Microbes and Infectious Diseases Adverse effects of Oxford–AstraZeneca COVID-19 vaccine among Egyptian healthcare workers

Background: The Coronavirus Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) sparked a global pandemic that resulted in huge health and economic losses. There have been almost two hundred million affirmed cases of COVID-19 to date, with over seven million deaths. Clinical trials on all three vaccines approved for use in the Egypt (Pfizer– Biotech, Oxford–AstraZeneca and Moderna) have demonstrated substantial vaccination efficacy. Numerous research groups had developed possible vaccines as early as December 2020. Despite promises from the World Health Organization and European Medicines Agency (EMA) that there was no evidence tying vaccination to potential adverse events including blood clots, numerous European countries interrupted utilization of the Oxford–AstraZeneca vaccine on March 11, 2021, and noted the adverse effects revealed. We aimed to characterize and analyze the adverse effects associated with the Oxford–AstraZeneca vaccination. Methods: This study was done following vaccination of 113 medical healthcare personnel and documentation of each participant's adverse event at the Research Institute of Ophthalmology between March and June 2021. Results : 45 (39.8%) patients with no vaccine related adverse effects symptoms, 62 (54.9%) patients with mild/moderate symptoms, and 6 patients with severe side effects (5.3%). The most frequently reported adverse effects in mild/moderate symptoms were bony aches 43 (69.3%), fever 32 (51.6%), localized arm pain 7 (11.3%), and GIT symptoms 2 (3.2%). Conclusion: AstraZeneca vaccinations have been associated with mild to moderate adverse events.


Introduction
The Chinese Center for Disease Control spotted in early December 2019 that the outbreak in Wuhan City was initiated by SARS-CoV-2 infection. After MERS-CoV-1 and SARS-CoV-1, the SARS-CoV-2 virus is the third member of the coronavirus family to trigger outbreaks in human history [1]. It is highly contagious and has the potential to spread rapidly over the world. Until 20 July 2022, WHO recorded global situation of 562,672,324 confirmed COVID-19 cases, involving 9,176,657 confirmed cases in Africa and 6,367,793 deaths globally. As of 19 July 2022, 12,166,921,655 vaccine doses have been administered globally [2]. SARS-CoV-2 RNA encodes for four structural proteins including spike (S), membrane (M), envelope (E), and Nucleocapsid (N), with the S protein comprised of two subunits S1 and S2. The receptor binding domain (RBD) is included within the S1 subunit and has high affinity for the angiotensin converting enzyme 2 (ACE2) receptor on the cell surface membrane. Infection is mediated by interaction of the SARS-CoV-2 RBD with the ACE2 viral receptor on host cells [3].
However, an increasing amount of data demonstrates the critical role of cellular responses in COVID-19 patient recovery and encouraged the use of vaccine techniques that stimulate T cell-mediated responses [7]; second-generation SARS-CoV-2 vaccines differ from the currently used vaccines as they are designed to generate immune responses to multiple SARS-CoV-2 proteins and in addition to the spike protein targeted by vaccines that are now in use so they may not necessitate frequent booster immunizations and provide enhanced protection against a wide variety of SARS-CoV-2 variants [8].
The AstraZeneca's COVID-19 vaccine is a chimp adenovirus that encodes the spike glycoprotein [9]. It was authorized for utilization in the European Union (EU) by (EMA) on 29 January 2021, regarding European Commission approval; safety and effectiveness of the AstraZeneca vaccine were ascertained through a short-term review of data obtained from clinical trials [10].
Historically, vaccination safety has been monitored using a mixture of active and passive surveillance. The passive surveillance system is the pharmacovigilance foundation; it comprised databases into which physicians and patients spontaneously investigate adverse events following immunization (AEFI) and adverse drug reactions (ADRs) which was not much investigated in Egyptian population [11]  All chronic conditions as diabetes, heart disease, liver disease, chronic kidney disease, neurological disease, and immunosuppressive disease; all been correlated with a higher risk of hospitalization or death when given COVID-19 [24,25]. Individuals with these circumstances have been given priority vaccination in several national programs [26][27][28].

Patients
The present study enrolled 113 medical staff participants and healthcare workers (doctors, nurses and healthcare personnel) at the Research Institute of Ophthalmology, Giza, Cairo, Egypt, between the period of March 2021 till June 2021.

Inclusion criteria of patients:
1. Participants above 18 years old. 2. Vaccination with oxford-AstraZeneca COVID-19 vaccine which was the programed vaccination status by the government to our institute.

The vaccination series all within the institute under supervision of the infection prevention control department (IPC). Exclusion criteria of patients:
1. Participants less than 18 years old. 2. Patients with certain chronic diseases who are not allowed to receive their vaccination with a signed physician report 3. Vaccines other than oxford-AstraZeneca COVID-19 vaccine 4. Vaccination in a place other than the research institute of ophthalmology 5. Participants who had COVID-19 infection at this time.

Ethical approval
The present study was conducted with the Code of Ethics of the World Medical Association, according to the principles expressed in the Declaration of Helsinki 2013. This study has been approved by the Local Research Ethics Committee of Research Institute of Ophthalmology, Giza, Cairo, Egypt. A written informed consent was provided by each participant before their inclusion in the study. Patients' confidentiality was preserved.

Study design and sample size
A cross-sectional, observational study was carried out including all medical staff (113) who agreed to be immunized against COVID-19 using AstraZeneca vaccine between March and June 2021.
The following data were gathered from the assessment after first dose of AstraZeneca's COVID-19 vaccine by history taking for symptoms and clinical signs for 12 weeks a follow up between the 2 doses, whether mild/moderate, severe or suggesting infection with COVID-19, all adverse effects were recorded as well as reported cases of positive COVID-19 PCR test.

Vaccination program
AstraZeneca's COVID-19 vaccine was given intramuscularly (0.5ml each). The first dose was administrated and follow up for any adverse effects was reported 24hrs, 72 hrs and 7 days' after first dose administration up to 12 weeks till administration of second dose. Vaccination program was done under the supervisor of the IPC department at the research institute of ophthalmology who had the authorization for the whole process from handling to vaccination delivery to strictly monitor practice and the assessment at the workplace.

Data collection
Adverse effects were reported after administration of first dose considering the severity whether mild/ moderate or severe according to the clinical signs and symptoms presented and reported by IPC team, actively surveyed after assessment of any adverse effect and investigations done to confirm the diagnosis. All reports were saved to avoid recall bias. Awareness vaccination program was given by IPC department during vaccination time about signs and symptoms of any side effect that could happen to be recorded. Clinical signs and symptoms were recorded asking every participant about constitutional symptoms (fever, fatigue), respiratory symptoms (cough, dyspnea), neurological symptoms (headache, loss of taste, and loss of smell), and GI symptoms (nausea, vomiting, abdominal pain, and diarrhea). Diarrhea was defined in this study according to the following WHO criteria: three or more loose stools/day or an increase in the number of motions as compared with usual. Frequency, severity, and duration of post COVID vaccination was assessed according to Kumar et al. [29] Statistical analysis Data was collected from medical records and was statically analyzed using SPSS program. the data was summarized using descriptive measures (e.g., means and standard deviations or median and IQR for continuous variables and percentages for categorical variables.
Chi square test and Mann Whitney U test were used as tests of significance to detect any significant difference between subjects who developed COVID infection after the first dose with those who didn't. p value ≤ 0.05 was considered significant

Results
In the present result, gender distribution in the vaccination program in our institute included 67 (59.3%) males than 46 (40.7%) females. By reporting the adverse effects after the first dose, the results showed 45 out of 113 with no vaccine related adverse effect about (40 %) while mild to moderate adverse effect reported 62 (54.9%) and the lowest for the severe adverse effects reporting 6 cases (5.3%) as shown in table (1).
In the present result, we analyzed the adverse effects of the healthcare staff after the first vaccination dose according to the severity of symptoms and clinical signs; results showed the majority 62 cases was mild to moderate adverse effects. Bony aches reported 43(69.3%) was the highest record followed by fever 32(51.6%) then localized arm pain 7(11.3%) and the least to GIT disorder only 2 cases (3.2%).
Our results reported 6 cases with severeadverse effects with equal analysis reported between GIT and headache 2 cases (33.3%) for eachand same results for fever, myositis and bony aches reported 1 case (16.7) for each shown in table (2).
In the present study, we evaluated the distribution of the healthcare vaccinated staff affected by COVID-19 after the first dose to differentiate between infection and vaccination adverse effects PCR was done for confirmation; reporting 7 cases out of 113 confirmed positive PCR along with signs and symptoms of the disease. Our result showed distribution of males 5 cases (71.4%) to females 2 cases (28.6%) out of the 7 cases.
Our results showed 4 out of 7 cases reported with no vaccine related adverse effects symptoms (57.1%) while 2 cases reported mild to moderate (28.6%) and only 1 case reported severe adverse effect shown in table (3).

Discussion
The agent responsible for COVID-19, SARS-CoV-2, poses an unprecedented threat to global economics and public health [30]. Safe, efficient, and affordable COVID-19 vaccines' development stays essential to minimize evolving virus strains in the current pandemic crisis and restoring normalcy in the future [31].
In the present study, the distribution of male was higher than females reporting 67 cases out of 113 this was in consistent to a previous study by Mediu et al. [32] who documented that gender had an impact factor in the immune response by vaccination in which Females in particular had stronger antibody response to certain vaccines and faster waning of antibody titer compared to men [33]. In addition, previous data has demonstrated the role of estrogen in women as an important downregulator of angiotensin-converting enzyme 2 which is a known SARS-CoV-2 receptor [34]. In fact, female patients infected with COVID-19 exhibit stronger T cell activation when compared to males [35].
We conducted 45 (39.8%) patients with vaccine related adverse effects symptoms, 62 (54.9%) patients with mild to moderate symptoms, and six patients with severe side effects (5.3%). The most frequently reported adverse effects in mild to moderate symptoms were bony aches 43 (69.3%), fever 32 (51.6%), localized arm pain 7 (11.3%), and GIT disorder in the form of diarrhea 2 (3.2%). however, all symptoms and signs subsided few days after vaccination, which contrasted with a study by Voysey et al. [10] who reported that the most noted negative reactions were injection site myalgia (44.0%), tenderness (63.7%), headache (52.6%), fatigue (53.1%), malaise (44.2%), and. (7.9 %). Furthermore, similar to some of the adverse effects noticed in a study by Zahid et al. in Bahrain, where pain at the injection site was observed in (31.03 %), myalgia was observed in (10.3 %), and nausea was observed in (3.45 %) [36]. All symptoms and clinical signs were due to reactogenicity and the physical manifestation of the inflammatory response to vaccination which may differ from person to another.
Following the initial dose, seven participants tested positive for COVID-19 infection. Initially, four of them reported no vaccine related adverse effect symptoms, two reported mild direct side effect symptoms, but one participant over 80 years old developed severe CNS symptoms. This was in line with a study conducted by Al Khames et al. which reported only two participants were hospitalized for COVID-19 infection following vaccination [37]. This can be explained by two ways whether the protective value of AstraZeneca vaccine in fully and one dose vaccinated was 76% effective at protecting against COVID-19 with symptoms for at least 90 days, according to late-stage-trial data published in The Lancet on February, 2021 [38] as there is no vaccine that provides that level of protection for any disease so we do expect in any vaccine program that there will be cases of disease among people who were fully vaccinated and certainly among some people who were partially vaccinated or due to antibodies reactions eliciting a slight symptoms of COVID-19 disease [39] or those patients with co-morbidities as hypertension, diabetes, cardiovascular and respiratory system diseases, and other underlying disease are more likely to develop serious illness requiring intensive care treatment associated with poorer clinical outcomes [40].
Our study found no vaccine related adverse effect of thrombosis, in contrast to a latest single study obtained from a study by Pulanić et al. from Croatia that found an elevation in the incidence of mixed pulmonary embolism (PE) and deep venous thrombosis (DVT), but not extracted PE or extracted DVT [41] Pandemic lockdowns and restrictions on physical activity were postulated to be the cause [42].
Muscle pain (inflammatory myositis), Fever, and injection site inflammation are all common side effects of foreign drug injection. They are the result of the innate immune system's interaction. When the body's macrophages or neutrophils detect vaccine molecules, they release cytokines, which are chemical signals that cause fever, chills, nausea, and muscle pain. If a foreign agent is implemented into the bloodstream, this cytokine response is anticipated [43]. Active immunizing antigens, preservatives, stabilisers, adjuvants, conjugating agents, and culture media used in vaccine preparation are all prospective allergens.
Type III hypersensitivity reactions include a wide range of delayed reactions that are primarily induced by the immune complexes encompassing T cells' formation. The most typical symptoms of postponed reactions are rashes, which include erythema, angioedema, and urticaria [44].

Study's limitations
Involve the small number of possible negative events, the vaccine's restricted safety data, and also the requirement to quantify each participant's antibodies and immunogenicity. This study, on the other hand, collected valuable data on this current topic. It found a very small number of adverse reactions correlated with the AstraZeneca's COVID-19 Vaccine that could have been caused by a variety of factors other than the vaccines. Underreporting combined with investigation biases. It deduced the vaccine seemed to be effective and safe, with benefits outweighing risks, and urged individuals to acknowledge vaccination when offered.

Conclusions
Out of 54,571 adverse reactions reported in the electric vehicle database, this study found mild to moderate adverse effects with few severe symptoms linked to the AstraZeneca's COVID-19 Vaccine. This finding should be interpreted with caution because underreporting combined with investigation biases may limit the findings' generalizability.

Recommendations
A potential COVID-19 vaccine must address these safety concerns to stop the current pandemic, avoid its recurrence, and avoid future epidemics with eliciting long lasting immunity and avoid disease progression.
Additional analyses predicated on more detailed adverse event findings, which include patient features and comorbidities, may allow for a more precise determination of causality.
Clinical trials examining the vaccine's efficacy in limiting disease, seeking to avoid infection, and reducing infectiousness, as well as studies investigating the vaccine's indirect impacts, can be used to evaluate these vaccine effects