key: cord-1023253-298900h5
authors: Abdulmoneim, S. A.; Aboelsaad, I. A. F.; Hanaa Hafez, D. M.; Almaghraby, A.; el-ganainy, s. o.; Alnagar, A.; Shaaban, R.; Elhadi, Y. A. M.; Deghidy, E. A.; Nour El-Deen, A. E.-S.; Salem, K. M.; Hamdy, N. A.; kabeel, S. G.; Elsherbeny, E. A. F.; Tahoun, M. M.; Ghazy, R. M.; Elfeshawy, N. I.; Elrewany, E.; khalil, A.
title: Systematic Review and Meta-analysis on COVID-19 Vaccine Hesitancy
date: 2021-05-18
journal: nan
DOI: 10.1101/2021.05.15.21257261
sha: 88763e0674f3b92a16fccfe6d3dd8aaf367fdd47
doc_id: 1023253
cord_uid: 298900h5

Background: The presented meta-analysis was developed in response to the publication of several studies addressing COVID-19 vaccines hesitancy. We aimed to identify the proportion of vaccine acceptance and rejection, and factors affecting vaccine hesitancy worldwide especially with the fast emergency approval of vaccines. Methods: Online database search was performed, and relevant studies were included with no language restriction. A meta-analysis was conducted using R software to obtain the random effect model of the pooled prevalence of vaccine acceptance and rejection. Egger regression test was performed to assess publication bias. Quality assessment was assessed using Newcastle-Ottawa Scale quality assessment tool. Results: Thirty-nine out of 12246 articles met the predefined inclusion criteria. All studies were cross-sectional designs. The pooled proportion of COVID-19 vaccine hesitancy was 17% (95% CI: 14-20) while the pooled proportion of COVID-19 vaccine acceptance was 75% (95% CI: 71-79). The vaccine hesitancy and the vaccine acceptance showed high heterogeneity (I 2 =100%). Case fatality ratio and the number of reported cases had significant effect on the vaccine acceptance as the pooled proportion of vaccine acceptance increased by 39.95% (95% CI: 20.1-59.8) for each 1% increase in case fatality (P<0.0001) and decreased by 0.1% (95% CI: -0.2-0.01) for each 1000 reported case of COVID-19, P= 0.0183). Conclusion: Transparency in reporting the number of newly diagnosed COVID-19 cases and deaths is mandatory as these factors are the main determinants of COVID-19 vaccine acceptance.

The wide use of vaccines has led to decreased mortality and morbidity of different transmissible diseases, this was a crucial factor in elimination of poliomyelitis in the Americas and the worldwide eradication of smallpox (1) . Vaccination programs depend on mass vaccination to be able to decrease incidence and prevalence of Vaccine Preventable Diseases (VPD). In addition to the proposed direct protection for vaccinated candidates, wide vaccination scope results in indirect shielding for the overall community by declined conveyance of VPD, thereby dampening the risk of infection for vulnerable individuals in the community (2) .

One of the main limiting factors for wide-spread of vaccination programs (especially for newly emerging vaccines) is vaccine hesitancy. The World Health Organization (WHO) named vaccine hesitancy as one of the top ten threats to global health in 2019, calling for research to identify the factors associated with this phenomenon (3) . Vaccine hesitancy is defined as a behavior of a delayed vaccine approval or even declined vaccination despite accessible vaccination services (4, 5) .

The pandemic COVID-19 caused by the recently discovered coronavirus-2019 (SARS-CoV-2) is strongly influencing the worldwide public health, culture, economy, and human social behavior. Despite all efforts since the beginning of the pandemic there is no approved medicine or treatment to cure COVID-19 till now, whereas vaccine development efforts are taking the highest priority as it can potentially save humanity by inducing immunity against COVID-19 (6) .

According to WHO, herd immunity against COVID-19, which is known as population immunity, can be achieved naturally by the exposed people who recovered from the virus by their own protective antibodies or by providing COVID-19 vaccination (7, 8) . Herd immunity for COVID-19 can be achieved on 70% of the single vaccinated dose individuals and 90% of the two vaccinated dose individuals (9) .

Vaccines typically require years of research and testing before reaching the clinic, but in 2020, scientists were racing against time to produce safe and effective coronavirus vaccines. Currently we have 14 approved vaccines for full use, 6 authorized in early or limited use, 27 vaccines in phase 3 trials, 36 vaccines in phase 2, 48 vaccines in phase 1 and 4 abandoned vaccines after trials. In addition, at least 77 preclinical vaccines are under active investigation in animals (10) . Unfortunately, the newly emerging vaccines for COVID-19 are faced nowadays with hesitancy to use in different countries. People showed concerns about both efficacy and possible side effects of these recently approved vaccines. Such hesitancy can have a heavy influence on vaccine delivery and the aimed wide uptake to control the pandemic (11) . After the announcement of several pharmaceutical manufactures the production of COVID-19 vaccines, social media started to discuss vaccine content widely across different platforms. The propagated information provides mostly non-factual data and from non-medical individuals (12) .

The presented systematic review & meta-analysis was developed in response to the publication of several studies addressing COVID-19 vaccines hesitancy. Identification of independent factors affecting vaccine hesitancy worldwide especially with the fast emergency approval of these vaccines.

This meta-analysis was guided by the 2020 Cochrane Handbook of Systematic Review and Meta-Analysis (13) , with respect to the preferred reporting items of the systematic review and meta-analysis (PRISMA) checklist (14) . Search was conducted for the hesitancy or refusal of COVID-19 vaccination through the published and grey literature using multiple databases; PsycINFO, ScienceDirect, Embase, Scopus, EBSCO, MEDLINE central/PubMed, ProQuest, SciELO, SAGE, Web of science, and Google scholar. Search terms were determined and approved after the consultation of PubMed help desk. The used keywords were added to Annex 1.

All studies reporting COVID-19 vaccine hesitancy, were included with no language restriction. Abstract-only papers as proposals, conference, editorials, author . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) 

Cochrane Q test and (I²) test was used to assess and measure heterogeneity between studies, considering I 2 ≥ 75% represents substantial heterogeneity and strength of evidence for heterogeneity is the P-value ≤ 0.05 from the Q test; according to Cochrane Handbook for Systematic Reviews of Interventions (13) . Due to substantial heterogeneity, DerSimonian and Laird random-effects models were applied to pool the outcomes.

. CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 18, 2021. ; https://doi.org/10.1101/2021.05.15.21257261 doi: medRxiv preprint Publication biases were assessed by visual inspection of the funnel plot and statistically by Begg's modified funnel plot and Egger's regression test (13) .

Quality assessment (QA) was assessed using Newcastle-Ottawa Scale quality assessment tool customized for cross-sectional studies (15) . The assessment was performed by two independent reviewers (DMH, EE) and further checked by two additional reviewers (SO EI-ganainy, AA).

R software was used to perform the meta-analysis and to pool the effect size (proportion); fixed or random effect model were used according to the studies' consistency. Meta-regression analysis was performed to examine the impact of confounders on the effect of vaccine hesitancy such as age, sex, and country. Results were presented in the Forest plots to visualize the degree of variation between studies.

Leave one-out sensitivity analysis was conducted to test the effect of each study on the pooled effect to determine the robustness of the obtained outcomes. Sub-group analysis was performed to categorize the vaccine hesitancy according to sample size studies.

To investigate the sources of high heterogeneity in the pooled prevalence of vaccine acceptance and hesitancy, meta-regression analysis was performed with different models including the main predictors of vaccine acceptance and hesitancy reported in included studies such as age, sex, educational level and setting. Additionally, number of reported cases, number of reported deaths, case fatality ratio and number of vaccinated people within each country until the end of January 2021 (16, 17), were examined as potential modifiers of vaccine acceptance and hesitancy and included in the meta-regression model.

. CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The flow diagram of the selection process is shown in figure 1 . From a total of 12246 potentially relevant articles, 1621 duplicate articles and 2944 citations published before 2019 were excluded. A total of 7681 citations were eligible for title screening.

Only 51 articles were eligible for full-text screening after removing irrelevant (7627) and duplicate articles (3). In total 34 articles were excluded after full text screening (2 duplicates and 29 irrelevant), 3 were retracted. Another 22 articles were added manually For quantitative assessment, there were 39 eligible articles. The inter-rater agreement for inclusion was κ=0.87 and for the quality assessment was κ=0.91.

. CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 18, 2021. ; Table 1 shows the main findings of included studies; all the studies were cross-sectional surveys. The total sample size was 173213 ranging from 351 in the study of Sharun et al, 2020 (18) reaching 32361 in the study of Paul et al, 2021 (19) . The highest presentation of female sex was in the study of Kowk, 2021 (20) followed by Wang 2020 (21) while the lowest proportion of females was in the study of Malik et al 2020 (22) . Age range was 15->85 in the study of Taylor 2020, the mean age of the study participants was the highest in the study of Taylor 2020 (23) 

Multiple factors were associated with vaccine hesitancy Table(1) . Previously receiving influenza vaccine is the main factor that determines the acceptance of COVID-19 vaccine. Individuals reporting intake of influenza vaccine were more likely to accept COVID-19 vaccine than those who did not receive it previously (21, 28, 33) .Some socio-demographic characteristics were considered to influence the acceptance of the vaccine. Being young was associated with no or not sure response towards the intake of COVID-19 vaccine (28, 38, 41) , while older individuals were more likely to accept the vaccine intake (24, 33). Regarding the gender, males were more likely to accept the vaccine rather than females (21, 33, 38, 45) .. Low education levels and income, being not employed in a full time job or retired were associated with refusal of the vaccine (19, 28, 38, 41) , while those with professional private work were more likely to accept the vaccine (21) . The marital status also affects the response to vaccine acceptance, being single or widowed were associated with hesitancy (38) , while married individuals were more likely to accept the vaccine (24). Racial and ethnic groups were noticed to affect the acceptance of vaccine. Black race and mixed ethnicity were associated with hesitancy towards the vaccine (28, 38) .Other factors that increase the acceptance towards the vaccine is the presence of trusted health systems (24), the fear from getting infected with the virus (33) and having chronic diseases (21) . While factors that increase the refusal of the vaccine involve the suspicion from its efficacy and effectiveness (21) , individuals may think . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 18, 2021. ;  about the side effects and do not believe that the vaccine will work, or they trust their immune system and are not afraid of getting sick (45) .

Using the random effect model, ( figure 5 ) the pooled proportion of COVID-19 vaccine hesitancy among 173213 participants recruited from 39 studies was 17% (95% CI: [14] [15] [16] [17] [18] [19] [20] . Vaccine hesitancy ranged from 55% (95% CI: 85-87) in the study of Unroe, 2020 (25) to 3% (95% CI: 3-4) in the study of Salali, 2020 (27) and 3% (95% CI: 2-3) in Chen, 2021 (52) , with high heterogeneity (I 2 = 100%). To identify the cause of such heterogeneity, researchers conducted Leave one out sensitivity analysis, sub-group analysis, or meta-regression, however, these analyses failed to explain this heterogeneity.

On the other hand, the pooled proportion of COVID-19 vaccine acceptance ( Figure (4) shows the results of the meta-regression models between the case fatality (%) and the proportion of vaccine hesitancy and vaccine acceptance, respectively by type of setting and study sample size.

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The vaccine for COVID-19 availability is a critical step to face the COVID-19 pandemic. But vaccine hesitancy represents a great threat to global health during this pandemic and limits the power of health systems to control the COVID-19 pandemic.

Hence, estimating the COVID-19 vaccine hesitancy represents a tool to design an action plan to improve the vaccine acceptance.

In this meta-analysis, there was large variability between the studies discussing COVID-19 hesitancy in terms of vaccine acceptance. We aimed to determine the reported that about 20% of the participants refused COVID-19 vaccine. They observed that differences across countries were very substantial and resulted in a heterogeneity above 90%. Furthermore, they declared that the trend of rejection increased with time.

The main determinants of COVID19 vaccine rejection were being female, of low educational level, or belonging to minor ethnicity. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 18, 2021. ; https://doi.org/10.1101/2021.05.15.21257261 doi: medRxiv preprint were common factors. Impacts of regional infection rates, gender, and personal COVID-19 experience were inconclusive. Unique COVID-19 factors included political party orientation, doubts toward expedited development/approval process, and perceived political interference. Many receptive participants preferred to wait until others have taken the vaccine; mandates could increase resistance.

We speculate that the difference in vaccine acceptance may be affected by vaccine efficacy and side effects. Vaccines' side effects range between local to systemic, and short to long term events. The reported common side effects are generally mild to moderate and last for a few days. These include injection site pain, fatigue, rigors, fever, muscle and joints pains. Less commonly, a vaccine recipient may develop allergic reaction or anaphylaxis, and neurological side effects; however they are rarely reported (63). There is a rising concern particularly related to reported thrombo-embolic events, particularly after administration of AstraZeneca vaccine in Europe, but the European Medicines Agency concluded that the benefits of the vaccine overweighs the potential risk of this rare side effect (64). In this context, Kaplan et al, (65) underlined that vaccine acceptance improved when vaccine efficacy exceeds 70%. Moreover, they addressed that minor side effects, such as a sore arm or fever lasting for a day did not affect vaccine acceptance, while major side effects in 1/100000 greatly affected vaccine acceptance.

These side effects may vary according to the type of vaccine used in each country. Emerging evidence suggests that both exposure to misinformation about COVID-19 and public concerns over the safety of vaccines may be contributing to the observed decline in intentions to be vaccinated, and this highlights the need for measures to address public acceptability, trust and concern over the safety and benefit of approved vaccines (66, 67) . This finding highlights the power of social media. Some studies emerged in the last months discussing the vaccine confidence in several populations, especially in countries with high burden of diseases like Pakistan (68) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 18, 2021. ; https://doi.org/10.1101/2021.05.15.21257261 doi: medRxiv preprint education, whether medical or nonmedical students, on their decision (35) .With the development of multiple effective vaccines, Immunization programs are only successful when there are high rates of acceptance and coverage (69) . To accomplish this, it is critical to understand vaccine-acceptance messaging to effectively control the pandemic and prevent thousands of additional deaths (70) .Individuals commonly considered COVID-19 to be a very severe disease, although they expected to experience less severe symptoms themselves. Individuals also worried more about transmitting the disease to others than about falling ill personally (71) .

The strongest predictor of intentions to accept a COVID-19 vaccine recommended by authorities was the degree to which respondents trusted the vaccine to be safe. Perceived vaccine safety explained 52% of the variance in intentions to vaccinate (72) .The study of Malik et al. shows that COVID-19 vaccine acceptance can be predicted with relatively high accuracy by readily available demographic characteristics. Since the beginning of the COVID-19 pandemic in the United States, it has been clear that low-income and communities of color are at higher risk for infection and death from COVID-19 (22) .

One of the main strength points in this study is the search strategy, we searched 12 different databases. Each citation was screened by two reviewers and disagreement was solved by a senior author. The same was done for quality assessment to ensure robust evidence. A large proportion of the included studies used quota (as opposed to probability-based sampling) and were pre-prints yet to be peer reviewed (as opposed to published journal articles). However, the type of sampling method used (quota vs. probability) had minimal impact on intentions estimates and that studies reported in pre-prints produced similar effect estimates as peer-reviewed journals. One of the main limitations was different tools used to assess vaccine acceptance in addition, the data collected either through face-to-face interview or through online data collection tools. We think that this may affect the internal validity of the study. However, we segregated analysis based on the method of data collection and the difference was not significant.

. CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 18, 2021. ; https://doi.org/10.1101/2021.05.15.21257261 doi: medRxiv preprint Conclusions COVID-19 vaccine rejection is low; however, continuous health education and social support is necessary to maintain the high acceptance rates. Time and residency have no significant effect on vaccine acceptance. However, the country-level case fatality and the officially reported number of cases were significant predictors of COVID-19 vaccine acceptance. That's why encouraging the health authorities to accurately follow & announce case fatalities could be a major contributing factor to increasing vaccine acceptance. We believe that this study will demonstrate public hesitancy and help further . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 18, 2021. ;  

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