al.. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2021. Vol. 384:403–416

            28. El Sahly HM, Baden LR, Essink B, Doblecki-Lewis S, Martin JM, Anderson EJ, et al.. Efficacy of the mRNA-1273 SARS-CoV-2 vaccine at completion of blinded phase. N Engl J Med. 2021. Vol. 385:1774–1785

            29. Creech CB, Anderson E, Berthaud V, Yildirim I, Atz AM, Melendez Baez I, et al.. Evaluation of mRNA-1273 Covid-19 vaccine in children 6 to 11 years of age. N Engl J Med. 2022. Vol. 386:2011–2023

            30. Logunov DY, Dolzhikova IV, Shcheblyakov DV, Tukhvatulin AI, Zubkova OV, Dzharullaeva AS, et al.. Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. Lancet. 2021. Vol. 397:671–681

            31. Dai L, Gao L, Tao L, Hadinegoro SR, Erkin M, Ying Z, et al.. Efficacy and safety of the RBD-dimer-based covid-19 vaccine ZF2001 in adults. N Engl J Med. 2022. Vol. 386:2097–2111

            32. Bravo L, Smolenov I, Han HH, Li P, Hosain R, Rockhold F, et al.. Efficacy of the adjuvanted subunit protein COVID-19 vaccine, SCB-2019: a phase 2 and 3 multicentre, double-blind, randomised, placebo-controlled trial. Lancet. 2022. Vol. 399:461–472

            33. Hager KJ, Pérez Marc G, Gobeil P, Diaz RS, Heizer G, Llapur C, et al.. Efficacy and safety of a recombinant plant-based adjuvanted covid-19 vaccine. N Engl J Med. 2022. Vol. 386:2084–2096

            34. Khobragade A, Bhate S, Ramaiah V, Deshpande S, Giri K, Phophle H, et al.. Efficacy, safety, and immunogenicity of the DNA SARS-CoV-2 vaccine (ZyCoV-D): the interim efficacy results of a phase 3, randomised, double-blind, placebo-controlled study in India. Lancet. 2022. Vol. 399:1313–1321

            35. Kremsner PG, Ahuad Guerrero RA, Arana-Arri E, Aroca Martinez GJ, Bonten M, Chandler R, et al.. Efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate in ten countries in Europe and Latin America (HERALD): a randomised, observer-blinded, placebo-controlled, phase 2b/3 trial. Lancet Infect Dis. 2022. Vol. 22:329–340

            36. Jara A, Undurraga EA, González C, Paredes F, Fontecilla T, Jara G, et al.. Effectiveness of an inactivated SARS-CoV-2 vaccine in chile. N Engl J Med. 2021. Vol. 385:875–884

            37. Can G, Acar HC, Aydin SN, Balkan II, Karaali R, Budak B, et al.. Waning effectiveness of CoronaVac in real life: a retrospective cohort study in health care workers. Vaccine. 2022. Vol. 40:2574–2579

            38. Jara A, Undurraga EA, Zubizarreta JR, González C, Acevedo J, Pizarro A, et al.. Effectiveness of CoronaVac in children 3 to 5 years during the SARS-CoV-2 Omicron outbreak in Chile. Nat Med. 2022. Vol. 28:1377–1380

            39. Ranzani OT, Hitchings MDT, Dorion M, D’Agostini TL, de Paula RC, de Paula OFP, et al.. Effectiveness of the CoronaVac vaccine in older adults during a gamma variant associated epidemic of covid-19 in Brazil: test negative case-control study. BMJ. 2021. Vol. 374:n2015

            40. Wu D, Zhang Y, Tang L, Wang F, Ye Y, Ma C, et al.. Effectiveness of inactivated COVID-19 vaccines against symptomatic, pneumonia, and severe disease caused by the delta variant: real world study and evidence - China, 2021. China CDC Wkly. 2022. Vol. 4:57–65

            41. Rearte A, Castelli JM, Rearte R, Fuentes N, Pennini V, Pesce M, et al.. Effectiveness of rAd26-rAd5, ChAdOx1 nCoV-19, and BBIBP-CorV vaccines for risk of infection with SARS-CoV-2 and death due to COVID-19 in people older than 60 years in Argentina: a test-negative, case-control, and retrospective longitudinal study. Lancet. 2022. Vol. 399:1254–1264

            42. AlHosani FI, Stanciole AE, Aden B, Timoshkin A, Najim O, Abbas Zaher W, et al.. Impact of the Sinopharm’s BBIBP-CorV vaccine in preventing hospital admissions and death in infected vaccinees: Results from a retrospective study in the emirate of Abu Dhabi, United Arab Emirates (UAE). Vaccine. 2022. Vol. 40:2003–2010

            43. Vokó Z, Kiss Z, Surján G, Surján O, Barcza Z, Pályi B, et al.. Nationwide effectiveness of five SARS-CoV-2 vaccines in Hungary-the HUN-VE study. Clin Microbiol Infect. 2022. Vol. 28:398–404

            44. Desai D, Khan AR, Soneja M, Mittal A, Naik S, Kodan P, et al.. Effectiveness of an inactivated virus-based SARS-CoV-2 vaccine, BBV152, in India: a test-negative, case-control study. Lancet Infect Dis. 2022. Vol. 22:349–356

            45. Lopez Bernal J, Andrews N, Gower C, Gallagher E, Simmons R, Thelwall S, et al.. Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant. N Engl J Med. 2021. Vol. 385:585–594

            46. Andrews N, Stowe J, Kirsebom F, Toffa S, Rickeard T, Gallagher E, et al.. Covid-19 Vaccine Effectiveness against the Omicron (B.1.1.529) Variant. N Engl J Med. 2022. Vol. 386:1532–1546

            47. Hitchings MDT, Ranzani OT, Dorion M, D’Agostini TL, de Paula RC, de Paula OFP, et al.. Effectiveness of ChAdOx1 vaccine in older adults during SARS-CoV-2 Gamma variant circulation in São Paulo. Nat Commun. 2021. Vol. 12:6220

            48. Nasreen S, Chung H, He S, Brown KA, Gubbay JB, Buchan SA, et al.. Effectiveness of COVID-19 vaccines against symptomatic SARS-CoV-2 infection and severe outcomes with variants of concern in Ontario. Nat Microbiol. 2022. Vol. 7:379–385

            49. Pritchard E, Matthews PC, Stoesser N, Eyre DW, Gethings O, Vihta KD, et al.. Impact of vaccination on new SARS-CoV-2 infections in the United Kingdom. Nat Med. 2021. Vol. 27:1370–1378

            50. Sheikh A, McMenamin J, Taylor B, Robertson C. SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness. Lancet. 2021. Vol. 397:2461–2462

            51. Bekker LG, Garrett N, Goga A, Fairall L, Reddy T, Yende-Zuma N, et al.. Effectiveness of the Ad26.COV2.S vaccine in health-care workers in South Africa (the Sisonke study): results from a single-arm, open-label, phase 3B, implementation study. Lancet. 2022. Vol. 399:1141–1153

            52. Gray G, Collie S, Goga A, Garrett N, Champion J, Seocharan I, et al.. Effectiveness of Ad26.COV2.S and BNT162b2 Vaccines against Omicron Variant in South Africa. N Engl J Med. 2022. Vol. 386:2243–2245

            53. Ma C, Sun W, Tang T, Jia M, Liu Y, Wan Y, et al.. Effectiveness of adenovirus type 5 vectored and inactivated COVID-19 vaccines against symptomatic COVID-19, COVID-19 pneumonia, and severe COVID-19 caused by the B.1.617.2 (Delta) variant: evidence from an outbreak in Yunnan, China, 2021. Vaccine. 2022. Vol. 40:2869–2874

            54. Abu-Raddad LJ, Chemaitelly H, Butt AA. Effectiveness of the BNT162b2 Covid-19 vaccine against the B.1.1.7 and B.1.351 variants. N Engl J Med. 2021. Vol. 385:187–189

            55. Bianchi FP, Germinario CA, Migliore G, Vimercati L, Martinelli A, Lobifaro A, et al.. BNT162b2 mRNA COVID-19 vaccine effectiveness in the prevention of SARS-CoV-2 infection: a preliminary report. J Infect Dis. 2021. Vol. 224:431–434

            56. Butt AA, Omer SB, Yan P, Shaikh OS, Mayr FB. SARS-CoV-2 vaccine effectiveness in a high-risk National Population in a Real-World Setting. Ann Intern Med. 2021. Vol. 174:1404–1408

            57. Chodick G, Tene L, Rotem RS, Patalon T, Gazit S, Ben-Tov, et al.. The effectiveness of the two-dose BNT162b2 vaccine: analysis of real-world data. Clin Infect Dis. 2022. Vol. 74:472–478

            58. Cohen-Stavi CJ, Magen O, Barda N, Yaron S, Peretz A, Netzer D, et al.. BNT162b2 vaccine effectiveness against Omicron in children 5 to 11 years of age. N Engl J Med. 2022. Vol. 387:227–236

            59. Fabiani M, Ramigni M, Gobbetto V, Mateo-Urdiales A, Pezzotti P, Piovesan C. Effectiveness of the Comirnaty (BNT162b2, BioNTech/Pfizer) vaccine in preventing SARS-CoV-2 infection among healthcare workers, Treviso province, Veneto region, Italy, 27 December 2020 to 24 March 2021. Euro Surveill. 2021. Vol. 26:2100420

            60. Gomes D, Beyerlein A, Katz K, Hoelscher G, Nennstiel U, Liebl B, et al.. Is the BNT162b2 COVID-19 vaccine effective in elderly populations? Results from population data from Bavaria, Germany. PLoS One. 2021. Vol. 16:e0259370

            61. Haas EJ, Angulo FJ, McLaughlin JM, Anis E, Singer SR, Khan F, et al.. Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data. Lancet. 2021. Vol. 397:1819–1829

            62. Hall VJ, Foulkes S, Saei A, Andrews N, Oguti B, Charlett A, et al.. COVID-19 vaccine coverage in health-care workers in England and effectiveness of BNT162b2 mRNA vaccine against infection (SIREN): a prospective, multicentre, cohort study. Lancet. 2021. Vol. 397:1725–1735

            63. Bernal JL, Andrews N, Gower C, Robertson C, Stowe J, Tessier E, et al.. Effectiveness of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines on covid-19 related symptoms, hospital admissions, and mortality in older adults in England: test negative case-control study. BMJ. 2021. Vol. 373:n1088

            64. Paris C, Perrin S, Hamonic S, Bourget B, Roué C, Brassard O, et al.. Effectiveness of mRNA-BNT162b2, mRNA-1273, and ChAdOx1 nCoV-19 vaccines against COVID-19 in healthcare workers: an observational study using surveillance data. Clin Microbiol Infect. 2021. Vol. 27:1699.e1695–1699.e1698

            65. Pawlowski C, Lenehan P, Puranik A, Agarwal V, Venkatakrishnan AJ, Niesen MJM, et al.. FDA-authorized mRNA COVID-19 vaccines are effective per real-world evidence synthesized across a multi-state health system. Med (N Y). 2021. Vol. 2:979–992.e978

            66. Regev-Yochay G, Amit S, Bergwerk M, Lipsitch M, Leshem E, Kahn R, et al.. Decreased infectivity following BNT162b2 vaccination: a prospective cohort study in Israel. Lancet Reg Health Eur. 2021. Vol. 7:100150

            67. Saciuk Y, Kertes J, Mandel M, Hemo B, Stein NS, Zohar AE. Pfizer-BioNTech vaccine effectiveness against Sars-Cov-2 infection: Findings from a large observational study in Israel. Prev Med. 2022. Vol. 155:106947

            68. Swift MD, Breeher LE, Tande AJ, Tommaso CP, Hainy CM, Chu H, et al.. Effectiveness of messenger RNA Coronavirus disease. 2019 (COVID-19) vaccines against severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection in a cohort of healthcare personnel. Clin Infect Dis. 2021. Vol. 73:e1376–e1379

            69. Tang L, Hijano DR, Gaur AH, Geiger TL, Neufeld EJ, Hoffman JM, et al.. Asymptomatic and symptomatic SARS-CoV-2 infections after BNT162b2 vaccination in a routinely screened workforce. JAMA. 2021. Vol. 325:2500–2502

            70. Tang P, Hasan MR, Chemaitelly H, Yassine HM, Benslimane FM, Al Khatib HA, et al.. BNT162b2 and mRNA-1273 COVID-19 vaccine effectiveness against the SARS-CoV-2 Delta variant in Qatar. Nat Med. 2021. Vol. 27:2136–2143

            71. Tartof SY, Slezak JM, Puzniak L, Hong V, Xie F, Ackerson BK, et al.. Durability of BNT162b2 vaccine against hospital and emergency department admissions due to the omicron and delta variants in a large health system in the USA: a test-negative case-control study. Lancet Respir Med. 2022. Vol. 10:689–699

            72. Thompson MG, Burgess JL, Naleway AL, Tyner H, Yoon SK, Meece J, et al.. Prevention and attenuation of Covid-19 with the BNT162b2 and mRNA-1273 vaccines. N Engl J Med. 2021. Vol. 385:320–329

            73. Chemaitelly H, Yassine HM, Benslimane FM, Al Khatib HA, Tang P, Hasan MR, et al.. mRNA-1273 COVID-19 vaccine effectiveness against the B.1.1.7 and B.1.351 variants and severe COVID-19 disease in Qatar. Nat Med. 2021. Vol. 27:1614–1621

            74. Florea A, Sy LS, Luo Y, Qian L, Bruxvoort KJ, Ackerson BK, et al.. Durability of mRNA-1273 against COVID-19 in the time of Delta: Interim results from an observational cohort study. PLoS One. 2022. Vol. 17:e0267824

            75. Li M, Liu Q, Wu D, Tang L, Wang X, Yan T, et al.. Association of COVID-19 vaccination and clinical severity of patients infected with delta or omicron variants - China, May 21, 2021-February 28, 2022. China CDC Wkly. 2022. Vol. 4:293–297

            76. McMenamin ME, Nealon J, Lin Y, Wong JY, Cheung JK, Lau EHY, et al.. Vaccine effectiveness of one, two, and three doses of BNT162b2 and CoronaVac against COVID-19 in Hong Kong: a population-based observational study. Lancet Infect Dis. 2022. [Cross Ref]

            77. Jara A, Undurraga EA, Flores JC, Zubizarreta JR, González C, Pizarro A, et al.. Effectiveness of an inactivated SARS-CoV-2 vaccine in children and adolescents: a large-scale observational study. SSRN Electron J. 2022.

            78. Premikha M, Chiew CJ, Wei WE, Leo YS, Ong B, Lye DC, et al.. Comparative effectiveness of mRNA and inactivated whole virus vaccines against COVID-19 infection and severe disease in Singapore. Clin Infect Dis. 2022. [Cross Ref]

            79. Team V.G.C.V.T. https://covid19.trackvaccines.org/vaccines/Accessed on 11 June 2022

            80. Altarawneh HN, Chemaitelly H, Ayoub HH, Tang P, Hasan MR, Yassine HM, et al.. Effect of prior infection, vaccination, and hybrid immunity against symptomatic BA.1 and BA.2 Omicron infections and severe COVID-19 in Qatar. medRxiv. 2022. 2022.2003.2022.22272745. [Cross Ref]

            81. Grgicˇ Vitek M, Klavs I, Ucˇakar V, Vrh M, Mrzel M, Serdt M, et al.. mRNA vaccine effectiveness against hospitalisation due to severe acute respiratory infection (SARI) COVID-19 during Omicron variant predominance estimated from real-world surveillance data, Slovenia, February to March 2022. Euro Surveill. 2022. Vol. 27:[Cross Ref]

            82. Price AM, Olson SM, Newhams MM, Halasa NB, Boom JA, Sahni LC, et al.. BNT162b2 Protection against the Omicron Variant in Children and Adolescents. N Engl J Med. 2022. Vol. 386:1899–1909

            83. Kildegaard H, Lund LC, Højlund M, Stensballe LG, Pottegård A. Risk of adverse events after covid-19 in Danish children and adolescents and effectiveness of BNT162b2 in adolescents: cohort study. Bmj. 2022. Vol. 377:e068898

            84. Amir O, Goldberg Y, Mandel M, Bar-On YM, Bodenheimer O, Ash N, et al.. Protection following BNT162b2 booster in adolescents substantially exceeds that of a fresh 2-dose vaccine. Nat Commun. 2022. Vol. 13:1971

            85. Al-Aly Z, Bowe B, Xie Y. Long COVID after breakthrough SARS-CoV-2 infection. Nat Med. 2022. Vol. 28:1461–1467

            86. González S, Olszevicki S, Salazar M, Calabria A, Regairaz L, Marín L, et al.. Effectiveness of the first component of Gam-COVID-Vac (Sputnik V) on reduction of SARS-CoV-2 confirmed infections, hospitalisations and mortality in patients aged 60-79: a retrospective cohort study in Argentina. EClinicalMedicine. 2021. Vol. 40:101126

            87. WHO. COVID-19 Weekly Epidemiological Update. https://www.who.int/docs/default-source/coronaviruse/situation-reports/20220222_weekly_epi_update_80.pdf?sfvrsn=31931200_3&download=trueAccessed on 5 June 2022

            88. Yoon SK, Hegmann KT, Thiese MS, Burgess JL, Ellingson K, Lutrick K, et al.. Protection with a third dose of mRNA vaccine against SARS-CoV-2 variants in frontline workers. N Engl J Med. 2022. Vol. 386:1855–1857

            89. Fleming-Dutra KE, Britton A, Shang N, Derado G, Link-Gelles R, Accorsi EK, et al.. Association of prior BNT162b2 COVID-19 vaccination with symptomatic SARS-CoV-2 infection in children and adolescents during omicron predominance. Jama. 2022. Vol. 327:2210–2219

            90. Jara A, Undurraga EA, Zubizarreta JR, González C, Pizarro A, Acevedo, et al.. Effectiveness of homologous and heterologous booster doses for an inactivated SARS-CoV-2 vaccine: a large-scale prospective cohort study. Lancet Glob Health. 2022. Vol. 10:e798–e806

            91. Zheng H, Cao Y, Chen X, Wang F, Hu Y, Song W, et al.. Disease profile and plasma neutralizing activity of post-vaccination Omicron BA.1 infection in Tianjin, China: a retrospective study. Cell Res. 2022. Vol. 32:781–784

            92. Bar-On YM, Goldberg Y, Mandel M, Bodenheimer O, Amir O, Freedman L, et al.. Protection by a Fourth Dose of BNT162b2 against Omicron in Israel. N Engl J Med. 2022. Vol. 386:1712–1720

            93. Regev-Yochay G, Gonen T, Gilboa M, Mandelboim M, Indenbaum V, Amit S, et al.. 4th Dose COVID mRNA Vaccines’ Immunogenicity & Efficacy Against Omicron VOC. medRxiv. 2022. 2022.2002.2015.22270948. [Cross Ref]

            94. Grewal R, Kitchen SA, Nguyen L, Buchan SA, Wilson SE, Costa AP, et al.. Effectiveness of a fourth dose of COVID-19 mRNA vaccine against the omicron variant among long term care residents in Ontario, Canada: test negative design study. Bmj. 2022. Vol. 378:e071502

            95. Kaku CI, Champney ER, Normark J, Garcia M, Johnson CE, Ahlm C, et al.. Broad anti-SARS-CoV-2 antibody immunity induced by heterologous ChAdOx1/mRNA-1273 vaccination. Science. 2022. Vol. 375:1041–1047

            96. Li JX, Wu SP, Guo XL, Tang R, Huang BY, Chen XQ, et al.. Safety and immunogenicity of heterologous boost immunisation with an orally administered aerosolised Ad5-nCoV after two-dose priming with an inactivated SARS-CoV-2 vaccine in Chinese adults: a randomised, open-label, single-centre trial. Lancet Respir Med. 2022. Vol. 10:739–748

            97. Cox RJ, Brokstad KA. Not just antibodies: B cells and T cells mediate immunity to COVID-19. Nat Rev Immunol. 2020. Vol. 20:581–582

            98. Ranzani OT, Hitchings MD, Leite de Melo R, de França GVA, Fernandes CdFR, Lind ML, et al.. Effectiveness of an inactivated Covid-19 vaccine with homologous and heterologous boosters against Omicron in Brazil. medRxiv. 2022. 2022.2003.2030.22273193. [Cross Ref]

            99. Accorsi EK, Britton A, Shang N, Fleming-Dutra KE, Link-Gelles R, Smith ZR, et al.. Effectiveness of homologous and heterologous Covid-19 boosters against Omicron. N Engl J Med. 2022. Vol. 386:2433–2435

            100. Wang W, Kaelber DC, Xu R, Berger NA. Breakthrough SARS-CoV-2 infections, hospitalizations, and mortality in vaccinated patients with cancer in the US between December 2020 and November 2021. JAMA Oncol. 2022. Vol. 8:1027–1034

            101. Simsek M, Yasin AI, Besiroglu M, Topcu A, Isleyen ZS, Seker M, et al.. The efficacy of BNT162b2 (Pfizer-BioNTech) and CoronaVac vaccines in patients with cancer. J Med Virol. 2022. Vol. 94:4138–4143

            102. Lee LYW, Starkey T, Ionescu MC, Little M, Tilby M, Tripathy AR, et al.. Vaccine effectiveness against COVID-19 breakthrough infections in patients with cancer (UKCCEP): a population-based test-negative case-control study. Lancet Oncol. 2022. Vol. 23:748–757

            103. Dagan N, Barda N, Biron-Shental T, Makov-Assif M, Key C, Kohane IS, et al.. Effectiveness of the BNT162b2 mRNA COVID-19 vaccine in pregnancy. Nat Med. 2021. Vol. 27:1693–1695

            104. Butt AA, Talisa VB, Yan P, Shaikh OS, Omer SB, Mayr FB. Real-world effectiveness of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mRNA vaccines in preventing confirmed infection in patients on chronic hemodialysis. Clin Infect Dis. 2022. Vol. 75:e617–e622

            105. Napuri NI, Curcio D, Swerdlow DL, Srivastava A. Immune response to COVID-19 and mRNA vaccination in immunocompromised individuals: a narrative review. Infect Dis Ther. 2022. Vol. 11:1391–1414

            106. Kwon JH, Tenforde MW, Gaglani M, Talbot HK, Ginde AA, McNeal T, et al.. mRNA vaccine effectiveness against COVID-19 hospitalization among solid organ transplant recipients. J Infect Dis. 2022. [Cross Ref]

            107. Davidov Y, Indenbaum V, Tsaraf K, Cohen-Ezra O, Likhter M, Ben Yakov G, et al.. A third dose of the BNT162b2 mRNA vaccine significantly improves immune responses among liver transplant recipients. J Hepatol. 2022. Vol. 77:702–709

            108. Au WY, Cheung PP. Effectiveness of heterologous and homologous covid-19 vaccine regimens: living systematic review with network meta-analysis. BMJ. 2022. Vol. 377:e069989

            109. Cao Y, Yisimayi A, Jian F, Song W, Xiao T, Wang L, et al.. BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection. Nature. 2022. Vol. 608:593–602

            110. Kaku CI, Bergeron AJ, Ahlm C, Normark J, Sakharkar M, Forsell MNE, et al.. Recall of pre-existing cross-reactive B cell memory following Omicron BA.1 breakthrough infection. Sci Immunol. 2022. Vol. 7:eabq3511

            111. WHO. This dashboard summarizes Officially reported COVID-19 vaccination data. https://app.powerbi.com/view?r=eyJrIjoiMWNjNzZkNjctZTNiNy00YmMzLTkxZjQtNmJiZDM2MTYxNzEwIiwidCI6ImY2MTBjMGI3LWJkMjQtNGIzOS04MTBiLTNkYzI4MGFmYjU5MCIsImMiOjh9Accessed on 12 June 2022

            Author and article information

            Compuscript (Shannon, Ireland )
            21 September 2022
            : 2
            : 1
            : e970
            [1 ]NHC Key Laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu Province, People’s Republic of China
            [2 ]School of Public Health, Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China
            Author notes
            *Corresponding authors: E-mail: jszfc@ 123456vip.sina.com (FZ) and jingxin42102209@ 123456126.com (JL)

            Edited by: Cao Chen, National Institute for Viral Disease Control and Prevention

            Reviewed by: Two reviewers chose to be anonymous.

            Copyright © 2022 The Authors.

            This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY) 4.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.

            : 14 June 2022
            : 06 August 2022
            : 23 August 2022
            Page count
            Tables: 2, References: 111, Pages: 16
            Funded by: National Natural Science Foundation of China
            Award ID: 82173584
            Funded by: Jiangsu Provincial Science Fund for Distinguished Young Researchers
            Award ID: BK20220064
            Funded by: Jiangsu Provincial Key Project of Science and Technology Plan
            Award ID: BE2021738
            This work was supported by the National Natural Science Foundation of China (grant number: 82173584), Jiangsu Provincial Science Fund for Distinguished Young Researchers (grant number: BK20220064), and Jiangsu Provincial Key Project of Science and Technology Plan (grant number: BE2021738).
            Review Article

            Parasitology,Animal science & Zoology,Molecular biology,Public health,Microbiology & Virology,Infectious disease & Microbiology
            SARS-CoV-2,COVID-19 vaccines,efficacy,boosting immunization,effectiveness


            Comment on this article