Characteristics of Oral Adverse Effects following COVID-19 Vaccination and Similarities with Oral Symptoms in COVID-19 Patients: Taste and Saliva Secretory Disorders

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which first emerged in Wuhan, China, in December 2019, had spread rapidly around the world. Since then, several COVID-19 waves occurred with appearance of different variants of SARS-CoV-2, resulting in SARS-CoV-2 infections of more than 704 million people worldwide and more than 7 million deaths as of 13 April 2024 [1]. Mass vaccination is one of the primary measures to be free from the threat of deadly infection with SARS-CoV-2 and keep the spread of COVID-19 under control. Immediately after the global pandemic, energetic efforts were made to develop COVID-19 vaccines throughout the world [2]. As of 2 December 2022, there were 242 vaccine candidates and 50 approved vaccines [3]. In early December 2020, BNT162b2 vaccine was first authorized for emergency use in the UK, with the subsequent approvals or authorizations in Bahrain, Canada, Mexico, Saudi Arabia, and the USA [4]. Representative COVID-19 vaccines are mRNA vaccine from Pfizer-BioNTech (BNT162b2, Comirnaty^®) and Moderna (CX‐024414, Spikevax^®), adenoviral vector vaccine from AstraZeneca (ChAdOx1-S, Vaxzervria^®), Johnson & Johnson/Janssen (Ad26.COV2.S, Jcovden^®), and CanSinoBIO (AD5-nCOV, Convidecia^®), spike protein subunit vaccine from Novavax (NVX‐CoV2373, Nuvaxovid^®), and inactivated virus vaccine from Sinovac (CoronaVac) and Sinopharm (BBIBP-CorV).

The advantage of vaccines outweighs the risk of their adverse events or side effects. However, there is increasing evidence that COVID-19 vaccines exhibit a variety of adverse effects, possibly leading to an increase in vaccination hesitancy. Besides pain at the injection site, vaccinated people suffer from fatigue, headache, myalgia, fever, nausea, vomiting, arthralgia, and chills [5], and rarely from serious events like anaphylaxis, myocarditis, thrombocytopenia, and Guillain Barré syndrome [6]. COVID-19 vaccination also has orofacial adverse effects such as Bell’s palsy, facial paralysis, face/tongue/palate swelling, and oral mucosal ulceration [7]. Drugs and medications, including vaccines, adversely affect taste perception [8] and salivary secretion [9], in which saliva secretory disorders frequently coincide with taste disorders. While oral adverse effects are rare in non-orally administered vaccines, COVID-19 vaccine recipients who are negative for reverse transcription-polymerase chain reaction (RT-PCR) complained of taste alterations [10] and oral dryness [11].

Patients infected with SARS-CoV-2 develop fever, headache, cough, dyspnea, myalgia, arthralgia, fatigue, myocarditis, arrhythmia, and chemosensory disorders. Interestingly, some of them have also been observed after receiving COVID-19 vaccines. Post-vaccination adverse effects have been related to COVID-19 symptoms as reported for headache, fever, fatigue, myalgia, and arthralgia [12‒14].

Although neither taste disorders nor saliva secretory disorders are life-threatening, both of these disorders have a negative impact on the overall quality of life and can cause other health complications. However, oral adverse effects following COVID-19 vaccination have been poorly understood in contrast to post-vaccination systemic and serious events [15‒17]. Oral side effects of COVID-19 vaccines were recently investigated by two different research groups, Arabzadeh Bahri et al. [18] and Riad et al. [19‒21]. Arabzadeh Bahri et al. [18] systematically reviewed anosmia or ageusia caused by COVID-19 vaccines, but their review was limited to only 11 cases and did not include saliva secretory disorders. Riad et al. [19‒21] performed a series of excellent studies to analyze adverse events within the oral cavity following COVID-19 vaccination. It was suggested that chemosensory disorders are not limited to the course of COVID-19 but also occur after COVID-19 vaccination [18] and their pathophysiological causes may be similar to those of COVID-19 symptoms [10]. However, there have been no reports that focus on similarities and/or differences between oral adverse effects following COVID-19 vaccination and oral symptoms in COVID-19 patients.

Taste disorders (taste impairments caused by gustatory dysfunction) are composed of ageusia (complete loss of taste sense), dysgeusia (distortion or alteration of taste sense), and hypogeusia (reduced sense of taste), and saliva secretory disorders (intraoral dry conditions caused by salivary dysfunction), of xerostomia (complaint of oral dryness) and dry mouth (feeling and objective finding of oral dryness). The aim of the present study was to characterize ageusia, dysgeusia, hypogeusia, xerostomia, and dry mouth following COVID-19 vaccination, and assess their similarities with oral symptoms in COVID-19 patients which may provide some clues to speculation of the underlying pathophysiology.

A literature search was conducted in databases, including PubMed, LitCovid, and Google Scholar. There have been inconsistencies in the description of taste disorders and saliva secretory disorders in the literature. In order to avoid ambiguity in expressing oral adverse effects, “ageusia,” “dysgeusia,” “hypogeusia,” “xerostomia,” and “dry mouth” were used as keywords for retrieving relevant articles in addition to “COVID-19,” “vaccination,” and “vaccine.” Keyword combinations were categorized into two groups, the COVID-19 vaccination and taste disorder group and the COVID-19 vaccination and saliva secretory disorder group. The keywords were combined with “OR” in each group and with “AND” for oral adverse effects following COVID-19 vaccination. The articles published since January 2021 were retrieved with a cutoff date of 31 July 2024 because COVID-19 vaccine was first authorized for emergency use in December 2020. The exclusion criteria were articles not published in English, non-peer-reviewed articles, case reports, studies recruiting participants not diagnosed by RT-PCR, and studies including patients with Sjögren’s syndrome. Cited articles in the retrieved articles were further searched for additional references. Collected articles were reviewed by title, abstract, and text for relevance.

In the evaluation of the vaccine type-dependence of taste and saliva secretory disorders, their prevalence after using different types of vaccines was analyzed by one-way ANOVA and the results were expressed as mean ± SD (values of *p < 0.05 and **p < 0.01 considered statistically significant). Oral adverse effects associated with spike protein subunit vaccines were not subjected to the statistical analysis because their prevalence data were reported by only one study.

COVID-19 patients are symptomatically characterized by ageusia, dysgeusia, hypogeusia, xerostomia, and/or dry mouth [22, 23], which have been referred to as one of the diagnostic criteria for COVID-19. While their prevalence is variable across studies, these oral symptoms of SARS-CoV-2 infection have a prevalence of 1–96% for taste disorders [24‒27] and 13–62% for saliva secretory disorders [25‒28].

Regarding post-vaccination oral adverse effects, the literature search yielded 374 and 75 articles for taste disorders and saliva secretory disorders, respectively. After removing duplicate articles, 243 and 41 articles remained for the initial screening of their titles and abstracts. After excluding articles meeting the exclusion criteria and not meeting the present study subject, 37 and 34 articles were selected and enrolled for evaluation of their full texts. After evaluation, 17 studies [19‒21, 29‒42] on ageusia, dysgeusia, and/or hypogeusia with a total of 108,988,864 vaccine recipients and 12 studies [19‒21, 32, 39, 41‒47] on xerostomia and/or dry mouth with a total of 2,814,320 vaccine recipients were used to characterize oral adverse effects following COVID-19 vaccination.

The narrative review indicated that COVID-19 vaccination can cause taste disorders and saliva secretory disorders, as shown in Figure 1, which was prepared by aggregating the prevalence data from the retrieved studies [19‒21, 29‒47]. Overall mean prevalence (±SD) was calculated to be 0.310 ± 0.355% for ageusia, 0.288 ± 3.984% for dysgeusia, 0.022 ± 1.307% for hypogeusia, 2.058 ± 4.448% for xerostomia, and 0.239 ± 2.399% for dry mouth. Oral adverse effects following COVID-19 vaccination are considered to occur in a certain number of vaccinated people, while they are rare compared with oral symptoms in COVID-19 patients. Vaccine recipients in the same cohort develop both taste disorders (a total of 5,732 reports by the recipients) and saliva secretory disorders (2,487), both dysgeusia (98) and xerostomia (69), or both dysgeusia (5,273) and dry mouth (2,418) [19, 21, 32, 39, 41, 42], indicating that impairments of taste perception and salivary secretion occur almost simultaneously after COVID-19 vaccination. High standard deviation values in the calculated prevalence suggest the possibility that the occurrence of taste and saliva secretory disorders is determined by some factors associated with COVID-19 vaccines and/or vaccine recipients. As observed in seasonal influenza vaccines [48], oral adverse effects of COVID-19 vaccines are presumed to differ by country/region, gender/sex, age (younger or older), vaccine type, vaccine manufacturer/brand, and vaccine dose [49, 50].

Oral adverse effects following COVID-19 vaccination were found to vary by country or region as shown by their prevalence in individual countries or regions in Figure 2, which was prepared as a box-and-whisker plot by using the available data on ageusia, dysgeusia, and/or hypogeusia [19‒21, 29‒42] and on xerostomia and/or dry mouth [19‒21, 32, 39, 41‒47]. Compared with the European region, the prevalence of ageusia is higher in Saudi Arabia and India (Fig. 2a). Dysgeusia is most prevalent in Pakistan, followed by India, Poland, Germany, and Turkey (Fig. 2b). India has a high prevalence of hypogeusia (Fig. 2c). Xerostomia and dry mouth are particularly prevalent in Pakistan (Fig. 2d) and China (Fig. 2e), respectively.

Similar to post-vaccination oral effects, oral symptoms in COVID-19 patients show a geographical difference in taste disorders that their prevalence is 48–62% in Europe (Italy, France, Spain, Germany, Switzerland, the UK, Denmark, Sweden, and Poland), 59–63% in North America (the USA and Canada), 76% in South America (Brazil), 4–13% in East Asia (China, Japan, South Korea, and Singapore), and 39–40% in the Middle East (Iran, Israel, Turkey, and Qatar) [24, 51]. In the European region, the prevalence of dysgeusia is highest in Belgium, followed by the UK, Italy, Germany, Poland, and France [51]. When comparing chemosensory dysfunction between different countries, the rates of ageusia and anosmia in Western countries, including the UK, Italy, France, Spain, Germany, and the USA, were higher than those in East Asian countries including China, Japan, South Korea, Singapore, and India (60.9% vs. 15.8%) [52]. A systematic review and meta-analysis indicated an ethnic difference in COVID-19 symptoms that Caucasians have three times the higher prevalence of gustatory and olfactory dysfunctions than Asians (54.8% vs. 17.7%) [53]. During the acute phase of SARS-CoV-2 infection, xerostomia and dry mouth were reported in 46% of Chinese patients, 30–46% of Italian patients, 56–62% of Israeli patients, and 60% of Iranian patients [28], respectively. Such geographical differences have been speculated to occur due to genetic variation in the patients [22]. There is variability in genes encoding angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) responsible for the entry of SARS-CoV-2 into host cells [54] as distinguished between European and Asian populations [55, 56]. However, geographical characteristics of oral symptoms in COVID-19 patients are not necessarily consistent with those of oral adverse effects following COVID-19 vaccination, which are not attributable to an ethnic or racial difference, but to other factors relating to vaccination.

Different types of COVID-19 vaccines have been used in the world, including mRNA vaccine, adenoviral vector vaccine, spike protein subunit vaccine, and inactivated virus vaccine. The incidence and risk of side effects following COVID-19 vaccination have been suggested to depend on the type of vaccine [57, 58], which is associated with the severity of side effects of vaccines [59]. Oral adverse effects of COVID-19 vaccines are related to their types as shown in Figure 3, which was prepared by statistically processing the prevalence data of each vaccine type on ageusia, dysgeusia, and/or hypogeusia [19‒21, 29‒42] and on xerostomia and/or dry mouth [19‒21, 32, 39, 41‒47]. Taste disorders, particularly dysgeusia, occur depending on the type of vaccine (Fig. 3a). The prevalence of dysgeusia is highest in inactivated virus vaccine, followed by adenoviral vector vaccine and mRNA vaccine. Saliva secretory disorders also depend on the type of vaccine (Fig. 3b). The prevalence of xerostomia is highest in inactivated virus vaccine, followed by adenoviral vector vaccine and mRNA vaccine. Dry mouth is more prevalent in adenoviral vector vaccines than other types of vaccines. Therefore, it is considered that inactivated virus vaccine and adenoviral vector vaccine cause taste and saliva secretory disorders more frequently compared with mRNA vaccine.

Usage rates (in percentage) of different types of COVID-19 vaccines in individual countries are shown in Figure 4 with those in the world (Fig. 4a) and Europe (Fig. 4b), which was prepared by using the rate reported for each country or region [19‒21, 29‒47]. The mRNA vaccines have been exclusively used in Czech (Fig. 4f), Slovakia (Fig. 4g), and Mexico (Fig. 4i). These countries show lower prevalence of dysgeusia and xerostomia (Fig. 2). Among other countries, the usage rate of mRNA vaccines is 93.12% in the USA (Fig. 4h), 79.13% in Germany (Fig. 4d), 75.71% in Poland (Fig. 4e), 64.33% in Australia (Fig. 4j), and 46.85% in the UK (Fig. 4c). Taste and saliva secretory disorders are not necessarily prevalent in the USA and Australia (Fig. 2). Besides mRNA vaccines, adenoviral vector vaccines have been used in Germany (Fig. 4d), Poland (Fig. 4e), and Saudi Arabia (Fig. 4k). Dysgeusia is more prevalent in Germany and Poland than in the UK, and ageusia is most prevalent in Saudi Arabia (Fig. 2). The usage rate of inactivated virus vaccines is 90.81% in China (Fig. 4o) and 69.63% in Pakistan (Fig. 4m). Adenoviral vector vaccines have been additionally used in these countries. Dry mouth is particularly prevalent in China and dysgeusia and xerostomia are most prevalent in Pakistan (Fig. 2). Inactivated virus vaccines have been exclusively used in Turkey (Fig. 4l), where the prevalence of dysgeusia is relatively high (Fig. 2). The usage rate of adenoviral vector vaccines and inactivated virus vaccines in India is 95.26% and 4.40%, respectively (Fig. 4n). India is characterized by the most prevalent hypogeusia and by considerably prevalent ageusia and dysgeusia (Fig. 2).

The occurrence of post-vaccination taste and saliva secretory disorders is influenced by the type of vaccine as shown in Figure 5, which was prepared based on their prevalence data for Europe [20], the UK [30], Germany [41], and Poland [39]. Dysgeusia and xerostomia are more prevalent in adenoviral vector vaccines compared with mRNA vaccines, supporting the vaccine type-dependence of oral adverse effects following COVID-19 vaccination.

Not only the type but also the manufacture or brand of COVID-19 vaccines may be related to post-vaccination oral adverse effects. The mRNA vaccines and adenoviral vector vaccines were compared between Pfizer-BioNTech and Moderna and between AstraZeneca and Johnson & Johnson/Janssen, respectively, by using the available prevalence data on taste and saliva secretory disorders in the world [38], Europe [20], the USA [19], and Australia [21]. Ageusia, dysgeusia, and dry mouth were reported by 0.381%, 0.500%, and 0.212% of Pfizer-BioNTech vaccine recipients (a total of 1,562,325), whereas reported by 0.443%, 0.386%, and 0.220% of Moderna vaccine recipients (685,303). Ageusia, dysgeusia, and dry mouth were reported by 0.360%, 0.436%, and 0.311% of AstraZeneca vaccine recipients (525,833), whereas reported by 0.270%, 0.241%, and 0.153% of Johnson & Johnson/Janssen vaccine recipients (69,259). The brand of vaccines seems to influence the incident rates of oral adverse effects following COVID-19 vaccination.

Chemosensory dysfunction of COVID-19 patients depends on whether they are male or female [53]. A gender difference is observed in oral symptoms in COVID-19 patients as the pooled prevalence of taste disorders is 53–64% in female patients but 25–40% in male patients [22]. Regarding COVID-19 saliva secretory disorders, xerostomia and dry mouth were reported by 63% of female patients but by 48% of male patients [24]. A cross-sectional analysis of COVID-19 patients indicated that the relative prevalence in females and males is 59% vs. 48% for ageusia and 24% vs. 18% for xerostomia [60].

Gender differences in oral adverse effects following COVID-19 vaccination and in oral symptoms in COVID-19 patients are shown in Figure 6. Relative prevalence of post-vaccination taste and saliva secretory disorders is higher in female vaccine recipients than in male vaccine recipients, as shown in Figure 6a, which was prepared by using the available data on mRNA or adenoviral vector vaccine administration in various countries [19‒21, 31, 39]. Vaccinated women mostly develop ageusia, dysgeusia, xerostomia, and dry mouth more frequently compared with vaccinated men. Relative prevalence of oral symptoms is higher in female COVID-19 patients than male COVID-19 patients as shown in Figure 4b, which was prepared by using the available data of various countries [60‒70]. When infected with SARS-CoV-2, women are more likely to develop ageusia, dysgeusia, xerostomia, and dry mouth than men. Similar to oral symptoms in COVID-19 patients, a gender difference is referred to as one of the characteristics of oral adverse effects following COVID-19 vaccination.

It has been suggested that women have a higher expression of ACE2 responsible for the cellular entry of SARS-CoV-2 than men, which may be related to either the sex hormones or the sex chromosomes [71]. Different prevalence of taste and saliva secretory disorders between females and males may be due to a gender difference in ACE2 expression in addition to that in the perception of taste [72] and the incidence of xerostomia [73].

Neurological and otolaryngological symptoms associated with COVID-19 depend on the age of patients [62, 74]. Age-related differences in oral adverse effects following COVID-19 vaccination and in oral symptoms in COVID-19 patients are shown in Figure 7. Vaccine recipients and patients were divided into two groups: the younger group (mostly ≤17 years old) and the older group (mostly ≥18 years old). Relative prevalence of post-vaccination taste and saliva secretory disorders is higher in older vaccine recipients than in younger vaccine recipients, as shown in Figure 7a, which was prepared by using the available data on mRNA or adenoviral vector vaccine administration of various countries [19‒21, 39]. Ageusia, dysgeusia, hypogeusia, xerostomia, and dry mouth are mostly more prevalent with increasing age. Relative prevalence of oral symptoms is higher in older COVID-19 patients than younger COVID-19 patients as shown in Figure 4b, which was prepared by using the available data from various countries [61, 62, 64, 65, 75‒77]. When infected with SARS-CoV-2, older patients mostly develop ageusia, dysgeusia, and dry mouth more frequently than younger patients. Similar to oral symptoms in COVID-19 patients, an age-related difference is referred to as one of the characteristics of oral adverse effects following COVID-19 vaccination.

Old age per se is closely associated with alterations in taste sense because taste detection thresholds increase with age and taste perception at supra-threshold levels is reduced in older adults [78]. Salivary secretin decreases with age and xerostomia occurs more frequently with increasing age [73]. A comparative study indicated that age is a risk factor for causing xerostomia [79]. Decreased salivary secretion not only produces oral dryness but also impairs taste perception [80]. These age-dependent features are consistent with age-related characteristics of oral adverse effects following COVID-19 vaccination.

Onset and persistence time of ageusia or dysgeusia are shown in Figure 8, which was prepared by aggregating the available data on taste disorders following COVID-19 vaccination [31, 33‒35] and in COVID-19 patients [60, 76, 81‒92]. Onset time (mean ± SD) was estimated to be 3.91 ± 2.12 days for vaccination and 3.58 ± 0.83 days for SARS-CoV-2 infection. Post-vaccination side effects mostly appear within the first week after injections of mRNA vaccines and adenoviral vector vaccines [41]. COVID-19 vaccine recipients experience taste alterations within 3 days after receiving vaccines [35] and most of them develop ageusia and dysgeusia within 1 week [18]. Persistence time (mean ± SD) was estimated to be 9.28 ± 10.47 days for vaccination and 28.83 ± 41.28 days for SARS-CoV-2 infection. Taste disorders are likely to last for a longer time in COVID-19 patients compared with vaccinated people. It was previously reported that ageusia and dysgeusia persist in 1–45% of COVID-19 survivors at follow-ups of 21–365 days [27]. In contrast to taste disorders, there have been no studies on the onset and persistence of saliva secretory disorders following COVID-19 vaccination in the literature.

Five basic tastes (sweet, bitter, umami, sour, and salty taste) are perceived by distinct taste-receptor cells within taste buds that are embedded in the epithelia of the tongue, palate, and epiglottis. Because taste receptors specifically interact with salty, sweet, sour, bitter and umami tastants [93], gustatory dysfunction qualitatively includes more severe impairment of specific taste. The specific taste disorder following COVID-19 vaccination has been suggested by a study by Mythri et al. [33] to investigate adverse oral effects in Indian people who received AstraZeneca vaccines. While taste disorders occurred in vaccine recipients, the prevalence of bitter and salty taste impairment was 20.0% and 15.0%, respectively.

Rogn et al. [94] objectively assessed specific taste disorders in Norwegian COVID-19 patients by using taste strips impregnated with solutions of four different taste qualities. They demonstrated that ageusia of bitter taste has the highest prevalence (66.7%), followed by ageusia of salty taste (37.0%), sour taste (33.3%), and sweet taste (3.7%). In a comparative study of Abalo-Lojo et al. [95], 75.7% of Spanish COVID-19 patients reported complete taste loss, in which the prevalence of ageusia of bitter, salty, and sweet taste was 8.1%, 4.1%, and 1.4%, respectively. However, Jordanian COVID-19 patients reported that salty taste is most frequently distorted, followed by sour, sweet, and bitter tastes [96]. Japanese COVID-19 patients developed multiple types of taste disorders, in which ageusia/hypogeusia of salty and umami taste had higher prevalence [97]. Although the number of relevant studies is limited, taste disorders following COVID-19 vaccination [33] and in COVID-19 patients [94, 95] may be characterized by bitter taste impaired more severely.

Adverse events of COVID-19 vaccines are related to the dose of vaccination [49]. When Korean healthcare workers received both doses of Pfizer-BioNTech vaccines, the rates of myalgia, fatigue, headache, chills, and fever were higher after the second dose than the first dose [98]. In Italian healthcare workers who received mRNA vaccines, pain at the injection site, fever, fatigue, and headache appeared more frequently after the second dose compared with the first dose [99]. Japanese people vaccinated with mRNA vaccines developed fever, headache, and chills that were more prevalent after the second dose than after the first dose [100]. When Taiwanese people received AstraZeneca and Moderna vaccines, 79% of them reported at least one adverse effect after the first dose, 50% after the second dose, and 84% after the third dose [101].

Riad et al. [19] retrospectively analyzed the Vaccine Adverse Event Reporting System (VAERS) to assess oral adverse events following COVID-19 vaccination. It was demonstrated that their prevalence after the first, the second, and the third dose were 0.687%, 0.826%, and 0.429% for ageusia; 0.736%, 0.476%, and 0.228% for dysgeusia; and 0.346%, 0.255%, and 0.127% for dry mouth; respectively. In an online survey-based cross-sectional study conducted in Pakistan, inactivated virus vaccines caused adverse effects (including dysgeusia) more frequently after the first dose than the second dose [32]. Although taste and saliva secretory disorders are likely to depend on the COVID-19 vaccine dose, whether their occurrence increases or decreases in the second and the third dose remains inconclusive.

COVID-19 patients with clinical manifestations frequently have hypertension, diabetes mellitus, and chronic pulmonary, thyroid, and/or kidney disease [24, 102‒104]. When having diabetes mellitus or hypertension, the patients develop not only more severe respiratory and constitutional symptoms but also more prevalent ageusia, hypogeusia, and xerostomia [105, 106].

After receiving Pfizer-BioNTech vaccines [107], AstraZeneca vaccines [108], and CanSinoBIO vaccines [109], the vaccine recipients with diabetes mellitus and hypertension suffered from systemic and local adverse effects more frequently than ones without any comorbidities. The occurrence of oral adverse effects following COVID-19 vaccination may be influenced by whether comorbid diseases are present or absent. In the literature, however, there have been no studies to compare post-vaccination taste and saliva secretory disorders between vaccinated people with and without comorbidity.

Having had COVID-19 before vaccination is a risk factor for increasing side effects of vaccines [59]. Alsaiari et al. [31] compared COVID-19 vaccine-induced adverse effects between vaccine recipients with different medical histories in a cross-sectional study including 2,718 Saidi Arabian participants. The prevalence of ageusia was 1.679% and 0.377% in vaccinated subjects with and without prior SARS-CoV-2 infection, respectively, suggesting that COVID-19 before vaccination enhances the risk of taste disorders following vaccination. Such enhancement may be explained as follows. COVID-19 taste disorders last for a long time in patients who have recovered from COVID-19 [110], and ageusia and dysgeusia can persist in COVID-19 survivors up to 1 year after recovery from the disease [27]. Viral shedding has been observed for an extended period after SARS-CoV-2 infection [111]. COVID-19 patients show viral RNA-positivity during and after the recovery period [112]. The virus remaining in vaccinated people who were previously infected with SARS-CoV-2 would contribute to oral adverse effects following COVID-19 vaccination. COVID-19 patients are symptomatically characterized by gustatory dysfunction [22, 23], which has been closely related to the diagnosis of SARS-CoV-2 infection and prediction of PCR swab positivity [113]. The increased awareness of ageusia or dysgeusia as COVID-19 symptoms may also make it easier to recognize taste alterations after receiving COVID-19 vaccines, possibly resulting in an increase in the prevalence of taste disorders.

Post-vaccination oral adverse effects raise the question of whether their prevalence is different between COVID-19 and non-COVID-19 vaccines. Riad et al. [19] evaluated more than 100 adverse events within the oral cavity following COVID-19 or seasonal influenza vaccination. The events reported by recipients of different vaccines in the USA were cross-tabulated to assess their relative prevalence. Although the distribution pattern of the most reported events was similar for both vaccines, the prevalence of taste and saliva secretory disorders were higher in COVID-19 vaccination than influenza vaccination. Riad et al. [21] also analyzed 84 oral adverse events associated with COVID-19 and influenza vaccines by using the Australian Database of Adverse Event Notifications. Their results revealed that taste and saliva secretory disorders are more common after COVID-19 vaccination compared with influenza vaccination, while most oral adverse events were shared by COVID-19 and influenza vaccine recipients. Gallagher et al. [114] recently compared the rates of smell and taste changes after receiving COVID-19 vaccines with those after receiving several other vaccines. In contrast to the studies of Riad et al. [19, 21], smell and taste were less likely to be disturbed by COVID-19 vaccination (first and booster) than influenza, tetanus, diphtheria, pertussis, and pneumococcal vaccination.

Characteristics of ageusia, dysgeusia, hypogeusia, xerostomia, and dry mouth following COVID-19 vaccination are summarized in Table 1. They have some similarities to oral symptoms in COVID-19 patients.

It is important for discussing oral adverse effects following COVID-19 vaccination to know their general incidence rate. Post-vaccination taste and saliva secretory disorders occur depending on many factors such as geographical difference, the type of vaccine, gender, age, vaccine dose, and medical history. Their prevalence in the general population is unlikely to be obtained from single-country or small cohort studies with a limited number of vaccinated subjects. A large-scale population-based survey or a worldwide cohort study may provide an estimate of the population-level prevalence. In a retrospective analysis using the VAERS data [19], a total of 690,853 reports from COVID-19 vaccine recipients in the USA indicated an overall prevalence of 0.722% for ageusia, 0.617% for dysgeusia, 0.020% for hypogeusia, and 0.301% for dry mouth. As a result of analysis of the European Union Drug Regulating Authorities Pharmacovigilance database [20], oral adverse effects following a total of 895,572,629 COVID-19 vaccinations in 32 European countries showed an overall prevalence of 0.296% for ageusia, 0.381% for dysgeusia, and 0.215% for dry mouth.

For SARS-CoV-2 to enter human cells, its spike protein binds to the cellular receptor ACE2 through a receptor-binding domain (RBD), followed by fusion between viral and cellular membranes mediated by TMPRSS2. The spike protein consists of two subunits, S1 subunit containing RBD and S2 subunit responsible for the membrane fusion [115]. Whole spike protein, S1 and S2 subunits, and RBD play critical roles as multiple antigens in the antibody responses induced by SARS-CoV-2 infection and COVID-19 vaccination.

Spike protein-encoding mRNA vaccines produce the spike protein in immunocompetent cells to enhance anti-SARS-CoV-2 immune responses. Tissue-resident and blood circulating immune cells, which are attracted to the injection site and regional lymph nodes, translate the vaccine-derived mRNA into the recombinant spike protein [116]. Adenoviral vector vaccines offer a platform to deliver the viral antigen, in which non-replicating adenovirus carries DNA encoding the spike protein into the nucleus [117]. Spike protein subunit vaccines contain the recombinant SARS-CoV-2 spike protein to elicit humoral and cellular immunity [118]. They can be a platform with high immunogenicity to neutralize SARS-CoV-2 variants. For inactivated virus vaccines, RBD on SARS-CoV-2 spike protein is an antigenic determinant for neutralizing antibodies. They are able to induce high titers of antibodies specific for the spike protein [119].

No matter whether it is derived from SARS-CoV-2 infection or COVID-19 vaccination, the spike protein could be a pathogenic factor for taste and saliva secretory disorders. Trougakos et al. [120] hypothesized that COVID-19 vaccine-mediating adverse effects are due to the vaccination-induced antigenic spike protein that has functionality as a ligand for ACE2 receptors and the molecular mimicry with human proteins. The following pathophysiological speculations focus on the spike protein’s potential to interact with ACE2, produce proinflammatory cytokines, and form antiphospholipid antibodies.

If vaccination-derived spike proteins enter the circulation to be distributed to cells and tissues of interest, they may participate in functional impairments of the susceptible target cells. Ogata et al. [121] measured SARS-CoV-2 proteins in blood collected from subjects without prior SARS-CoV-2 infection who received two doses of mRNA vaccines. They confirmed that S1 subunit antigen and spike protein antigen are produced by vaccination and that the S1 antigen is detected as early as 1 day after the first vaccine injection and the spike protein is detectable for 15 days. Free-floating spike proteins and their subunits are expected to interact with ACE2 receptors expressed in various cells and tissues [119]. When spike peptides (including S1 full length subunit) were intravenously injected into mice, the S1 subunit was found to co-localize in the endothelial cells of brain microvessels with ACE2, interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α) [122].

Each taste bud is composed of 50–100 taste receptor cells that have three distinct types to perceive five basic tastes: type I cells for salty taste, type II cells for sweet, bitter, and umami taste, and type III cells for sour taste. ACE2 is abundantly distributed in human taste buds containing taste receptor cells [123]. It was found that not only ACE2 is expressed on the type II taste receptor cells within the taste buds of COVID-19 patients with taste disorders but also replicating SARS-CoV-2 is present in taste buds and type II taste receptor cells of COVID-19 patients [124]. In addition, ACE2 was reported to be distributed in ductal, acinar, and myoepithelial cells of human salivary glands [123] and co-localizes with TMPRSS2 [125]. ACE2 is also expressed in human major and minor salivary glands [126]. Matuck et al. [127] conducted postmortem biopsies of the salivary glands of patients who died of COVID-19 and the following RT-PCR, ultrastructural, and immunochemical analyses. They demonstrated not only the infection and replication of SARS-CoV-2 in parotid, submandibular, and minor salivary glands, but also the high expression of ACE2 in ductal epithelial cells and serous acinar cells of these salivary glands.

Given the fact that ACE2 is expressed in taste buds and salivary glands and SARS-CoV-2 is able to replicate in both of them, the virus could target taste receptor cells and salivary gland cells to impair their physiological functions by cytopathic effects [128]. ACE2 has also been suggested to regulate taste perception as exemplified in gustatory side effects of ACE2 inhibitors [129]. As well as SARS-CoV-2 infection-derived spike protein, COVID-19 vaccination-derived spike protein (and subunits) is considered to interact with ACE2 expressed on cells relevant to taste perception and salivary secretion to affect them adversely. The co-localization of ACE2 in taste buds and salivary glands is consistent with the simultaneous occurrence of taste disorders and saliva secretory disorders following COVID-19 vaccination.

Females have higher expression of ACE2 in different tissues compared with males [130]. Because ACE2 expression is upregulated by estrogen and the gene encoding ACE2 is located on X chromosome, ACE2 should be over-expressed in females [131]. The interaction between spike protein and ACE2 would be greater in vaccinated women than vaccinated men, producing a gender difference in taste and saliva secretory disorders.

Expression levels of ACE2 in oral mucosal tissues are higher in elderly COVID-19 patients than younger COVID-19 patients [132]. ACE2 is expressed in oral tissues (tongue and salivary gland) more highly in the elderly group (41–70 years old) than the younger group (18–40 years old) [133]. The interaction between spike protein and ACE2 would be greater with aging, being consistent with an age-related difference in taste and saliva secretory disorders.

In some cases, the impairment of bitter taste is more prevalent in both vaccine recipients [33] and COVID-19 patients [94, 95]. Bitter taste is mediated by type II taste cells, in which not only ACE2 is expressed but also SARS-CoV-2 can replicate [124]. The vaccination-derived spike protein is presumed to preferentially affect ACE2-expressing type II taste receptor cells to produce the disorder specific to bitter taste.

If spike protein and subunits are closely associated with the impairment of taste perception, their post-vaccination appearance and presence should correlate with the onset and persistence of taste disorders. Antigenic spike protein and S1 subunit are detected in the blood as early as 1 day after the first vaccine dose and are detectable for at least 15 days [121]. Ageusia and dysgeusia appear within 3 days following COVID-19 vaccination, and they last for more than 1 week.

Taste disorders [134] and saliva secretory disorders [135] are commonly due to inflammation. Cytokines are detected in the blood of patients infected with SARS-CoV-2 and the cytokine storm is associated with COVID-19 severity [136]. Proinflammatory cytokines are also over-expressed in COVID-19 patients [137]. Because taste receptor cells are vulnerable to inflammation, their functions can be adversely affected by IL-6 and TNF-α [138]. When mice were experimentally infected with SARS-CoV-2, strong immunoreactions of TNF-α and IL-1β were detected in salivary glands [139], suggesting the possibility that excessive inflammatory responses cause saliva secretory disorders.

Nakayama et al. [140] administered mRNA vaccines to mice and collected muscle tissues on days 0–7 and 2–4 weeks after the first dose, and found the production of TNF-α and IL‐6 in tissue samples on day 1. Ostrowski et al. [141] determined proinflammatory cytokines in human blood 8–16 days after COVID-19 vaccination. Both mRNA and adenoviral vector vaccines increased IL-6, IL-8, IL-10, and TNF-α immediately after their injections, while adenoviral vector vaccines produced a larger increase in these cytokines than mRNA vaccines. These results are consistent with the vaccine type-dependent characteristics of oral adverse effects that dysgeusia, xerostomia, and dry mouth are more prevalent in adenoviral vector vaccine recipients than mRNA vaccine recipients.

SARS-CoV-2 spike proteins interact with ACE2 receptors to trigger several molecular processes in the virally infected cells with the resultant production of IL-6 and other proinflammatory cytokines [142]. Human lung epithelial cells produce IL-6, IL-1β, and TNF-α in response to SARS-CoV-2 spike proteins [143]. Montezano et al. [144] addressed the question of whether the interaction between SARS-CoV-2 spike protein and ACE2 receptor causes inflammation by exposing human endothelial cells to the spike protein and S1 subunit. They confirmed that the S1 subunit enhances IL-6 production and causes endothelial inflammation via ACE2. The spike protein and subunits derived from COVID-19 vaccination are considered to produce proinflammatory cytokines with the subsequent inflammation in taste receptor cells and salivary gland cells, resulting in their functional impairments.

Infections with human immunodeficiency virus, hepatitis virus, and adenovirus are accompanied by an increase in antiphospholipid antibodies [145]. Xiao et al. [146] reported that antiphospholipid antibodies are detected in the blood of patients infected with SARS-CoV-2. COVID-19 patients show positivity for antiphospholipid antibodies, which is variable depending on the severity of the disease [147]. Interestingly, antiphospholipid antibodies are closely associated with not only viral infection but also vaccination [148, 149]. Anti-cardiolipin IgG antibodies are increased in the blood by both COVID-19 vaccination and SARS-CoV-2 infection [150]. When serum antiphospholipid antibody titers were measured before and after administration of COVID-19 mRNA vaccines, post-vaccination antibody titers targeting phosphatidylethanolamine were significantly increased compared with pre-vaccination [151].

Antiphospholipid syndrome characterized by the presence of antiphospholipid antibodies shares pathophysiological features with COVID-19 symptoms [152]. Ageusia was reported to occur in antiphospholipid syndrome [153] and dry mouth is included in the clinical presentations of antiphospholipid antibodies [154]. SARS-CoV-2 spike protein S1 and S2 subunits form a phospholipid-like epitope and the cross-reactivity between the spike protein and phospholipids has been presumed for antiphospholipid antibody development [151]. It is hypothesized that antiphospholipid antibodies formed through the intermediary of the spike protein are partly responsible for taste and saliva secretory disorders following COVID-19 vaccination.

The present study has several limitations. The number of enrolled vaccinated subjects differs among retrieved studies. Due to a variation in the sample size and the used methodology, the prevalence shown in the present study may not necessarily reflect that of post-vaccination taste and saliva secretory disorders in the general population. The number of retrieved studies on oral adverse effects following COVID-19 vaccination is much smaller compared with that on oral symptoms in COVID-19 patients. In addition, because of heterogeneity in the designs and data of post-vaccination studies, a statistical analysis could not be performed for assessing the characteristics of oral adverse effects. The prevalence of ageusia, dysgeusia, hypogeusia, xerostomia, and dry mouth should be referred to as indicative rather than definitive values. In all the retrieved studies, taste and saliva secretory disorders following COVID-19 vaccination were analyzed based on subjective (self-reported) impressions or feelings of taste abnormality and oral dryness, whereas those in COVID-19 patients were at least partly analyzed by objective tests. Consequently, oral adverse effects reported by vaccinated people are potentially biased.

To the best of our knowledge, the present study is the first comprehensive report of oral adverse effects following COVID-19 vaccination to compare with oral symptoms in COVID-19 patients. Taste and saliva secretory disorders have previously been considered one of the symptoms specific to SARS-CoV-2 infection. However, ageusia, dysgeusia, hypogeusia, xerostomia, and dry mouth can also occur in a certain number of vaccinated people as the consequences of COVID-19 vaccination, while they are rare compared with oral symptoms of SARS-CoV-2 infection. Post-vaccination adverse oral effects share some characteristics with COVID-19 oral symptoms, such as higher prevalence in females and older subjects, onset time, and specific taste disorder in some cases. Antigenic spike protein is produced by COVID-19 vaccination and pathogenic spike protein is introduced by SARS-CoV-2 infection. The spike protein may be responsible for the pathophysiology underlying taste and saliva secretory disorders. Although neither taste disorders nor saliva secretory disorders are life-threatening, both of these disorders have a negative impact on the overall quality of life and can cause other health complications. The present results do not deny the advantage and efficacy of vaccination against COVID-19, but attention should be paid to oral adverse effects following COVID-19 vaccination as well as oral symptoms in COVID-19 patients.

The authors have no conflicts of interest to declare.

The present study was supported by JSPS KAKENHI (Grant No. 20K10152) and JSPS KAKENHI (Grant No. 24K12106).

Hironori Tsuchiya designed and conducted the present study. Hironori Tsuchiya and Maki Mizogami reviewed the retrieved articles, analyzed the data, and prepared the manuscript. All authors approved the final manuscript.

All data generated by the present study are included in this article.