SCHOOL OF PUBLIC HEALTH COLLEGE OF HEALTH SCIENCES UNIVERSITY OF GHANA ADVERSE EVENTS FOLLOWING IMMUNIZATION WITH NEWLY INTRODUCED COVID-19 VACCINE FOR PERSONS WHO HAVE RECEIVED AT LEAST ONE DOSE, AWUTU SENYA EAST MUNICIPALITY, CENTRAL REGION, GHANA BY RICHARD OSEI BUABENG (10806290) THIS THESIS IS SUBMITTED TO THE UNIVERSITY OF GHANA, LEGON, IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE AWARD OF A MASTER OF PHILOSOPHY IN APPLIED EPIDEMIOLOGY AND DISEASE CONTROL DEGREE DECEMBER 2021 University of Ghana http://ugspace.ug.edu.gh i DECLARATION I do hereby declare that this is my own independent research and that the works of other researchers were well acknowledged. The study was undertaken under the guidance and supervision of Prof. Col. Edwin Andrews Afari (Rtd) and Dr. Samuel Sackey of the Department of Epidemiology and Disease Control, School of Public Health, University of Ghana, Legon. I declare my compliance with good conduct to the principle and guidelines of the ethical review committee. This work has not been previously submitted either in whole or in part for the award of a degree in this institution or elsewhere. Candidate 30th September, 2022 Richard Osei Buabeng Date Supervisor (Primary) …………………………………………. 30th September, 2022 Prof. Col. Edwin Andrews Afari (Rtd) Date Supervisor (Secondary) …………………………………………. 30th September, 2022 Dr. Samuel Oko Sackey Date University of Ghana http://ugspace.ug.edu.gh ii ABSTRACT Introduction: Vaccines are a critical public health tool in the fight against the COVID-19 pandemic. COVISHIELD, a recombinant simian adenovirus-based COVID-19 vaccine, had been granted emergency use authorization in Ghana. Because the vaccine’s early phase trials were not conducted in Ghanaians, no adverse events following immunization (AEFIs) linked to the vaccination had been identified among Ghanaians prior to the vaccine’s deployment on March 2, 2021. This study aimed to assess the AEFIs of COVISHIELD in the Awutu Senya East Municipality (ASEM). Methods: A prospective observational follow-up study was conducted from August to October 2021 among vaccinees aged 18 years and above. Those who consented were enrolled and subsequently followed up for adverse events within 24 hours and on days 7, 21, and 56 after the immunization. Participants were recruited from all 5 sub-municipalities in ASEM. Data was collected through face-to-face administration of questionnaires to participants at the point of enrolment. Follow-ups were done post-vaccination via telephone calls. Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA 23). According to the Division of AIDS (DAIDS Version 2.1), adverse events were assessed for severity. Data was input into Excel, cleaned, and exported to STATA I/C 16 (Stata Corp LLC, Texas, USA) for analysis. Cumulative AEFI incidence was described across sociodemographic study participant variables. A 95% confidence interval was also determined for the cumulative incidence of AEFIs across participant characteristics. Pearson's chi-square test was performed to assess the relationship between AEFIs and socio-demographic factors. Approval was granted for the conduct of the study on 2nd August 2021 by the Ghana Health Service Ethics Committee. Results: The overall incidence of AEFIs among the 550 vaccinees who were followed for 56 days was 16.7% (92/550). The incidence was higher in the younger age group. The AEFIs experienced were more severe among participants 60 years and older than in the younger group. University of Ghana http://ugspace.ug.edu.gh iii Most participants (71.7% [66/92]) who experienced AEFIs had only one event and the AEFIs experienced were mostly Grade 1 – mild (77.2% [71/92]), and Grade 2 – moderate (20.7% [19/92]) severity. No serious AEFIs were reported. More than half (52.2% [48/92]) of those who developed AEFIs observed them by the next day after the vaccination. AEFIs resolved at a median time of 2 days from onset. Asthenia (32.6% [30/92]) was the commonest AEFI, followed by headache (28.3% [26/92]), body pain (18.5% [17/92]), pyrexia (17.4% [16/92]), and injection site pain (17.4% [16/92]). The risk of AEFI incidence among the younger age group (those aged 18 to 29 years and 30 to 39 years) had 4 times increased risk of AEFI compared to older ones (those aged 70 years and over). Also, the risk of AEFI incidence was 56% higher among females than in males. Conclusion: The incidence of AEFIs among the participants in the Awutu Senya East Municipal was relatively low. The events were generally mild and they disappeared quickly without hospitalization. It is, therefore, recommended that the general public get vaccinated through the national COVID-19 vaccination roll-out organized by the Expanded Program on Immunization. University of Ghana http://ugspace.ug.edu.gh iv DEDICATION This work is dedicated to all frontline health professionals who worked diligently in resource- constrained hospitals to care for COVID-19 patients when there was no vaccination and the world was only now learning about the disease. University of Ghana http://ugspace.ug.edu.gh v ACKNOWLEDGEMENT I would like to thank my supervisor Prof. Col. Edwin Afari (Rtd), as well as Dr. Samuel Sackey for their guidance throughout this project. Many thanks to all faculty members and staff of the GFELTP especially Prof. Ernest Kenu, Dr. Donne Ameme and Mr. Charles Lwanga To my mentor, Dr. Paul Dsane-Aidoo, I say thank you for your guidance right from the conceptualization of the topic to the writing of the final dissertation. I would like to convey my appreciation to everyone at FDA - Mrs Mimi Darko, the CEO, Dr Yvonne Adu Boahen, Mr George Sabblah, and Amma Frempomaa Asare – for their help during the project. I am indebted to the Awutu Senya East Municipality's District Health Director and Disease Control Officers for their efforts in compiling the data. This effort would not have been possible without the financial assistance of the West African Health Organization - many thanks. I also want to thank all who agreed to participate in the study. Finally, I would want to express my heartfelt thanks to my wife, Linda Akosua Buabeng, and daughter, Akosua Ayimaa Buabeng, for their unwavering support. University of Ghana http://ugspace.ug.edu.gh vi Table of Contents DECLARATION .................................................................................................................... i ABSTRACT ........................................................................................................................... ii DEDICATION ...................................................................................................................... iv ACKNOWLEDGEMENT ..................................................................................................... v LIST OF FIGURES ................................................................................................................. i LIST OF TABLES ................................................................................................................. ii LIST OF ABBREVIATIONS .............................................................................................. iii CHAPTER ONE ........................................................................................................................ 1 INTRODUCTION ..................................................................................................................... 1 1.1 Background ...................................................................................................................... 1 1.2 Problem statement ............................................................................................................ 3 1.3 Conceptual Framework .................................................................................................... 6 1.4 Justification .................................................................................................................... 11 1.5 Research Questions ........................................................................................................ 12 1.6 Objectives ....................................................................................................................... 12 General Objective ............................................................................................................. 12 Specific Objectives ........................................................................................................... 12 CHAPTER TWO ..................................................................................................................... 13 LITERATURE REVIEW ........................................................................................................ 13 2.1 Introduction .................................................................................................................... 13 2.4 Overall incidence of AEFI with ChAdOx1 nCoV-19 (COVISHIELDTM ).................... 15 2.5 Common Adverse Events ............................................................................................... 16 2.6 Serious Adverse Events .................................................................................................. 18 2.7 Effect of Age on AEFI incidence ................................................................................... 19 2.8 Time to onset of AEFI with ChAdOx1 nCoV-19 vaccine ............................................. 21 2.9 Rare AEFIs linked to ChAdOx1 nCoV-19 vaccine ....................................................... 22 2.10 COVID-19 vaccination-associated myelitis ................................................................. 24 CHAPTER THREE ................................................................................................................. 26 METHODS .............................................................................................................................. 26 3.1 Study Design .................................................................................................................. 26 3.2 Study Area and Participants ........................................................................................... 26 3.3 Study Variables .............................................................................................................. 28 3.3.1 Dependent Variable ................................................................................................. 28 3.3.2 Independent Variables ............................................................................................. 29 University of Ghana http://ugspace.ug.edu.gh vii 3.4 Sample Size Determination ............................................................................................ 29 3.5 Sampling technique ........................................................................................................ 31 3.6 Vaccination Process ....................................................................................................... 31 3.7 Inclusion Criteria ............................................................................................................ 32 3.8 Exclusion Criteria ........................................................................................................... 32 3.9 Data Collection techniques and tools ............................................................................. 32 3.10 Data Storage and Processing ........................................................................................ 32 3.11 Statistical Data Analysis............................................................................................... 34 3.12 Quality control.............................................................................................................. 36 3.13 Ethical clearance .......................................................................................................... 36 3.14 Sponsorship .................................................................................................................. 37 CHAPTER FOUR .................................................................................................................... 38 RESULTS ................................................................................................................................ 38 4.1 Demographic Characteristics of the Study Population .................................................. 38 4.2 Medical History of participants ...................................................................................... 39 4.3 Cumulative Incidence of AEFI ...................................................................................... 40 4.4 Frequency of AEFI experienced among study participants ........................................... 43 4.5 Time to Onset of AEFI ................................................................................................... 45 4.6 Severity of AEFI conditions among participants who experienced any AEFI .............. 45 4.7 AEFI Classification ........................................................................................................ 48 4.8 Association between AEFI Severity and Number of AEFI per Participant ................... 50 4.9: Outcome of AEFI .......................................................................................................... 50 4.10 Risk of AEFI Incidence among Study Participants ...................................................... 52 CHAPTER FIVE ..................................................................................................................... 58 DISCUSSION .......................................................................................................................... 58 5.1 Cumulative Incidence of AEFI ...................................................................................... 58 5.2 Type, Severity, Time-to-Onset and Outcome of AEFI .................................................. 59 5.3 Risk of Age, Sex, Place of Residence and Medical History on AEFI Occurrence ........ 62 5.4 Strengths and Limitations .............................................................................................. 62 CHAPTER SIX ........................................................................................................................ 63 CONCLUSIONS AND RECOMMENDATIONS .................................................................. 63 6.1 Conclusions .................................................................................................................... 63 6.2 Recommendations .......................................................................................................... 63 REFERENCES ........................................................................................................................ 65 APPENDICES ......................................................................................................................... 81 University of Ghana http://ugspace.ug.edu.gh viii APPENDIX I: ETHICS APPROVAL ................................................................................. 81 APPENDIX II: PARTICIPANT’S INFORMATION SHEET ............................................ 82 APPENDIX III: CONSENT FORM .................................................................................... 85 APPENDIX IV: RESEARCH QUESTIONNAIRE ............................................................. 88 University of Ghana http://ugspace.ug.edu.gh i LIST OF FIGURES Figure 1.1: Conceptual Framework adopted and modified from Hervé et al., 2019. ............. 10 Figure 3. 1 Map of Awutu Senya East Municipal ................................................................... 27 Figure 4. 1: Pre-existing Medical Conditions among Participants .......................................... 40 Figure 4. 2: AEFI classified by System Organ Class among Participants ............................... 48 Figure 4. 3: AEFI classified by High Level Term among Participants .................................... 49 Figure 4. 4: AEFI classified by Preferred Term among Participants ...................................... 49 Figure 4. 5: Association between Severity of AEFI and Number of AEFI ............................. 50 Figure 4. 6: Maximum Recovery Days among Participants with AEFIs ................................ 51 Figure 4. 7: Association between Number of Recovery Days and Severity of AEFIs ............ 51 Figure 4. 8: Association between Number of Recovery Days and Number of AEFIs ............ 52 Figure 4. 9: Model assessment of the multivariable Poisson regression model ...................... 57 University of Ghana http://ugspace.ug.edu.gh ii LIST OF TABLES Table 4. 1: Demographic characteristics and medical history of study participants ............... 38 Table 4. 2: Medical History of Study Participants ................................................................... 39 Table 4. 3: Cumulative Incidence of AEFI among study participants by Age, Sex and Place of Residence ................................................................................................................................. 40 Table 4. 4: Cumulative Incidence of AEFI among Study Participants by Medical History .... 42 Table 4. 5: Number of AEFI experienced among Study Participants...................................... 43 Table 4. 6: Severity of AEFI conditions among Participants who experienced any AEFI ..... 45 Table 4. 7: Poisson regression model of the Incidence of AEFI among Study Participants ... 56 University of Ghana http://ugspace.ug.edu.gh iii LIST OF ABBREVIATIONS AEFI Adverse Events Following Immunization ASEM Awutu Senya East Municipal DAIDS Division of AIDS EMA European Medicines Agency EPI Expanded Programme on Immunization FDA Food and Drugs Authority GFELTP Ghana Field Epidemiology Laboratory Training Program GHS Ghana Health Service HCW Health Care Workers ISRR Immunization Stress Related Response MenACWY Meningococcal Vaccine MHRA Medicines and Healthcare Products Regulatory Agency MOH Ministry of Health SII Serum Institute of India UNICEF United Nations International Children Emergency Fund VAERS Vaccine Adverse Event Reporting System WAHO West African Health Organization WHO World Health Organization University of Ghana http://ugspace.ug.edu.gh 1 CHAPTER ONE INTRODUCTION 1.1 Background Vaccines serve a critical role in the prevention of infectious illnesses in all communities across the globe (Greenwood, B. 2014). However, they may have unfavourable consequences referred to as adverse events following immunization (AEFI) when administered. This is “any untoward medical occurrence which follows immunization and which does not necessarily have a causal relationship with the usage of the vaccine” (Mehta et al., 2000). Common adverse events to immunizations might include swelling, redness at the injection site, fever, pain, and a rash (WHO, 2010). In December 2019, a group of individuals with unexplained pneumonia was linked to a seafood marketplace in Wuhan, China, and was later determined to be infected with 2019-nCoV, a new coronavirus (Zhu et al, 2020). Due to the virus's resemblance to the coronavirus that causes severe acute respiratory syndrome (SARS-CoV), a lineage B betacoronavirus, it was given the name SARS-CoV-2 (Lu et al., 2020). SARS-CoV-2 is the infectious virus that causes Coronavirus Disease 2019 (COVID-19), and infection with it can result in a range of clinical signs, ranging from asymptomatic infection to severe acute respiratory failure and death (Folegatti et al., 2020). As of January 30, 2020, the World Health Organization (WHO) proclaimed the COVID-19 outbreak to be a public health emergency of international concern. On March 11, 2020, the WHO declared COVID-19 to be a global pandemic. There have been about 157.29 million confirmed cases globally with 3.28 million deaths as of May 10, 2021 (WHO, 2021a). Africa has recorded 3.32 million cases with 83,650 deaths as of May 10, 2021 (WHO, 2021b) and as of April 25, 2021, Ghana had announced a total of 93,011 confirmed cases with 783 deaths. University of Ghana http://ugspace.ug.edu.gh 2 There was no effective antiviral therapy for COVID-19 as of January 2020, and the treatment plan was just supportive, including preventive antibiotics, steroid administration and oxygen supplementation (Yanai, H., 2020). However, vaccination remains a popular option in therapeutic alternatives and among the most profitable and safest public health measures for controlling infectious diseases (Amorij, 2012; Luyten, J., & Beutels, P., 2016). The World Health Organization (WHO) estimates that current vaccines prevent nearly two million deaths in children under the age of five per year. (Arístegui et al. 2003; Duclos et al, 2009). The Expanded Programme of Immunisation (EPI) has assisted in reducing infant mortality in Ghana. The morbidity rates of vaccine-preventable illnesses such as measles and poliomyelitis have also decreased significantly. For instance, measles has not caused any deaths since 2003, and in 2011 Ghana was recognized as having achieved eradication status for maternal and neonatal tetanus (Gyaase et al., 2021). As of March 2, 2021, less than a year after the WHO declared COVID-19 a pandemic disease, the global research community had collaborated to develop at least 308 vaccine candidates, with 16 of them already in Phase III trials (Shrotri et al., 2021). Meanwhile, adverse events (AE) from such vaccinations are of concern. These safety issues have resulted in vaccine hesitancy with the misconception that vaccines pose a risk of infection and are not safe for use (WHO, 2014). Vaccination rates have decreased in some countries as a consequence. Among Ghanaian adults, a study was undertaken before emergency-use authorization of some COVID- 19 vaccines in Ghana. When Acheampong et al., investigated the population, they discovered that 28% were "undecided" about getting the vaccine, while 21% were "somewhat unlikely or very unlikely" to get the vaccine (Acheampong et al., 2021). In order to document the safety profile of newly introduced vaccines in the population, Ghana has a national AEFI surveillance system that is dependent on voluntary monitoring and reporting by healthcare professionals. In the last decade, improved AEFI monitoring has University of Ghana http://ugspace.ug.edu.gh 3 increased AEFI reporting from many monitoring departments in Ghana. This surveillance system has been activated during the COVID-19 vaccination campaign. However, because of the large number of people being vaccinated, there is a risk of an apparent increase in the number of AEFIs during the vaccine campaigns (UNICEF, 2005). Recipients of the vaccines may not report mild AEFIs to the hospital, resulting in under- and biased reporting. Passive AEFI surveillance, according to studies, detects about 1 to 10 per cent of incidents. (Choe et al, 2011). Active collection of AEFI reports and assessing them is one way to preserve public trust in the COVID-19 vaccines. These findings will boost public confidence and help COVID- 19 vaccines gain a greater reputation. The successful communication of the reality of the benefit-to-risk ratios for the vaccine would encourage widespread optimism as well as inform policy. As a part of the campaign to get people vaccinated, social mobilization events were held at the national, regional, and local levels. Health, education and information authorities were consulted on information management; media houses were sensitized; materials and radio jingles were made; banners and posters were printed in both official and local languages. The vaccination campaign provided an opportunity to document the safety of vaccines in the Ghanaian population by assessing adverse events related to the COVID-19 vaccine in Awutu Senya East Municipality. 1.2 Problem statement In Ghana, the Ministry of Health announced the first two cases of COVID-19 in a press statement dated May 12, 2020. (MoH, 2020). Both cases were imported as a result of the persons returning from Norway and Turkey. Since then, the case count has increased, and according to statistics from the Ghana Health Service, Government of Ghana (GHS, 2021), Ghana reported a total of 93,011 confirmed cases with 783 deaths as of April 25, 2021. The primary control method against disease transmission is vaccination, which comes with adverse events. Adverse drug events have evolved as a significant clinical and public health University of Ghana http://ugspace.ug.edu.gh 4 concern in developed and developing nations, accounting for between 5% to 35% of hospital admissions (Howard et al., 2007). Adverse events are one of the top 10 causes of death and significantly increase the cost of treatment in the United States and Europe (Beijer et al., 2002; Kongkaew et al., 2008). In Canada, a study found the adverse event rate of occurrence to be 7.5 per 100 hospital admissions; meaning 185,000 out of 2.5 million hospital admissions annually are associated with adverse events (Baker et al., 2004). The burden of adverse events on healthcare is proportionately higher in developing nations, owing to a high disease rate, hunger, and healthcare services with insufficient resources (Bates et al., 1997). A total of 522,313 doses of the Covishield vaccine had been administered in Ghana as of April 1, 2021, with 1,733 people reporting AEFIs; this means that the reporting rate was approximately 3 reports for every 1,000 doses administered (SAFETYWATCH Update No. 04, 2021). Causality was determined for five significant AEFI reports that had investigations completed, although there were 15 serious AEFIs. The Committee found three of the serious AEFIs to be coincidental. Even though there was a clear correlation between the two remaining cases and vaccination delivery, conclusive proof of a vaccine-related incident could not be found, thus patients in those two cases were monitored indefinitely (SAFETYWATCH Update No. 04, 2021). These adverse events may occur as a result of the vaccine’s intrinsic properties such as the vaccine recipient's age, sex, race/ethnicity, weight and pre-existing medical condition (Pittman et al., 2002; Weber et al., 2014). Additionally, the vaccine's administration and composition parameters, such as the method of injection or the location where the vaccination is administered, might affect the vaccine's safety profile in a specific person (Hervé et al., 2019). The occurrence of AEFI might also be a result of coincidence, accidents or immunization- related anxiety (Siegrist et al., 2007). It is critical for both the vaccinee and the healthcare professionals who suggest and deliver vaccinations to be aware of the potential adverse effects of the vaccine. A person may refuse to get additional doses of vaccination if it is thought to be University of Ghana http://ugspace.ug.edu.gh 5 overly reactogenic. This could result in low vaccination rates and a lack of community protection as a consequence. For effective vaccination programs to control the spread of a disease, it is crucial to maintain high vaccination rates. The pandemic has put significant strain on healthcare services that provide care to COVID-19 patients, as well as disrupted non-COVID-19 healthcare delivery, causing detrimental economic consequences (Folegatti et al, 2020). While the majority of COVID-19 patients have a mild to moderate condition, up to 5%-10% may have a severe, possibly fatal course, necessitating the development of effective drugs (WHO, 2020). Respiratory arrest, septic shock, disseminated intravascular coagulation, and myocardial damage are also common causes of death from COVID-19 (McGonagle et al., 2020). Protecting vulnerable populations such as the elderly and those with comorbidities, particularly those with compromised immune systems, will be made easier by the introduction of a safe and efficacious vaccine for COVID- 19 (Pramod et al., 2021). However, vaccinations sometimes cause adverse events (Mehta et al., 2000; WHO, 2010), which have significant financial consequences in clinical practice. Many findings have found that the morbidity and mortality caused by these AEFIs is a significant health issues for healthcare providers and the general population (Sultana, Cutroneo, & Trifir, 2013). These adverse events also lead to a misconception that vaccines pose a risk of infection and are not safe for use (WHO, 2014). These concerns contribute to widespread vaccine apprehension, resulting in decreased vaccine uptake and failure to achieve vaccination targets (herd immunity) necessary to control the COVID-19 outbreak. On March 27, 2020, the president declared a partial lockdown of four major cities (Accra, Tema, Kasoa, and Kumasi) beginning March 30, 2020, based on recommendations from the Ministry of Health and the Ghana Health Service (Antwi-Boasiako, et al., 2021; Danquah, M., & Schotte, S., 2020). Kasoa, a peri-urban community in the Awutu Senya East Municipal (ASEM) District in Ghana's Central region, was one of the towns most hit by the COVID-19 University of Ghana http://ugspace.ug.edu.gh 6 epidemic. Additionally, ASEM was selected as the study site since it is home to various ethnic groups, cultures, and tribes from Ghana (Gbagbo, F. Y., 2020). Furthermore, since it was one of the most impacted areas in terms of COVID-19 infections, the ASEM District was among the first to get COVID-19 vaccinations throughout the roll-out. The purpose of the study was, therefore, to assess adverse events related to the COVID-19 vaccine in Awutu Senya East Municipality. 1.3 Conceptual Framework Toxicity studies employing cell cultures and animal models are used to examine vaccine safety at various stages of the development process, from pre-clinical toxicology through rigorous clinical trials (Di Pasquale et al., 2016). Even after a vaccine has been licensed, it still has the potential to induce adverse reactions. Vaccine recipients' age, sex, race/ethnicity, weight, immunity and pre-existing medical condition are all extrinsic and intrinsic variables that may contribute to the development of AEFIs (Pittman et al., 2002; Weber et al., 2014). Yamoah et al., 2019, reported that healthcare professionals need to improve their knowledge, perception and practices through more sensitization on AEFIs and vaccine safety to improve reporting of AEFIs (Yamoah et al., 2019). Additionally, the vaccine's administration and composition parameters, such as the method of injection or the location where the vaccination is administered, type of antigen, and vaccine formulation, might affect the vaccine's safety profile in a specific person (Hervé et al., 2019). The occurrence of AEFI might also be a result of coincidence, accidents or immunization- related anxiety (Siegrist et al., 2007). Some of the factors interact with each other. For instance, the antigen dose might determine the final dose number and the appropriate dosage per age. The physiological properties of the vaccine, when altered, could affect intrinsic factors such as age, sex and medical history leading University of Ghana http://ugspace.ug.edu.gh 7 to the occurrence of AEFI. Administration and product handling factors could also interact with vaccine product factors – inadequate storage could affect the physiological properties of the vaccine. Figure 1.1 illustrates factors that may trigger AEFIs. The immune and neurological systems' physiological activities change throughout life. These alterations have ramifications for the body's response to vaccine-induced adverse effects. As the immune system grows throughout infancy and adolescence, AEFI reporting rates rise. Higher tolerance for pain and disease symptoms and/or a decrease in innate immune defences may explain why reporting rates of AEs decline in adulthood. Older persons tend to have lower levels of interleukin 6 & 10, and c-reactive protein in their bloodstream after immunization, which might explain why they experience fewer systemic adverse events, such as fever (El Yousfi et al., 2005). Females have a greater prevalence of injection-site symptoms following immunization than males (Cook, I. F., 2009; Klein et al., 2010) and may have a higher risk of acute hypersensitivity responses (Griffioen et al., 2014). Possible factors include genetic or hormonal variations. For instance, a woman's body may have a higher tolerance for injection site inflammation because of differences in skin thickness, cardiac output, and neuronal structure between men and women. (McCarthy et al., 2017). Human (or programme) errors during the process of immunization also cause AEFIs. Adverse reactions may occur when vaccination is administered by a route other than the prescribed one (Herzog, C. 2014; Dolan et al., 2017). As a general rule, most vaccinations are given via intramuscular injection, and optimum vaccination practice demands that the injection site be stretched to decrease discomfort, redness, and the danger of developing an abscess following injection (Masika et al., 2016; Zuckerman JN, 2000). The failure of various vaccination programs has been linked to healthcare professionals’ lack of knowledge and perceptions concerning vaccine storage and delivery, as well as the probable AEFIs connected with vaccine University of Ghana http://ugspace.ug.edu.gh 8 products (Netterlid et al., 2009; Gahunia et al., 2013). Temperature changes might further cause vaccine ingredients to convert to hazardous forms, which could induce AEFIs (Comes et al., 2018; WHO, 2015). If a substance is used after its expiration date, it can lose its effectiveness or become nonviable. Local and anaphylactic reactions are all possible vaccine-induced adverse effects. Components of vaccines such as adjuvants might induce adverse events when injected. It has been noted that higher volumes of injection (0.8ml and above) might elicit more discomfort than smaller doses (Zijlstra et al., 2018). Although rare, vaccine-related adverse effects are documented at a rate of 4.8 to 83.1 per 100,000 doses of the most widely used vaccinations. Although the precise incidence of actual adverse responses to regular vaccinations is unknown, estimates for the majority of vaccines vary from 1 per 500,000 to 1 per 1,000,000 doses (Fritsche et al., 2010). Some formulations may increase the risk of life-threatening allergic responses because they include allergens such as gelatine or egg proteins. But although severe allergic responses to immunizations are very uncommon, they can occur (approximately 1 per 1,500,000 doses). There is a wide spectrum of adverse outcomes that have been linked to vaccines (Fritsche et al., 2010). Immunization anxiety-related reactions (psychological stress) can also result in AEFIs. In anticipation of injection, some individuals become stressed and respond negatively. The substance of the vaccine has nothing to do with this reaction. Some people have a fear of needles, which makes these responses worse. Mass hysteria may occur during group immunization, especially if a vaccinee faints or exhibits other symptoms such as itching or limb weakness. The manner and type of adverse injuries recorded can also be influenced by public opinion and apprehension of safety concerns. At the time of vaccination, the vaccine can be associated with non-vaccine-related occurrences. For mass vaccination programs, such temporal correlations are inescapable due to a large number of vaccine doses being given. University of Ghana http://ugspace.ug.edu.gh 9 Vaccine safety and public confidence in vaccinations might be improved if healthcare professionals have adequate knowledge of vaccines and their related adverse events, which they can then pass on to patients and others in their communities (Masika et al., 2016). Certain practices by healthcare professionals have the potential to decrease vaccination efficacy. A common example is the pre- and post-vaccination usage of analgesics such as ibuprofen and paracetamol to reduce pain, fever, and inflammation related to vaccination (Manley et al., 2007). Such actions may interfere with the body's antibody response to the antigenic agent in vaccinations, limiting their capacity to inhibit the proliferation of the targeted disease-causing organisms (Prymula et al., 2009). But a systematic review found that antipyretics given after vaccination helped lower vaccine-induced fever and had no effect on the body's ability to mount an effective immune response (Das et al., 2014). It must be the practice of healthcare professionals to check vaccinations regularly to ensure that they are always maintained at temperatures that are consistent with the cold chain to avoid any contamination (Yakum et al., 2015). Negative perceptions among healthcare providers include the belief that reporting an AEFI such as an injection abscess would make them feel guilty for causing injury and being accountable for the incident, as well as the belief that integrating primary clinical tasks with AEFI reporting is difficult (Masika et al., 2016). Figure 1.1, as adopted and modified from Hervé et al., 2019, illustrates the factors that lead to AEFI. University of Ghana http://ugspace.ug.edu.gh 10 Figure 1.1: Conceptual Framework adopted and modified from Hervé et al., 2019 illustrating the factors that lead to Adverse Events Following Immunization. Occurence of AEFIs Intrinsic Factors • Age • Sex • Psychological stress • Dose number • Medical history • Ethnicity/Place of residence • Knowledge • Perception and practice Coincidental Factors • Accidents Administration & Product Handling Factors • Administrative route errors • Administrative technique • Needle length • Inadequate storage Vaccine Product Factors • Injection route • Antigen dose • Physiochemical properties • Batch defect University of Ghana http://ugspace.ug.edu.gh 11 1.4 Justification Actively soliciting for AEFIs through direct patient follow-up may have provided additional information and contributed to the identification of mild AEFIs that may otherwise have gone undetected by passive surveillance systems. In Ghana, for instance, only 21% out of 59.50% of physicians who saw a patient with an adverse event reported to the National Pharmacovigilance Centre (NPC) in 2011 (Sabblah et al., 2014). It was critical to keep a close eye on COVID-19 vaccine safety, particularly because the vaccines being used in the campaign were not just novel, but went through emergency use authorization (expedited registration). Also, none of the early phase trials of the vaccines was conducted in the Ghanaian population, so, no AEFIs related to the vaccine had been identified in Ghanaians prior to the vaccines’ deployment on March 2, 2021. In addition to existing spontaneous reporting systems and healthcare database studies (secondary data), a prospective follow-up study would be complimentary to these systems in various ways. It was more adapted to capturing the more common adverse events, such as those that were not medically attended. Extensive safety information, such as illness progression and the effect of adverse events was produced. Furthermore, unlike spontaneously provided data, the denominator of the analyzed cohort was known (in real-time), allowing AEFI frequencies to be estimated and immediately compared to data collected before licensing. Profiling safety issues of medicines through AEFI reporting was to inform reasonable use. It was, therefore, important to actively solicit for AEFIs to provide baseline data for the COVID- 19 vaccine and eventually contribute to improved signal detection and timely evaluation of safety signals. Furthermore, the findings were to help the Food and Drugs Authority (FDA) and Expanded Programme on Immunization (EPI) reliably educate the population, create public interest in the vaccine, and keep the immunization campaign going. University of Ghana http://ugspace.ug.edu.gh 12 1.5 Research Questions 1. What is the incidence of AEFIs among persons living in Awutu Senya East Municipality (ASEM) who received at least one dose of the COVID-19 vaccine? 2. What are the types, severity, time-to-onset and outcome of reported AEFIs among persons living in ASEM who received at least one dose of the COVID-19 vaccine? 3. Are there possible risk factors for reported AEFIs among persons living in ASEM who received at least one dose of the COVID-19 vaccine? 1.6 Objectives General Objective 1. To assess AEFIs related to the COVID-19 vaccine among residents of ASEM who received at least one dose. Specific Objectives 1. To determine the incidence of AEFI among persons living in ASEM who received at least one dose of the COVID-19 vaccine. 2. To determine the type, severity, time-to-onset and outcome of AEFI among residents of ASEM who received at least one dose of the COVID-19 vaccine 3. To assess the risk of age, sex, place of residence and medical history on AEFI occurrence following COVID-19 vaccination among residents of ASEM who have received at least one dose of the COVID-19 vaccine. University of Ghana http://ugspace.ug.edu.gh 13 CHAPTER TWO LITERATURE REVIEW 2.1 Introduction The globe was attacked by a significant public health danger towards the end of 2019, the COVID-19 epidemic, which has swiftly afflicted millions of individuals throughout the world. This viral infection is particularly important since it causes death in both healthy individuals and the elderly. COVID-19 mortality is greater than seasonal influenza mortality (Gates, 2020). Furthermore, COVID-19 is highly contagious, with the average infected individual infecting two or three other persons, even if they are asymptomatic (Hoehl et al., 2020). As a result, the illness has posed a global challenge to healthcare systems and services. 2.2 SARS-Cov-2 Disease Progression The 2019-novel coronavirus (2019-nCoV) was first designated by the WHO (Guo et al., 2020) on January 12, 2020. The current information is that during the prodromal phase, infected individuals create a large amount of virus in the upper respiratory system, with a subsequent predilection for the lower respiratory tract (Chan et al., 2020). COVID-19 has also been linked to a variety of additional systemic symptoms (Cascella et al., 2021). Several preventative methods have been suggested to slow the virus's spread due to its unique characteristics and mechanism of transmission. In reaction to the virus, enormous and diligent efforts have been made all across the world. Intensified disease surveillance, community spread mitigation, the creation of serological testing, as well as the start of vaccine development (Heymann et al., 2020). Ghana implemented countrywide steps including border closures, quarantine of sick individuals, contact tracing, testing, and a three-week lockdown in Accra and Kumasi, which were identified as the virus's epicentres. Immunizing the population through Emergency Use Authorization of some vaccines has been adopted by Ghana to augment the other measures to control the virus. University of Ghana http://ugspace.ug.edu.gh 14 Vaccines today are both safe and effective. During the pre-licensure stage, they are subjected to stringent safety checks. Effective immunization campaigns include high-quality vaccines and safe immunization procedures (Joshi et al., 2018). Like most pharmaceuticals, vaccines can have adverse effects. However, vaccines seldom cause serious adverse reactions, and the most frequent reactions are mild and self-limiting. Even so, they are not fully risk-free (Mehta et al., 2000). COVID-19 vaccines, like other vaccines, are linked with adverse events, and because of a large number of people being immunized in a campaign, the possibility of an apparent increase in AEFIs cannot be ruled out (UNICEF, 2005). Even though Ghanaian authorities licensed two vaccination brands (Sputnik V and COVISHIELDTM), only COVISHIELDTM has been utilized since the country's roll-out. 2.3 The COVISHIELD Vaccine (ChAdOx1 nCoV-19) COVISHIELDTM vaccine is made up of the SARS-CoV-2 Spike (S) surface glycoprotein, which is expressed by human cytomegalovirus major immediate-early promoter, which includes intron A, and a human tissue plasminogen activator leader sequence at the N terminus. Oxford University developed the COVISHIELDTM vaccine, which has a commercial production and supply arrangement with AstraZeneca. Serum Institute of India (SII) has signed a commercial-scale production and supply deal with AstraZeneca for India and global markets. Dosage and storage COVISHIELDTM is an intramuscular (IM) injection solution in a vial that is stored at 2 – 8°C. The COVISHIELDTM is available in a formulation buffer (10 mM L-Histidine and Histidine HCl, 7.5% (w/v) Sucrose, 35 mM Sodium Chloride, 1 mM, Magnesium Chloride, 0.1 % (w/v) Polysorbate 80, 0.1 mM Disodium Edetate (EDTA), 0.5% (v/v) Ethanol, pH 6.1 to 7.1 in Water for Injection). University of Ghana http://ugspace.ug.edu.gh 15 The product is delivered as a sterile, transparent to virtually particle-free and slightly opalescent solution. An aluminium flip-off lid and a bromobutyl rubber stopper seal the transparent tubular glass vial containing COVISHIELDTM, which is then ready for use. Vials of one, two, five, ten and twenty doses are available. Immunization schedule In a two-dose schedule, the vaccine is delivered intramuscularly in the deltoid at intervals of 8-12 weeks. For each mL of infusion, genetically modified human embryonic kidney (HEK) 293 cells are used to produce 5 × 1010 simian adenoviral particles. 2.4 Overall incidence of AEFI with ChAdOx1 nCoV-19 (COVISHIELDTM ) In a report of a phase 1/2 trial in the UK, where 1,077 participants were assigned to the treatment (ChAdOx1 nCoV-19 (n=543) or the control (MenACWY (n=534) groups, Folegatti et al., 2020, indicated that 67% and 38% had AEFIs in both the treatment and control arms respectively. These AEFIs were typically mild to moderate in severity. The treatment group received the Covishield vaccine, and the control group received the meningococcal vaccine (MenACWY). The incidence in the control group was not a placebo, hence, cannot be reflective of the general incidence of the population without any intervention. In another clinical trial, after the first dose, 74% of persons vaccinated with the standard dose had at least one local symptom. The incidence during the second dose was 67% of persons vaccinated with the standard dose (Ramasamy et al., 2020). Various countries have started rolling out these vaccines and real-world data are being reported. Kaur et al., 2021, reported on post-approval safety data on Covishield use in healthcare professionals in northern India. AEFIs were observed in 40% of participants after the first dose and approximately 16% of participants after the second dose. These events were much less compared to the AEFI rate seen in the UK-based population study of Oxford-AstraZeneca’s ChAdOx1 vaccine. Another study among healthcare professionals in South India reported a University of Ghana http://ugspace.ug.edu.gh 16 higher AEFI incidence of 69.7%. The AEFIs were all minor (Inbaraj et al., 2021). Jayadevan et al., 2021 also reported that 65.9% of respondents in their survey said they had had at least one post-vaccination symptom. In the Republic of Korea, a total of 1,503 Healthcare professionals were vaccinated, with 994 (994/1,503, or 66.1%) reporting AEFIs (Jeon et al., 2021). The incidence in Korea as per this report is similar to that of India. Nepal began the first round of COVID-19 immunization with the Covishield vaccine for frontline healthcare professionals in January 2021. After the first dose of the vaccine was provided at one of the sentinel sites for immunization, active surveillance of AEFI was done. The incidence (85.04%) was higher than those seen in India (Shrestha et al., 2021). 2.5 Common Adverse Events Most of the AEFIS seen with the ChAdOx1 nCoV-19 vaccine has been typically mild to moderate in severity. In the study reported by Folegatti et al., 2020, pain was reported by fewer subjects when prophylactic paracetamol was used: 50% and 32% in the treatment and control groups respectively. On the first day following immunization, the degree of local and systemic reactions was at its peak. In the first two days following vaccination with ChAdOx1 nCoV-19, an adjusted study of the impact of preventative paracetamol on adverse effects of any severity revealed substantial decreases in pain, fever, chills, muscular ache, headache, and malaise. Unsolicited adverse events in the 28 days after vaccination that were thought to be perhaps, probably, or definitely connected to treatment were mostly mild and moderate, and they went away over the follow-up period. Laboratory adverse events that were thought to be at least probably attributable to the study intervention were mostly mild or moderate in intensity and self-limiting. In the treatment group, 46% of participants had transient haematological alterations from baseline (neutropenia), compared to 7% in the control group (Folegatti et al., 2020). University of Ghana http://ugspace.ug.edu.gh 17 Systemic AEFIs with or without local (injection site) involvement was seen in around 31% of participants, while only local site involvement was observed in 9% of people, as previously described by Kaur et al., 2021. Fever, malaise, and headache were the most frequently reported systemic AEFIs, accounting for 15.2%, 8.7%, and 5.8% of those surveyed, respectively. Only 28.7% of the AEFIs were classed as 'moderate' in severity, while 70.4% of them were categorized as mild. Based on causation assessment and the suspicion of an immunization stress response, the one serious AEFI was classed as "probable" (ISRR). It took an average of one day for AEFI victims to fully recover. Paracetamol (82), antihistamines (7), and tramadol (2) were all utilized to treat 91 patients with AEFIs. Inbaraj et al., 2021 also indicated that, when participants were asked to rate the severity of AEFIs, 51.8% perceived it as mild, while (3.2%) rated it as severe. The most prevalent symptom was a body ache (46.8%), followed by a headache (30.3%) and a fever ((22%). Many (39% of patients) were prescribed drugs to treat their symptoms, and one patient had to be admitted to the hospital for further monitoring. 39.4% of them reported symptoms between four and twenty-four hours after receiving the vaccine, while 22.3% reported symptoms up to one day later. (Inbaraj et al., 2021). In the Nepal study, Shrestha et al (2021) reported that 84.9% of the AEFI cases were minor. Some of the systemic AEFIs, however, were shown to be more common among people who had previously been infected with COVID-19. Those who used self-medication for symptom alleviation were 55.6%, 8.2% took time off work, and 0.76% went to the hospital for the AEFIs to be resolved. The majority of AEFIs that occurred after the first dose of vaccination were minor and went away within a few days (Shrestha et al., 2021). In another study in India (Kataria et al., 2021), soreness and discomfort at the injection site were the most common solicited adverse events reported by daily diary cards, whereas fever, headache, myalgia, tiredness, joint pain, and nausea were the most common solicited systemic University of Ghana http://ugspace.ug.edu.gh 18 adverse events reported on day 1. The bulk of local and systemic adverse effects occurred in the first two days following vaccination, and then disappeared. Subjects above the age of 50 had lower levels of reactogenicity. There were no adverse events that necessitated a hospital visit or the ER. When patients were divided into groups based on whether or not they had previously had COVID-19 disease, no significant differences in adverse events were found. A study by Jayadevan et al., (2021) found that 45% of people had fatigue, 44% had myalgia, 34% had fever, 28% had headaches, 27% had pain at the injection site, and 12% had joint pain. Within the first 12 hours, 79% of those who reported symptoms noticed them. COVID-19 was reported by 8.7%. Their symptom profile was similar to that of individuals who had no prior experience. Fatigue (92.9%) and malaise were the most often reported systemic AEFIs (83.8%) as indicated by Jeon et al., (2021). Fever (temperature 38°C) was reported by a very small number of healthcare professionals (27.6%). Two healthcare professionals (0.2%) experienced a high temperature over 40°C, and three healthcare professionals experienced severe diarrhoea (0.3%). The most prevalent local AEFIs reported by responders were grade 1 or 2 pain (87.6%) and soreness (61.2%) at the injection site. Most of the local AEFIs were grade 1 or 2. However, the number of grade 3 or higher local AEFIs was higher than the number of systemic AEFIs. It took about the same amount of time for all AEFIs for the first and most severe adverse events to start. Most of the AEFIs appeared in the first 1 to 3 days after being vaccinated and quickly went away. 2.6 Serious Adverse Events A review of four studies as reported by Voysey et al., 2021, found the Covishield vaccine to be safe against the COVID-19 virus among 12, 021 (out of 23,745) participants who were in the treatment group. The vaccine had a good safety record in all four studies, with serious adverse events (SAE) and adverse events of special interest (AESI) evenly distributed across University of Ghana http://ugspace.ug.edu.gh 19 the trial arms. SAEs occurred in 168 (0.7%) of the people who took part in the study - 79 (0.7%) of them were in the treatment group and 89 (0.8%) were in the control group. People in both treatment and control groups had 175 events. Three of them were thought to have been caused by either the experimental or control vaccination. Even though 84.9% of the AEFI cases found in the study reported by Shrestha et al (2021) were minor, 0.05% were serious AEFIs. In the Indian study by Kataria et al., (2021), no SAEs were reported among the 1638 evaluated participants. According to Kaur et al., 2021, two AEFIs (0.62%) were of grade 3 severity, while one AEFI (0.3%) was 'serious' and required hospitalization. On the basis of causality assessment and suspicion of an immunization stress- related response, the single serious AEFI was characterized as 'possible'. In this subset of 730 patients, no significant AEFIs or deaths were observed. Shrestha et al., (2021) did not find any additional AEFI except for one incidence of anaphylaxis. Thirteen of the respondents in the study reported on by Jeon et al., (2021) went to the emergency room or outpatient clinic. Within 10 minutes of receiving the vaccine, one patient had dyspnea, nausea, and hypotension, and was sent to the emergency room. The patient thereafter improved on his own and was discharged after getting supportive care. None of the cases required hospitalization. (Jeon et al., 2021). 2.7 Effect of Age on AEFI incidence The majority of COVID-19-related deaths (74%) occur in adults over the age of 65 (WHO, 2020; Mueller et al., 2020). According to several studies, age is by far the most significant risk factor for COVID-19-related mortality (Williamson et al.,2020; Santesmasses et al., 2020). COVID-19 severity, on the other hand, is highly linked to comorbidities including hypertension, diabetes, obesity, cardiovascular illness, and respiratory disorders (Mueller et al., 2020). According to the WHO, COVID-19 vaccine candidates must be aimed at the most at- risk groups, including older adults, have a favourable safety profile, be effective as measured University of Ghana http://ugspace.ug.edu.gh 20 by prevention of virologically proven illness or transmission, or both, and provide at least 6 months of protection for people at ongoing risk of exposure to SARS-CoV-2 (Funk et al., 2021). Certain studies have established the safety data of the ChAdOx1 nCoV-19 vaccination in various age groups. In the Ramasamy et al (2020) trial, 88 % of the 18–55-year-olds, 73% of the 56–69-year-olds, and 61% of the 70-plus-year-olds reported at least one local symptom following the main immunization with standard-dose ChAdOx1 nCoV-19. Seventy-six per cent of participants between the ages of 18 and 55, 72% of those between the ages of 56 and 69, and 55% of those over the age of 70 had at least one local symptom following the recommended dosage of ChAdOx1 nCoV-19 booster vaccine. After receiving the low-dose ChAdOx1 nCoV-19 vaccine as their primary immunization, participants in all age categories showed a similar pattern, although with fewer overall adverse reactions than those who received the standard-dose vaccine. Recipients of ChAdOx1 nCoV-19 reported no serious local effects (Ramasamy et al., 2020). Jayadevan et al., (2021) also reported that as people became older, their chances of developing symptoms dropped. Symptoms were reported by 81% of those in the 20-29 years age group, 80% of those in the 30-39 years group, 68% of those in their 50-59 years group, 58% of those in their sixth decade, 45% of those in their seventh decade, 34% of those in their eighth decade, and 7% of those in their ninth decade (9th decade, 80-90 years). Post-vaccination AEFI symptoms were more common in women (74.7 %) than in men (58.6 %). Individuals under the age of 35 (98.9%) were more likely to report systemic and local AEFIs than those above the age of 51. (94.6%). AEFIs were found to be more severe in younger participants (aged under 35) than older ones, according to Jeon et al, who conducted the study (2021). For the most part, the younger age group had a higher incidence and severity of local and systemic AEFIs, except for arthralgia and diarrhoea (Jeon et al., 2021). University of Ghana http://ugspace.ug.edu.gh 21 2.8 Time to onset of AEFI with ChAdOx1 nCoV-19 vaccine AEFIs were observed within 30 minutes of receiving the vaccination after the second dosage in the Kaur et al (2021) study. AEFIs were found in seven people out of a total of 802 participants (0.9%). Three recipients had systemic AEFIs, while four subjects only showed local involvement. All seven AEFIs were classified as 'mild.' The average time for complete recovery was two days. In addition, 730 people were studied for AEFIs that occurred within 24 hours, between 24 hours and 7 days after immunization, but not within 30 minutes. Among these, 93 vaccine recipients (12.73%) experienced AEFIs within 24 hours, while 22 (3%) acquired AEFIs after day 1 and until day 7 post-vaccination, respectively. AEFIs were thus detected in 115 recipients (15.7%) till day seven; 99 (13.6%) had a systemic engagement with or without local site reactivity, whereas 16 had solely local involvement (2.2%). Following the exclusion of 72 persons who were lost to follow-up, a total of 730 individuals were included for analysis of AEFIs occurring within 24 hours, between 24 hours and 7 days of vaccination, but not within 30 minutes of immunization. Among these, 93 vaccine recipients (12.73%) experienced AEFIs within 24 hours, while 22 (3%) acquired AEFIs after day 1 and until day 7 post-vaccination, respectively. AEFIs were thus detected in 115 recipients (15.7%) till day seven. 99 (13.6%) had a systemic engagement with or without local site reactivity, whereas 16 had solely local involvement (2.2%). The median time to complete recovery for AEFIs developing within 24 hours of vaccination was 2 days, as was the time to complete recovery for AEFIs occurring between 24 hours and 7 days of immunization. Most participants (39.4%) reported symptoms between four and twenty-four hours after receiving the vaccine, whereas 22.3% reported symptoms one day later, according to the research done by Inbaraj et al (2021). Following immunization, most people experienced mild or no local or systemic side effects for 2 days or less, according to research by Kataria et al (2021). For participants who reported AEFIs in the Jayadevan et al (2021), most (79%) of them University of Ghana http://ugspace.ug.edu.gh 22 noticed the AEFIs within the first 12 hours. Their symptom profile was similar to that of individuals who had no prior experience. Jeon et al. (2021) in Korea similarly reported on the onset of the AEFI in their investigation in Korea. Both the earliest and most severe adverse events occurred within the same time frame following vaccination. The majority of AEFIs appeared during the first 1 to 3 days after immunization and disappeared quickly. The majority of AEFIs were recorded on the first day following immunization, and systemic AEFIs improved quicker than local AEFIs (Jeon et al., 2021). 2.9 Rare AEFIs linked to ChAdOx1 nCoV-19 vaccine In Europe, the ChAdOx1 nCoV-19 vaccine was approved at the end of January 2021 and began widespread usage in February 2021. An investigation into a probable vaccine-related death was announced by Austrian authorities on March 7. A few days later, Denmark and Norway were investigating claims of blood clots and death following vaccination. After Germany's decision on March 15, many other countries followed suit. (Wise, J. (2021); Mahase, E. (2021). According to the European Medicines Agency (EMA) and the World Health Organization (WHO), the vaccine's advantages outweigh any potential risks. It was acknowledged that there could be a "possible" link to blood clots, which could be classified as "very rare" side effects. The cause of the clots is unknown, and the investigation is still ongoing. About 20 million doses of vaccination had been administered, resulting in 79 cases of thrombosis with low platelets, the UK medicines regulatory agency reported. Nineteen people have lost their lives as a result of the incidences that have been reported. In general, four persons out of every million who receive the vaccination are at risk of blood clots (Mahase, E., 2021). University of Ghana http://ugspace.ug.edu.gh 23 Several factors have been related to pulmonary embolism (PE), as well as deep vein thrombosis (DVT). Cancer, advanced age, smoking, hereditary or acquired thrombophilic disorders, past thromboembolism, and hospitalization for congestive heart failure or acute exacerbation of chronic obstructive pulmonary disease are only a few instances of genetic or naturally occurring causes. PE and DVT have been related to an increased risk of death and morbidity. Their natural occurrence ranges from 56 to 182 per 100,000 persons, which should be evaluated against the three PE deaths per 20 million vaccinated people. (Tobaiqy et al., 2021; Postigo et al., 2018). According to a recent study from Croatia, the frequency of combined DVT with PE but not isolated PE or isolated DVT has increased (Mahase, 2021). As Europe is divided on vaccination safety, the WHO thinks the deployment of the AstraZeneca vaccine should continue (Mahase, 2021). In their research of non-COVID-19 patients admitted to the hospital during the pandemic, the authors observed a much older age group (60.8 17.2 years vs. 68.5 16.8 years) (Mahase, 2021). In Europe, a rare AE occurs five out of every 10,000 people (500/million). AE that affects one in 50,000 or 20 individuals per million is considered very uncommon. Seventy-nine (79) thrombotic incidents recorded concerning the AstraZeneca vaccination would be carefully labelled as extremely uncommon occurrences based on a basic calculation of 20 million patients (approximately, 4/million) who received the immunization (Schafer, 2003). It would be difficult to connect the AstraZeneca immunization to thrombotic events based on spontaneous reports. Because there is a lack of safety and clinical data on vaccination use in the targeted community, statistical figures may be deceiving because of the underreporting and small numbers of persons exposed to the vaccines. In addition, there are a number of other factors that contribute to the situation such as the many unknown comorbidities that individuals may have exacerbate the problem. (Tapson, 2005; Slišković et al., 2021; Sardella and Lungu, 2019). University of Ghana http://ugspace.ug.edu.gh 24 Although the AstraZeneca vaccine has received the most attention, adverse reactions to other COVID-19 vaccinations have also been reported. Deep vein thrombosis and pulmonary embolism cases linked to the Moderna vaccine were found in the EMA database, however, no deaths were reported (Tobaiqy et al., 2021). In a similar search for Pfizer vaccination reports, 11 patients experienced pulmonary embolism as a result of the Pfizer vaccination, and two of them died (Tobaiqy et al., 2021). Folegatti et al., 2020 reported that the control group experienced one significant adverse event – a new diagnosis of haemolytic anaemia after immunization. Throughout the trial, the person was clinically healthy. The incident was described as a suspected unexpected serious adverse reaction relating to the meningococcal vaccine and not ChAdOx1 nCoV-19. 2.10 COVID-19 vaccination-associated myelitis AEFI can cause neurological consequences ranging from facial palsy to stroke, which can be severe. A total of 254 (2.69%) of the 9442 AEFI associated with Pfizer-BioNTech, Moderna, and Johnson & Johnson's COVID-19 vaccines were neurological in origin, according to the CDC's Vaccine Adverse Event Reporting System (VAERS); of these, 9 instances had transverse myelitis (Goss et al., 2021). Malhotra et al., 2021, reported the first case of myelitis in India linked to ChAdOX1 nCoV-19 (Oxford/AstraZeneca, COVISHIELDTM) vaccination. During the trial phase, the recombinant ChAdOX1 nCoV-19 vaccination was linked to two cases of myelitis. One had multiple sclerosis in the background, while the other was referred to be a potentially connected incident (Mahase, E., 2020; Voysey et al., 2021). Even with comparable reported occurrences with the current vaccination and those recorded in the CDC's- VAERS, it's critical to keep things in perspective: India has provided a total of 50.84 million doses through March 23, 2021. (Malhotra et al., 2021). With a yearly incidence of 1–4 cases per million (Transverse Myelitis Consortium Working Group (TMCWG), 2002), a myelitis University of Ghana http://ugspace.ug.edu.gh 25 event after more than 50 million vaccination doses seems reasonable. It is thought that the advantages of vaccination continue to exceed the hazards. University of Ghana http://ugspace.ug.edu.gh 26 CHAPTER THREE METHODS 3.1 Study Design It was a prospective observational follow-up study conducted from August to October 2021 in the Awutu Senya East Municipality to assess the incidence of AEFIs. Persons who came to the vaccination centres in ASEM were approached and briefed on the study. Those who were interested and consented were recruited. Enrolment began with obtaining information on any medical incident/condition and medications within the past 4 weeks prior to being vaccinated. Information on vaccination and subsequent adverse events was collected from each participant using a questionnaire. The questionnaire was administered by Research Assistants who captured the baseline information on participants’ demography, medical history and vaccination detail at enrolment. Follow-up telephone calls were made to enrolled participants 24 hours after immunization and on days 7, 21, and 56. Data on the type, severity, onset and outcome of adverse events experienced by participants were captured during the follow-up calls. In order to do the analysis, the data was uploaded to STATA I/C 16 (Stata Corporation LLC, Texas, USA). 3.2 Study Area and Participants The study was conducted in the Awutu Senya East Municipal, which is one of the Central Region’s twenty-two (22) districts. The Municipality of Awutu Senya East is located in the Eastern section of the Central Region, between latitudes 5°45 south and 6°00 north, and longitudes 0°20 west to 0°35 east. On the east, it is bounded by the Ga South Municipal Assembly (in the Greater Accra Region), on the north by the Awutu Senya District, and on the west and south by the Gomoa East District. Opeikuma, Adam Nana, Kpormertey, Ofaakor, Akwelley, Walantu, and Zongo are the major settlements in the Municipality. Most of the inhabitants of the Municipality are Guans and University of Ghana http://ugspace.ug.edu.gh 27 speak Awutu. The Gas, Akans, Ewes, Wala/Dagaba, Moshies, Basares, and countless more minor tribes are among the other settler tribes with various ethnic origins. Akan is the primary language used, while English is the official language. According to reports, Kasoa, the capital city, is one of Ghana's towns with the fastest growth rates (Ministry of Finance, 2018). The population of the Municipality is currently estimated at 131,721 (projected with a 2.8% growth rate from the 2000 Population and Housing Census). The municipality has a 94.1% urban population and a 5.9% rural population as well. Commerce (both official and informal), agro- processing, and wholesale and retail trade are the Municipal's primary economic drivers. About 35.7% of the working population in the Municipality is employed by trading and associated businesses, according to the 2010 Population and Housing Census. There are many additional sectors of the economy, such as production, wholesale/retail trade, and transportation services (Ghana, G. S. S., 2010). Figure 3. 1 Map of Awutu Senya East Municipal (ASEM) University of Ghana http://ugspace.ug.edu.gh 28 The municipality's health services are delivered by several sectors, including the government (about 60%) and private health establishments. For efficient health administration, the municipality is split into five (5) sub-municipalities – Akwelley, Kasoa North, Kasoa Main, Odupong Kpehe, and Opeikuma. There were five vaccination centres in the municipality – one at each sub-municipality, and these centres participated in a 2-week long vaccination campaign. Table 3. 1: Summary of Sub-Municipal Profile Sub-Municipals Population Communities Outreach points CHPS Zones Akwelley 26344 24 14 6 Kasoa North 25027 10 10 6 Kasoa Main 34247 14 8 6 Odupong Kpehe 23710 7 5 3 Opeikuma 22393 12 5 3 Municipal Total 131721 67 42 24 Source: Awutu Senya Municipal Health Directorate, 2020 The proportion of the estimated population who qualify for the COVID-19 vaccination was 60.1% (79,113/131,721). This proportion is made up of adults aged 18 years and above. All persons aged 18 years and above who received the COVID-19 vaccine at the Awutu Senya East Municipality's vaccination clinics and were willing to participate in the study were enrolled. 3.3 Study Variables 3.3.1 Dependent Variable In this study, the dependent variable was adverse events following immunization with the COVID-19 vaccine. Regarding the AEFIs, participants were asked about local site symptoms such as pain, erythema, swelling, tenderness, and the degree of physical activity limitation. They were also questioned about systemic symptoms such as fever, fatigability, myalgia, University of Ghana http://ugspace.ug.edu.gh 29 arthralgia, headache, nausea, vomiting, diarrhoea, rash, chest tightness and dyspnoea. Information on the onset of AEFIs, the severity of AEFIs, the treatments needed to manage AEFIs, the outcomes of AEFIs, the time it took to fully recover, and the causality of AEFIs were documented. 3.3.2 Independent Variables Individual parameters such as age and sex were used as independent variables in this study. Participants’ medical history, including existing co-morbidities, any presenting symptoms at the time of vaccination or sickness (medical event) within the past 7 days, concurrent medication history, and history of allergy to any known stimuli were also used as independent variables. Dose number and place of residence were also captured. 3.4 Sample Size Determination This was a longitudinal study of people who had received the COVID-19 vaccine and were followed up for 8 weeks. There was no control group; hence, the sample size estimation for independent cohort studies was used to calculate the minimum sample size: 𝑛 = [𝑧1−𝛼/2√( 1+1 𝑚 )�̅�(1−�̅�)+𝑧1−𝛽√𝑝0(1−𝑝0) 𝑚 +𝑝1(1−𝑝1)] 2 (𝑝0−𝑝1)2 Where: • n represents the minimum sample size of desired participants to identify true relative risk with a 2-sided Type-I error • m represents the number of participants (control) per experimental participant • Z1-β represents the desired power • Z1-α/2 represents a standard value for the corresponding level of confidence. • 𝑝0 represents the incidence of events in controls University of Ghana http://ugspace.ug.edu.gh 30 • 𝑝1 represents the estimated incidence or proportion with any incident of adverse event following COVID-19 immunization with COVISHIELD • �̅� = 𝑝1+𝑚𝑝0 𝑚+1 Studies that had examined the safety and reactogenicity of COVISHIELD vaccines had yielded ambiguous results on the incidence of adverse events: 74% by Ramasamy et al., 2020, 40% after the first dose and 16% after the second dose by Kaur et al., 2021, 69.7% by Inbaraj et al., 2021, 85% by Jayadevan et al., 2021, and 66.1% by Jeon et al., 2021. Studies other than the clinical trials did not include controls. Folegatti et al., 2020, reported 67% AEFI incidence among the COVISHIELD group and 38% among the controls, however, this was not a placebo but an active control (Meningococcal A vaccine). None of the incidences of AEFI had been identified with the Ghanaian population. Because there were no Ghanaian-specific data, the incidence of variables with the minimum sample size was used, which is the 40% reported by Kaur et al., 2021 and assumed 30% AEFI incidence in control. Hence, m = 1, Z1-β = 1.282 (90% power), Z1-α/2 = 1.96 (at 95% CI), 𝑝0 = 0.3, 𝑝1 = 0.4 �̅� = 0.4+1∗ 0.3 1+1 = 0.35 𝑛 = [1.96√( 1+1 1 )∗0.35(1−0.35)+1.282√0.3(1−0.3) 1 +0.4(1−0.4)] 2 (0.3−0.4)2 𝑛 = [1.96 ∗ 0.675 + 1.282 ∗0.671]2 (−0.1)2 𝑛 = [1.323 + 0.86]2 0.01 n = 476.55 ≈ 477 University of Ghana http://ugspace.ug.edu.gh 31 A 15% loss to follow-up was considered based on the Kaur et al., 2021 study; which was additional 72 vaccinees. Therefore, the minimum sample size for the study was calculated to be 549 vaccinees. However, the estimated minimum sample size was rounded up to 550. 3.5 Sampling technique Participants were sampled from five vaccination centres in the Municipality – one Vaccination Centre randomly selected from each sub-municipality. The sample size for each vaccination centre was calculated proportionately to the sub-municipality’s population size. The average vaccine uptake per the vaccination centres was 55 persons per day for the 2-week long COVID- 19 vaccination campaign. Members of the public who came to the vaccination centres to receive the COVID-19 vaccine were approached and spoken to by trained Research Assistants. They explained the study's aim to the potential participants and those who consented were recruited into the study. The selection of individuals was based on inclusion criteria and the individual’s willingness to provide information during the follow-up period. As part of the routine vaccination process, all vaccine recipients were observed at vaccination centres for 30 minutes after receiving the vaccine. Enrolled individuals were contacted by phone 24 hours after immunization and on days 7, 21, and 56. 3.6 Vaccination Process The vaccine used for the campaign was COVISHIELD. The vaccination was given in two doses of 0.5 mL each, separated by 8-12 weeks, and administered intramuscularly in the deltoid. Each dosage of 1ml comprises 5 × 1010 simian adenoviral particles generated in the genetically engineered human embryonic kidney (HEK) 293 cells. Healthcare professionals at the vaccination centres took turns sensitizing the public on the COVID-19 vaccine and other vaccination-related issues. This included common AEFIs associated with the vaccines and how to report them. University of Ghana http://ugspace.ug.edu.gh 32 3.7 Inclusion Criteria Anyone aged 18 years and above who resided in the Awutu Senya East Municipality and visited one of the selected COVID-19 immunization locations. 3.8 Exclusion Criteria Anyone eligible per the inclusion criteria (3.7) but would not be available for the follow-up calls was excluded from the study. 3.9 Data Collection techniques and tools Data was collected through a face-to-face administration of a questionnaire to participants at the point of enrolment. Follow-ups were done post-vaccination via telephone calls. Participants' demographic data – enrolment and follow-ups, as well as their medical histories, were captured using a data collection tool (checklist). To gather information on adverse events, an updated national AEFI checklist was used. Information was captured on Google Forms. Participants were followed-up within 24 hours after immunization and on days 7, 21, and 56 (window period +/-2 days). To ensure minimal or no loss to follow-up, a second telephone contact of someone living in the same house as the participant was obtained at the time of enrolment to ensure that participants were reached on follow-up days. The Research Assistants called those who had missed their specified follow-up dates and kept trying until they were reached within the window period. 3.10 Data Storage and Processing Data collected was stored on a computer and protected with a password. Codes were used to identify participants. Data would be made available on a need-to-know basis. The adverse events data gathered was coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 23. There are five levels to the MedDRA hierarchy, arranged from very specific to very general. At the most specific level, called “Lowest Level Terms” (LLTs), there are more than 80,000 University of Ghana http://ugspace.ug.edu.gh 33 terms that parallel how information is communicated. These LLTs reflect how an observation might be reported in practice. This level directly supports assigning MedDRA terms within a user database. Each member of the next level, “Preferred Terms” (PTs), is a distinct descriptor (single medical concept) for a symptom, sign, disease diagnosis, therapeutic indication, investigation, surgical or medical procedure, and medical social or family history characteristic. Related PTs are grouped into “High Level Terms” (HLTs) based upon anatomy, pathology, physiology, aetiology or function. HLTs, related to each other by anatomy, pathology, physiology, aetiology or function, are in turn linked to “High Level Group Terms” (HLGTs). Finally, HLGTs are grouped into “System Organ Classes” (SOCs) which are groupings by aetiology (e.g., Infections and infestations), manifestation site (e.g., Gastrointestinal disorders) or purpose (e.g., Surgical and medical procedures). For this study, the AEFIs were grouped into 3 - System Organ Class, High Level Term and Preferred Term. The severity of adverse events was assessed according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1. The DAIDS grading table provides an AE severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: Grade 1 indicates a mild event; Grade 2 indicates a moderate event; Grade 3 indicates a severe event; Grade 4 indicates a potentially life-threatening event or death. Those graded “Mild” are symptoms causing no or minimal interference with usual social and functional activities with intervention not indicated. AEs graded “Moderate” are symptoms causing greater than minimal interference with usual social and functional activities with intervention indicated. AEs graded as “Severe” are symptoms causing the inability to perform usual social and functional activities with intervention or hospitalization indicated. The most severe are those graded as “Potentially Life- threatening” and they are symptoms causing the inability to perform basic self-care functions with intervention indicated to prevent permanent impairment, persistent disability, or death. University of Ghana http://ugspace.ug.edu.gh 34 The data collected on the sheets were checked for errors and missing values. Data were then entered into Google Form (Microsoft Excel), checked for errors, and exported to STATA I/C 16 (Stata Corp LLC, Texas, USA) for analysis. 3.11 Statistical Data Analysis For categorical variables, frequency and percentage were used, and for continuous variables, median and interquartile ranges were used to describe the characteristics of study participants. Pre-existing medical conditions among study participants were described using the bar chart. The AEFIs among study participants were described using bar charts in three different systems of description namely, high level term description, preferred term definition and system organ class for AEFIs. The cumulative incidence of AEFIs was described across the various socio-demographic characteristics of study participants. A 95% confidence interval of the cumulative incidence of AEFIs was also estimated across the various characteristics of the study participants. The association between the cumulative incidence of AEFIs and socio-demographic factors was assessed using Pearson's chi-square test. Using the number of days to experience AEFIs in the first two months after vaccination as a time variable, the incidence rate and the corresponding 95% confidence were also estimated across the various demographic characteristics. The number of different AEFIs was further described across the demographic characteristics of the study participants and Fischer’s exact chi-square test was used to assess the significance of the association. The association between demographic characteristics and severity of AEFIs among those who experience AEFIs were also assessed using Fischer’s exact chi-square test. Further analysis was performed to assess the relationship between the various AEFIs experienced and the severity of AEFIs using Fischer’s exact test. The multivariable analysis was performed using the Poisson regression model to estimate the crude and adjusted incidence rate ratio and identify the factors independently associated with University of Ghana http://ugspace.ug.edu.gh 35 the incidence of AEFIs. First, the crude risk ratio of AEFIs was estimated across the various characteristic of study participants without controlling for any other variable and time using the Poisson regression model. In the second model, the time to experience AEFIs or exit the study was adjusted for each variable in estimating the incidence rate ratios using the Poisson model. Lastly, together with time to experience AEFIs or exit the study at two months, the age group, sex, sub-district, presentation of symptoms at the time of vaccination, known allergies, medical event in the last 7 days, pre-existing medical condition, medication at the time of vaccination and medication in the past 7 days were all run together in a multiple Poisson regression model to estimate the adjusted incidence rate ratio of AEFIs among the participants. Corresponding 95% confidence intervals of all rate ratios were estimated. The predictive power of the final Poisson regression model was assessed using the Area Under the Receiver Operating Characteristic Curve (AUROCC). This indicates the model's ability to differentiate between two diagnostic groupings (in this case, those with AEFI and those without AEFI). The higher the AUROCC, the more accurately the Poisson regression model predicts those with AEFIs and those without AEFIs. A good model has an AUROCC close to 100%, indicating a high degree of separability. A model with an AUROCC close to 0 has the poorest possible metric of separability. In actuality, it implies that it is reciprocating the effect. And when AUROCC reaches 50%, the model has absolutely no class separation capability. The fitness of the model was assessed using the Deviance goodness of fit test. Finally, multicollinearity between the independent variables was evaluated in the final model using the variance inflation factor (VIF) below the threshold of 10. When there is a correlation between the predictors (i.e. the independent variables), we get multicollinearity, which might skew the findings of the regression analysis. In the presence of multicollinearity, the variances of the estimated coefficients tend to be overstated. Increases in R-squared, a measure of multicollinearity's effect on model fit, are another negative consequence. The VIF calculates an estimate for the degree to which multicollinearity in the model inflates the variance of a University of Ghana http://ugspace.ug.edu.gh 36 regression coefficient. VIFs greater than 10 indicate severe multicollinearity that has to be corrected for, whereas VIFs of 1 indicate that there is no association between the specific predictor and the other predictor variables. All statistical significance in this study was considered at an alpha level of 0.05. STATA IC version 16 was used to perform all analyses in this study. 3.12 Quality control Healthcare staff were recruited and qualified as Research Assistants to ensure high-quality data. During data gathering, the Research Assistants were monitored by frequent site visits. Data was captured on a paper form and later transferred onto the Google Form. Data input fields were designed to have built-in consistency and range checks. Five per cent (5%) of the completed forms were sampled and double followed up by the principal investigator. COVD-19 were remedied with appropriate precautions. The use of a nose mask, social distancing, hand washing, and the use of hand sanitisers were among these strategies. Participants who did not have were given a nose mask and instructions on how to follow COVID-19 safety measures. To minimize congestion, study participants were approached and talked to individually and not put into groups. 3.13 Ethical clearance The Ethical Review Committee of the Ghana Health Service approved the protocol for this study. The approval was granted for the conduct of the study on 2nd August 2021 with ethics approval number GHS-ERC 024/06/21 (Appendix I). Permission was sought from the Awutu Senya East Municipal Health Directorate to conduct this study (Appendix II). The participants were adequately informed about the study's goal. Although there was no direct risk or advantage to participating in this research, participants were informed that they would be required to answer a few questions from Research Assistants who would contact them often during the study period. They were advised that they could drop out of the research at any time. University of Ghana http://ugspace.ug.edu.gh 37 If they had further questions about the study, they could contact the principal investigator (PI) and Academic Supervisor. Participants were also informed that any information they provided would be kept completely confidential and utilized strictly for the study's purposes. Access to data collected was limited to the PI and supervisors on a password-protected computer. They were told that the collected data would be devoid of their names and other personal identifiers. Those who accepted to participate in the study were asked to sign or thumbprint a consent form before any information was gathered from them. Participants who experienced AEFIs were advised to follow the Ghana Health Service protocols by visiting a nearby government facility for treatment. 3.14 Sponsorship This study was supported by the Ghana Field Epidemiology Laboratory Training Program (GFELTP) in collaboration with the West African Health Organization (WAHO). University of Ghana http://ugspace.ug.edu.gh 38 CHAPTER FOUR RESULTS 4.1 Demographic Characteristics of the Study Population Five hundred and fifty (550) adults between the ages of 18 years and 90 years who consented to be part of the study were recruited from five sub-districts in the Awutu Senya East Districts and followed for 8 weeks. The median age was 60 years (IQR = 44, 66). Table 4.1 shows the distribution of age groups with ages between 60 – 69 years with the highest number of participants of 35.1% (193/550) and 18 – 29 years being the lowest at 7.5% (41/550). Two hundred and eighty-eight (52.4%) were males and 262 (47.6%) were females. Participants were recruited from each of the 5 sub-municipals proportionate to the population size as shown in Table 4.1 with the majority of participants recruited from Kasoa North, 26% (143/550), followed by Akwelley with 20% (110/550), and the lowest of participants from Odupongkpehe with 16.9% (93/550). Each sub-district had a vaccination centre. Table 4. 1: Demographic characteristics of study participants Variables Frequency (N=550) Percentage Frequency Age (years), median (IQR) 60.0 (44.0, 66.0) Age group 18-29 years 41 7.5 30-39 years 67 12.2 40-49 years 72 13.1 50-59 years 93 16.9 60-69 years 193 35.1 70+ years 84 15.3 Sex Female 262 47.6 Male 288 52.4 Sub-Districts Akwelley 110 20 Kasoa main 105 19.1 Kasoa north 143 26 Odupongkpehe 93 16.9 Opeikuma 99 18 University of Ghana http://ugspace.ug.edu.gh 39 4.2 Medical History of participants Six participants (1.1%) presented symptoms at the time of vaccination with symptoms ranging from headache, body pains, shivering and whitlow. Participants with known allergies were 12 (2.2%) and those who had had any medical event in the last 7 days before the vaccination were 13 (2.4%). Two hundred and twenty-nine (41.6%) participants had pre-existing conditions and two hundred and twelve (38.5%) of the participants were on medication at the time of vaccination. Table 4.2 shows the medical history of the study participants. Table 4. 2: Medical History of Study Participants Variables Frequency (N=550) Percentage Frequency Presenting Symptoms at the Time of Vaccination No symptoms at the time of vaccination 544 98.9 Any symptoms at the time of vaccination 6 1.1 Presenting Symptoms at the Time of Vaccination Body Pains 1 16.7 Headache 3 50.0 Shivering 1 16.7 Whitlow 1 16.7 Known Allergies Allergies absent 538 97.8 Allergies present 12 2.2 Medical Events (sickness) in the Last 7 days No Medical event 537 97.6 Presence of Medical event 13 2.4 Pre-existing Conditions (e.g., diabetes, hypertension, etc) No medical condition 321 58.4 Presence of a medical condition 229 41.6 Medication(s) at the time of Vaccination None taken 338 61.5 On medication at the time 212 38.5 Medication(s) in the past 7 days No medication 331 60.2 On medication 219 39.8 Hypertension accounted for the highest pre-existing condition, 80.3% (184/229); followed by diabetes, 30.1% (69/229). Figure 4.1 shows the relative frequency of pre-existing medical conditions among study participants prior to vaccination. University of Ghana http://ugspace.ug.edu.gh 40 Figure 4. 1: Pre-existing Medical Conditions among Participants 4.3 Cumulative Incidence of AEFI The overall cumulative incidence of AEFI among the participants was 16.7% (92/550) (95% CI: 13.8, 20.1). Among the age groups, those who were between the ages of 18 years and 29 years had the highest incidence of AEFI, 26.8% (11/41) (95% CI: 15.5, 42.3). The age group with the lowest incidence of AEFI was those aged 70 years and above, 10.7% (9/92) (95% CI: 5.7, 19.4). Table 4.3 shows that the cumulative incidence of AEFI increased with decreasing age group, thus, the younger the age group, the higher the AEFI incidence and this was statistically significant (p=0.048). The incidence of AEFI among females was 20.6% (54/262) (95% CI: 16.1, 26.0) and among males was 13.2% (38/250) (95% CI: 9.7, 17.6). The incidence among females and males was statistically significant (p=0.02). The sub-district with the highest incidence was Odupongkpehe, 19.4% (18/93) and Opeikuma had the lowest incidence of 13.1% (13/99). However, the incidence among the sub-districts was not statistically significant (p=0.732). University of Ghana http://ugspace.ug.edu.gh 41 Table 4. 3: Cumulative Incidence of AEFI among study participants by Age, Sex and Place of Residence Experienced any AEFI Total No AEFI AEFI 95% CI of AEFI Chi- square P-value Variables N n (%) n (%) Total sample size 550 458 (83.3) 92 (16.7) (13.8, 20.1) Age group 11.1 0.048 18-29 years 41 30 (73.2) 11 (26.8) (15.5, 42.3) 30-39 years 67 50 (74.6) 17 (25.4) (16.4, 37.1) 40-49 years 72 58 (80.6) 14 (19.4) (11.9, 30.2) 50-59 years 93 77 (82.8) 16 (17.2) (10.8, 26.3) 60-69 years 193 168 (87.0) 25 (13.0) (8.9, 18.5) 70+ years 84 75 (89.3) 9 (10.7) (5.7, 19.4) Sex 5.4 0.020 Female 262 208 (79.4) 54 (20.6) (16.1, 26.0) Male 288 250 (86.8) 38 (13.2) (9.7, 17.6) Sub-Districts 2.0 0.732 Akwelley 110 89 (80.9) 21 (19.1) (12.8, 27.5) Kasoa main 105 87 (82.9) 18 (17.1) (11.1, 25.6) Kasoa north 143 121 (84.6) 22 (15.4) (10.3, 22.3) Odupongkpehe 93 75 (80.6) 18 (19.4) (12.5, 28.7) Opeikuma 99 86 (86.9) 13 (13.1) (7.8, 21.3) All tests are Pearson’s chi-square test. CI: confidence interval The incidence among those who presented symptoms or those without symptoms at the time of vaccination was 16.7%. The incidence among those who presented symptoms at the time of vaccination and those who did not was not statistically significant (p=1.0). Participants with known allergies also had the same incidence of 16.7% as those with unknown allergies. Among them, the incidence was not statistically significant (p=1.0). Those with pre-existing conditions such as hypertension and diabetes had an AEFI incidence of 17% (39/229) and those without any pre-existing condition had an AEFI incidence of 16.5% (53/321). The incidence among those with or without pre-existing conditions was not statistically significant (p=0.872). Some participants were taking medications (mostly antihypertensives and antidiabetics) at the time of the vaccination and they had an AEFI incidence of 17.5% (37/212). Those who were University of Ghana http://ugspace.ug.edu.gh 42 not on any medication at the time of vaccination had an incidence of 16.3% (55/283). The incidence among those taking medication at the time of vaccination and those who were not taking any medication was not statistically significant (p=0.718). Table 4. 4: Cumulative Incidence of AEFI among Study Participants by Medical History Experienced any AEFI Total No AEFI AEFI 95% CI of AEFI Chi- square P-value Variables N n (%) n (%) Total sample size 550 458 (83.3) 92 (16.7) (13.8, 20.1) Presenting Symptoms at the Time of Vaccination # 1.000 No symptoms at the time of vaccination 544 453 (83.3) 91 (16.7) (13.8, 20.1) Any symptoms at the time of vaccination 6 5 (83.3) 1 (16.7) (2.3, 63.2) Known Allergies # 1.000 Allergies absent 538 448 (83.3) 90 (16.7) (13.8, 20.1) Allergies present 12 10 (83.3) 2 (16.7) (4.2, 47.8) Medical Events in the Last 7 days # 0.247 No Medical event 537 449 (83.6) 88 (16.4) (13.5, 19.8) Presence of Medical event 13 9 (69.2) 4 (30.8) (12.0, 59.1) Pre-existing Conditions (e.g., diabetes, hypertension, etc) 0.0 0.872 No medical condition 321 268 (83.5) 53 (16.5) (12.8, 21.0) Presence of medical condition 229 190 (83.0) 39 (17.0) (12.7, 22.5) Medication(s) at the time of Vaccination 0.1 0.718 None taken 338 283 (83.7) 55 (16.3) (12.7, 20.6) On medication at the time 212 175 (82.5) 37 (17.5) (12.9, 23.2) Medication(s) in the past 7 days 0.1 0.750 No medication 331 277 (83.7) 54 (16.3) (12.7, 20.7) On medication 219 181 (82.6) 38 (17.4) (12.9, 23.0) #: Fisher’s exact chi-square test. All other tests are Pearson’s chi-square test. CI: confidence interval University of Ghana http://ugspace.ug.edu.gh 43 4.4 Frequency of AEFI experienced among study participants The total number of individual AEFIs experienced was 124 and this was among 92 study participants. This is because some participants had more than 1 AEFI. Participants who experienced only 1 AEFI constituted 71.7% (66/92) of all those who had AEFIs and with an AEFI incidence of 12% (66/550). Those who had exactly 2 AEFIs constituted 21.7% (20/92) of all who had AEFIs with an incidence of 3.6% (20/550). The highest number of AEFIs experienced by an individual was 3 and they constituted 6.5% (6/92) of all those who had AEFIs, with an AEFI incidence of 1.1% (6/550). Among the age groups, 18 to 29 years had the highest AEFI incidence for those who experienced only 1 AEFI (17.1% (7/41)) and th