A landscape on disorders following different COVID-19 vaccination: a systematic review of Iranian case reports

COVID-19 as the most recent global pandemic, typically presents as lower respiratory tract infection which may lead to severe symptoms [1, 2]. To date, vaccines have been one of the most effective ways to control the infectious diseases [3, 4]. Fortunately, vaccination against COVID-19 was explored at the right time and led to fast outcomes through different platforms and hopefully pandemic control [5, 6]. Nevertheless, booster shots are still recommended as the immunity wanes over the time and new variants are capable to escape from immune system [7, 8].

From another point of view, the quick procedure of vaccine development could possibly have lately unsolicited events beside the immunity protection. Many studies have shown SARS-CoV-2 manifestations through which the virus affects the host in various presentations even in a late episode [9, 10]. As the number of vaccinated individuals grows up, the knowledge of possible and probable vaccine effect develops through case reports and safety studies [11, 12].

Although the exact mechanism through which the vaccine components can manipulate human body is not clear yet, the cumulative and comparative data would bring sufficient data especially by the follow-up programs.

Early studies on COVID-19 vaccines-related adverse events (AEs) mainly reported local reaction at the site of the injection and some temporary systemic side effects which normally lasted few days, among which fever, headache and fatigue were the most common ones. Moreover, further investigation indicated that the AEs are mostly mild, hence individual daily activities are not normally interfered with [13, 14]. A cross-sectional study in Nepal, presented higher rate of vaccine adverse events after the first dose of both vaccines, while a follow-up study from Iran demonstrated that the vast majority of the vaccine-related AEs were set after receiving the booster shots [15, 16]. It should be also noticed that, COVID-19 vaccination has been the most recently administrated vaccine worldwide and the massive studies and reports on the related side effects are naturally highlighted. However, comparison of advantages and disadvantages of COVID-19 vaccines has shown that it is still recommended. It has been assumed that there will be more in cardiovascular diseases due to spike proteins encoded in vaccines [17, 18]. Furthermore, there is a possible threat of unknown organ hurt caused by the immunization which is still hidden. Thus, any type of study in this era regarding vaccine safety seems highly practical for future vaccine programs. Along with the different type of the conducted studies on COVID-19 vaccination, case report studies have been massively published. Owing to the fact that this kind of study provides a detailed report of many aspects, including symptoms, diagnosis and follow-up of individuals, they could possibly bring a new insight to the COVID-19 vaccines-related side effects. Furthermore, these reports usually describe a novel or unusual incidences in a faster window time than cross-sectional research or follow-up studies. According to several case reports post-vaccination against COVID-19, the present study aimed to classify the new onset of disorders in Iranian individuals with no previous related medical history. The present data provides a better overview of documented COVID-19 vaccine-related disorders along with the cases’ characteristics and the treatment/follow-up after administration of primary and/or booster doses. Furthermore, the screened disorders post vaccination are classified based on the organ involvement to facilitate the recognition of adverse events prevalence, time of the incidence and the final outcome.

The initial search yielded 437 studies. After duplication removal, 250 papers were investigated regarding the titles and abstracts from which 128 articles were excluded according to the eligibility of the criteria including the case reports which had the same medical history or those with insufficient data. Eventually 40 manuscripts met the criteria of the systematic review.

A total of 64 cases including 31 females and 33 males with a mean age of 47.67 ± 17.69 and a range of 18 to 91 were investigated from whom 60% had no remarkable medical history. The previous history of COVID-19 was rare among the cases and all the COVID-19 PCR tests were negative at the time of manifestation (Tables 1, 2, 3 and 4).

The reported COVID-19 vaccines in the studied cases included BBIBP–CorV (Sinopharm).

(n = 35), ChAdOx1 nCoV-19 (AstraZeneca) (n = 22), Sputnik V (n = 6) and COVAXIN (n = 1).

The median of duration between the vaccination and any appeared event was 7 days (range: 1–60). Of 64 cases, 52 ones experienced a type of manifestation post-first dose, 10 post-second dose and only 2 after the booster shot.

COVID-19 vaccine triggered different manifestations from which cutaneous disorders (Table 1) were spotted as the most frequent one accounting for 43.7% (n = 28) followed by neurologic problems (Table 2) in 25% of the cases (n = 16). Other unsolicited events included blood/vessel involvement (n = 6), cardiovascular involvement (n = 5), ocular disorders (n = 4), liver disorder/failure (n = 2), graft rejection (n = 2) and one metabolic disorder (Tables 3 and 4). The median duration of improvement after the symptom onset was 10 (range: 2–120) days.

Cutaneous involvement presented in various forms, such as alopecia, lichen planus, rash, dermatitis and stromal keratitis. Notably, the dermal manifestation occurred equally on both men and women among whom only one person had a history of COVID-19. The other interesting finding is that rare diseases were also screened such as Steven–Johnson syndrome, Morphea and Toxic Epidermal Necrolysis (TEN). BBIBP–CorV, ChAdOx1-S and Sputnik V vaccines led to 21, 6 and 1 cutaneous disorders, respectively. Finally, almost 90% of the skin manifestations were fully or significantly improved after the applied treatment (Fig. 2, Table 1).

In addition to type of disorders, we also evaluated the recovery time as well. To achieve that, the provided data were categorized to 6 outcomes as resolved, significant improvement, partial improvement, under treatment, not-treated and expired. Based on the outcome statement of the studied cases, of 64 incidences, 13 were resolved, 33 were significantly improved and 10 were partially improved. 4 cases were under treatment, one remained untreated and 2 cases expired. Three studies did not mention the outcome. Therefore, 73% of all the cases were either significantly improved or fully recovered from the incidence.

According to the available statements, 20 cases were hospitalized and 22 ones were recommended to be followed-up in the schedule varying from 14 days to 6 months.

Neurological problems were mostly induced by ChAdOx1-S (n = 8) followed by BBIBP–CorV (n = 5) and Sputnik V (n = 3). Guillain–Barre syndrome and Bell’s palsy were the most common ones. Totally, 62.5% of these problems met significant improvement or were resolved (Fig. 2, Table 2).

The most serious vaccine outcomes might be acute liver failure which was captured in two ChAdOx1-S recipients and led to expiration. Both cases were young (34 and 35 years) with no similar medical history (Table 4). Both incidence occurred post-first injection one after 2 and the other after 8 days [52, 53].

Massive vaccination campaigns have been launched since December 2020, applying mRNA vaccines and also the viral vector-based vaccine as well as inactivated viral-based and recombinant protein vaccines. By the end of January 2023, more than 5 billion individuals were fully vaccinated [42]. Thus, there is an increasing rate of reports over the adverse events associated with the administrated vaccines in the real world. General symptoms which have been normally screened include weakness, fever/chills, body pain, headache and local injection-site reactions. These symptoms are usually transient and do not normally need to be treated with specific medical care.

Herein, we discussed 64 cases of 40 studies who experienced unsolicited events after vaccinating against COVID-19. The applied vaccines included viral-vector and inactivated virus-based vaccines. We tried to select the case reports with new onset of the symptoms in whom the pre-existing comorbidity was not as same as the triggered adverse events. Various disorders were captured induced by different vaccines suggesting that the type of a specific regimen is not the only factor in outcomes. Moreover, there is not enough clues to support the triggered manifestations and their association with the applied vaccine. However, the healthy individuals who did not have any remarkable medical history and experienced serious events suggest that this potency of COVID-19 vaccine must be considered.

The common reported adverse events of ChAdOx1-S vaccine were pain at the injection site, fever, lethargy, muscle pain and headache which were mostly screened after the first dose of the vaccine [60]. The investigation by Pasteur Institute of Iran on ChAdOx1-S vaccine showed that a higher incidence of symptoms including fatigue, chills and myalgia were seen among homologous ChAdOx1-S recipients rather than those of a heterologous ChAdOx1-S/PastoCovac Plus group [61]. Moreover, irritability, nausea, myalgia, and chills some hours after vaccination with AZD1222 were reported in Nepal [62]. In addition to common adverse events, severe disorders were captured as postural drop in blood pressure, abdominal cramps, syncope and urticarial [63]. In this review, we found that ChAdOx1-S mostly led to neurological incidences, including encephalopathy [20], acute vestibular neuritis [34] and Guillain–Barre syndrome [38]. Although the safe administration of vaccines is a crucial factor, many unusual events following ChAdOx1-S vaccine have been reported. The Concern about neurological abnormalities regarding COVID-19 vaccines firstly rose in 2020 when some cases of Guillain–Barré syndrome and transverse myelitis were screened post-Oxford/ChAdOx1-S vaccine [64, 65]. In a recent comprehensive study on COVID-19 vaccines-related AEs, the most common observed neurological disorder was also Guillain–Barre syndrome. However, no association between the vaccines and the syndrome has been confirmed yet [66].

On the other hand, ChAdOx1-S has been the only cause of liver disorder in forms of Fulminant hepatitis [53] and acute liver failure which led to death in both cases in the present studied cases [52]. The previous studies on liver injury after COVID-19 vaccination of different platforms showed that mRNA-based vaccines and the vector-based ones both contributed to the captured disorders among which Pfizer‐BioNTech vaccine led to a liver failure [67]. Liver injury following COVID-19 vaccination is also investigated in a systematic review on individuals who got to Moderna (mRNA–1273), Pfizer–BioNTech BNT162b2 mRNA or ChAdOx1 nCoV-19 vaccine. Nevertheless, in those cases, pre-existing comorbidities was common as 69.6%, such as liver disease. The mortality rate due to live disorders was reported 4.3% [68].

The other adenovirus-based vaccine, Sputnik V, was also previously reported with fever/chills, general discomfort, headache arthralgia, myalgia, asthenia, tenderness as the common side effects [69, 70]. Similar to ChAdOx1-S, this vaccine mostly led to neurologic manifestations as Bell’s Palsy and Facial Paresis [31, 35]. Previous review study found Pfizer and Moderna vaccines as the most common reported causes of Bell’s palsy; however, COVAXIN and Sputnik V also led to it as well [71].

According to conducted studies in China, inactivated viral-based vaccines led to adverse events including injection site pain, lethargy and muscle pain 15.6% after the first and 14.6% after the second dose among the healthcare workers. The most common is pain at the injection site, followed by fatigue, muscle pain, and headache [72, 73]. Furthermore, two serious events as multiple sclerosis and emesis were also recorded with hospitalization requirement [74, 75].

In the present review, BBIBP–CorV vaccine resulted in corneal graft rejection in to cases a week after the first dose of injection [59]. In a study by Shah AP et al., four cases with a history of keratoplasty developed rejection after being vaccinated with mRNA-1273 [76]. This incidence has also been reported after adenovirus vector (AZD1222) and mRNA (BNT162) vaccines [77]. A systematic review also showed that Cornea rejection was the most reported organ rejection after vaccination against COVID-19, followed by kidney and liver rejections [78].

Dermal abnormalities have been the most frequent reported incidences after BBIBP–CorV vaccine among which new-onset lichen planus (LP) was observed in 6 cases [29]. Nevertheless, rare conditions were also screened, such as Toxic Epidermal Necrolysis [27], Morphea [25] and Pemphigus vulgaris [28]. Notably, of 28 skin disorders in the reported cases in this review, 20 cases got BBIBP–CorV vaccine. The other study from Iran evaluated the cutaneous reactions post-COVID‐19 vaccination which presented that most of the individuals showed symptoms after injection of ChAdOx1-S, BBIBP–CorV, Sputnik V, and COVAXIN vaccines [79].

Herpes zoster has been reported in case series and has also been documented in the Center of Disease Control following COVID-19 vaccines (VAERS). There are more than 1000 cases with mRNA vaccine-triggered herpes zoster in VAERS, mostly aged over 60 [80]. We also found a reported case of Herpes Zoster in a 60-year-old healthy woman 6 days after the first dose of BBIBP–CorV vaccine [25]. It has been suggested that molecular mimicry between the human components and vaccine‐induced proteins could lead to pathological autoantibodies generation and hence, autoimmunity accordingly [81].

As previously discussed, a quarter of the investigated cases experienced neurological involvements mostly as Guillain–Barré syndrome [38] and Bell's palsy caused [35] which were triggered by adenovirus-based vaccines and also BBIBP–CorV. Although the most incidences were captured post-first dose, a 60-year-old man presented Guillain–Barré syndrome 20 days after the BBIBP–CorV booster shot [82]. The correlation between Bell's palsy and vaccinations has been introduced previously, such as influenza H1N1 monovalent vaccine and intranasal inactivated influenza vaccine [83, 84]. Similar to other unknown mechanisms of vaccine induced problems, precise pattern of neurologic disorders is still under question. Some hypothetical thoughts though propose that autoimmune phenomenon as a result of host molecules mimicry with the vaccine antigen could activate auto‐reactive T cells [85].

Blood/vessels involvement were also reported in 6 cases as vasculitis, thrombotic thrombocytopenia, Cerebral venous sinus thrombosis, acquired thrombotic and lymphocytic vasculopathy caused by BBIBP–CorV and ChAdOx1-S [20, 44‐46, 86]. Notably, all the cases presented the manifestation after the first dose of vaccination. A review study showed that thrombotic complications occurred 5–25 day post-first dose of ChAdOx1-S vaccinated individuals in which the thrombosis site was mostly in cerebral veins [87]. Although the exact mechanism of the events is not well-understood, the pre-existing antibodies such as heparin-PF4 antibody in the cases might give rise to the manifestations [88]. In addition, vasculitis precipitation has been also detected after other vaccines against hepatitis B virus (HBV), influenza virus and human papillomavirus (HPV) [89].

Although the discussed disorders have been screened post-vaccination, it is suggested that host immune responses are strongly the potential cause of the events. It is to say that, anti-spike immune responses might be linked to post-vaccine syndromes as all the vaccines against COVID-19 encode the whole or a part of spike protein. In addition to spike protein, anti-idiotypic antibodies can bind to the ACE-2 receptor as well [90]. Furthermore, the generated autoantibody stemming from molecular mimicry and independent immune-dysregulation may both contribute to a symptom onset [91]. However, it must be taken to attention that these mechanisms are still theoretical and have not been established as causal factors yet. Further studies are crucial to provide enough evidence.

In the present review, a comprehensive overview of COVID-19 vaccine-related case reports has been conducted. The classification of the vaccine-related AEs could make the recognition much easier and would contribute to further vaccine administration as well. Nevertheless, this study is only based on case reports which normally include inherent data quality and causality limitations and provides conclusive evidence of a causal relationship between the administered vaccines and the adverse events. Eventually, a comprehensive causality assessment in future studies to establish a more robust link between vaccinations and adverse events is of a high value owing to the fact that assessment the causality based on case reports would not be sufficient to draw general conclusions about vaccine safety. Eventually, case reports are often subject to selective reporting, which might have influenced the findings.

The present review showed that various unsolicited adverse events have been captured as case reports in Iran. Interestingly, all the vaccine platforms could result in similar unsolicited events. Although, clinical trials provide safety data, the long-term evaluation of newly launched vaccines are essential to keep the public trust balanced.

COVID-19 has been the most recent mass vaccination program due to the broad range of infection world-wide. Thus, it is not far from view to face some rare disorders or late onset of a disease. Considering the advantage of the vaccination against SARS-CoV-2 which eventually led to the chaos management globally, the number of unsolicited AEs are not significant. However, the collective data from different populations would result in a better perspective for further vaccination program. The high risk individuals including those with a history of serious disease or comorbidities and those with immunodeficiency conditions should be vaccinated with the utmost caution. Future research to establish causality, the importance of continuous vaccine safety monitoring and the potential benefit–risk assessment for different populations are strongly recommended.