Introduction

The COVID-19 pandemic first made itself known in 2019 and bought the world to a devastating halt. Since then, several anti-SARS-CoV-2 vaccines have been created, tested and subsequently administered to the human population in different parts of the world: in hopes of countering rapid spread of SARS-CoV-2 and; reducing the morbidity and mortality1,2. With the evolution of the SARS-CoV-2 virus and surge of it’s variants of concern, many countries are encouraging booster doses of these vaccines for continued immunity against the same3. While they offer immune effectiveness against the SARS-CoV-2 virus, several adverse effects or reactogenicities have also been reported following these vaccinations3,4.

Side effects or adverse reactions have also been reported in the oral cavity which may cause dysphagia, dysarthria and; alter the overall nutritional status and sense of well-being of an individual. With the government agencies pushing for booster doses against SARS-CoV-2, it is imperative to investigate oral side effects in depth as they have the potential to cause significant morbidity and affect the quality of life. Hence, this study aimed to evaluate the COVID-19 vaccination induced oral lesions, oral side effects or oral adverse effects.

Methodology

The present systematic review investigated the COVID-19 vaccine induced oral lesions, oral side effects or oral adverse effects as reported in the English literature. The study has been conducted and reported in accordance with the 2020 guidelines of preferred reporting items of systematic review (PRISMA)5.

Search strategy

An initial search strategy was developed using the MeSH terms ‘COVID 19 Vaccines’ AND ‘oral lesions’ AND ‘adverse effects’ with pilot search conducted on the Pubmed/ MEDLINE database. The final search strategy was refined by including the alternative terms (as suggested by the MeSH database) of ‘COVID 19 Vaccines’, ‘oral lesions’ and ‘Adverse effects’ and; the following databases were searched: Pubmed/ MEDLINE, Web of Science, Scopus, EMBASE and Google Scholar. All articles published till 30th June, 2022 in English language were considered for review. The results from the databases were exported to the an online tool: RAYYAN- intelligent systemic reviews6 - wherein duplicates were removed.

Inclusion and exclusion criteria

All studies fulfilling the PECO criteria were included in the review. The primary aim was to include all case reports, case series and observational studies describing oral lesions/ oral adverse effects (outcome) following anti-SARS-CoV-2 vaccination (exposure) within human population. All conference abstracts, reviews, letters to editors and correspondences were excluded. A study was also excluded if the type of vaccine was not mentioned.

Variables

Data collection was aimed at elucidating information regarding age, gender, ethnicity, country (where vaccination was received), comorbidities, time of the first appearance of the lesions, clinical description of the lesions, diagnosis of lesions, other tissues/ organs affected, concurrent adverse effects, treatment and management provided and; follow-up, if available.

Risk of bias

Risk of bias of the included studies was performed independently via the Joanna Briggs Institute Critical Appraisal tools for use in JBI Systematic Reviews7,8 by two review authors (SI Tables 3, 4). Any discrepancies were resolved by consultation with a third reviewer. The study variables were extracted by two blinded independent investigators in an excel spreadsheet which were later matched by a third investigator.

Data extraction

Following identification of studies via the aforementioned search strategy, blinded title and abstract screening was conducted via an online tool: RAYYAN- intelligent systemic reviews6. All the studies fulfilling the PECO criteria and the inclusion criteria were selected by 2 independent reviewers for full text screening. All conflicts were resolved in consultation with a third investigator.

Data analysis

A qualitative synthesis was performed with descriptive analysis for variables under study. A working classification (Table 1) was developed by categorizing the final diagnosis of the oral lesions post-COVID-19 vaccination.

Table 1 Classification of oral adverse events following COVID-19 vaccination.
Full size table

Results

Figure 1 depicts the study flow in the form of PRISMA chart. Following removal of duplicate search results, abstract and title screening; full text screening and risk of bias analysis: a total of 5 case reports and 2 case series were included for data extraction which comprised of 18 independent cases (Table S1)9,10,11,12,13,14,15. Majority of the cases were from South Korea (n = 09) and Italy (n = 05) followed by one case each from USA, India, Saudi Arabia and Iran. All the cases were published between 2021 and 2022. None of the included studies provided data on ethnicity of affected individuals. The vaccines following which occurrence of oral lesions have been reported are BNT162b2 (n = 10), AZD1222 (n = 06), mRNA 1273 (n = 01) and BBIBP-CorV(n = 01). The average age of occurrence of the oral lesions following COVID-19 vaccination was 59.94 years with an age range of 15–88 years. Only 3 cases were reported in individuals below 25 years of age (young adults) and all these subjects had received mRNA-based vaccinations (Tables S1 and S2).

Fig. 1
figure 1

PRISMA flow-chart.

Full size image

67% of the affected individuals were females (n = 12) with female to male ratio being 2:1. 77.8% (n = 14) of the reported cases had comorbidities or relevant past medical history: the most common comorbidity being hypertension (n = 07). Other reported comorbidities were osteoporosis (n = 03), diabetes (n = 02), hypothyroidism (n = 02), lichen planus (n = 02), cerebral infarction (n = 02), gastric disorders (n = 02), cardiac disorders (n = 01), mucous membrane pemphigoid (n = 01) and cerebrovascular stroke (n = 01).

Nearly 78% of the oral lesions occurred after first dose of COVID-19 vaccination. mRNA based BNT162b2 vaccine showed oral lesions after both first (n = 06) and second doses (n = 04) with one case having recurrent lesions after second dose; recombinant AZD1222 vaccine showed appearance of oral lesions only after first dose (n = 06); mRNA 1273 vaccine had lesions after first dose (n = 01) and; BBIBP-CorV after second dose (n = 01).

The median time taken for the first appearance of oral lesions after vaccination was 2 days with interquartile range (IQR) being 6 days. None of the affected individuals received any oral treatment prior to appearance of the lesions. The diagnosis of the lesions varied with Erythema multiforme minor, lichen planus, burning mouth syndrome and herpetic presentation having highest numbers (Table S2). Other reported diagnosis were trigeminal neuropathy, palatal petechiae, Sweet syndrome, secondary immune thrombocytopenia, toxic epidermal necrolysis and oral candidiasis. The median time duration of treatment was 18 days (derived from data of 15 cases); IQR of 18 days.

Discussion

Advent of SARS-CoV-2 brought about a worldwide change in the quality of life. It may be attributed to the initial reporting of high mortality and long-term morbidities associated with the viral infection. Many vaccines were initially developed to tackle the rapid spread and reduce the severity of symptoms of SARS-CoV-2. Since then, real world evidence regarding vaccine effectiveness, immunogenicity, safety and reactogenicity is being provided by several countries to ensure continued vaccine safety. We performed a Boolean search on Pubmed/ MEDLINE database with the key words: ‘adverse effects’, ‘COVID-19 vaccine’ and ‘real world’ with filter applied for meta-analysis. A single study (meta- analysis) was found which evaluated and compared all the SARS-CoV-2 vaccine effectiveness and safety in real-world studies without any demographic restrictions. The study reported an overall pooled incidence rate of 1.5% (95% CI: 1.4–1.6%) for adverse events with higher incidence of adverse events in health care workers and AZD1222 vaccine group. The authors also noted that most of the included studies collected adverse events within 7 days after vaccination and that the reporting of the adverse events in large population (size > 100,000) was much lower than that of small to medium population size. In 2021, Beatty et al. reported that the vaccine brand, age, number of vaccine doses, gender and history of COVID-19 infection were the strongest factors associated with adverse effects (AEs) following COVID-19 vaccination. This real-world digital cohort study reported that 64.9% of participants (n = 8682) reported adverse effects after first dose of BNT162b2 or mRNA-1273 and 80.3% participants (n = 11140) reported adverse effects after two doses of BNT162b2 or mRNA-1273 or 1 dose of JNJ-78436735. Fatigue, muscle pain, headache, chills, redness/swelling at the injection site, joint pain, and fever were the most common vaccine adverse effects16. Others have reported acute myocardial infarction, Bell palsy, cerebral venous sinus thrombosis, Guillain-Barré syndrome, myocarditis/pericarditis, pulmonary embolism, stroke, and thrombosis with thrombocytopenia syndrome as serious outcomes of COVID-19 mRNA vaccination17.

Of the four vaccines found to produce oral lesions in our review: two are mRNA vaccines (BNT162b2 and mRNA 1273), one is a viral vector vaccine (AZD1222) and one is an inactivated vaccine (BBIBP-CorV)18. The reported oral lesions can be primarily categorized as immune mediated events (n = 08), neurological events (n = 02), infectious events (n = 04) and others (n = 03) (Table 1).

Immune mediated events were reported after BNT162b2 (n = 04) and AZD1222 (n = 03); neurological manifestations after AZD1222 (n = 02); infectious lesions after BNT162b2 (n = 03) and AZD1222 (n = 01); other events (n = 03) after BNT162b2, mRNA 1273 and AZD1222. Diagnosis was unspecified in two reports10,12. A recent systematic review on immune-mediated adverse events post-COVID vaccination reported that the viral vector- based vaccines showed increased adverse events of thrombotic thrombocytopenic purpura/cerebral venous thrombosis/pulmonary embolism in comparison to mRNA based vaccines and inactivated virus vaccines and; mRNA based vaccines showed increased adverse events of renal complication, ocular complications and myocarditis in comparison to viral vector- based vaccines and inactivated virus vaccines19. Immune dysregulation caused by SARS-CoV-2 has been hypothesized to produce oral lesions20. In principle, this hypotheses can be extended to include SARS-CoV-2 vaccines as these vaccines rely on the native viral spike protein for inducing neutralising antibodies in the host21. Structural similarities have been documented between viral spike protein and human proteins which can account for molecular mimicry and misleading the immune system22. Clinical trials are currently underway to determine immune responses to COVID-19 vaccination23 and their results would determine further pathway for the clinical research.

Cutaneous lesions have been reported after COVID-19 vaccination, primarily: type I and type IV hypersensitivity reactions. It has been proposed that immune dysregulation caused by COVID-19 vaccinations may lead to viral reactivation24. In our study we found two cases of herpetic lesions (herpes zoster and herpes simplex) occurring in older individuals (>60 years) with hypertension as a common comorbidity. Data from vaccine adverse event reporting system (VAERS)- an open surveillance system in United States (U.S)- revealed that oral herpes was the most common adverse event reported post-COVID-19 vaccination25. A recent study on real world evidence assessing frequency of herpes zoster amongst individuals post-COVID-19 vaccination in comparison to unvaccinated individuals reported a risk ratio of 1.802 (95% CI = 1.680- 1.932). The authors reported a statistically higher incidence of herpes zoster post COVID-19 vaccination, albeit labeling it as a rare adverse drug reaction26. Alternatively, another U.S study has determined no risk for herpes zoster post-COVID-19 vaccination27. The varying results may be due to the differences in the type of vaccine administered or due to population-based differences.

In our study, we found female preponderance of oral AEs post-COVID-19 vaccination- similar to the results of Riad et al.25, Spirito et al.28 and Beatty et al.16. Female predilection for autoimmune diseases has been previously explored and several theories are afloat to explain the gender differences in immune mediated disorders including variation in immune reactivity, epigenetics, genetic predisposition and target organ susceptibility29,30.

In our study, older age group was found to have increased oral lesions following COVID-19 vaccination. This reinforces the role of adverse event charting in senior citizens, maintenance of a symptom diary and active counseling at the vaccination centers. It is imperative to re-evaluate such events in terms of health equity and health economics as such adverse events account for increased medical expenses and raises questions regarding health cost reimbursement. For a better perspective: In 2021, it was estimated that COVID-19 would cost low- and middle-income countries 52 billion US$, each four weeks to provide an effective healthcare response31.

Mucosal immunity against SARS-CoV-2 has been touted to determine the severity of symptoms in infected individuals. Prior exposure to mucosa (oral or nasal) of an antigen can ramp up not only the mucosal immunity but can also prime the systematic immune system as well32. The idea of establishing sterilizing immunity33 (elimination of a pathogen before it replicates in the host) has led to suggestion of the shift to mucosal COVID-19 vaccines which may be administered orally or nasally34. However, considering the oral adverse effects: this concept would require in-depth investigation before it’s promulgation in human population. Efforts are underway to understand the effects of oral mucosal immunity and oral microbiome on COVID-19 infection35.

Limitations

There is a scarcity of published literature on oral adverse effects following COVID-19 vaccination. Reporting bias, subclinical infections and poor sensitization of the affected individuals might account for the same.

Conclusion

We have concluded through our systematic review that there are several oral lesions and oral adverse effects that are seen primarily post first dose of vaccination. These were mostly seen in geriatric females with comorbidities. Most of the reactive lesions appeared within one week of mRNA based or recombinant vaccine administration and treatment was completed within approximately three weeks. Thus, it can be concluded that it is imperative to have an in-depth knowledge of oral side effects of post-COVID vaccination as they have the potential to cause significant morbidity and affect the quality of life.