What do we already know about this topic? Coronavirus disease 2019 (COVID-19) vaccines have been developed and authorized for emergency use to protect against COVID-19, a highly contagious and potentially deadly disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. The vaccines work by teaching the immune system to recognize and fight the virus, which can prevent illness or reduce the severity of symptoms. However, like all vaccines, COVID-19 vaccines can cause side effects, which can range from mild to severe. Some common side effects include pain or swelling at the injection site, fever, fatigue, headache, muscle aches, and chills.

Reports of more serious side effects, such as blood clots and heart inflammation, have also emerged, although these are rare. The risk of adverse reactions varies depending on the vaccine and the individual, and health authorities continue to monitor and investigate any safety concerns related to the vaccines

How does your research contribute to the field? Given this background, the research described in the title is focused on evaluating the level of SARS-CoV-2 anti-spike receptor binding domain (RBD) immunoglobulin G (IgG) of COVID-19 Vaccines prevalence and nature of adverse reactions specifically among health staff in Duhok Province, Iraq, who received COVID-19 vaccines.

What are your research’s implications toward theory, practice, or policy? The results of this research could provide important insights into the safety and efficacy of COVID-19 vaccines, particularly among healthcare workers, and inform future vaccination policies and practices in the region.

Coronavirus disease is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) known as COVID-19, which is a beta coronavirus that has emerged as 1 of the most contagious viruses in recent history. ^{Reference Salzberger, Buder and Lampl1} Historically, coronaviruses have caused 3 major outbreaks in the past 2 decades: SARS (severe acute respiratory syndrome), MERS (Middle East respiratory syndrome), and the most recently emerged COVID-19. ^{Reference Harrison, Lin and Wang2} The COVID-19 outbreak was first detected in the Wuhan province of China in December 2019. ^{Reference Mackenzie and Smith3}

The World Health Organization (WHO) declared SARS-Cov-2 as a public health emergency on January 31, 2020. In addition, COVID-19 attained the status of a very high-risk category in February 2020 and was declared a pandemic in March 2020. ^{Reference Dhama, Patel and Sharun4} Globally, at the time of writing this study, there have been 533,816,957 confirmed cases of COVID-19, including 6,309,633 deaths. Contrarily, a total of 11,864,214,773 vaccine doses have been administered. Whereas, in Iraq, 2,330,049 confirmed cases and 25,223 deaths have been recorded, with a total of 18,353,783 vaccine doses having been administered. ⁵ A total of 15,409 cases were reported, particularly in Duhok in 2020. ^{Reference Merza, Aswad and Sulaiman6}

The wide spread of COVID-19 has affected numerous individuals’ lives across the world and limited the movement of people outside their homes and territories. Many control measures were implemented to control the pandemic, such as movement restriction, social distancing, and wearing masks in crowded places, as well as a health education campaign to improve handwashing and avoid places where infections were likely. However, these precautionary measures were not able to control the pandemic, but they have resulted in a pandemic wave over time. ^{Reference Otani, Ohta and Sano7}

Currently, the COVID-19 vaccine is 1 of the preventative strategies that could help to keep the pandemic under control. Many manufacturers created and delivered vaccines worldwide, including Pfizer and BioNTech, which introduced the first COVID-19 vaccine in December 2020. Even though the vaccinations provide a reasonable amount of protection against COVID-19 and reduce the mortality rate, their efficacy varies from 1 type of vaccine to another. Having mentioned that a high vaccination rate can end the COVID-19 pandemic, vaccination is being promoted globally. ^{Reference García-Montero, Fraile-Martínez and Bravo8,Reference Rogliani, Chetta and Cazzola9}

mRNA (BNT162b2 and mRNA-1273), adenoviral vector-based (ChAdOx1 nCoV-19, Ad26.CoV2.S, and Gam-COVID-Vac), and inactivated virus (CoronaVac and Sinopharm) vaccines are the most widely used vaccine types. Several studies have demonstrated the varying effectiveness of these vaccines. In phase 3 clinical trials, the BNT162b2 vaccine (from Pfizer and BioNTech) demonstrated 95% efficacy, whereas the ChAdOx1 vaccine (from the University of Oxford and AstraZeneca) demonstrated 74% efficacy. ^{Reference Jara, Undurraga and González10} The European Medicines Agency has authorized the use of both of these COVID-19 vaccines (BNT162b2 and ChAdOx1). Other countries carried out their own studies to explore the vaccine’s efficacy. For example, Turkey reported an 83.5% efficacy for CoronaVac (from Sinovac), whereas Chile reported a 64.9% efficacy. ^{Reference Voysey, Clemens and Madhi11,Reference Tanriover, Doğanay and Akova12} Meanwhile, the WHO approved the CoronaVac (from Sinovac) vaccine, assessing its efficacy at 51%. The reported differences in vaccine efficacy might be due to many reasons, including population differences or polymorphisms that were circulating in different places at the time. It is not clear and needs further research to find out the level of effectiveness of each vaccine and how long it protects people in the real world because all COVID-19 vaccines did not pass through a normal process for the normal vaccine development process, which usually takes 10-14 y, and there are new strains of the virus.

Antibodies serve as the initial line of defense during a natural COVID-19 infection, where their levels might be altered by factors such as illness severity and comorbidities. It is believed that antibodies against the SARS-CoV-2 spike protein, and specifically the RBD, play a crucial role in both stimulating the immune response and neutralizing the virus. Because the virus continues to spread and mutate, it is anticipated that immune-evasive forms may arise. ^{Reference Harvey, Carabelli and Jackson13,Reference Volkan14} Studies have proven the necessity of high spike antibody titers to develop a protective immune response against SARS-CoV-2 infection. Studies have also shown a link between new infections and an increase in RBD IgG antibody titers. These results show that antibody titers are an important protective factor against SARS-CoV-2 infection. ^{Reference Earle, Ambrosino and Fiore-Gartland15} While the vital role of vaccines is known to increase the level of the immune system, it is unknown how long the immunological response to the various vaccines will last and whether additional doses will be required.

Among the issues involved with vaccination is the possibility of adverse effects. COVID-19 vaccines were developed in record time to ensure that most of the population got vaccinated at the earliest time. Consequently, the side effects of vaccines have been seen among populations all over the world. The rate of adverse reactions to COVID-19 vaccinations varies by country because the kinds of vaccines administered vary as well. From mild to severe adverse reactions have been documented, including localized reactions like swelling, redness, and a rash at the injection site, as well as systemic reactions like dyspnea and anaphylaxis. ^{Reference Feng, Phillips and White16} Due to the widespread misinformation and people’s perceptions of adverse reactions to vaccines, many people choose not to get vaccines and avoid vaccination altogether. Low vaccination rates can impede the establishment of herd immunity at the level of the community. ^{Reference Freeman, Loe and Chadwick17} The level of serum IgG is linked to the severity and length of adverse reactions to vaccines. People might be willing to get vaccinated and deal with the side effects if they know how their immune systems will react to COVID-19 vaccines over time and what kinds of side effects they might have. Clarifying the adverse reactions as per vaccine and individual characteristics are critical for mitigating the fear of COVID-19 vaccination and regaining a safer world with herd immunity. But there is not much known about the level of anti-SARS-CoV-2 IgG and the kinds of side effects of the COVID-19 vaccine at the moment. The way a person reacts to a vaccine depends on both the type of vaccine and the person. ^{Reference Jacobson, Swan and Adegbenro18} Currently, Iraq has received different types of COVID-19 vaccines with no detailed efficacy data for these vaccines. However, the level of immunity to the 2019-nCoV vaccination and its lifetime in the community is unknown. Therefore, this research investigated the IgG level and adverse reactions to COVID-19 vaccines (ChAdOx1/AZD1222, BNT162b2, and BBIBP-CorV) among health-care workers over the course of a 9-mo period.

Methods

Study Design

A longitudinal study through the panel design was conducted to study the COVID-19 vaccines’ stimulation to the immunity status as well as adverse side effects among staff in health-care facilities in Duhok province in Kurdistan region, Iraq. Participants of this study received 1 of the 3 available vaccines (Pfizer BioNTech [BNT162b2], Oxford/AstraZeneca [ChAdOx1], and Sinopharm [BBIBP-CorV]), and the time period for this study was between June 2021 and June 2022 for those who were working in public health-care facilities in Duhok Province, Iraq.

Participants

The study recruited 300 health staff from public health-care facilities in Duhok province, of which 300 participants were included in the first phase 1 mo after the second dose; 279 participants in the second phase 5 mo after the second dose; and 256 participants in the third phase of 9 mo after the second dose. Following inclusion criteria, the present study recruited health staff who received 2 doses of the COVID-19 vaccine. Vaccine types varied and included Pfizer BioNTech (BNT162b2), Oxford/AstraZeneca (ChAdOx1), and Sinopharm (BBIBP-CorV). Participants were included in this study if they gave consent and were willing to participate and commit to studying requirements. Contrary, people with cancer or human immunodeficiency virus (HIV) disease were excluded. The study sample was recruited using a vaccine database from the Duhok health governorate through a random sampling method. Initially, 904 healthcare workers who completed their vaccination by receiving 2 doses were recorded in the vaccination department and included in the original database for each vaccine. Then simple random sampling was performed using the Excel random formula to select 100 individuals for each vaccine to be included in the study.

Procedure

Blood collection was done between June 2021 and June 2022 in 4 places (Hevi hospital, Azadi teaching hospital, Directorate of preventive health affairs, and General Directorate of Health in Duhok, Iraq). For each round of sample collection, 3 ml of blood were taken from each participant, put in a tube, and put in the fridge. This was done so that there were 50 samples for each round of testing, because the Mini VIDAS machine could only test 50 samples at a time. SARS-CoV-2 anti-spike RBD IgG was then measured. The samples were tested in the public health central laboratory in Duhok province. The assay VIDAS SARS-CoV-2 IgG (Biomerieux SA) had European CE marking authorization. Per the assay’s recommended definition, the positive anti-spike RBD IgG response in the study was defined as a test value of 1.0 index or more, and the reported assay specificity was 99.9% (from the package insert). Assays were run on the VIDAS Mini VIDAS System. A set of questions were also included in a questionnaire to collect data about sociodemographic information (eg, age, sex, level of education, job title, and year of service). Then a blood sample was collected from each participant after 1 mo, 5 mo, and 9 mo after the second dose of the vaccine to determine the immunity stimulation status. In addition, information on the immediate adverse reactions to COVID-19 vaccines was gathered.

Data Collection and Measurement

Interpretation of results for SARS-CoV-2 anti-spike RBD IgG antibody has been performed after the SARS-CoV-2 control results have been reviewed, determined, validated, and were acceptable following the description in Table 1.

Table 1. Interpretation of results

Technique to Reduce Bias

In this study, certain procedures were taken to minimize the bias, such as using the same kits and machine for all tests over the 3 different times of test. One person took the sample for all participants, and 2 laboratory technicians worked on the entire test and procedure. In the meantime, simple random sampling was also used as another strong point.

Statistical Methods

The descriptive characteristics of the participants were presented using mean (SD) or number (percentage). The IgG level and participants’ response to the COVID-19 vaccine were reported in mean (SD) and number (percentage). Positivity at mo 1, 5, and 9 among participants with different characteristics was analyzed using a Pearson chi-squared test (Fisher’s exact or chi-squared test). Comparisons of IgG levels of COVID-19 vaccines between different time periods for each vaccine were examined using the Bonferroni correction test. Additionally, the comparisons of IgG antibody levels 1 mo after the second dose of the COVID-19 vaccine among different age groups and genders were conducted using a 1-way analysis of variance (ANOVA) and independent t-test, respectively. The significance level for differences was set at a P-value of less than 0.05. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS), Version 23.

Results

This study recruited 300 health staff from public health-care facilities in Duhok province. Slightly above half of the participants were female (51.7% female) from 21 to 72 y of age (mean of age = 30.33; SD = 8.53). Nearly half (47%) of the respondents were between 31 and 40 y old. Most of the participants had high education levels (49.3% had college degrees). Underweight as a single symptom was not observed among any participants, while overweight and obese were observed at 43.7% and 12%, respectively, as shown in Table 2.

Table 2. Socio-demographic profile of participants

To further explore the relationship between socio-demographic background and SARS-CoV-2 anti-spike RBD IgG antibody positivity after 1 mo from the second dose of the COVID-19 vaccine, we carried out chi-square analyses and the results showed that age, body mass index (BMI), and smoking status had a significant relationship with SARS-CoV-2 anti-spike RBD IgG antibody positivity. Contrarily, among other demographic backgrounds, gender showed no significant relationship. Regarding the level of SARS-CoV-2 anti-spike RBD IgG antibody, this study found that 90% of the samples exceeded the positivity threshold of more than 1 AU for SARS-CoV-2 anti-spike RBD IgG antibody positivity despite the background differences (Table 3).

Table 3. Distribution and association of SARS-CoV-2 anti-spike RBD IgG positivity level according to the demographic profile of participants after 1, 5, and 9 mo from the second dose of COVID-19 vaccines

In the second part of the study, participants were monitored for SARS-CoV-2 anti-spike RBD IgG antibodies over the course of 9 mo. Antibody titers were obtained from each participant after 1 mo, 5 mo, and 9 mo after the second dose of the COVID-19 vaccine for the 3 available types of vaccines. As shown in Table 4, the study showed that mean values of the SARS-CoV-2 anti-spike RBD IgG antibody were significantly decreased from 52.12 to 29.02 and 6.49 in 1, 5, and 9 mo, respectively (P < 0.0001). The overall difference was significant between mo 1 and mo 5 and 9, and between mo 5 and 9 (further detail in Figure 1).

Table 4. Mean of SARS-CoV-2 anti-spike RBD IgG antibody among health staff after 1, 5, and 9 mo from the second dose of COVID-19 vaccines

Bonferroni correction was performed for statistical analyses.

Figure 1. Level of positivity of SARS-CoV-2 anti-spike RBD IgG antibody over 9 mo after the second dose of COVID-19 vaccine.

This study also evaluated the level of SARS-CoV-2 anti-spike RBD IgG antibody among participants over 9 mo. As shown in Figure 2, the mean of SARS-CoV-2 anti-spike RBD IgG antibodies among the receivers of (BNT162b2) vaccine was higher over the course of 1 mo, 5 mo, and 9 mo after the second dose compared with (ChAdOx1) and (BBIBP-CorV), which came in second and third place and statistically significant over the time (P = 0.0001), respectively.

Figure 2. Mean of SARS-CoV-2 anti-spike RBD IgG antibody among health staff after 1, 5, and 9 mo from the second dose of COVID-19 vaccines.

Furthermore, after 1 mo from the second dose of COVID-19 vaccine receiver, the mean IgG level was found to be higher in younger people (mean 34 for < 60-y-olds) as compared to older people (mean = 22 for > 60-y-old) and was statistically significant at P < 0.0084, whereas sex had no significant association (P = 0.7395 and P = 0.3948) with the IgG levels against the RBD antibody over the 1 and 5 mo from the second dose of COVID-19 vaccine receiver while in mo 9, sex was significant association (P = 0.0001) with the IgG levels against the RBD antibody since the mean of female (mean = 3.45) was higher than the male (mean = 0.26). More details in Table 5.

Table 5. Mean of SARS-CoV-2 anti-spike RBD IgG antibody among health staff after 1, 5, and 9 mo from the second dose of COVID-19 vaccines

The relationship between adverse effects and the type of vaccine received during the first 12 h to 1 mo after the first and second doses was also explored. The results showed that fever (58%) was the most prevalent after the first dose of the ChAdOx1, and (43% of participants had a fever for BNT162b2 and (23% for BBIBP-CorV), followed by muscle pain, joint pain, and shoulder pain for both doses. A list of the adverse reactions to the COVID-19 vaccine is shown in Table 6.

Table 6. Distribution of participants according to an adverse reaction by type of COVID-19 vaccines from 12 h to 1 mo after the first and second dose of vaccines

Regarding the uncommon adverse reactions following the COVID-19 vaccines, among participants who reported an adverse reaction, a small percentage also experienced uncommon reactions, including increased appetite change, sex activities, and monthly periods among female participants. More details are shown in Table 7.

Table 7. Distribution of uncommon adverse reactions by type of COVID-19 vaccines during 12 h to 1 mo