key: cord-0703767-w1n3hgxe
authors: Mohammed, Ibrahim; Nauman, Areej; Paul, Pradipta; Ganesan, Sanjith; Chen, Kuan-Han; Jalil, Syed Muhammad Saad; Jaouni, Shahd H.; Kawas, Hussam; Khan, Wafa A.; Vattoth, Ahamed Lazim; Al-Hashimi, Yasmeen Alavi; Fares, Ahmed; Zeghlache, Rached; Zakaria, Dalia
title: The efficacy and effectiveness of the COVID-19 vaccines in reducing infection, severity, hospitalization, and mortality: a systematic review
date: 2022-02-03
journal: Hum Vaccin Immunother
DOI: 10.1080/21645515.2022.2027160
sha: 6bfe37546201c8a7974140fe0b7aa9528066c034
doc_id: 703767
cord_uid: w1n3hgxe

With the relatively rapid development of the COVID-19 pandemic, vaccine development has become crucial for limiting disease transmission. The accelerated growth in the approved COVID-19 vaccines has sparked concerns about their efficacies which have been assessed by many studies. This systematic review compares the efficacy and effectiveness of seven COVID-19 vaccines. A comprehensive systematic literature search was performed using several databases to identify studies reporting the effectiveness or the efficacy of the vaccines. Only 42 studies met our inclusion criteria, which revealed that the COVID-19 vaccines have successfully reduced the rates of infections, severity, hospitalization, and mortality among the different populations. The full-dose regimen of the Pfizer/BioNTech vaccine is the most effective against infections with the B.1.1.7 and B.1.351 variants. Despite of the high effectiveness of some of the COVID-19 vaccines, more efforts are required to test their effectiveness against the other newly emerging variants.

As of June 2, 2021, the COVID-19 pandemic has caused almost 172 million infections and 3.5 million deaths worldwide. 1 COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first identified in December 2019 in Wuhan, China.

SARS-CoV-2 is analogous to the coronaviruses that cause severe acute respiratory syndrome (SARS-CoV) and Middle East respiratory syndrome (MERS-CoV). 2 The relatively rapid sequencing of its genome allowed for diagnostic testing, epidemiologic tracking, and the development of both preventative and treatment methods. 3 Indeed, the development of vaccines is central for limiting SARS-CoV-2 transmission. 4

According to the McGill COVID-19 vaccine tracker system, there are currently ongoing trials on more than 120 vaccine candidates, of which 17 have been granted approval in multiple countries. 5

The development of a new vaccine may take 10-15 years. The phases of vaccine development involve the pre-clinical studies including testing the safety and immunogenicity of the vaccine using animal, models. This will be followed by 3 phases of human clinical trials starting by testing the safety and immunogenicity in small groups in phase one then larger groups in phases 2 and 3. Before the vaccine is used for public, it has to be approved by the Food and Drug Administration (FDA) of the USA, or European Medicines Agency in EU. Due to the urgent need to develop a protective vaccine against SARS-CoV-2, the phases of vaccines development have been combined to accelerate the process. 21 Developing COVID-19 vaccines within a short timeframe has raised several concerns about the safety and efficacy of the vaccines. For example, in one of the UK hospitals, Robbins et al., 2021 reported that 27 of the 174 (16%) COVID-19 inpatients during weekend in February had previously received a COVID-19 vaccine. 22 However, the study did not specify the type of vaccine or the number of doses received. Furthermore, in a study conducted in New York City and included all the employees and students of Rockefeller University campus, two women tested COVID-19 positive and were symptomatic after more than 2 weeks following receiving the second dose of the Pfizer/ BioNTech or the Moderna vaccines; viral analysis showed different SARS-CoV-2 variants of clinical importance that indicated a potential risk infection following vaccination. 23 This raised a concern that vaccinated individuals may remain susceptible to COVID-19.

While vaccine efficacy is determined in the clinical trials under controlled conditions, vaccine effectiveness assesses the vaccine among the real populations. 24 In the setting of this new pathogen, it is challenging to evaluate potential vaccine candidates' clinical effectiveness. Because there has been a scarcity of large-scale analysis comparing the efficacy of the multiple available candidate vaccines against confirmed COVID-19 infection, the goal of this systematic review was to compare the efficacy/effectiveness of candidate vaccines in reducing the number of infections, deaths, and severity of infection. Figure 1 diagrammatically illustrates the different sections of the review to facilitate the comprehensive understanding of its structure.

We conducted a comprehensive search that prioritized sensitivity for comprehensiveness. The following databases were searched in the end of April 2021 (see appendix I): PubMed, Medline (Ovid, 1946 -April 2021), Embase (Ovid, 1974 (Ovid, − 2021 , Scopus, Web of Science, Science Direct, MedRxiv, and Lens.org. All searches were limited by year to 2020 through 2021 (or current date). No language restrictions were used, and all searches, where allowed, employed a combination of controlled vocabulary and keywords. A total of 48,292 articles were retrieved through initial searching. Results were imported into EndNote (version 19) and initial de-duplication was conducted using the Bramer methodology,which reduced the total number of articles to 19, 736 An additional 3,428 duplicates were removed when references were imported into Covidence, leaving 16,308 unique articles for initial screening.

During the screening phase, the studies reporting the efficacy, or the effectiveness of the COVID-19 vaccines were selected. We mainly focused on the studies that reported the reduction of COVID-19 infection, severity, hospitalization, mortality or viral load. No restrictions were made about country, age or gender. Any duplicated articles were removed and reviews or any articles that did not include primary data were excluded from the study. Studies that were not in English or those that did not specify the type of COVID-19 vaccine were excluded. Articles devoid of original patient data were excluded from the study. Title and abstract as well as full-text screening were conducted by two different reviewers for each study using Covidence and disagreements were resolved by consensus. Demographic and clinical data of patients reported in each study (whenever data were available) were extracted independently by two different reviewers and disagreements were resolved by consensus. Extracted data included age, sex, type of vaccines and the efficacy/effectiveness of each vaccine in reducing COVID-19 infections, severity, hospitalization and mortality rate. Categorical variables were expressed as percentages while continuous variables were expressed as mean standard deviation or range of results. Data were extracted from each study by two different reviewers. Figure 2 shows the results of database search and screening. The flow diagram summarizes the details of our protocol. After removing the duplicates, a total of 16,308 studies were retrieved, and among those, 277 studies were selected for full-text screening. Only 42 studies that met the inclusion criteria were included. A total of 235 studies were excluded as 214 studies were irrelevant to the data of interest, 18 were without primary data, 1 was an ongoing study, 1 was not in English, and 1 used animal models. Tables 1 and 2 illustrate the highest efficacy and effectiveness values reported for each vaccine after the first and second dose respectively. In most of the included studies, the results were reported as 95% confidence intervals (CI). For simplicity, we specified the confidence level only whenever a value other than 95% was reported. Table 3 summarize the results from 5 studies where vaccine  effectiveness was not assessed by determining the number  of reduced COVID-19 infections, infection severity, hospitalization or mortality rate. 35, 44, 47, 51, 53 The different methods of assessment of vaccine effectiveness is shown for each study.

Supplementary Tables (ST) 1-4 summarize the types of studies and number of vaccinated and control participants in each study for each vaccine. ST1 and 2 summarize the reported efficacy values for each vaccine after the first and second doses, respectively, while ST3 and 4 summarize the reported effectiveness values for each vaccine after the first and second doses respectively. Furthermore, Tables 1 and 2 compare the highest efficacy and effectiveness values for each vaccine after the first and second doses, respectively. Results for the J&J vaccine have been reported only in the tables of the second dose (ST2 and Table 2 ) as only one dose is required for full vaccination.

Our results yielded 20 studies on the Pfizer/BioNTech vaccine: 1 randomized, controlled trial and 19 population-based studies. The trial included 18,198 vaccinated participants who were compared to 18,325 controls in efficacy and effectiveness [25] 0 15 [25, 26, 30, 31, 33, 34, [38] [39] [40] [41] 43, 50, 52, 54, 55, 60] [27] 1 [55] AstraZeneca 63.9 (46.0-75.9) at 22-90 days after vaccination [65] 74% (HR 0.26 (CI 0.19-0. 35) reduction in risk of testing positive.

at ≥28 days after vaccination [38] NR NR 100 (97.5% CI one sided with lower limit:72 · 2) at ≥22 days after vaccination [65] 37% protection against hospitalization [30] ** NR NR 2 [49, 65] 2 [30, 38] J&J ----------Sputnik 91.6 (CI 85.6-95.2) at ≥21 days after vaccination [48] NR 100 (CI 94.4-100.0) at ≥21 days after vaccination [48] NR NR NR NR NR 1 [48] [63] 80 (CI 59-90) [36] NR NR NR NR NR NR 0 7 [27, 32, 36, 52, [62] [63] [64] *This was the dominant variant in the location of the study's participants during the study period, suggesting that the indicated vaccine in the 1 [56] 13 [25, 27, 29, 31, 34, [39] [40] [41] 50, 52, 54, 55, 60, 66] analyses. 56 The number of vaccinated and unvaccinated individuals in the 19 included population studies are reported in ST1-ST4.

Our results yielded three studies on the 

Six studies were retrieved by our search on the Oxford/ AstraZeneca vaccine: 1 was a pooled analysis of 4 randomized controlled trials, 3 were randomized, controlled trials, and 2 were population-based studies. The pooled analysis included 8,581 unvaccinated subjects who were compared to 8,597 vaccinated subjects. 65 The trial by Knoll 

The results of our search yielded 1 randomized controlled trial on the J&J vaccine, which included 21,895 vaccinated participants who were compared to 21,888 unvaccinated persons in an efficacy analysis. 59

Our results yielded 1 randomized controlled trial on the (Sputnik V) vaccine, which included 14,964 vaccinated participants with one dose who were compared to 4,902 unvaccinated persons in an efficacy analysis. 48

The results of our search yielded 1 randomized controlled trial on the Novavax vaccine, which included 2,188 unvaccinated participants who were compared to 2,199 vaccinated persons in an efficacy analysis. 61

The results of our search yielded 2 population-based studies on the Sinovac vaccine. 

The results of our search yielded 8 population-based studies reporting vaccine effectiveness in populations receiving ≥1 vaccine type: 6 with populations receiving the Moderna or the Pfizer/BioNTech vaccines, 27, 32, 36, 52, 63, 64 1 with a population receiving Moderna, Pfizer/BioNTech, or the J&J vaccine, 58 and 1 where the population received the Moderna or the Pfizer/BioNTech vaccine with <0.1% of the included participants with unknown data on the given vaccine. 62 The number of vaccinated and unvaccinated individuals in the 6 included population studies are reported in ST1-ST4. In the study involving the J&J vaccine, data from 4,338,099 vaccinated persons was used to determine vaccine effectiveness. 58 Finally, in the study where <0.1% of the included participants had unknown data on the given vaccine, 45,327 unvaccinated participants were compared to 3,006 vaccinated subjects in an effectiveness analysis. 62

Our research yielded five studies where vaccine effectiveness was reported based on nasopharyngeal viral load or the correlation between vaccination rates and positive PCR tests 35, 44, 47, 51, 53 (Table 3 ).

The accelerated growth in the approved COVID-19 vaccines has sparked concerns about their efficacies which have been assessed by many studies. This systematic review compares the efficacy and effectiveness of seven COVID-19 vaccines through 42 included studies. Furthermore, multiple SARS-CoV-2 virus subtypes were discovered worldwide during the second wave of the pandemic. eThe nomenclature system established by WHO on May 31 for naming and tracking SARS-CoV-2 variants of concern are as follows: 1) Alpha (B. 67 As a result of the emergence of the new variants, several research groups conducted studies to assess the efficacy of the approved vaccines against each variant. The next sections summarize the efficacy versus the effectiveness of the newly developed COVID-19 vaccines against SARS-CoV-2 in general and against the new variants whenever reported.

Vaccine efficacy has been defined by multiple outcomes in several studies. Laboratory-confirmed COVID-19 or SARS-CoV-2 infection, according to the US Food and Drug Administration (FDA), are valid primary endpoints for vaccination effectiveness trials (FDA). To quantify the efficacy attributable to the vaccination, outcome data from randomized controlled trials (RCTs) are frequently reported as a proportionate decrease in illness between vaccinated and control participants. 68, 69 Provided that an immunological correlate of protection is established, vaccine efficacy can also be tested by assessing the percent of recipients who elicit a certain immune response. 68, 70 Vaccine efficacy is usually expressed as a relative risk reduction (RRR). It employs the relative risk (RR) which is the ratio of attack rates with and without vaccination. 71 While RRR only evaluates those who could benefit from the vaccination, the absolute risk reduction (ARR), the difference between attack rates with and without the vaccine, takes into account the entire population. 71 ARRs are often overlooked since they provide a considerably smaller effect magnitude than RRRs. 71 ARR is used to calculate vaccine effectiveness, which is defined as the number of people who need to be vaccinated to prevent one additional case of COVID-19 (1/ARR). 71 To understand the difference between effectiveness and efficacy results, it is important to note the variables affecting both measures. For instance, the ARR and the number needed to vaccinate are sensitive to background risk with a greater risk translating to a higher effectiveness. 71 When only RRRs are used and ARRs are not considered, reporting bias is seen, affecting vaccination efficacy interpretation. 71 Differing study protocols in primary endpoints, placebo types, study populations, and varying background infection risks make comparing vaccines with the currently available data more difficult. 71 Furthermore, the question of whether a vaccination of a certain efficacy in one group would have the same efficacy in another population with different characteristics remains unresolved. 71 Vaccine efficacy is determined in a controlled clinical trial by comparing how many people who received the vaccine acquired the infection to how many people who received the placebo developed the same infection. 24 Vaccine effectiveness, on the other hand, is an assessment of how well vaccines perform in a less controlled setting. 24 While the controlled setting in a clinical trial involves a diverse population including people of all ages, genders, races, and medical conditions, it cannot perfectly represent the whole population, hence the need for studies assessing vaccine effectiveness. 24 25 This study highlights the lower effectiveness of the first dose of the Pfizer/BioNTech vaccine against infection with this particular variant. The highest effectiveness was observed by Hunter and Brainard where effectiveness was assessed in a reanalysis of a retrospective study conducted by Chodick et al. in an Israeli cohort. Vaccine effectiveness was calculated for each day from day 13 to day 24. 43, 72 The reanalysis revealed that the effectiveness of the Pfizer/BioNTech vaccine increased gradually, beginning 14 days after administration of the first dose, and eventually reached a peak of 91% effectiveness on day 21. As highlighted by Abu-Raddad et al., the effectiveness is significantly low against the B.1.351 variant. 25 Effectiveness of the first dose against severe infection ranged from 0 (CI 0-19), a value seen against the B.1.351 variant, 25 26 In a total of 170 SARS-CoV-2 infections documented in this population, 89 (52%) were unvaccinated, 78 (46%) were positive after the first dose, and 3 (2%) were positive after the second dose. Infection rate in the unvaccinated cohort was 7.4 per 10,000 person-days compared to 5.5 per 10,000 person-days 1-14 days after the first dose and 3.0 per 10,000 person-days 15-28 days after the first dose. Adjusted rate reductions of infection were 30% (CI 2-50) for days 1-14, increasing to 75% (72-84) for days 15-28 after the first dose. The study results confirmed a significant reduction in SARS-CoV-2 infection after the first vaccine dose. In addition, authors suggested that the reduction supports postponing the second vaccine dose in countries which would benefit from increased population coverage with a single vaccine dose. 26 The vast difference in effectiveness of the first dose against severe infection can be explained by the fact that the lowest value was seen specifically against the B.1.351 variant. As highlighted by Abu-Raddad et al., the effectiveness was significantly low against the B.1.351 variant. 25 Effectiveness of the first dose against infection requiring hospitalization ranged from 43 (CI 33-52) 30 up to 85 (CI 71-92) 26 at 15-28 days after vaccination. The lowest effectiveness was reported by Bernal et al. in a test negative casecontrol study where they examined the effectiveness of the Pfizer/BioNTech vaccine in individuals aged ≥70 old in England. 30 Cases vaccinated with a single dose of the vaccine had a 43% (CI 33-52%) lower risk of hospitalization and a 51% (CI 37-62%) lower risk of death. This data translates to an effectiveness of approximately 80% for a single dose of the vaccine in preventing hospitalization, with one dose of Pfizer/BioNTech vaccine being 85% effective at preventing COVID-19 -related death. 30 The authors concluded that a single-dose vaccination with Pfizer/BioNTech vaccine significantly reduced symptomatic SARS-CoV-2 infections and provided protection against severe illness. This protection was maintained for the follow-up duration of >6 weeks.

Additionally, with the variant of concern (VOC 202012/01) being the predominant variant in the study period in the UK, the authors suggest this likely reflects effectiveness of the Pfizer/BioNTech vaccine against this variant. 30 The highest effectiveness was observed by Amit et al. 26 The effectiveness of the first vaccine dose against infections requiring hospitalization is very similar in both population-based studies.

Effectiveness of the first dose against fatal disease ranged from 0 (CI 0-19), a value seen against the B.1.351 variant, 25 73 Therefore, this study suggests an average effectiveness of the vaccine over multiple strains. The observed plateau in infection incidence in later periods for vaccinated persons potentially suggests that the Pfizer/BioNTech vaccine is also effective for the B.1.1.7 variant. 34 This study suggests high effectiveness of the Pfizer/ BioNTech vaccine for preventing symptomatic COVID-19 and for hospitalization, severe disease, and death. The vast difference in effectiveness of the first dose against fatal disease can be explained by the fact that the lowest value was seen specifically against the B.1.351 variant. In addition, Abu-Raddad et al. reported a combinedeffectiveness value against both fatal disease and severe or critical illness, hence possibly lowering the observed value. 25 This difference highlights the concept that different study protocols and endpoint variables make comparing the effects of vaccines more difficult. 71 No studies in our search measured the vaccine efficacy of the first dose.

The efficacy of the first vaccine dose against infection was 95.2 (CI 91.2-97.4) at ≥14 days after vaccination. 28 Baden et al. conducted a phase 3 randomized, placebo-controlled, observer-blinded study, where individuals, enrolled from 99 US sites, were assigned in a 1:1 ratio to receive the Moderna vaccine or placebo (saline). 28 With the aim of determining vaccine efficacy in protection against symptomatic COVID-19 infection at least 14 days after the second dose in patients with no prior SARS-CoV-2 history, efficacy analysis was conducted on a population of 14,073 individuals in the placebo group, compared to fully vaccinated 14,134 individuals. In the total 196 infection cases included in the primary efficacy analysis, 11 occurred in the vaccinated cohort (3.3 per 1000 person-years; CI, 1.7-6.0), compared to 185 in the placebo cohort (56.5 per 1000 person-years; CI, 48.7-65.3). In addition, a total of 30 individuals had severe COVID-19 infection, all of whom belonged to the placebo cohort; this data suggests that the vaccine has significant efficacy in preventing severe COVID-19 disease. 28

The effectiveness of the first dose against infection was 51.7 (CI 37.3-63.0) at ≥7 days after vaccination against infection. 55 As discussed earlier, Pawlowski et al. noted that the lower effectiveness observed in their studies, as compared to the efficacy values seen in clinical trials, could be attributed to the fact that individuals receiving the vaccination are mostly at high risk of infection. Threfore, there may be an overrepresentation in the cohort leading to undervalued effectiveness. In addition, vaccinated individuals may engage in higher risk behaviors, such as social gatherings. 55 Importantly, the observed difference highlights the notion mentioned earlier that in efficacy studies that tend to utilize mostly RRRs, and overlook ARRs, a reporting bias might be seen, hence affecting vaccination efficacy interpretation. 71 Importantly, these findings suggest that two doses of the Oxford/AstraZeneca vaccine have no efficacy in preventing mild-to-moderate COVID-19 disease due to the B.1.351 variant. 49 Voysey et al. conducted a multinational study comprised three single-blinded randomized controlled trials and one double-blinded randomized controlled trial. 65 The three single-blinded randomized controlled trials include a phase 1/2 UK trial (COV001), which recruited adults between 18 and 55 years old, a phase 2/3 UK trial (COV002), which recruited adults >18 years old with a focus on high-risk personnel and healthcare workers, and a phase 3 Brazil trial (COV003), which had the same recruiting criteria as COV002. The double-blinded randomized controlled trial (COV005) took place in South Africa and recruited adults between 18 and 65 years old. All 4 aforementioned trials were conducted between April 23, 2020 and December 6, 2020, and a total of 24,422 participants were recruited. With an assigning ratio of 1:1, each participant either received 2 doses of Oxford/AstraZeneca vaccine or 2 doses of saline placebo. The overall vaccine efficacy after 14 days of second-dose recipience was 66.7% (CI 57.4-74.0), compared to 76.0% (CI 59.3-85.9) after 22 days of first-dose recipience. 65 Voysey et al. noted that the discrepancy in the first-and second-dose vaccine efficacy could be attributed to several factors, such as the intensity of the COVID-19 pandemic in different countries as well as the length of the prime-boost interval between first-and second-dose vaccine recipience. 65 As shown in the study, longer prime-boost interval (≥ 12 weeks) indicated higher vaccine efficacy, 81.3% (CI 60.3-91.2%), whereas shorter prime-boost interval (< 6 weeks) indicated lower vaccine efficacy, 55.1% (CI 33.0-69.9%). 65 Efficacy of the first dose against infection requiring hospitalization was only reported in one study and was 100 (97.5% CI one sided with lower limit: 72.2) at ≥22 days after vaccination. 65 

The effectiveness of the first dose against infection ranged from 73 (CI 27-90) at ≥35 days after vaccination 30 up to an observed 74% (HR 0.26 (CI 0.19-0.35)) reduction in the risk of infection at ≥28 days after vaccination. 38 In a retrospective cohort study by Glampson et al., unvaccinated and vaccinated individuals who had received at least one vaccine dose (57% Pfizer/BioNTech and 42% Oxford/AstraZeneca) were included; the data were obtained directly from active hubs or electronic health records and fed into a multivariable Cox regression model for analysis. 38 The infection rates were found to be 0.09% and 0.13% among those vaccinated in weeks 1 and 2 postvaccination, before falling to 0.10% in week 3 and further declining with time. This translated to a decrease in infection rates 2 weeks after vaccination to rates equal to or lower than in the general population (0.19%). The authors also suggested that there could be a depreciation of the effects of single-dose vaccination due to a rise in infection rates in frail care home residents 7 weeks post vaccination. 38 The effectiveness of the first dose against infection requiring hospitalization was reported in one study as a 37% protection against infection requiring hospitalization. 30 4.2.4.1. Efficacy against infection, severe infection, hospitalization, and mortality. The efficacy against infection was 91.6 (CI 85.6-95.2) at ≥21 days after vaccination and 100 (CI 94.4-100.0) against severe infection at ≥21 days after vaccination. 48 In a study by Logunov et al., the investigators conducted a double-blinded, phase 3 randomized control trial in Russia on participants aged ≥18 years old with the aim of determining the efficacy and safety of the Gam-COVID-Vac vaccine. 48 21,977 participants were stratified into groups by age (18-30 years; 31-40 years; 41-50 years; 51-60 years; and >60 years) and were randomized 3:1 to receive either the vaccine or a placebo. With 14,964 participants assigned to the vaccine group and 4,902 to the placebo group, results indicated 78 cases of COVID −19 in participants who had received the 2nd dose, 16 belonging to the vaccine group and 62 to the placebo group. Vaccine efficacy was determined to be 91.6% (Cl 85.6-95.2) from day 21 after the 1st dose that is the day of receiving the 2nd dose. No cases of moderate or severe COVID −19 21 days after the 1st dose was noted in the vaccine group, and 20 cases were reported in the placebo group, translating to an efficacy against moderate or severe COVID −19 of 100% (94.4-100). 48 The study highlights a high efficacy of the Sputnik V vaccine against COVID-19 infection, with an even higher efficacy value against severe infection. No studies in our search measured the vaccine effectiveness.

The reported effectiveness against infection was 49.4 (CI 13.2-71.9) at ≥14 days after vaccination, a value suggested to be valid against the P.1 variant. 42 In a retrospective, test-negative, matched case-control study by Hitchings et al., investigators sought to assess the effectiveness of the Sinovac vaccine in HCWs in Manaus, Brazil, which was widely affected by the epidemic Gamma (P.1) variant. 42 Analysis of effectiveness was conducted after administration of one dose and two doses. The main outcome assessed was symptomatic SARS-CoV-2 infection. Of the one dose casecontrol pairs that were matched by age, neighborhood, and calendar time, analysis revealed that vaccination with at least one dose was associated with a 0.50-fold reduction, a vaccine effectiveness of 49.6 (CI 11.3-71.4) in the odds of developing symptomatic SARS-CoV-2 infection ≥14 days after first-dose administration. On the contrary, analysis of the two-dose casecontrol pairs that were also matched revealed a low effectiveness of 36.8 (CI 54.9-74.2) against symptomatic SARS-CoV-2 infection ≥14 days after second-dose administration. It was also found that vaccinated HCWs had a much greater likelihood of being infected than their unvaccinated counterparts, 0-13 days after first dose (OR 2.11, CI 1. 36-3.27) . The authors concluded that administration of at least one dose of Sinovac is effective against Gamma (P.1) variant transmission. 42 However, the observed low effectiveness of the two-dose regimen questions the vaccine's efficacy and suggests that more studies on the vaccine's efficacy are needed. No studies in our search measured the efficacy of the first dose.

The observed effectiveness of the first vaccine dose in studies with populations receiving the Moderna or the Pfizer/BioNTech vaccine ranged from 67.1 (CI 30.9-84.5) against infection at ≥15 days after vaccination 27 up to 80 (CI 59-90) at ≥14 days after vaccination. 63 Effectiveness values of the first dose against severe infection or infection requiring hospitalization, and fatal illness were reported in only one study and were 77 (CI 71-82) and 64.2 (CI 13.0-85.2), respectively. 64 In the study where <0.1% of the included participants had unknown data on the given vaccine, a 72% reduction in the risk of infection was observed after the first dose. 61 Polack et al. used an ongoing multinational, placebo-controlled, observer-blinded trial for individuals ≥16 years old. 56 The primary end points included confirmed infection after 7 days of second dose and efficacy in participants with and without prior infection. Vaccine efficacy was 95% (CI: 90.3-97.6%) in participants with no prior infections and 94.6%% (CI: 89.9-97.3%) including those with prior infection history. Further analyses showed that the vaccine efficacy was largely consistent over subgroups such as age, race, coexisting conditions when compared to the overall population. Incidence of SARS-CoV-2 cases when comparing both the vaccine and control groups showed divergence after 12 days after the first dose of the vaccine -where the vaccine group had a lower incidence -and improved efficacy for vaccine recipients 7 days after the second dose. 56 The two studies highlight the significantly high efficacy of the full-dose regimen of the Pfizer/BioNTech vaccine in preventing infection.

The observed effectiveness of the second dose against infection ranged from 46 (CI 28-59) within 0-7 days after second dose 54 up to 99.5 (CI 97.0-99.9) at ≥35 days after vaccination. 66 In their study, Moustsen-Helms et al. aimed to assess the effectiveness of two doses of Pfizer/ BioNTech vaccine in long-term care facility residents (LTCF) and healthcare workers in Denmark. 54 The study is a retrospective population-based cohort study where all longterm facility residents and all HCW living in Denmark either at the start of vaccination or immigrated before the end of the study were included. In LTCF residents, findings showed the vaccine effectiveness was 52% 0-7 days after the second dose and this was increased to 64% >7 days after the second dose. In HCW population, vaccine effectiveness was 46% 0-7 days after second dose which significantly increased to 90% >7 days after the second dose. The authors concluded that the analysis confirms that two vaccine doses offer significant protection against COVID-19 in two critical groups in Denmark, the elderly population and the healthcare workers, who are both at a higher risk of infection. 54 Yelin et al. conducted a prospective, non-randomized, uncontrolled study in Maccabi Healthcare Services (MHS), Israel between December 19, 2020 and February 25, 2021. 66 All data used in this study were extracted from MHS electronic health record (EHR) and a total of 1,723,509 participants were included. Since the data were extracted from the EHR, all participants had their RT-qPCR test results, city of residence, age, sex, and comorbidities tagged. The outcome of this study was defined as a participant having a positive RT-qPCR test on a specific calendar day and was termed observation. Using all the observations in the study, vaccine effectiveness was found to increase starting at day 12 after first-dose recipience and ultimately plateau at 95% effectiveness after 35 days of first-dose recipience. 66 Regarding age, the odds ratio of vaccine effectiveness, 0.74 (CI, 0.52-1.06), in the elder participants (81-90 years old), was mildly lower compared to the younger participants (17-80 years old). As for comorbidities, vaccine effectiveness decreased significantly for type 2 diabetics, immunosuppressed participants, and Chronic Obstructive Pulmonary Disease (COPD) patients, with odds ratios of vaccine effectiveness being 0.73 (CI 0.59-0.91), 0.67 (CI 0.53-0.83), and 0.55 (CI 0.38-0.80), respectively. Apart from vaccine effectiveness in infection prevention, Pfizer/BioNTech vaccine also showed great symptomatic infection prevention, with 99.5% vaccine effectiveness (CI, 097.0-99.9%) in symptomatic infection prevention after 35 days of first-dose recipience. 66 Overall, Pfizer/BioNTech vaccine appeared effective in both infection prevention and symptomatic infection prevention for the B.1.1.7 variant, which was the main variant circulating in Israel during the study period. 66 The observed results from population-based studies verify the high efficacy seen in the controlled studies and support the conclusion two doses of the Pfizer/BioNTech vaccine are significantly effective in preventing infection.

Effectiveness against severe infection ranged from 88.8 (CI 75.5-95.7) 55 up to 100.0 (CI 81.7-100.0) at ≥14 days after vaccination, a value reported for the B.1.1.7 variant, and also up to 100.0 (CI 73.7-100.0) at ≥14 days after vaccination, a value reported for the B.1.351 variant. 25 The lowest effectiveness was reported by Pawlowski et al. in a retrospective study that included 31, 069 vaccinated subjects who were propensity matched to an unvaccinated group of 31, 069 patients. 55 The study assessed vaccine effectiveness via Kaplan Meier analysis for incidence of SARS-CoV-2. Pawlowski et al. suggested that the lower effectiveness, as compared to the efficacy values seen in clinical trials, could be attributed to the fact that individuals receiving the vaccination are mostly at a high risk of infection so there may be an overrepresentation in the cohort leading to undervalued effectiveness and also to the fact that vaccinated individuals may engage in higher risk behaviors, such as social gatherings. 55 The highest values, against the B.1.1.7 and the B.1.351 variants were reported by Abu-Raddad et al. and strongly support the conclusion that the two-dose regimen is highly efficacious against severe infection due to both variants of concern. 25 Effectiveness of the second dose against infections requiring hospitalization ranged from 75.6 (52.8-87.6) at 35-41 days after the first dose 50 up to 100 (CI 51.4-100). 55 The lowest effectiveness was reported by Mason et al. in a study conducted on the older population of England. The study was a matched case-control study where vaccinated individuals aged 80-81 were matched to controls (those younger who became eligible for vaccination at a later time) aged 76-77 and vaccinated individuals aged 82-83 to controls aged 78-79. 50 Also, vaccinated individuals aged 80-81 were matched to controls aged 72-73, and vaccinated individuals aged 82-83 to controls aged 74-75. Three outcomes were examined: SARS CoV-2 infection, COVID-19 related emergency hospital attendance, and COVID-19 related hospitalizations. The findings demonstrated BNT1262b vaccine effectiveness against the B.1.1.7 variant across all three outcomes over the follow-up period between vaccinated and control groups (unvaccinated). The effectiveness was found to be 50.1% for hospital admissions from days 21-27. By day 35-41, the estimated effectiveness increased to 75.6%. The authors concluded that the Pfizer/ BioNTech vaccine is effective in reducing COVID-19 related hospitalizations and that the vaccination of older adults in England on a national aspect reduced the burden of the virus. 50 The highest value was reported by Pawlowski et al. 55 Overall, the observed results from the population-based studies confirm the high efficacy in preventing hospitalizations seen in studies with controlled settings. Furthermore, the results from the study by Mason et al. suggest that the vaccine is effective against the B.1.1.7 variant.

Effectiveness of the second dose against fatal infections ranged from 74 (90% CI 58-81) 60 25 The lowest value was reported by Salazar et al. in a study where investigators quantified using regression models, the effect of administering the Pfizer/BioNTech vaccine on to residents of long-term care facilities in terms of COVID-19 related deaths and infections. 60 The study estimated that vaccination of 70% of residents prevented 74% of deaths. In addition, results suggested that high vaccination coverage was able to prevent 3 out of 4 deaths in subsequent weeks. The highest values against the B.1.1.7 variant and the B.1.351 variant were reported by Abu-Raddad et al. and strongly support the conclusion that the two-dose regimen is highly efficacious against fatal infection due to both variants of concern. 25 

The efficacy of the second dose against infection was 94.1 (CI 89.3-96.8) at ≥14 days after vaccination, and 100 (CI could not be estimated to 1.0) against severe infection. 28 1-93.9 ), both 2 weeks after the second dose. In participants fully vaccinated with either vaccine, vaccine effectiveness against symptomatic infection was 91.3% (CI 79.7-96.3) and was 68.3% (CI 28.5-86.0%) against asymptomatic infection. The authors concluded that currently available mRNA-based vaccines induce significant protection against both symptomatic and asymptomatic SARS-CoV-2 infection and against severe infection, as evident by having no hospitalizations observed in the fully vaccinated cases cohort. 27 Effectiveness of the second dose against severe infection and infection requiring hospitalization were reported in one study and were 86.0 (CI 71.6-93.9) at ≥7 days after vaccination and 100 (43.3-100) at ≥7 days after vaccination, respectively. 55 The observed effectiveness values, along with the efficacy values, strongly support the conclusion that the two-dose regimen of the Moderna vaccine is highly efficacious in preventing COVID-19 infections, including those severe and requiring hospitalization.

For the second dose of the Oxford/ AstraZeneca vaccine, the efficacy against infection ranged from 10.4 (CI −76.8-54.8) at ≥14 days after vaccination, a value seen against the B.1.351 variant 49 up to 80.7 (CI 69.2-87.9) at ≥14 days after vaccination. 46 The results by Madhi et al. suggest that even the two-dose regimen of the Oxford/AstraZeneca vaccine does not confer significant efficacy against infection with the B.1.351 variant, as seen with the first dose as well. 49 The study by Emary et al. is an ongoing, multicenter, single-blinded trial in phase 2/3, conducted in the UK where participants aged 18 or above are randomized 1:1 to receive either the Oxford/AstraZeneca vaccine or a control meningococcal vaccine (Men ACWY). 46 The aim of the study was to determine the efficacy of the Oxford/AstraZeneca vaccine against the B.1.1.7 variant as compared to the other variants. The results indicate that 499 participants had developed COVID-19 infection. From the participants, 1524 NAAT positive swabs were collected, and 323 swabs collected from 256 participants were also sequenced. Thirty-four (28.3%) of the primary symptomatic cases that had sequencing available belonged to the B. 46 These findings support the conclusion that (AZD1222) vaccine is potentially efficacious against the B.1.1.7 variant. No studies in our search measured the effectiveness of the second dose. 4.3.4.1. Efficacy against infection, severe infection, hospitalization, and mortality. The efficacy of one dose was 66.9 (CI 59.1-73.4) at ≥14 days after vaccination against infection, 83.5 (54.2-96.9 ) at ≥28 days after vaccination against severe infection, 100 (CI 74.3-100.0) at ≥28 days after vaccination against infection requiring hospitalization. 59 In a study by Sadoff et al., the investigators assessed the efficacy of the J&J vaccine by performing a randomized, double blind, placebo controlled, phase 3 trial. 59 This was done by injecting participants with either the vaccine or a placebo and comparing the number of moderate-tosevere cases in each group 14 days and 28 days after injection, as well as the safety of the injections. The results showed that the overall vaccine efficacy was 66.9 (CI 59.1-73.4) at ≥14 days after vaccination, specifically 63.7% in the 18-59 years old aged group and 76.3% in the group over 60 years of age. There were 5 COVID-19 related deaths in the placebo group and none in the vaccine group. The authors concluded that a single dose of the J&J vaccine protected against symptomatic and asymptomatic infections and was efficacious in preventing severe or critical disease requiring hospitalizations or deaths. 59 Furthermore, the study's cohorts in the USA, South Africa, and Brazil had the following dominant variants Wuhan-Hu-1, B.1.351, and P.2 and Wuhan-Hu-1, respectively. The results of the study support the conclusion that the J&J vaccine is significantly efficacious against these variants after 1 dose. No studies in our search measured the vaccine effectiveness.

In a study by Shinde et al., the safety and efficacy of the Novavax vaccine against the B.1.351 variant was assessed by conducting a randomized, placebocontrolled, observer-blinded trial consisting of participants randomly allocated to receive either two doses (21 days apart) of the NVX-CoV2373 vaccine or saline placebo. 61 HIV-negative patients and those with controlled HIV were included. Efficacy analysis results from 2,684 participants who were seronegative at baseline (with 94% of them being HIVnegative and 6% being HIV-stable) showed 15 and 29 symptomatic COVID-19 positive cases (post day 28) among NVX-CoV2373 vaccine-given participants and placebo-given participants respectively, translating to a vaccine efficacy of 49.4%. Among baseline seronegative participants without HIV, there were 11 and 27 symptomatic COVID-19 positive cases in participants given NVX-CoV2373 and in placebo-given participants respectively, translating to a vaccine efficacy of 60.1%. Of the 44 COVID-19 positive cases, 41 had genome sequencing data available and, from these, 38 were identified as the B.1.351 variant. Vaccine efficacy was then calculated to be 51.0% against this variant in solely HIV-negative participants and 43.0% in both HIV-negative and HIV-stable participants. 61 Based on these data, the NVX-CoV2373 vaccine is significantly efficacious against COVID-19 infection, with document efficacy against the B.1.351 strain of SARS-COV-2. No studies in our search measured the vaccine effectiveness. 4.3.6.1. Effectiveness against infection, severe infection, hospitalization, and mortality. The effectiveness of the second dose against infection ranged from 37.9 (CI 46.4-73.6) at ≥14 days after vaccination 42 up to 73.8 (CI 57.0-84.8) at ≥5 weeks after vaccination. 37 In a study by Faria et al., between February 23, 2020 and March 28, 2021, data were recorded on the weekly numbers of symptomatic COVID-19 cases confirmed by RT-PCR in HCWs in Hospital das Clinicas (HC). 37 These data were compared to the weekly number of COVID-19 cases in São Paulo. 74 After HCW vaccination, the number of COVID-19 cases in São Paulo increased, while the number of cases in the HCWs did not. Estimated vaccine effectiveness was 50.7 (CI 33.3-62.5); 51.8 (CI 30.0-66.0); 68.4 (CI 51.0-80.8); and 73.8 (CI 57.0-84.8) for the weeks 2, 3, 4, and 5 after the second dose of Sinovac, respectively. In 2021, there were 9 HCW hospitalizations in HC due to COVID-19 (6 unvaccinated, 1 had one vaccine dose, and 2 had 2 doses), one of which died and was not vaccinated. Among randomly examined 142 HCWs' respiratory samples, 67 (47%) variants of concern (VOC) were detected: 57 (P1), 5 (B.1.1.7), and 5 were other VOC not identified by the researchers' methods. The study outlines a reduction of confirmed symptomatic cases of COVID-19 compared to the expected numbers considering the epidemiological situation in the community. 37 The high prevalence of P1 is likely due to the epidemiological circumstances of the region. P1 became the predominant strain in Brazil, 37 64 up to 100 (undefined CI). 27 In the study where <0.1% of the included participants had unknown data on the given vaccine, an 80% reduction was seen after the second dose. 62 In the study on the population receiving the Moderna, Pfizer/ BioNTech, or the J&J vaccine, the second vaccine dose resulted in an 82% reduction in the number of new infections for patients older than 65 years and a 70% reduction in patients younger than 65 years. 58 Also, an 80% reduction in the number of hospitalizations for those older than 65 years and a 60% reduction lower for those younger than 65 years were seen. 58 In addition, a reduction of 92% was seen in the number of fatalities in patients older than 65 years and a reduction of 87% in those younger than 65 years. 58

Based on the highest reported effectiveness values in the included studies, the second dose of Pfizer was more effective in reducing the rates of infection, severity, hospitalization and mortality compared with the first dose. The reduction in the rate of infection in a Pfizer fully vaccinated population reached 99.5% while 100% protection against severity, hospitalization and mortality was reported after the second dose. Similarly, the second dose of Moderna, increased the infection reduction rate compared with the first dose. Moderna full vaccination achieved 80-100% protection against severity and hospitalization. While none of our included studies reported any effectiveness data following the second dose of AstraZeneca, the first dose achieved up to 74% and 37% reduction in the rate of infection and hospitalization, respectively. No data were available to compare the effectiveness of the first and second doses of Sputnik and Sinovac vaccines. Full vaccination with J&J vaccine requires a single dose, which provides relatively lower protection rates against infection and severe infections compared with the results obtained from the Pfizer fully vaccinated populations. However, a single dose of J&J vaccine achieved a 100% reduction in the rate of hospitalization.

In order to compare the effectiveness of full vaccination in reducing infection, severity, hospitalization and mortality, Pfizer vaccine is taken as an example due to data availability. While 100% protection was reported against severity, hospitalization, and mortality following Pfizer full vaccination, including the B1.1.7 and B.1.351 variants, lower level of protection was reported against infection in general especially against the B.1.351 (75%).

Several studies reported vaccine effectiveness by documenting the number of positive PCR tests or the NVL. In a study by McEllistrem et al., the viral loads of partially vaccinated nursing home residents with asymptomatic infection within 21 days of their first dose were retrospectively compared to those of their unvaccinated peers within the same time period. 51 The mean log10 viral loads, representing the amount of measurable virus in nasopharyngeal samples, were found to be significantly lower (p = .004, non-overlapping ranges) in vaccinated residents (7.1 (CI 5.4-8.8)) compared to unvaccinated residents (9.5 (9.3-9.8)). In this study, the significantly lower NVL measured in vaccinated residents as compared to unvaccinated residents (9.5 (9.3-9.8)) supports the authors' conclusion that nationwide single-dose strategies are viable public health approaches. 51 At Hull University Teaching Hospitals, Lillie et al. analyzed SARS-CoV-2 Nucleic Acid Amplification Tests (NAAT) results conducted on all symptomatic staff, along with routine asymptomatic clinical staff testing with Lateral Flow Device (LFD), beginning January 4 th , 2021. 47 By this date, 827 (8.3%) subjects received their first vaccine dose, increasing to 8243 (82.5%) by the end of the week of February 22, 2021 . Results showed that the number of positive cases decreased from 120 in the week of January 4 to 10 in the week of February 22. In addition, significant negative correlations between PCR positive cases and cumulative vaccination (Pearson's R = −0.9061, p = .0019), and between vaccine coverage and symptomatic PCR testing rates (Pearson's R = −0.8972, p = .0025) were identified. Positive tested staff members who self-isolated decreased by 72% from the week of January 11 to that of February 23. In this study, the significant negative correlations between PCR positive cases and cumulative vaccination, and between vaccine coverage and symptomatic PCR testing rates outline a significant efficacy of the BNT162b2 vaccine against infection, with a single dose associated with a significant decrease in positive PCR tests in both symptomatic and asymptomatic HCWs. 47 In a study by Jones et al., an equal number of vaccinated and unvaccinated asymptomatic HCWs were PCR-tested at the Cambridge University Hospitals NHS Foundation Trust. 44 PCR tests were done on an HCW population of ~9000. Vaccinated HCWs were further stratified into <12 days or ≥12 days post-vaccination, since this time point, in the phase III clinical trial, was when protection against symptomatic infection appeared. 56 In comparison to 13/3535 positive tests in HCWs <12 days post-vaccination and 4/1989 positive tests in HCWs ≥12 days postvaccination, 26/3252 tests from unvaccinated HCWs were positive, implying a fourfold lower incidence of asymptomatic SARS-CoV-2 infection in HCWs ≥12 days after vaccination compared to unvaccinated HCWs, with a relatively intermediate impact in HCWs <12 days after vaccination. When analyses were performed on both symptomatic and asymptomatic HCWs testing positive, a significant reduction in infections was also observed: 56/3370 positive tests in the unvaccinated cohort compared to 8/2018 tests ≥12 days post-vaccination, implying a 4.2-fold reduction. It is important to note that, in all groups, the incidence of previous SARS CoV-2 infection was comparable, indicating that study results were not impacted by prior seropositivity. In this study, the significantly lower incidence of SARS-CoV-2 infection in HCWs ≥12 days after vaccination compared to unvaccinated HCWs suggests that a single dose of BNT162b2 provides short-term immunity against asymptomatic SARS-CoV-2 infection. 44 In an observational study by Daniel 50-2.19% ) in those partially vaccinated, and 4/8121 (0.05%, 95% CI 0.01-0.13%) in fully vaccinated individuals (p > .01 for all results). In this study, the decreased incidence of infections seen in partially and fully vaccinated individuals as compared to the unvaccinated subjects supports the conclusion that mRNA vaccines provide a significant protection against infection. 35 In a matched pairs analysis of electronic health records of two groups of nursing homes, one where residents were partially vaccinated with an mRNA vaccine 12-16 days earlier than residents in the second group, Mor et al. revealed that the earlier vaccinated group (12,157 residents over 136 facilities) had a predicted 2.5 fewer infections per 100 at-risk residents per week (CI 1.2-4.0) than the later vaccinated group (13,221 residents over 144 facilities). 53 Similarly, the reduction in the 5 week-cumulative infection rates was an estimated 5.2 cases per 100 at-risk residents (CI 3.2-7.3) as a result of vaccination. A 1.1-3.8 fewer hospitalizations and/or deaths per 100 infected residents per day was also observed in the earlier vaccinated group. In this study, lower infections, hospitalizations, and deaths were seen in the earlier vaccinated group as compared to the later vaccinated group, suggesting that the mRNA vaccines protect against new COVID-19 infections and reduce morbidity and mortality. 53 -2   4.6.1. B.1.1.7 The highest reported effectiveness for the first dose of any vaccine against infection with B.1.1.7 variant in the included studies was 70 (CI 55-85) at ≥21 days after vaccination reported by Hall et al. for the Pfizer/BioNTech vaccine. 41 Hall et al. conducted a prospective cohort study on staff aged ≥18 years old working in hospitals in the UK. Participants were split into either the positive cohort that includes positive antibodies or a history of infection, or the negative cohort that includes negative antibodies and no history of infection. Vaccine effectiveness against COVID-19 infection 21 days after the first dose was 70 (CI 55-85) and increased to 85 (CI 74-96) after the second dose of the vaccine. These findings suggest that the vaccine is able to prevent both symptomatic and asymptomatic infections and is effective against the B1.1.7 variant that was the most dominant at the time of the study. 41 34 The highest effectiveness for the second dose of any vaccine against severe or fatal infection with B.1.1.7 variant was 100 (CI 81.7-100) at 14 days after vaccination, reported for the Pfizer/BioNTech vaccine. 25 The highest effectiveness for the second dose of any vaccine against infection with B.1.1.7 variant requiring hospitalization was 100 (CI 51.4-100) reported for the Pfizer/ BioNTech vaccine. 55 Based on this data, we conclude that the full-dose regimen of the Pfizer/BioNTech vaccine is the most effective against infections with the B.1.1.7 variant.

In all the studies that we have analyzed, the highest effectiveness for the first dose of any vaccine against infection with the B.1.351 variant was , reported for the Pfizer/BioNTech vaccine. 25 Furthermore, the first dose of the Pfizer/BioNTech vaccine was not effective against severe or fatal infections with the B.1.351 variant (0 (CI 0-19) ). 25 Based on these data, we conclude that with the current vaccines, none are sufficient, in the first dosage, to protect against infections with the B.1.351 variant. In all the studies that we have analyzed, the highest effectiveness for the second dose of any vaccine against infection with the B.1.351 variant was 75.0 (CI 70.5-78.9) at ≥14 days after vaccination, reported for the Pfizer/BioNTech vaccine. 25 The highest effectiveness for the second dose of any vaccine against severe or fatal infection with the B.1.351 variant was 100 (CI 73.7-100) at 14 days after vaccination, reported for the Pfizer/BioNTech vaccine. 25 Based on these data, we conclude that the full-dose regimen of the Pfizer/BioNTech vaccine is the most effective against infections with the B.1.351 variant.

In all the included studies, the only effectiveness for the first and second doses of any vaccine against infection with the P.1 variant was 49.4 (CI 13.2-71.9) at ≥14 days after vaccination and 37.9 (CI 46.4-73.6) at ≥14 days after vaccination, respectively. 42 These results were reported for the Sinovac vaccine and suggest that Sinovac may be potentially effective against the P.1 variant.

Our original systematic search results did not retrieve any studies assessing the effectiveness of the vaccines against the B.1.617.2 as the variant has newly emerged. However, we discuss here some of the recent publications addressing this issue. A study in the USA revealed that the prevalence of the B.1.617.2 (Delta) variant increased rapidly over the month of July 2021 with decreasing prevalence of other variants in the meantime. For instance, prevalence of variant B.1.1.7 (Alpha) in Minnesota decreased dramatically from 75% to 15% in July while B.1.617.2 increased from 5% to 72%. 76 Monitoring outcomes over this period thus provide an insight over effectiveness of vaccines against this variant. In this study, the effectiveness of Moderna decreased from 86% (95% CI: 81-90.6%) during the January -July period to 76% (95% CI: 58-87%) in July, while the effectiveness of Pfizer decreased from 76% (95% CI: 69-81%) in the period of January -July to 42% (95% CI: 13-62%). 76 Considering the significant change in prevalence of variant B.1.617.2 and the large decrease in effectiveness, this points to a decreased effectiveness of both vaccines on the B.1.617.2 variant, with a more pronounced decrease seen with the Pfizer vaccine. A similar comparison by the same study of other states found similar changes in effectiveness coinciding with the month of July's increase in prevalence of variant B. 

Some of the analyzed studies highlighted flaws in their methods, such as the lack of sufficient ethnic varieties in the population sampled to determine a vaccine's efficacy. Furthermore, studies assessed the vaccines' efficacy values at different follow-up times, hence affecting the efficacy value seen, and making it more difficult to compare data to studies with much shorter or longer follow-up times. Additionally, in several studies, the vaccinated population was not stratified into those who received the first dose and the second dose. In multiple studies, vaccine effects were assessed after a relatively long follow-up time (for instance, at 35-41 days after the first dose in the study by Mason et al., 50 hence first dose effects may have been assessed in patients who already received the second dose. Such methodology may have exaggerated the effects of vaccines in those particular populations.

Despite the speed with which multiple vaccines candidates were developed and the consistently emerging approvals in multiple countries worldwide, our results revealed that COVID-19 vaccines successfully reduced the rates of infections, severity, hospitalization and mortality among the different populations since the vaccines rollout started. The Pfizer/BioNTech vaccine was the most extensively studied among the COVID-19 vaccines with >90% effectiveness against infection, severe infection, infection requiring hospitalization and mortality after the second dose. The effectiveness of the Moderna vaccine after the second dose was >80% against infection, severe infection and infection requiring hospitalization. While none of the included studies reported the effectiveness of the AstraZeneca vaccine after the second dose, it was 80.7% efficacious against infection after the second dose and 74% effective against infection after the first dose. A single dose of the J&J vaccine was >60% effective against infection, severe infection and infection requiring hospitalization. While no effectiveness values were reported for the Sputnik, Novavax, Sinovac vaccines after the second dose, the efficacies of the later 2 were 60.1% and 73.8%, respectively, against infection after the second dose. It is important to note that the relatively low effectiveness values of some vaccines that were obtained in some studies could be attributed to the dominance of certain viral variants within certain populations. The full-dose regimen of the Pfizer/ BioNTech vaccine is the most effective against infections with the B.1.1.7 and B.1.351 variants. Despite of the high effectiveness of the newly developed COVID-19 vaccines in reducing the rates of infections, hospitalization/severity and mortality, more efforts are required to test the efficacy/effectiveness of these vaccines against the other newly emerging variants.

Johns Hopkins coronavirus resource center

A novel coronavirus from patients with pneumonia in China

Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review

An updated review of sars-cov-2 vaccines and the importance of effective vaccination programs in pandemic times

McGill COVID-19 vaccine tracker

COVID-19: a review of therapeutic strategies and vaccine candidates

Novel vaccine technologies: essential components of an adequate response to emerging viral diseases

Spatial and temporal control of RNA stability

Optimization of lipid nanoparticles for intramuscular administration of mRNA vaccines

Safety and immunogenicity of two RNA-based covid-19 vaccine candidates

An mRNA vaccine against SARS-CoV-2 preliminary report

Evaluation of the mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates

Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial

ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques

Ad26 vector-based COVID-19 vaccine encoding a prefusion-stabilized SARS-CoV-2 spike immunogen induces potent humoral and cellular immune responses

Vaccines based on replication incompetent Ad26 viral vectors: standardized template with key considerations for a risk/ benefit assessment

Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia

Phase 1-2 trial of a SARS-CoV-2 recombinant spike protein nanoparticle vaccine

Immunogenicity and safety of a SARS-CoV-2 inactivated vaccine in healthy adults aged 18-59 years: report of the randomized, double-blind, and placebo-controlled phase 2 clinical trial

Effect of an inactivated vaccine against SARS-CoV-2 on safety and immunogenicity outcomes: interim analysis of 2 randomized clinical trials

A review of the progress and challenges of developing a vaccine for COVID-19

SARS-CoV-2 infection despite vaccination: an under-reported COVID-19 cohort

Vaccine breakthrough infections with SARS-CoV-2 variants

Vaccine efficacy, effectiveness and protection

Effectiveness of the BNT162b2 Covid-19 vaccine against the B.1.1.7 and B.1.351 variants

Early rate reductions of SARS-CoV-2 infection and COVID-19 in BNT162b2 vaccine recipients

Prevention of COVID-19 by mRNA-based vaccines within the general population of California

Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine

BNT162b2 mRNA Covid-19 vaccine effectiveness among health care workers

Early effectiveness of COVID-19 vaccination with BNT162b2 mRNA vaccine and ChAdOx1 adenovirus vector vaccine on symptomatic disease, hospitalisations and mortality in older adults in England

Effectiveness of the BNT162b2 vaccine in preventing COVID-19 in the working age population -first results from a cohort study in Southern Sweden

COVID-19 vaccine impact on rates of SARS-CoV-2 cases and post vaccination strain sequences among healthcare workers at an urban academic medical center: a prospective cohort study

Effectiveness of the Pfizer-BioNTech COVID-19 vaccine among residents of two skilled nursing facilities experiencing COVID-19 outbreaks -Connecticut

BNT162b2 mRNA Covid-19 vaccine in a nationwide mass vaccination setting

Early evidence of the effect of SARS-CoV-2 vaccine at one medical center

Covid-19: moderna and Pfizer vaccines prevent infections as well as symptoms, CDC study finds

Performance of vaccination with CoronaVac in a cohort of healthcare workers (HCW) -preliminary report

North West London Covid-19 vaccination programme: real-world evidence for vaccine uptake and effectiveness

Protection of previous SARS-CoV-2 infection is similar to that of BNT162b2 vaccine protection: a three-month nationwide experience from Israel

SARS-CoV-2 new infections among health care workers after the first dose of the BNT162b2 mRNA Covid-19 vaccine

COVID-19 vaccine coverage in health-care workers in England and effectiveness of BNT162b2 mRNA vaccine against infection (SIREN): a prospective, multicentre, cohort study

Effectiveness of CoronaVac among healthcare workers in the setting of high SARS-CoV-2 Gamma variant transmission in Manaus, Brazil: a test-negative case-control study

Estimating the effectiveness of the Pfizer COVID-19 BNT162b2 vaccine after a single dose. A reanalysis of a study of 'real-world' vaccination outcomes from Israel

Infect Dis (Except HIV/AIDS)

Singledose BNT162b2 vaccine protects against asymptomatic SARS-CoV-2 infection

Oxford-AstraZeneca COVID-19 vaccine efficacy

Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 VOC 202012/01 (B.1.1.7). SSRN J [Internet

First dose of BNT162b2 mRNA vaccine in a healthcare worker cohort is associated with reduced symptomatic and asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection

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

Efficacy of the ChAdOx1 nCoV-19 Covid-19 vaccine against the B.1.351 variant

Effects of BNT162b2 mRNA vaccine on Covid-19 infection and hospitalisation among older people: matched case control study for England

Single dose of an mRNA severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) vaccine is associated with lower nasopharyngeal viral load among nursing home residents with asymptomatic coronavirus disease 2019 (COVID-19)

COVID-19 registries study group. Direct and indirect effectiveness of mRNA vaccination against SARS-CoV-2 infection in long-term care facilities in Spain

Short-term impact of nursing home SARS-COV -2 vaccinations on new infections, hospitalizations, and deaths

Vaccine effectiveness after 1st and 2nd dose of the BNT162b2 mRNA Covid-19 vaccine in long-term care facility residents and healthcare workers -a Danish cohort study

FDA-authorized COVID-19 vaccines are effective per real-world evidence synthesized across a multi-state health system

Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine

Impact of vaccination on new SARS-CoV-2 infections in the UK

Outcomes of COVID-19 vaccination efforts in Florida from

Safety and efficacy of single-dose Ad26.COV2.S vaccine against Covid-19

High coverage COVID-19 mRNA vaccination rapidly controls SARS-CoV-2 transmission in long-term care facilities

Preliminary efficacy of the NVX-CoV2373 Covid-19 vaccine against the B.1.351 variant

Impact of the coronavirus disease 2019 (COVID-19) vaccine on asymptomatic infection among patients undergoing preprocedural COVID-19 molecular screening

Interim estimates of vaccine effectiveness of BNT162b2 and mRNA-1273 COVID-19 vaccines in preventing SARS-CoV-2 infection among health care personnel, first responders, and other essential and frontline workers -eight

Real world effectiveness of COVID-19 mRNA vaccines against hospitalizations and deaths in the United States

Singledose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials

Associations of the BNT162b2 COVID-19 vaccine effectiveness with patient age and comorbidities

Tracking SARS-CoV-2 variants

What defines an efficacious COVID-19 vaccine? A review of the challenges assessing the clinical efficacy of vaccines against SARS-CoV-2

Vaccine epidemiology: efficacy, effectiveness, and the translational research roadmap

World Health Organization. Correlates of vaccine-induced protection: methods and implications [Internet]. World Health Organization

COVID-19 vaccine efficacy and effectiveness-the elephant (not) in the room

The effectiveness of the first dose of BNT162b2 vaccine in reducing SARS-CoV-2 infection 13-24 days after immunization: real-world evidence

Israel to extend COVID vaccine drive to anyone over 16 starting Thursday

Monitoramento de novas variantes de SARS-CoV-2 no Município de São Paulo

Comparison of two highly-effective mRNA vaccines for COVID-19 during periods of Alpha and Delta variant prevalence

Impact of delta on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK

Effectiveness of Covid-19 vaccines against the B.1.617.2 (Delta) variant

We would like to thank Mr. Sa'ad Laws for his help during the early phases of this project including developing the search strategy and importing papers. We would like also to thank Weill Cornell Medicine-Qatar for the continuous support and to specifically thank Weill Cornell Medicine -Qatar Distributed eLibrary for funding the publication of this article.

No potential conflict of interest was reported by the author(s).

The author(s) reported there is no funding associated with the work featured in this article. 

The data that supports the findings of this study are available in the supplementary material of this article.