Introduction

In early December 2019, the Chinese Center of Disease Control reported that SARS-CoV-2 infection is the cause of the outbreak that started in Wuhan City [1]. SARS-CoV-2 virus is the third member of coronaviruses that causes epidemics in human history following SARS-COV and MERS. It is highly infectious and can spread globally and rapidly [2]. Until now, there are more than two hundred million confirmed cases of COVID-19 including more than seven million deaths [3].

Vaccines mimic the virus—or part of the virus—so they can protect against stimulation of the immune system to produce antibodies. Their safety standards must be higher than other medicines as they are used for the prevention of infectious diseases in healthy people and reduction of morbidity and mortality without long-lasting effects [4, 5].

For that reason, scientists are in a race with time to discover new vaccines against COVID-19. There are more than 170 candidate vaccines that are now being followed up by the World Health Organization (WHO) [6]. The first COVID-19 vaccines were approved shortly after the initial phase 3 safety and efficacy studies [7]. Clinical trials of all three vaccines authorized for use in the UK (Pfizer–BioNTech, Oxford–AstraZeneca, and Moderna) have reported high vaccine efficacy [8,9,10].

Large post-licensing epidemiological studies are needed to complement the results of pre-licensing trials to estimate the efficacy of these vaccines at the population level in real-world conditions, because vaccine development normally takes a very long period to confirm that vaccines are safe and effective before they are used.

This rapid systematic review was initiated because no systematic review had been conducted to determine the safety and efficacy of AstraZeneca ChAdOx1 nCoV-19 vaccine especially after publishing a number of case series which revealed serious adverse effects associated with the vaccine such as life-threatening thrombocytopenic thrombosis.

Methods

Study design

The study was designed as a systematic review according to PRISMA guidelines [11]. All steps of this study were pre-specified, and the protocol was registered on Clinicaltrial.gov: NCT05060861.

Search strategy

On May 22, 2021, we searched PubMed, Google Scholar, Scopus, WOS, and MEDLINE databases for all articles in English regarding the safety and efficacy of the SARS-CoV-2 vaccine ChAdOx1 nCoV-19. The search strategy can be retrieved in supplementary digital material 1. Materials available as gray literature were followed and searched in pre-print platforms (MedRxiv, BoiRxiv), protocols, WHO reports, conference posters, thesis, or trial registers in ClinicalTrial.gov.

Study selection

Two authors (I.A.M and M.A) independently completed all searches and removed all duplicate records. We selected the articles based on titles and abstracts. The second and last screening stage was performed by two authors (I.A.M and M.A), and discrepancies and doubts were solved by a consensus with two more authors (R.S, I.H.I). We critically appraised the full text of each study that was included if respected one of the following inclusion criteria: (1) P: volunteers (aged 18 years old or more), (2) I: ChAdOx1 nCoV-19 vaccine, (3) C: any comparator vaccine 4) O: Efficacy and Safety, (5) study design: Randomized controlled trials, retrospective studies, cohort, case-control, case series, survey, and recommendation, (6) Language: only English

Data extraction

A data extraction form was created in word. Data were extracted by three authors (R.S., I.A.M. and M.A.) comprising the following data (if applicable): (1) study name (author/year), (2) study design, (3) study period, (4) setting (institute, city, and country), (5) study protocol number, (6) aim of study, (7) main and secondary outcome, (8) target population, (9) main age of study population, (10) classification of population according to gender, (11) sample size, (12) dose, (13) method of evaluation, and (14) conclusion

Risk of bias assessment

We did not appraise the quality of included studies due to urgency and need of rapid appraisal of published data in this topic.

Statistical analyses

The statistical analysis was performed using open meta-analyst software [12,13,14]. Dichotomous and continuous data were pooled as untransformed proportion (PR) and standardized mean difference (SMD), respectively, in a random-effects model with 95% confidence interval (CI). Heterogeneity was assessed by observation of the graphs on forest plots and measured by chi-square test and I-square tests for the degree of the heterogeneity. Between studies, significant heterogeneity was defined as a chi-square test with p<0.1 and I2 tests >50% [15]. We considered the endpoints statistically significant with p value <0.05. Irrespective of the between-study heterogeneity, subgroup analysis was done for all efficacy endpoints based on the method by which the efficacy was measured in the included studies, and the adverse events were measured depending on the number of cases developed these adverse events after vaccination.

Results and evidence synthesis

Out of 477 retrieved articles, fifteen are included [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30]. Figure 1 provides all details about the study selection process. All the selected articles are concerned with the evaluation of the AstraZeneca ChAdOx1 nCoV-19 vaccine. Three of them are concerned with the effectiveness of the ChAdOx1 nCoV-19 vaccine [18, 23, 29], while thirteen (one is common with the group of the effectiveness) consider the adverse effects associated with the vaccine [16, 17, 19,20,21,22,23,24,25,26,27,28, 30]. Because thrombosis is a serious adverse effect developed after ChAdOx1 nCoV-19 vaccination, it was placed in a special group to be analyzed separately [16, 20, 24,25,26,27,28, 30] (Table 1).

Fig. 1
figure 1

PRISMA Flow Diagram of the Present Systematic Review

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Table 1 Summary of included studies
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Efficacy outcomes

Three studies reported the effectiveness of the ChAdOx1 nCoV-19 vaccine. A total of 1,078,284 persons received the 1st dose and responded to the effectiveness evaluation so they are included in the analysis. The overall effect size significantly favored the effectiveness of the vaccine.

  • Two studies evaluated the effectiveness by decreasing SARS CoV-2 positive tests after vaccination, in which 458,130 received the 1st dose and responded to effectiveness evaluation so included in analysis. ChAdOx1 nCoV-19 vaccine significantly decreased the positive SARS-CoV-2 tests, 291806 of 458130 had negative test results after vaccination (PR= 0.675, 95% CI [0.528, 0.822], P < 0.001). The pooled studies were heterogeneous (chi-square p<0.001, I2=99.99%) (Fig. 2).

  • Two studies (one study is common between 2 groups) evaluated the effectiveness by decreasing the hospitalization, in which 965,434 received the 1st dose and responded to effectiveness evaluation so included in the analysis. ChAdOx1 nCoV-19 vaccine significantly decreased hospital admission, 752,904 of 965,434 were not hospitalized after the vaccination (PR= 0.74, 95% CI [0.466, 1.014], P < 0.001), the pooled studies were heterogeneous (chi-square p<0.001, I2=99.99%) (Fig. 3).

  • Two studies evaluated the effectiveness in elderly. In which 965,434 received the 1st dose and responded to effectiveness evaluation so included in the analysis. ChAdOx1 nCoV-19 vaccine significant in elderly, 756,357 of 965,434 had -ve SARS-CoV-2 test results and were not hospitalized after vaccination (PR= 0.745, 95% CI [0.480, 1.010], P < 0.001), the pooled studies were heterogeneous (chi-square p<0.001, I2= 99.999%) (Fig. 4).

Fig. 2
figure 2

Effectiveness by decrease SARS positive after vaccination

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Fig. 3
figure 3

Effectiveness by decreasing hospital admission

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Fig. 4
figure 4

Effectiveness in elderly

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Safety outcomes

Seven studies reported the safety of the ChAdOx1 nCoV-19 vaccine. A total of 635,109 persons received the 1st dose and responded to safety evaluation so included in analysis. Of them 427,613 were female (PR=0.683, 95% CI [0.569, 0.797], P < 0.001). The pooled studies were heterogeneous (chi-square p<0.001, I2 = 99.983%).

  • Analysis showed that 123,969 of 353,302 have more than one side effect, (PR=0.717, 95% CI [0.339, 1.094], P<0.001), the pooled studies were heterogeneous (chi-square p<0.001, I2 = 99.99%).

  • A total number of 86,811 of older population -who were vaccinated- showed at least one side effects (PR=0.439, 95% CI [0.245, 0.633], P<0.001), the pooled studies were heterogeneous (chi-square p<0.001, I2 = 99.997%).

  • Also, 36,191 of younger population—who were vaccinated—showed at least one side effects (PR=0.579, 95% CI [0.143, 1.014], P<0.001), the pooled studies were heterogeneous (chi-square p<0.001, I2 = 99.998%).

  • Malaise (75.20%), headache (23.86%), fatigue (22.39%), vomiting (21.06%), chills (15.80%), joint pain (12.30%), fever (9.08%), muscle pain (8.48%), nausea (5.84%), diarrhea (2.58%), and bleeding (0.02%) are the most reported systemic side effects of ChAdOx1 nCoV-19 vaccine (Table 2).

  • Local pain (11.53%), itching (2.48%), swelling (3.07%), redness (2.41%), and skin rash (0.50%) are the most reported local side effects of ChAdOx1 nCoV-19 vaccine (Table 2).

  • Death was reported in only 18 of 281,272 among the vaccinated population, this is insignificant value, (PR=0.148, 95% CI [− 0.211, 0.508], P =0.418), the pooled studies were heterogeneous (chi-square p <0.028, I2= 79.161%). figures is in supplementary material 2

Table 2 Recorded adverse effects of ChAdOx1 nCoV-19 vaccine
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Thrombosis outcomes

Eight studies reported thrombosis adverse events of the ChAdOx1 nCoV-19 vaccine. 281347 received the 1st dose of AstraZeneca vaccine and responded to thrombosis adverse events evaluation so included in analysis. Two hundred twenty-two thousand twenty-six of them are female (PR=0.784, 95% CI [0.755, 0.814], P < 0.001). The pooled studies were homogeneous (chi-square p = 0.404, I2= 3.415%).

  • Standardized mean difference of age in the cases of thrombotic adverse events = 41.519 years old (95% CI [36.352, 46.686], p< 0.001), platelet count = 39.873×109/L (95% CI [27.387, 52.359], p< 0.001), aPTT Activated partial thromboplastin time = 29.943 s, (95% CI [25.406, 34.481], p< 0.001), INR peak = 1.271 (95% CI [1.152, 1.391], p< 0.001), fibrinogen = 1.444 g/l, (95% CI [1.015, 1.872], p< 0.001), and D-dimer = 33.047 mg/l (95% CI [22.703, 43.392], p< 0.001). The pooled studies were heterogeneous (chi-square p ≤ 0.001, I2= 90.204%, 95.818%, 95.724%, 85.277%, 88.658%, and 93.423%, respectively).

  • The studies recorded 33 cases—of total 17,132,686 vaccinated—having thrombotic adverse reactions and this is an insignificant value (PR=0, 95% CI [− 0.000, 0.000], P = 0.371). The pooled studies were heterogeneous (chi-square p = 0.033, I2= 78.123%).

  • Thirty-one cases showing more than one thrombotic adverse reaction - of total 33 who had thrombotic adverse reaction, (PR= 0.515, 95% CI [0.281, 0.749], P < 0.001). The pooled studies were heterogeneous (chi-square p < 0.001, I2= 84.009%).

  • The most reported thrombotic adverse events are deep venous thrombosis (77 cases), thrombosis in other organs/areas (57 cases), cerebral venous sinus thrombosis (46 cases), pulmonary embolism (23 cases), and splanchnic vein thrombosis (23 cases) (Table 2).

  • Twenty- nine of 281,334 is the number of deaths in the studies that reported thrombotic adverse reactions (PR= 0.132, 95% CI [0.008, 0.257], P < 0.001). The pooled studies were heterogeneous (chi-square p ≤ 0.001, I2= 79.289%). Figures are in supplementary material 3

Discussion

This investigation involved a systematic review and meta-analysis of RCTs, cohorts, case series, case reports, case-control, and cross-sectional studies to summarize the efficacy and safety of the ChAdOx1 nCoV-19 vaccine. This investigation comprised 9 cohorts, 2 case reports, 1 RCTs, 1 case series, 1 case-control, and 1 cross-sectional study with a total sample size of 1,368,188 patients, 107,8284 of them were analyzed to evaluate the efficacy, and 635,184 were analyzed to evaluate the safety, with 345,280 common between two groups.

The study findings revealed that the first doses of the ChAdOx1 vaccines were associated with protection against COVID-19 admission to hospital and a decrease in the number of positive cases among the vaccinated population. A vaccine effect of 78% for protection against hospitalization and 63.7% for decreasing in the number of +ve cases among the vaccinated population. In the elderly age group, based on a pooled analysis for the vaccine, we observed vaccine efficiency of 78.3%.

The most reported systemic adverse effects associated with ChAdOx1 vaccine are malaise (75.20%), headache (23.86%), fatigue (22.39%), vomiting (21.06%), chills (15.80%), joint pain (12.30%), fever (9.08%), muscle pain (8.48%), nausea (5.84%), diarrhea (2.58%), and bleeding (0.02%). The percentage of older people with at least one adverse event (22.7%) is larger than the percentage of younger people with at least one adverse event (21.13%).

Cases with thrombotic adverse events had mean platelet count = 39.873 × 109/L, (lower than normal mean) and Activated partial thromboplastin time (aPTT) = 29.943 s (within normal value). Despite these values, thrombosis also occurred. However, the recorded INR peak was 1.271, this value is lower than normal range and this may stimulate thrombosis formation. The fibrinogen level was1.444 g/l, and D-dimer 33.047 mg/l. The most reported thrombotic adverse events were deep venous thrombosis (77 cases), thrombosis in other organs/areas (57 cases), cerebral venous sinus thrombosis (46 cases), pulmonary embolism (23 cases), and splanchnic vein thrombosis (23 cases).

The increasing number of reports on rare thrombotic events after SARS-CoV-2 vaccination draw public attention and led to concerns regarding the safety of this vaccine due to the uncertainty of the origin of these undesired reactions

The limitations of this study include the small number of potential thrombotic adverse events which were contained from case reports and case series but it shouldn't be neglected because these are serious adverse events that lead to death. The quality of the included studies was not evaluated to decide the importance of the included data, due to lack of time during the pandemic.

However, this study has provided valuable information about the safety and efficacy of the ChAdOx1 vaccine from trusted databases with a large sample size and summarizes all the literature which is published until the time of searching.

Finally, the observed clinical and laboratory features of the VITT are exceptional and rare and the reported side effects cannot lead to death mostly and are relieved by medical treatment except in a few cases. Therefore, the value of COVID-19 vaccination to provide critical protection should be considered higher compared to the significant health risk of COVID-19. With the better recognition of this rare complication and the availability of efficient therapies, the risk-benefit ratio of ChAdOx1 nCoV-19 might be reconsidered further.

Conclusions

All selected articles are based on published literature about the viral vector COVID-19 vaccine “ChAdOx1 nCoV-19.” The main message is that the value of COVID-19 vaccination ChAdOx1 nCoV-19 to provide critical protection should be considered higher compared to the significant health risk of COVID-19. Further updates are needed to follow the emerging vaccines and recognize their safety and efficacy against different variants of the novel virus