Prevalence of COVID-19 Vaccine Hesitancy and Its Associated Factors among Chronic Disease Patients in a Resource Limited Setting in Ethiopia: A Cross-Sectional Study

Background . Te COVID-19 pandemic disproportionately afects patients with chronic diseases. Tus, chronic disease patients are among the frst high-risk population groups to get vaccinated. Tis might be challenged by vaccine hesitancy as it is one of the top ten global health issues for 2019. Furthermore, vaccination myths and conspiracy theories have been proliferating, and the developing world can readily embrace them, which might cause vaccine hesitancy. However, there is a paucity of evidence regarding chronic illness patient’s willingness to be vaccinated. As a result, the aim of this study is to determine the magnitude of vaccine hesitancy and associated factors among chronic disease patients in Ethiopia. Method . An institutional-based cross-sectional study was conducted among adult ambulatory chronic disease patients who were selected using stratifed sampling technique from June 1 to August 1, 2021. Data were collected through a face-to-face interviewer-administered questionnaire. Vaccine hesitancy was measured based on a questionnaire which was adapted from the reviewed literature. Bivariable and multivariable logistic regression was used to identify factors, and variables with p < 0 . 05 were considered statistically signifcant. Result . A total of 422 respondents participated in the survey; the response rate was 99.7%. Te mean age of the participants was 45 years ± 16.95 and 228 (54%) of them were male. Almost half of the respondents (49.5%) were hesitant toward the COVID-19 vaccine. Participants who were male (AOR =1.56, 95% CI: 1.03, 2.35), having good knowledge about the COVID-19 vaccine (AOR =1.60 95% CI: 1.06, 2.41) and having a comorbidity (AOR =3.36, 95% CI: 1.73, 6.56), were factors associated with the acceptance of the COVID-19 vaccine. Conclusion . Te level of COVID-19 vaccine hesitancy was high. Te COVID-19 vaccine’s acceptability was infuenced by being a man, having knowledge about the vaccine and having comorbidities. Furthermore, the most prevalent reason for refusing to take the vaccination is a fear that it may not be safe. As a result, public awareness campaigns should concentrate on delivering more information about the COVID-19 vaccine’s safety and efcacy. Furthermore, it is critical to disseminate accurate information, particularly among women, and to educate people about the vaccine.


Introduction
COVID-19 is a respiratory morbidity caused by a severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) [1].It is a global public health pandemic [2].Te World Health Organization (WHO) declared it an international public health emergency on January 30, 2020, and appealed to all countries to work together to reduce the wide transmission of COVID-19 [2].Worldwide, numerous activities such as physical distancing and other preventive measures are being undertaken to alleviate this emergency [3].But mass vaccination is vital to control transmission [3].Several brands of vaccines have been developed and distributed around the world [4].On March 13, 2021, the Ethiopian Ministry of Health launched the COVID-19 vaccine, and the deployment plan prioritizes the frst doses for health and essential workers and other at-risk groups.Tus, chronic disease patients are among the frst high-risk population groups to get vaccinated [5]."Tis might be challenged by vaccine hesitancy as it is one of the top ten worldwide health threats for 2019 [3].Te term "vaccine hesitancy" refers to a "delay in accepting or refusing immunization notwithstanding the availability of vaccination services [6]."Te COVID-19 pandemic disproportionately afects patients with chronic diseases [7][8][9][10].Previous research has depicted individuals with chronic illnesses as being less likely to be vaccine hesitant [11,12].However, there is a paucity of evidence regarding chronic illness patients' willingness to be vaccinated [13].Furthermore, vaccination myths and conspiracy theories have been proliferating, and the developing world can readily embrace them and might cause vaccine hesitancy.A previous study has reported the global acceptance level for COVID-19 vaccines was suboptimal [14].In addition, the availability of evidence regarding safety and efcacy which might be a factor in vaccine acceptance, a narrative review showed that currently available vaccines are highly efective but there are concerns regarding their safety and adverse efects [15].Similarly, a Chinese study discovered only slightly more than half of their population (54%) planned to get vaccinated [16].Moreover, it is reported that the majority of Indians would accept the vaccine in India; even a small proportion of hesitancy should be addressed [17].On the other hand, in the case of developed countries, a U.S study reported that almost a ffth (22%) of the respondents were vaccine hesitant [18].
However, there were signifcant demographic diferences in vaccination acceptance, with black Americans reporting lower COVID-19 vaccine acceptance (40%) than other racial groups [19].In Ethiopia, there is a considerable disparity between studies conducted in the Gurage zone [20] and Addis Ababa [21], with 37.4 percent and 19.1 percent, respectively.As a result, addressing the magnitude of COVID-19 vaccine hesitancy in diferent settings is recommended.During the study period, the vaccine was available only to health care professionals and chronic disease patients, but later on, as of November 2021, it became available for the entire population starting at the age of 12.As of 24 November 2021, a total of 370,712 confrmed cases and 6,702 deaths have been reported in Ethiopia, and more than 5.4 million people have been vaccinated [22].
In addition, there is inadequate evidence regarding chronic disease patient's level of vaccine hesitancy [20].Tus, this study is aimed at assessing the magnitude of vaccine hesitancy and associated factors among chronic disease patients in Ethiopia.

Study Design, Study Setting, and Study
Period.An institutional-based cross-sectional study was conducted at a referral hospital in the northwest of Ethiopia among ambulatory chronic disease patients.Non-communicable chronic disease patients' follow-up runs from Monday to Friday, and cardiovascular diseases like hypertension, chronic respiratory diseases like asthma, epilepsy, and type II diabetes are the top chronic disease morbidities in the hospital during the study period.Te study was conducted from June 1 to August 1, 2021.

Population of the Study.
Te source population was all patients with a noncommunicable chronic disease who were attending in the northwestern of Ethiopia, could speak the local language, Amharic, and had the ability to provide informed consent.While the study population were all patients with noncommunicable chronic disease who visited the hospital during the data collection period.

Inclusion and Exclusion Criteria.
All adult patients whose ages were greater than or equal to 18 years and who were on chronic disease follow-up were included in the study.Tose participants who did not give consent to participate and those who were not able to respond to the questionnaire because of critical illness, dementia, psychosis, or profound deafness were excluded from the study.

Sample Size and Sampling
Procedure.Te sample size for the current study was calculated by using a single population proportion formula with a 95% confdence level and a proportion of vaccine hesitancy 50% to get maximum sample size and relative precision was assumed to be 5%.With a 10% nonresponse rate, the total sample size was found to be 423.
It was calculated as shown in the following equation: Te participants for this study were selected using a stratifed random sampling with proportional allocation technique.Stratifed sampling is appropriate to have a representative sample of the population under study since it is useful for a population with subsets of known size where the subsets make up diferent proportions of the whole [23].Te stratifcation was made by using the prevalent chronic diseases in the study setting.Te stratifcation includes hypertension, heart diseases, chronic kidney disease, diabetes mellitus, and the remaining chronic diseases were categorized as other chronic diseases hoping for vaccine hesitancy diference among patients with diferent chronic cases.Tus, stratifcation was done after gaining the number of patients in each disease, and then proportional allocation was done based on the following formula: sample size/ population size x stratum size.Ten random samples were selected from each stratum using a lottery method.

Data Collection Instrument and Procedure.
Clarifcation was given on the purpose of the study.Ten respondents who met the inclusion criteria were interviewed face-to-face by using structured and pretested questionnaires that were adapted from reviewed literature [24][25][26].
Te questionnaire used to assess vaccine hesitancy and reasons for refusal was a validated tool which developed by Maria Cordina, Mary A. LaurI, and Josef Lauri and used after obtaining permission [25].Tis questionnaire was used previously, and it has been established that it is appropriate, sensitive, reliable, and valid [25].Data were collected by three-degree level pharmacy students who have taken threeday training before the data collection and were fuent in the local language Amharic.Te reason for using pharmacists for data collection was to give health education at the end of data collection for those who were vaccine hesitant.Te trained data collectors were supervised by a supervisor.Te questionnaire was initially developed in English and translated to Amharic language which is the local language of the study area and back to English to maintain consistency.Te questionnaire was pretested on 22 participants, and the reliability (internal consistency) of the translated tools was assessed with Cronbach's alpha coefcient of 0.94 for knowledge about COVID-19 vaccine, 0.79 for attitude toward COVID-19 vaccine, and 0.86 for vaccine hesitancy, respectively, which reported acceptable reliability of the questionnaire.Te face validity of the questionnaire was assessed by experts and to assess the convergent validity, associations were examined between vaccine hesitancy and attitude towards the COVID-19 vaccine.Similarly, those participants who scored higher in the attitude domain showed lower vaccine hesitancy score compared to participants who did not.Te questionnaire has six components: sociodemographic characteristics, clinical characteristics, knowledge about COVID-19 vaccine questions, attitude towards COVID-19 vaccine, source of information, and general attitude towards vaccines and fnally, the questioner ends with COVID-19 vaccine acceptance and reasons for refusal related questions.Te responses were measured on a likert scale with 1 being "strongly disagreed/not at all," and 5 being "strongly agreed/very much" and categorized based on the mean score [25].

Data Quality Control and Assurance.
A pretest was done among 22 chronic medical patients which were 5% of the total sample size, to assure the quality of the data, and those participants who were involved in the pretest were excluded from the fnal analysis.Some items were modifed, and appropriate amendments were made after the pretest result.Training was provided for data collectors and supervisors about the objective of the study, confdentiality of information, participants' right, and ethical aspects before data collection.On a daily basis, supervision was done.Te supervisor and principal investigator checked the completeness, accuracy, and consistency of the questionnaire.Te collected data were entered into Epi Info 7 to maintain consistency and accuracy.Finally, a multivariable logistic regression analysis was run to control the confounding variables.

Data Processing and Analysis.
After the data were entered into Epi Info 7, they were transferred to Statistical Package for Social Science (SPSS) version 23 for analysis.Descriptive statistics (frequencies, percentages, mean, median, standard deviation, and interquartile range) were reported for the important variables.Associations between variables were assessed using the Chi-square test.Te association between the dependent variable and independent variables was identifed by a binary logistic regression model.Variables with a p value of less than 0.2 in the bivariable binary logistic regression were ftted in the multivariable logistic regression to control confounding variables.An adjusted odds ratio (AOR) with a p value <0.05 and 95% CI was reported, and the association between the dependent variable and the independent variables was determined.Overall model ftness was checked with the Hosmer and Lemeshow test, and the model was ft with a p value of >0.05.
2.9.Ethical Consideration.Tis study was reviewed and ethically approved by the Institutional Review Committee of the School of Pharmacy, University of Gondar with the Advances in Public Health approval number of (UOG-SOP272/2021) on 23/6/2021.Te data collected were kept anonymous and no personal identifer was used.A written informed consent was obtained from the study participants and participation in the study was fully voluntary.Te criteria set by the declaration of Helsinki were followed while conducting this study.

Operational Defnition
2.10.1.Vaccine Hesitancy.Vaccine hesitancy was explored using one question.Respondents were asked whether they would take or had taken COVID-19 vaccine with possible responses being yes, no, or unsure.Tose that answered no or unsure were considered as vaccine hesitant [25].

Knowledge about the COVID-19
Vaccine.Seven items were used to assess respondents' knowledge about the COVID-19 vaccine.Correctly answering the question received one point, while incorrect responses was given zero points.Respondents who scored 70% and above were categorized as having good knowledge [24].

Sociodemographic and Clinical
Characteristics.In this study, 423 participants were approached, and 422 participants agreed to take part in the study, giving a response rate of 99.7%.Te mean age of the participants was 45 years ± 16.95 and 228 (54%) of them were male.Slightly less than one-third (29.9%) of the participant's educational level were college and above.Two hundred seventy-three (64.7%) of the participants were urban dwellers, and 32.7% of the participants were self-employed.In this study, 194 (46%) of the participants had an average monthly income of ≥3500 Ethiopian Birr.Among the study participants, 287 (68%) of them were married.In this study one hundred forty-seven (34.8%) of the participants had hypertension, followed by diabetes mellitus 145 (34.4%).Meanwhile, slightly less than two-third of the respondents 273 (64.7%) took two to four medications (Table 1).

Knowledge about the COVID-19
Vaccine.About half of the participants (215, or 50.9%) had good knowledge about the COVID-19 vaccine.Moreover, in this study, 342 (81%) of the participants knew that COVID-19 can be prevented by the vaccine.Half of the participants (211 or 50%) knew that AstraZeneca and Covishield are the two vaccines used in Ethiopia, while the other half of the participants answered incorrectly.
More than half of the participants (226 or 53.6%) did not know that the vaccine is given two times within 28 days apart.On the other hand, three-quarters (316, or74.9%) of the respondents correctly answered that the vaccine is provided for free in Ethiopia.
Te majority of the participants 349 (82.7%) knew that the provision of the vaccine was provided on a voluntary basis.
More than three-quarters (331 or 78.4%) of the respondents knew that healthcare professionals, chronic patients, and elders are prioritized for vaccination.About half of the respondents (215 or 50.9%) correctly knew that the COVID-19 vaccine had been started.

Attitudes towards the COVID-19 Vaccine and General
Attitudes towards Vaccines.Slightly less than one-third (28.9%) of the participants chose "disagree" for the statement "in general, vaccines are safe," and 116 (27.5%) participants chose "agree" for the same statement and 174 (17.5%) of the participants reported that they know someone who had a bad reaction to a vaccine.Almost half of the participants (210 or 49.8%) agreed that it is important to get the vaccine to protect people from COVID-19.More than a quarter (28.7%) of the participants agreed that pharmaceutical companies are going to develop safe and efective COVID-19 vaccines.Seventy-four (17.5%) participants agreed that vaccines made in Europe or America are safer than those made in other countries.One hundred forty-eight (35.1%) of the participants chosen "agreed" to the statement "my concerns about related side efects will prevent me from taking a vaccine for the prevention of COVID-19."Most of the study participants (258 or 61.1%) thought that most Ethiopians would refuse to take the COVID-19 vaccine.While more than half (58.8%) of participants strongly disagreed that the government will make the vaccine available for all citizens free of charge.All statements on attitude signifcantly correlated with vaccine hesitancy but the efect size is small (Tables 2 and 3).

Sources of Trusted Information about the COVID-19
Vaccine.Te fndings revealed that the majority of 334 (79.1%) of the participants trusted health institutions as sources of information towards the COVID-19 vaccine, followed by media (television, radio, and newspapers) with 120 (28.4%) (Table 4).

Factors Associated with Vaccine Hesitancy among Noncommunicable Chronic
Patients.Demographic factors and clinical factors such as gender, residency, comorbidity, knowledge, and sources of information were assessed for their association with hesitancy toward the COVID-19 vaccine among chronic disease patients.As shown in Table 5, hesitancy for the COVID-19 vaccine among the participants was signifcantly associated with gender, presence of comorbidity, and knowledge towards the COVID-19 vaccine.
Sex, residency, number of family members, comorbidities, number of medications, knowledge about the vaccine, and source of trusted information were all associated with vaccine hesitancy at p < 0.2 after the bivariate binary logistic regression was run.Te multivariable binary logistic regression analysis revealed that sex, comorbidity, and knowledge were found to be signifcantly associated with the hesitancy level of the respondents.In this study, sex was found to afect vaccine hesitancy.
Te odds of accepting COVID-19 vaccine were about 1.5 times (AOR � 1.56, 95% CI: 1.03, 2.35) higher for males than their female counterparts.With regard to comorbidity, the odds of accepting COVID-19 vaccine were about three times (AOR � 3.36, 95% CI: 1.73, 6.56) higher for persons with comorbidities as compared to those participants without comorbidity.Knowledge towards COVID-19 vaccination was signifcantly associated with the odds of accepting the COVID-19 vaccine.It was found that the odds of accepting the COVID-19 vaccine among those respondents who had good knowledge were about 1.6 times (AOR � 1.60 95% CI: 1.06, 2.41) higher than those respondents who had poor knowledge.Table 6 shows the bivariable and multivariable regression in detail.

Discussion
Te goal of this study was to determine vaccine hesitancy and associated factors among noncommunicable chronic disease patients in Ethiopia.Vaccine hesitancy was found to be 207 (49.1%), (95% CI, [46][47][48][49][50][51][52][53][54][55][56].Tis proportion is insufcient to obtain herd immunity because, according to estimations of the basic reproduction number, with an estimated reproductive number (R) of 3, COVID-19 herd immunity may be attained by immunizing at least 70% of the population, provided the vaccine is 100% efective [27].Te rapid development of these vaccinations within a year explains the substantial vaccine reluctance.Some people are concerned about the vaccines' safety because of their unprecedented speed [28][29][30].Furthermore, this study was conducted among chronic disease patients and evidence suggested that chronically ill people in lower-income countries have a signifcant hesitancy about obtaining the vaccine due to misleading information and inadequate communication [31].Despite this, chronic disease patients may be hesitant to receive the vaccine due to concerns about unintended side efects [4,32,33].
Another reason for the lower COVID-19 vaccination acceptance rate could be the fragmented healthcare system in sub-Saharan African countries, which could hinder vaccine uptake because the healthcare system is a reliable source for patients to determine whether or not to get the vaccine [49].
Furthermore, studies conducted in Ethiopia (68.6%), the United States (64%), and Turkey (70.8%) found higher vaccine hesitancy rates.Tese diferences could be in part due to the timing of studies, where these studies were conducted just before the start of the vaccination program or in the early stages of vaccination, where efcacy and safety data was still being collected at the time of the surveys, which increases vaccine hesitancy as medical mistrust specifc to COVID-19, Antivax groups' statements, conspiracy theories, myths, and misperceptions, questions about the speed of vaccine development and long-term side efects, and expert opinion on challenges with the COVID-19 vaccine were proliferating in the national media.References [50][51][52][53] this in turn leads to vaccine hesitancy as belief in COVID-19 conspiracies was associated with lower vaccination intentions [54].Furthermore, because the majority of the studies were conducted using online modalities such as social media, study participants may be vulnerable to false information via social media as widespread misinformation about the pandemic, misleading healthcare information, conspiracy theories, and mistrust to vaccines are released on diferent social media, such as Facebook, Twitter, and YouTube, leading to vaccine refusal [55][56][57][58].In addition, concerns on the safety of two Adeno-viruses based vaccines (from AstraZeneca and Johnson and Johnson) may deter people who are already hesitant and give room for the spread of misinformation [59].It is recommended that new and specifc educational programmes are transmitted among the young generation to mitigate controversial issues regarding COVID-19 vaccines [60].
Vaccine acceptance is higher among males compared to females.Tis lends weight to the concept that females are more hesitant than males.Previous studies were inconclusive on the association between hesitancy and gender, where women were found to have higher [21,45,61] or lower [29,62,63] hesitancy compared with men.

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With regard to comorbidity, the odds of having vaccine acceptance were about three times higher for persons with comorbidities as compared to those participants without comorbidity.Tis conclusion is backed up by fndings which reported people with comorbid illnesses are more likely to accept COVID-19 immunization [31].
Tis could be owing to the fact that individuals with comorbid medical conditions may perceive a greater danger of severe repercussions or death as a result of SARS-COV-2 infection, and as a result, they may be more ready to obtain the vaccine, as demonstrated by studies which reported multiple comorbidities increase the risk of death from COVID-19 [64].
Another fnding of the current study revealed that vaccine reluctance was substantially linked to knowledge of COVID-19 immunization.Tis conclusion is consistent with research conducted in Southeast Asia and England that found comparable results [65,66].Tis result is explained by the fact that having a solid understanding of the COVID-19 vaccine will aid in understanding the vaccine's benefts, and the perception of having a good understanding of COVID-19 vaccines is linked to better vaccination acceptability.

Limitations of the Study.
Because of the cross-sectional nature of the data, this study is limited in that it lacks temporal relations between the exposure and outcome variables.Furthermore, another drawback of this study was the self-reported nature of the questionnaires used, and since the study was carried out in the initiation stage of vaccination, it might overestimate the vaccine hesitancy.Tus consecutive study is recommended especially after

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November 2021 as the vaccine is available to the general population starting from this time.Moreover, the data collection instrument was not validated in our study and was limited by a lack of factor analysis, so we would like to recommend future researchers determine the psychometric properties of the questionnaire.

Conclusion
Te level of the COVID-19 vaccine hesitancy was high.Te COVID-19 vaccine's acceptability was infuenced by being a man, being aware of the vaccine, and having comorbidities.Furthermore, the most prevalent reason for refusing to take the vaccination is a fear that it may not be safe, followed by a short development period and a lack of information.As a result, public awareness campaigns should concentrate on delivering more information about the COVID-19 vaccine's safety, signifcance, and efcacy.Furthermore, it is critical to disseminate accurate information, particularly among women, and to educate people about the vaccine.

Practical Implications
Combating vaccine hesitancy is a necessary frst step toward mass immunization.As a result, it would be better if many stakeholders, such as policymakers, community leaders, and governments, collaborated efectively to promote vaccination acceptability by raising awareness about the COVID vaccine.
It is suggested that stakeholders create and implement relevant measures.It is recommended that stakeholders devise and put in place appropriate strategies to provide the best targeted and tailored information to the public to convince them about the necessity of COVID-19 vaccination by efectively communicating on safety and efcacy, along with greater transparency on vaccine development, to ensure successful mass immunization programs related to the COVID-19 vaccine.Moreover this study will help in designing public educational campaigns and programs regarding the efectiveness of the vaccines and side efect and adverse efects of vaccines.In addition, laws and policies can be developed to reduce controversial issues regarding COVID-19 vaccines.On the other hand, data on vaccination is important to accurately estimate the hesitancy of the population and helps in underlying the need for the allocation of additional resources to combat the vaccine hesitancy and also reduce the burden of COVID-19 related morbidity and mortality.

Table 1 :
Sociodemographic and clinical characteristics of chronic noncommunicable disease patients in Northwest Ethiopia, 2021 (N � 422).

Table 4 :
Trusted source of information among chronic patients in Northwest Ethiopia (N � 422).

Table 5 :
Factors correlated with vaccine hesitancy of chronic medical patients in Northwest Ethiopia in 2021.
Signifcance at p < 0.05.Te bold values are those variables which were signifcant at p<0.05.

Table 6 :
Factors associated with vaccine hesitancy of chronic medical patients in Northwest Ethiopia in 2021.Te bold values indicate the signifcant values at p<0.05.