Exploring the reported adverse effects of COVID-19 vaccines among vaccinated Arab populations: a multi-national survey study
Since the beginning of the COVID-19 pandemic, the focus of research has primarily been on COVID-19 symptoms and vaccinations. Despite the widespread administration of millions of vaccine doses worldwide, concerns about the safety and efficacy of vaccinations continue to be raised. To address this, our study aimed to investigate the adverse events (AEs) associated with different types and doses of COVID-19 vaccines across six Arabic countries during the fourth wave of the pandemic.
The variation in the number of vaccinated participants among the studied Arab countries reflects differences in vaccine availability and compulsory vaccine regulations. For example, Saudi Arabia initiated vaccination for children aged 12 and older in July 2021 and mandated that all citizens and residents receive a booster dose by February 2022. In contrast, compulsory vaccination policies and booster doses had not been implemented in the remaining five countries at the time of data collection46,47,48.
The pattern of AEs after each dose aligns with previous reports49. This may be attributed to the cumulative immunological effect of the second dose rather than a direct immunological response50. We observed a lower frequency of AEs after the second dose with many types of vaccines compared to the first dose. However, we reported an increase in the frequency of AEs after the Sputnik V vaccine, local AEs after the Sinopharm vaccine, systemic AEs after the Pfizer-BioNTech vaccine, and serious AEs after the Johnson & Johnson (J&J) vaccine. Previous studies have shown different trends, with higher local and systemic AEs reported after the second dose of Pfizer-BioNTech and AstraZeneca vaccines26,50,51,52.
In our study, the most prevalent local AEs, such as pain, redness, and swelling at the injection site, were reported after the Pfizer-BioNTech, AstraZeneca, and Sinopharm vaccines. Previous studies conducted in the reported varying percentages were reported after the first and second doses20,26,53. The most commonly reported general AEs were fatigue, body aches, fever, headache, and myalgia, which is in line with published studies20,49.
Headache was reported in more than 50% of participants after the AstraZeneca vaccine54,55,56. There are no details about the pathophysiologic mechanisms, whether the intracellularly synthesized spike protein is produced by using mRNA vaccines, or the protein triggers the immune response from activated anti-inflammatory mediators such as prostaglandins, nitric oxide, and cytokines. Headache is the leading symptom of cerebrovascular thrombosis (CVT), including vaccine-induced ones. So, it’s important to distinguish between vaccine-induced headaches and those caused by cerebrovascular thrombosis54,55,56.
Visual disturbances were reported by a small number of participants. There are reported cases of transient loss in the visual field due to possible acute vasospasm of the artery in the postchiasmatic visual pathway, triggered by the COVID-19 vaccine that resolved after two hours57. In other cases, macular detachment and severe choroidal thickening were detected causing visual loss and suggesting a potential inflammatory or autoimmune response to the vaccine58,59,60.
Elevations in blood pressure were observed among some vaccinated participants, which is consistent with reports of blood pressure surges after mRNA vaccines and an increase in home blood pressure after the first mRNA vaccine dose. Some patients required modification of anti-hypertensive drugs. This may be attributed to nervousness or white-coat hypertension. However there was no baseline data, and BP follow-up over a long period after vaccination is very important56,61.
Menstrual changes were reported among vaccinated females and it is noteworthy that by September 2, 2021, over 30,000 COVID-19-vaccinated females had reported menstrual changes to the United Kingdom’s Medicines and Healthcare Products Regulatory Agency (MHRA) Yellow Card surveillance system12,62. This might be a result of immunological effects on the hormones that regulate the menstrual cycle or biological effects of immune cells on the uterus lining, which contribute to the tissue’s cyclical building and breaking down12,63.
Rheumatological symptoms such as bone pain, myalgia, body aches, and weariness were reported in our study, similar to some studies conducted in Italy, Libya, Iran, China, and Turkey61,63,64,65,66,67. These symptoms might be attributed to the immune response triggered by the vaccine, leading to transient inflammation and musculoskeletal discomfort26,68. It is important to note that these symptoms are generally self-limiting and resolve within a few days after vaccination. The association between COVID-19 vaccination and the occurrence of certain symptoms remains uncertain when compared to other vaccines. The hyper-inflammatory response triggered by the COVID-19 vaccine raises concerns about its potential as a risk factor for inflammatory musculoskeletal disorders. This cytokine activation can be attributed to the SARS-CoV-2 spike protein, other components of the vaccine, or the adenoviral vector used67,68.
New-onset autoimmune manifestations, including Guillain-Barré syndrome (GBS), rheumatoid arthritis, and systemic lupus erythematosus, have been reported in eleven cases following COVID-19 vaccination, particularly after the first dose. The precise nature of the link between the COVID-19 vaccine and autoimmune symptoms is still unclear, whether it is coincidental or causal. Molecular mimicry, the generation of specific autoantibodies, and the influence of specific vaccination adjuvants are all thought to play a role in the development of autoimmune diseases63,69. For instance, we documented one case of GBS, a rare autoimmune neurological disorder that affects the peripheral nerves and nerve roots. GBS has been associated with other vaccines such as rabies, hepatitis A and B, influenza, and more recently, the COVID-19 vaccine70,71.
In this study, we documented the occurrence of symptoms suggesting vaccine-induced myocarditis and pericarditis, including chest pain (88 cases), shortness of breath (103 cases), and sensations of a fast-beating, fluttering, or pounding heart (34 cases). These presentations align with the CDC report on these conditions72. Our findings are consistent with previous research indicating that COVID-19 vaccine-related myocarditis primarily affects young men and is more commonly associated with mRNA vaccines such as those developed by Pfizer-BioNTech and Moderna73.
We observed a statistically significant difference in the occurrence of serious adverse events (AEs) among different vaccine types. We identified 10 cases of VITT out of 3,239 vaccine doses, which is a rare syndrome involving venous or arterial thrombosis at unusual sites such as cerebral venous thrombosis (CVT) and splenic thrombosis. Additionally, we found 10 cases of thrombosis out of 3,239 vaccine doses, a comparable rate to reports from the US (17 cases of VITT, 14 cases of thrombosis out of 7,000 participants after the J&J vaccine) and lower than the European Medicines Agency (EMA) (222 cases of thrombosis out of 35 million participants after the AstraZeneca vaccine)74,75. VITT occurs when DNA leaks from the imperfect adenoviral vector used in AstraZeneca and J&J vaccines, infects cells, binds to platelet factor 4 (PF4), and triggers the production of anti-PF4 autoantibodies76.
We also discovered a significant increase in post-vaccination COVID-19 cases among individuals previously infected with COVID-19. Such findings may raise the issue of the benefit of vaccines for people who were previously infected with SARS-CoV-2. It is noteworthy that a study conducted in Kentucky (May–June 2021), reported an odds ratio of 2.34 (95% CI 1.58–3.47) of re-infection among unvaccinated participants compared to those who were fully vaccinated, suggesting that full vaccinations after a past SARS-CoV-2 infection provide additional protection by decreasing its transmissibility by shortening the duration of infectivity and so decrease the transmissibility77. Therefore, vaccination should be offered to all eligible individuals regardless of their previous infection status. While there is limited epidemiological evidence supporting the benefits of vaccination for previously infected individuals, our study supports the notion.
Regarding the frequency of post-vaccination COVID-19 in relation to the number of doses, the interpretation of the increase in infections after the second dose is still uncertain. Cumulatively, they were part of the sample that received the first dose, resulting in a significantly lower difference. Notably, the second dose can cause up to a tenfold increase in antibody levels, a stronger T-cell response, as well as more changes in the immune cells. Moreover, multiple variants of SARS-CoV-2 have emerged, primarily focused on the spike protein, a crucial element for developing vaccine candidates. Diverse vaccinations are currently undergoing clinical trials and demonstrating remarkable outcomes, however, their effectiveness still requires evaluation in various SARS-CoV-2 variants4,20.
Strengthens and Limitations:
We carried out a multicenter study in six Arab countries that included the assessment of AEs associated with eight different vaccine types. We were able to identify several associated factors with post-vaccination AEs, which can aid in monitoring and follow-up efforts during and after vaccination campaigns. Additionally, our study included patients from a previous wave of COVID-19, allowing us to track AEs across different vaccine doses. However, it is important to acknowledge the limitations of our study. Firstly, being an observational study, it is susceptible to bias and confounding issues. Secondly, the use of an online self-administered survey introduces limitations such as data accuracy concerns due to recall bias, sampling bias (as more than 80% of participants were well-educated), and availability bias (excluding individuals who couldn’t access or use the Internet, and those who were illiterate or deceased). Thus, our study population may not represent the entire population. Furthermore, assessing SARS-CoV-2 infection rates after vaccination is complicated by the presence of the delta variant and other variants of concern, especially as the immunity from previous vaccinations may be waning. The timing between the first and second doses is relatively close together, but the interval between the second and third doses can vary widely across countries. The availability of COVID-19 confirmatory testing in the studied countries also affects the diagnosis of infection rates, potentially missing asymptomatic cases. Another limitation is the lack of assessment of participants’ pre-COVID-19 vaccine health status, making it challenging to differentiate pre-existing health issues from those related to the COVID-19 vaccine. The use of a reporting system for the participants to report the AEs themselves can introduce bias in exaggerating or underreporting some AEs. Although these limitations exist, our findings are consistent with those of other international studies. Lastly, the variation in response rate among countries with a low number of responses in some e.g. Syria may be due to the method of sample collection using an online questionnaire, compounded by political unrest in some countries (e.g. Syria) hindering internet access. It is important to interpret the data of vaccine and AE rates while considering such political conditions for further extensive studies. Such variation can affect the generalizability and comparisons of results among such countries.
