The Outcome of BNT162b2, ChAdOx1-Sand mRNA-1273 Vaccines and Two Boosters: A Prospective Longitudinal Real-World Study

To date, the effectiveness of COVID-19 vaccines and booster doses has yet to be evaluated in longitudinal head-to-head studies. This single-center longitudinal study assessed the effectiveness of ChAdOx1 nCoV-19, BNT162b2, and mRNA-1273 vaccines and assessed two BNT162b2 boosters in 1550 participants, of whom 26% had comorbidities. In addition, the SARS-CoV-2 antibody dynamics was monitored. A group of 1500 unvaccinated subjects was included as the controls. The study’s endpoint was the development of virologically-proven COVID-19 cases after vaccine completion, while the secondary endpoint was hospitalizations due to severe COVID-19. Overall, 23 (4.6%), 16 (3%), and 18 (3.8%) participants vaccinated with ChAdOx1 nCoV-19, BNT162b2, and mRNA-1273, respectively, developed COVID-19 after vaccine completion, with an effectiveness of 89%, 92%, and 90%. Ten COVID-19 cases were reported in participants with comorbidities, three of whom were hospitalized. No hospitalizations occurred after boosters. SARS-CoV-2 antibody levels peaked 2–4 weeks after the second vaccine dose but declined after a mean of 28.50 ± 3.48 weeks. Booster doses significantly enhanced antibody responses. Antibody titers ≤ 154 U/mL were associated with a higher risk of COVID-19 emergence. Thus, COVID-19 vaccines effectively reduced COVID-19 and prevented severe disease. The vaccine-induced SARS-CoV-2 antibody responses declined after 28–32 weeks. Booster doses induced significant maintained responses. SARS-CoV-2 antibody levels may help determine the timing and need for vaccine booster doses.

The genome of SARS-CoV-2 consists of 30,000 nucleotides which encode four structural proteins. The nucleocapsid (N) protein is responsible for packaging the RNA genome, and the membrane (M) protein is accountable for shaping the virions. In addition, the spike (S) and envelope (E) proteins are critical for virions assembly and release, as well as several (18 years and above) eligible for any studied vaccines were enrolled and followed between March 2021 and September 2022.
In the initial phases of this real-life study, not all COVID-19 vaccines were available. Due to the unavailability of an alternative vaccine, the vaccination of individuals with an allergy to a component of the available COVID-19 vaccine or individuals with severe allergic reactions or anaphylaxis after a previous dose of the available COVID-19 vaccine was postponed until other vaccines were available. Patients with medical conditions that warrant delaying the vaccination were temporarily exempted until resolution, invited to join the study, and followed until they could join. If they agreed and provided informed consent, they were enrolled and followed as a control group.
Vaccinated participants and non-vaccinated control subjects were followed at specific time intervals until the end of the study. Participants (vaccinated) and non-vaccinated (controls) were advised to report to the hospital to get tested for COVID-19 using RT-PCR when they developed any symptoms, even mild, or were in contact with COVID-19-positive patients. Participants who tested positive were considered "cases". In addition, COVID-19related hospitalizations for participants were monitored and reported.
Enrolled subjects were followed at specific time points, namely two weeks after the first dose, then two, four, six, and eight months after the second vaccine dose and first booster dose, respectively. After the second booster, one or two follow-up visits were scheduled. Follow-up visits included physical examination, the COVID-19 antigen test, and SARS-CoV-2 antibody testing.
All vaccinated participants (active groups) and temporarily unvaccinated individuals (control group) provided written informed consent before vaccination, enrollment in the study, and study-related investigations. The study was conducted according to the standards of medical research, including the International Conference on Harmonization (ICH), the Council for International Organizations of Medical Sciences (CIOMS), and the Declaration of Helsinki. Prince Sattam Bin Abdulaziz University Review Board approved and monitored the study (Approval number: REC-HSD-103-2021).

Inclusion, Exclusion Criteria, and Control Group
All adults aged 18 years or older were eligible for inclusion if they consented to enrollment in the study and agreed to attend the follow-up visits and perform the necessary laboratory investigations. Individuals with a proven allergy to any of the components of a COVID-19 vaccine were not vaccinated with the vaccine that contains that component.
Individuals with anaphylaxis to a previous dose of one of the COVID-19 vaccines were not provided the second dose of the same vaccine. Persons with a history of severe recurrent thrombosis, thrombosis with thrombocytopenia (TTS), or heparin-induced thrombocytopenia, previous episodes of capillary leak syndrome, cerebral venous sinus thrombosis, antiphospholipid syndrome with thrombosis not enrolled in the ChAdOx1 nCoV-19 vaccine study arm, and were considered for one of the mRNA vaccines.
Vaccination was postponed, and individuals were designated temporary exemption according to the criteria of the Public Health Authorities in the following conditions: In the early phase of the study, data about the vaccine's safety in pregnant women were limited. Thus, for pregnant women, particularly those with high-risk pregnancies, vaccination was postponed until delivery.
Control group: Subjects with temporary vaccine exemption were invited to join the study as a control group. If they provided informed consent, they were followed until the cause of exemption was resolved and they received the vaccine.

Assessment of Vaccine Effectiveness and Measurement of the Study Outcomes
This study's primary endpoint was to compare the effectiveness of each vaccine in preventing RT-PCR-confirmed COVID-19 cases and COVID-19-related hospitalizations versus those not vaccinated. The secondary endpoint was to compare and monitor the SARS-Cov-2 antibody responses to the different vaccines. During the study, vaccinated or unvaccinated participants developing fever or respiratory symptoms were tested immediately by COVID-19 RT-PCR. Positive cases were followed through home isolation or hospitalization and beyond.

COVID-19 Vaccines Registration, Documentation, and Management
Saudi Arabia has developed a unique and advanced COVID-19 reporting and vaccine registration system through a smartphone or web-based applications: Sehaty, Anat, and Tawakalna (https://ta.sdaia.gov.sa/ accessed on 25 November 2022), respectively. The web-based platforms are considered central repository systems that include COVID-19 PCR results in COVID-19 vaccine data, including the type of delivered vaccine, date, the timing of vaccines, location of vaccination center, and recorded adverse events. In addition, each vaccinated individual was provided with an electronic health passport with a barcode that verifies a person's immunization status.

Adverse Events (AEs) Recording and Reporting
All adverse events were reported by the study participants and recorded. Participants with AEs were provided with the appropriate management and advice. Severe and unusual adverse events were registered in a special Ministry of Health platform for the recording of AEs.

Measurement of Anti-SARS-CoV-2 Antibody Levels
Serum was collected using standard sampling tubes or tubes containing separating gel. Neutralizing antibody IgG against the SARS-CoV-2 spike protein subunit (S1) was measured using enzyme-linked immunosorbent assay (ELISA) kits according to the manufacturer's instructions (Elecsys ® Anti-SARS-CoV-2 assay, Roche Diagnostics, NJ, USA). The assay uses a recombinant protein representing the nucleocapsid (N) antigen in a double-antigen sandwich assay format, which favors the detection of high-affinity antibodies against SARS-CoV-2. In addition, Elecsys ® Anti-SARS-CoV-2 detects antibody titers, which have been shown to correlate positively with neutralizing antibodies in neutralization assays.

Statistical Analysis
We used descriptive statistics to describe the demographic and clinical data of the participants receiving the BNT162b2, mRNA-1273, or ChAdOx1-nCoV-19 vaccines. As appropriate, a comparison of means between vaccinated participants and controls was carried out using the Analysis of Variance (ANOVA) or Kruskal-Wallis test. A Mann-Whitney test was used for pairwise comparisons as a post hoc or follow-up analysis if the test showed differences between the groups. The tested vaccine's effectiveness (VE) (percentage reduction in COVID-19 incidence in a vaccinated group compared to a nonvaccinated group) was assessed by assessment of parameters. The relative risk (RR) is the risk of the outcome in the treated group (Y) compared to the risk in the control group. The RR, its standard error, and 95% confidence interval are calculated according to Altman, 1991. Absolute risk reduction (ARR) is the difference in risk between the control group (X) and the treatment group (Y). Relative risk reduction (RRR) is the percent reduction in risk in the treated group (Y) compared to the control group (X). The effectiveness = 1-RR × 100%. The number needed to treat (NNT) is the number of patients that need to be treated to prevent one additional bad outcome. The same approach assessed the rate of COVID-19-related hospitalizations [25]. Receiver operating curve (ROC) analysis was used to evaluate the anti-SARS-CoV-2 antibody test diagnostic ability to discriminate COVID-19 positive and negative subjects and the optimal cutoff values. Statistical analysis was performed using SPSS 20 statistical software.( IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY, USA; IBM. Corp)

Demographics and Characteristics of Enrolled Subjects
This study was conducted at the Prince Sattam Bin Abdulaziz University Hospital and Vaccination Center, Kharj, Kingdom of Saudi Arabia, between March 2021 and September 2022. Initially, 4145 vaccinees were screened for eligibility for the study. Eligible individuals who provided informed consent (n = 1500) were enrolled and prospectively followed until the end of the study (Figure 1). Participants received one of the COVID-19 vaccines: ChAdOx1 nCoV-19 (Cambridge, UK) (Group A; n = 503), BNT162b2 (BioNTech-Pfizer, Mainz, Germany) (Group B; n = 521), or mRNA-1273, (Moderna, Cambridge, MA, USA) (Group C; n = 476). The study cohort completed the two vaccination doses and received the BNT162b2 vaccine's first and second booster doses. The participants' follow-ups ranged between 12 to 18 months after vaccination. Pfizer, Mainz, Germany) (Group B; n = 521), or mRNA-1273, (Moderna, Cambridge, MA, USA) (Group C; n = 476). The study cohort completed the two vaccination doses and received the BNT162b2 vaccine's first and second booster doses. The participants' followups ranged between 12 to 18 months after vaccination. Figure 1. The flow of participants through the study. The figure shows the flow of participants through the study. Initially, 4154 subjects were screened. A total of 3535 were eligible; however, only 1500 subjects agreed to join the study, provided informed consent, and were enrolled. Subjects with temporary vaccine exemption were those recovering from natural COVID-19, those treated with immunosuppressive therapy, and pregnant women.
The control group included 1500 individuals who were either ineligible due to a documented allergy to components of both vaccines (95; 6.3%) or developed myocarditis or pericarditis after a dose of mRNA vaccine (9; 0.6%) or were temporarily exempted from vaccination as a control group. The causes of temporary exemption were previously confirmed COVID-19 (683; 45.53%), severe allergic reactions, or adverse events caused by a previous dose of a COVID-19 vaccine (ChAdOx1-nCoV-19) (187; 12.47%) or contraindication to a vaccine with no available alternative vaccine (174; 11.6%), severe medical conditions or major surgeries (153; 10.2%), high-risk pregnancy (275; 18.33%), and 172 (11.46%) due to other causes such as patients receiving immunotherapy or monoclonal antibody for COVID-19. The control subjects with temporary exemptions were followed until the cause of postponing vaccination was resolved (3-9 months). By the end of the study, that caused 1089 subjects (78%) to be vaccinated.
The active vaccinated cohort included 767 (51.13%) Saudis and 733 (48.87%) non-Saudis (p = 0.02) ( Table 1). There were no significant differences in participants' ages or gender in the three vaccinated groups and the control subjects. Among the vaccinated participants, 1416 (94.4%) did not experience previous natural COVID-19 infection and were vaccine naïve. Eighty-four (5.7%) participants reported previous attacks of COVID-19 4-6 months before enrollment in the study. Among the enrolled subjects, 1114 (74.3%) vac- Figure 1. The flow of participants through the study. The figure shows the flow of participants through the study. Initially, 4154 subjects were screened. A total of 3535 were eligible; however, only 1500 subjects agreed to join the study, provided informed consent, and were enrolled. Subjects with temporary vaccine exemption were those recovering from natural COVID-19, those treated with immunosuppressive therapy, and pregnant women.
The control group included 1500 individuals who were either ineligible due to a documented allergy to components of both vaccines (95; 6.3%) or developed myocarditis or pericarditis after a dose of mRNA vaccine (9; 0.6%) or were temporarily exempted from vaccination as a control group. The causes of temporary exemption were previously confirmed COVID-19 (683; 45.53%), severe allergic reactions, or adverse events caused by a previous dose of a COVID-19 vaccine (ChAdOx1-nCoV-19) (187; 12.47%) or contraindication to a vaccine with no available alternative vaccine (174; 11.6%), severe medical conditions or major surgeries (153; 10.2%), high-risk pregnancy (275; 18.33%), and 172 (11.46%) due to other causes such as patients receiving immunotherapy or monoclonal antibody for COVID-19. The control subjects with temporary exemptions were followed until the cause of postponing vaccination was resolved (3-9 months). By the end of the study, that caused 1089 subjects (78%) to be vaccinated.
The active vaccinated cohort included 767 (51.13%) Saudis and 733 (48.87%) non-Saudis (p = 0.02) ( Table 1). There were no significant differences in participants' ages or gender in the three vaccinated groups and the control subjects. Among the vaccinated participants, 1416 (94.4%) did not experience previous natural COVID-19 infection and were vaccine naïve. Eighty-four (5.7%) participants reported previous attacks of COVID-19 4-6 months before enrollment in the study. Among the enrolled subjects, 1114 (74.3%) vaccinated participants reported no diseases or health disorders, while 386 (25.7%) participants had one or more comorbidities. The chronic health disorders included diabetes, hypertension, dyslipidemia, cardiac disease, chronic liver disease, chronic renal disease, hemoglobinopathies, neurologic or psychiatric disorders, autoimmune disorders, and malignancies (Table 1). Among the patients with hemoglobinopathies, 88% and 12% had sickle cell anemia and thalassemia, respectively. The autoimmune diseases included systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriasis, and Hashimoto's thyroiditis. The participants with malignancies included patients with breast cancer, lymphoma, and prostate cancer who completed their therapeutic approaches. The control group had more comorbidities since patients with advanced chronic diseases were initially temporarily exempted from vaccination.
Although the endpoint was the development of COVID-19 cases after vaccine completion, the study also monitored the COVID-19 instances after the first vaccine dose. As shown in Table 1, there was a significant difference in the COVID-19 cases that developed after the first doses of ChAdOx1 nCoV-19, BNT162b2, and mRNA-1273, with the highest issues developing after ChAdOx1 nCoV-19. Table 3 summarizes the emergence of COVID-19 cases after vaccine completion and booster doses versus unvaccinated control subjects. COVID-19 infections were significantly higher in unvaccinated individuals, with the highest COVID-19 incidence in patients with autoimmune diseases, malignancies, people with diabetes, particularly those with uncontrolled diabetes, and patients with hemoglobinopathies (Table 3). Among the participants who developed COVID-19 after completing the second dose of the vaccines, 73.7% had comorbidities. The reported COVID-19 incidents were significantly lower in vaccinated versus unvaccinated participants with comorbidities. The vaccine effectiveness in patients with diabetes mellitus, obesity, autoimmunity, and malignancies ranged between 80% and 86%, which is lower than VE in participants without chronic diseases and those with other comorbidities. None of those who received booster vaccines developed a severe illness that required hospitalization. Figure 2 is a Kaplan-Meier graph that demonstrates the time to event (the occurrence of COVID-19 cases in the three study groups and control subjects).  The relative risk (RR), its standard error, 95% confidence interval, relative risk, absolute risk reduction, and number needed to vaccinate (NNV) is calculated according to Altman, 1991. * Significant. ** Highly significant.

SARS-CoV-2 Antibody Dynamics
The study demonstrated that the SARS-CoV-2 antibodies were slightly higher in participants vaccinated with either BNT162b2 or mRNA-1273 than ChAdOx1 nCoV-19; however, the difference was insignificant (p = 0.716) (data are not shown). As shown in Figure 2, SARS-CoV-2 antibodies rose gradually after the first vaccine dose and peaked two to four weeks after the second dose. Although the levels of antibodies remained elevated until six months in the three groups, a gradual decline was detected between 24 to 32 weeks (mean 28.50 ± 3.48 weeks) post-vaccination (Figure 3a). The booster doses resulted in the antibody titers with levels that exceeded those after the second vaccine dose. The ROC curve analysis showed that antibody titers ≤ 154 U/mL were associated with an increased risk of acquiring COVID-19 with a sensitivity and specificity of 98% and 99%, respectively (Figure 3b). Patients with comorbidities tended to have slightly lower humoral responses than healthy participants. Furthermore, antibody titers declined earlier (between 16-28 weeks) in vaccinated participants with comorbidities compared to those without.

SARS-CoV-2 Antibody Dynamics
The study demonstrated that the SARS-CoV-2 antibodies were slightly higher in participants vaccinated with either BNT162b2 or mRNA-1273 than ChAdOx1 nCoV-19; however, the difference was insignificant (p = 0.716) (data are not shown). As shown in Figure 2, SARS-CoV-2 antibodies rose gradually after the first vaccine dose and peaked two to four weeks after the second dose. Although the levels of antibodies remained elevated until six months in the three groups, a gradual decline was detected between 24 to 32 weeks (mean 28.50 ± 3.48 weeks) post-vaccination (Figure 3a). The booster doses resulted in the antibody titers with levels that exceeded those after the second vaccine dose. The ROC curve analysis showed that antibody titers ≤ 154 U/mL were associated with an increased risk of acquiring COVID-19 with a sensitivity and specificity of 98% and 99%, respectively (Figure 3b). Patients with comorbidities tended to have slightly lower humoral responses than healthy participants. Furthermore, antibody titers declined earlier (between 16-28 weeks) in vaccinated participants with comorbidities compared to those without.

Discussion
This prospective, longitudinal, test-negative, real-world study compared the effectiveness, outcomes, and safety of three COVID-19 vaccines: ChAdOx1 nCoV-19, BNT162b2, and mRNA-1273, and evaluated the role of the vaccine boosters in a broad, representative patient population at different ages and ethnicities in diverse clinical settings, where many patients have multiple comorbidities. The study also measured the

Discussion
This prospective, longitudinal, test-negative, real-world study compared the effectiveness, outcomes, and safety of three COVID-19 vaccines: ChAdOx1 nCoV-19, BNT162b2, and mRNA-1273, and evaluated the role of the vaccine boosters in a broad, representative patient population at different ages and ethnicities in diverse clinical settings, where many patients have multiple comorbidities. The study also measured the anti-SARS-CoV-2 antibodies' levels at other time points after vaccination. Overall, the study provides real-world evidence that the three tested vaccines conferred significant protection against COVID-19 infections and reduced severe outcomes that require hospitalization and COVID-19-related mortalities. The three vaccines were also well tolerated. However, the anti-SARS-CoV-2 antibody titers and, consequently, COVID-19 vaccine effectiveness waned with time but were regained with the booster doses.
The current study demonstrated that the effectiveness of ChAdOx1-nCoV-19, BNT162b2, and mRNA-1273 was 89%, 92%, and 90%, respectively, where the effectiveness of BNT162b2 was significantly higher than ChAdOx1 nCoV-19; however, no significant difference was detected between ChAdOx1 nCoV-19 and mRNA-1273 vaccines. The effectiveness of the vaccines in the current study was comparable with the efficacy or effectiveness rates reported by previous studies [26][27][28][29]. Although the study's endpoint was the development of COVID-19 cases following the second vaccine dose, we also monitored patients after the first vaccine dose to investigate the magnitude of protection conferred by such a dose. Although the immune response to the vaccines has not been fully developed, our findings showed that vaccinated participants, irrespective of the type, were at lower risk of developing COVID-19 and diseaserelated hospitalizations compared to unvaccinated individuals in similar prophylactic settings. However, the COVID-positive cases were significantly higher after the first dose of ChAdOx1 nCoV-19 than those detected after BNT162b2 or mRNA-1273 vaccination. This finding may be attributed to the long interval between the first and second ChAdOx1 nCoV-19 and the changes in the adopted prophylactic measures. Given the first dose's beneficial effects, distributing the vaccines among those eligible as quickly as possible, after providing for the most vulnerable broad mass vaccination campaigns may be beneficial for controlling the viral spread and severe COVID-19-related morbidities and mortalities in resource-limited countries with irregular vaccine supplies [30].
The current study demonstrated a significant reduction in post-vaccination COVID-19 incidents and severe disease after the second dose of the three vaccines. Thus, the present study results lend further credence to the findings of several studies [28,[31][32][33] that showed the critical role of vaccine completion in reducing infection and COVID-19-related severe disease. The confirmed COVID-19 infections detected after vaccine completion were 57/1500 (3%), and none of the cases was associated with severe symptoms in this study cohort. Our findings are comparable to those of a study that showed 39 of 1497 (2.8%) fully vaccinated healthcare workers developed post-vaccination SARS-CoV-2 breakthrough incidents [34]. Vaccine breakthrough infections may occur following several vaccines that may result from viral factors, including the emergence of variants, transmissibility rates, immune evasion, or host determinants such as age, comorbidities, and immune status may result in postvaccination confirmed infections [35]. This study did not assess the prevailing SARS-CoV-2 variants; however, the impact of comorbidities was investigated.
Few countries provided COVID-19 vaccine boosters. In KSA, two booster doses were administered, the first 6-8 months after vaccine completion and the second eight months after the first booster dose. In KSA, initially, priority was given first to elderly persons and high-risk individuals then boosters were offered on a larger scale. After the first vaccine booster, only 10 minimally symptomatic vaccine breakthroughs were detected. No confirmed COVID-19 infections occurred after the second vaccine booster. The current study also demonstrated that the anti-SARS-CoV-2 titers decline 24-28 weeks after vaccine completion per other reports. However, administering the first and second COVID-19 vaccine boosters was associated with a significant increase in anti-SARS-CoV-2 levels and a subsequent sharp reduction in breakthrough infections. Overall, this study showed that booster doses have significantly reduced breakthrough vaccine infections and the risk of hospitalization or death in participants without and with comorbidities.
This study showed that some comorbidities influenced the vaccines' effectiveness and odds of acquiring COVID-19 after vaccination. Most post-vaccination symptomatic COVID-19 cases and related hospitalizations were observed in patients with comorbidities. Patients with diabetes mellitus, autoimmune diseases, malignancies, and participants with BMI > 40 showed lower VE and were more susceptible to infections and severe COVID-19 than healthy participants. Our findings and others [36,37] demonstrated that unvaccinated obese participants (BMI > 40) showed high susceptibility to acquiring and developing severe COVID-19 and increased risk of hospitalization. Furthermore, obese participants, particularly those with severe obesity (BMI > 40 kg/m 2 ), had lower VE than participants with reasonable BMI. Obesity is prevalent in KSA, as a national survey conducted between 1995 and 2000 found that the overall prevalence of obesity among Saudi adults was 36% [38]. Thus, obese patients are considered a high-risk group that must be prioritized for vaccination. In agreement with previous studies, this study showed increased incidence and severity of COVID-19 in patients with diabetes. Diabetes is a public health problem in Saudi Arabia; the World Health Organization (WHO) reported that Saudi Arabia ranks second highest in the Middle East and is seventh in the world for the rate of diabetes [39]. This study showed that COVID-19 infection occurred in 35% of diabetic unvaccinated control diabetic subjects. Some patients, particularly those with uncontrolled diabetes, developed a severe disease that needed hospitalization despite implementing strict prophylactic measures. Other studies reported similar observations [40][41][42][43][44][45]. Diabetes is a chronic disease associated with several metabolic, vascular, and immunologic abnormalities that can affect our response to pathogens. Hyperglycemia and insulin resistance induce oxidative stress and enhance the production of glycosylation end products (AGEs) and proinflammatory cytokines, which mediate tissue inflammation [46]. The inflammatory process may lead to higher infection susceptibility [46]. Unvaccinated cancer patients and those with autoimmune diseases were found in the current study to be highly susceptible to COVID-19 infection with severe symptoms. One study [47] enrolled 23,266 participants with cancer and 1,784,293 without cancer. A total of 10,404 positive COVID-19 cases were reported. Compared with participants without cancer, those living with cancer had a 60% increased risk of acquiring COVID-19. Cancer patients on current chemotherapy or immunotherapy treatment had a 2.2-fold increased risk of a positive test [47]. The present study showed reasonable vaccine response in patients with comorbidities, including diabetes, obesity, cancer, and autoimmune disease. After the second booster vaccine dose, no vaccine breakthrough was reported in this cohort. The findings of this study and another study [48] stress the benefit of booster vaccine doses in the high-risk population.
The COVID-19 vaccines' effectiveness demonstrated in this study was coupled with a low risk of adverse events. The adverse events of the three types of vaccines assessed in the current study are comparable to those reported in several studies [28][29][30][31][32][33]. Serious vaccine adverse events, severe allergic reaction/anaphylaxis, Guillain-Barré syndrome, thrombosis, thrombocytopenia, seizures, and myocarditis observed in this study were rare as they occurred in 10 (0.66%) participants, all of whom had comorbidities. Thrombosis without or with thrombocytopenia has been reported after COVID-19 vaccines [49,50]. The severe allergic reactions that occurred shortly after vaccination were promptly managed in the hospital. Two pre-vaccine controlled sickle cell disease (SCD) study participants developed vaso-occlusive crisis (VOC) and thrombosis shortly after AstraZeneca, an observation previously reported by some studies [51,52]. SCD patients vaccinated with BNT162b2, or mRNA-1273 did not suffer post-vaccine VOC. A patient with diabetes and valvular heart disease developed deep venous thrombosis following ChAdOx1 nCov-19 vaccine. One patient vaccinated with ChAdOx1 nCov-19 vaccine developed optic neuritis four days after receiving the vaccine and responded to steroid therapy. Recently, multiple reports were published on the development of optic neuropathy following COVID-19 vaccination [53]. Thus, high-risk patients with hypercoagulable states should be thoroughly investigated before vaccination, and careful selection of the suitable COVID-19 vaccine is recommended. Our study demonstrated myocarditis in two patients following BNT162b2 and ChAdOx1 nCov-19 vaccines, a post-vaccination observation reported by several studies [54][55][56]. Post-SARS-CoV-2 vaccination, Guillain-Barre syndrome occurred in the current study in a diabetic participant vaccinated with the BNT162b2r vaccine; however, the patient responded to steroids [57][58][59]. Collectively, our findings and the results of several studies demonstrated the safety of the COVID-19 vaccines and the rare occurrence of serious adverse events. Thus, the benefits of vaccination against SARS-CoV-2 are substantial and outweigh the associated risks.
In agreement with several studies [60][61][62], SARS-CoV-2 antibodies rose gradually after the first vaccine dose. However, significantly high titers were achieved after the second dose of ChAdOx1 nCoV-19, BNT162b2, and mRNA-1273 vaccines. A gradual decline in antibody titers over time was detected in our cohort between 24 and 32 weeks, an observation reported by several groups [60][61][62][63]. The booster doses evoked high SARS-CoV-2 antibody levels that exceeded those after the second vaccine. Although participants with comorbidities had slightly lower humoral immune responses and showed earlier antibody titer decay, they responded well to the booster vaccines as breakthrough infections were detected after the second booster. In this study cohort, participants with antibody titers ≤154 U/mL were at increased risk of acquiring COVID-19. Establishing a cutoff of SARS-CoV-2 that may predict an increased risk of post-vaccination breakthrough infections may help prioritize persons for COVID-19 boosters, individualizing the timing of boosters and conferring better protection, particularly with patients with comorbidities. Further prospective extensive studies are needed to investigate if monitoring the dynamics of SARS-CoV-2 antibodies SARS-CoV-2 antibodies may play a role in prioritizing the use of a limited supply of vaccines.
This study has several limitations. First, the study has not addressed the impact of vaccines on the various SARS-CoV-2 variants that emerged since the introduction of the COVID-19 vaccines. Diagnosis of post-vaccine COVID-19 was based on participants' self-reporting of symptoms. Thus, there may be a probability of missing asymptomatic cases. Finally, the study has not assessed vaccine efficacy and safety in individuals younger than 18 and children younger than 12.
In conclusion, the three evaluated COVID-19 vaccines were tolerable, safe, and effective in reducing COVID-19 and preventing severe disease. Furthermore, COVID-19 vaccination showed effectiveness and safety in individuals with comorbidities and those without any underlying medical disorders. In addition, the vaccine-induced SARS-CoV-2 antibody responses gradually decline. Booster vaccine doses induced significant maintained responses. SARS-CoV-2 antibody levels may help determine the timing and need for vaccine booster doses, particularly in patients with comorbidities.