A systematic review on mucocutaneous presentations after COVID-19 vaccination and expert recommendations about vaccination of important immune-mediated dermatologic disorders.

With dermatologic side effects being fairly prevalent following vaccination against COVID‐19, and the multitude of studies aiming to report and analyze these adverse events, the need for an extensive investigation on previous studies seemed urgent, in order to provide a thorough body of information about these post‐COVID‐19 immunization mucocutaneous reactions. To achieve this goal, a comprehensive electronic search was performed through the international databases including Medline (PubMed), Scopus, Cochrane, Web of science, and Google scholar on July 12, 2021, and all articles regarding mucocutaneous manifestations and considerations after COVID‐19 vaccine administration were retrieved using the following keywords: COVID‐19 vaccine, dermatology considerations and mucocutaneous manifestations. A total of 917 records were retrieved and a final number of 180 articles were included in data extraction. Mild, moderate, severe and potentially life‐threatening adverse events have been reported following immunization with COVID vaccines, through case reports, case series, observational studies, randomized clinical trials, and further recommendations and consensus position papers regarding vaccination. In this systematic review, we categorized these results in detail into five elaborate tables, making what we believe to be an extensively informative, unprecedented set of data on this topic. Based on our findings, in the viewpoint of the pros and cons of vaccination, mucocutaneous adverse events were mostly non‐significant, self‐limiting reactions, and for the more uncommon moderate to severe reactions, guidelines and consensus position papers could be of great importance to provide those at higher risks and those with specific worries of flare‐ups or inefficient immunization, with sufficient recommendations to safely schedule their vaccine doses, or avoid vaccination if they have the discussed contra‐indications.

acute, adverse effect, adverse event, adverse event following immunization, allergy, angioedema, AstraZeneca, AstraZeneca/Oxford, atopic dermatitis, Bharat, collagen vascular disease, Comirnaty, COVID‐19 vaccine, cutaneous, cyanosis, delayed, delayed‐type hypersensitivity, dermatology, ecchymosis, edema, erythema multiforme, exanthematous rash, herpes, hidradenitis suppurativa, inflammatory bowel disease, injection site reaction, Janssen, Johnson & Johnson, late, local site reaction, maculopapular rash, mastocytosis, Moderna, morbilliform rash, mucocutaneous, mucosal, pemphigoid, pemphigus, Pernio, Petechia, Pfizer, Pfizer‐BioNTech, pityriasis rosea, pruritus, psoriasis, purpura, remote site reaction, rheumatic disorders, SARS‐Cov‐2, side effect, Sinopharm, Sinovac, Sputnik, urticaria, vaccine, Vaccine Adverse Event Reporting System, zoster 1. INTRODUCTION 1.1. Rationale The global impact of the Coronavirus Disease 2019 (COVID‐19) pandemic does not need to be underscored. Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) spread rapidly throughout the world and left tragic consequences, and vaccination appears to be a mainstay for overcoming this contagious calamity. Many candidate vaccines have been developed against SARS‐COV‐2, using different vectors and methods of production, which fall into different vaccine types. To name a few: - 1. mRNA vaccines Pfizer‐BioNTech “Comirnaty” (BNT162b2, tozinameran) 1 , 2 , 3 , 4 Moderna (mRNA‐1273) 5 , 6 , 7 , 8 - 2. Adenovirus viral vector vaccines Oxford–AstraZeneca (Covishield, Vaxzevria,ChAdOx1SnCoV‐19, AZD1222) 9 , 10 , 11 , 12 , 13 , 14 Sputnik V (Gam‐COVID‐Vac) 15 , 16 Janssen (Ad26.COV2.S, JNJ‐78436735)(Johnson & Johnson) 19 , 20 - 3. Protein subunit vaccines MF59‐adjuvanted spike glycoprotein‐clamp vaccine 23 SCB‐2019 24 CoV2 preS dTM‐AS03 25 ZF2001 (ZIFIVAX or ZF‐UZ‐VAC‐2001) 26 V‐01 27 EpiVacCorona (Aurora‐CoV) 28 - 4. Inactivated virus vaccines Sinovac (CoronaVac) 29 , 30 , 31 Sinopharm BIBP (BBIBP‐CorV) 32 , 33 Sinopharm WIBP (WIBP‐CorV) 34 Covaxin (BBV152, Bharat Biotech) 35 KCONVAC (Minhai) 36 IBMCAMS vaccine (Institute of Medical Biology) 37 - 5. Virus‐like particle vaccines CoVLP 38 From these many candidates, seven COVID‐19 vaccines have been approved by WHO, 39 namely: Pfizer‐BioNTech “Comirnaty” (BNT162b2, tozinameran), Moderna (mRNA‐1273), Janssen (Ad26.COV2.S, JNJ‐78436735)(Johnson & Johnson), Oxford–AstraZeneca (AZD1222), Covishield (Serum Institute of India, Oxford–AstraZeneca formulation), Sinopharm BIBP (BBIBP‐CorV)(Vero Cells), and Sinovac CoronaVac. 39 Although studies have showed overall acceptable efficacy, safety, and tolerability of all available COVID‐19 vaccines, 3 , 8 , 13 , 14 , 30 , 40 , 41 with the accelerated pace of vaccine production, distribution, and administration, several steps of vaccine development were condensed and got fast‐tracked which increased the probability of unsolicited adverse reactions, warranting further attention to the potential side effects of these vaccines, 42 , 43 and an international effort to report the observed reactions, through the Vaccine Adverse Event Reporting System (VAERS), 44 or other registries. Previous studies have revealed the main side effects to include localized pain, swelling or redness at the injection site, along with constitutional or COVID‐like symptoms, mostly comprised of generalized weakness, myalgia, headache, fever and chills, joint pain, nausea, and diarrhea. 45 Of note, mucocutaneous adverse events encompass a large number of post‐vaccination reactions: local injection site reactions as previously mentioned, delayed large local reactions, morbilliform rashes, urticaria, erythema multiforme, delayed inflammatory reactions to dermal fillers, erythromelalgia, lichen planus, varicella‐zoster, herpes simplex, pityriasis rosea, petechiae, purpura, and mimickers of COVID‐19 infection cutaneous manifestations (e.g., pernio or chilblains), which have predominantly been insignificant and self‐limited. 46 , 47 1.2. Objective With dermatologic side effects being fairly prevalent after COVID vaccination, and the multitude of studies aiming to report and analyze these events, the need for an extensive investigation on previous studies seemed urgent, in order to provide a comprehensive body of information about these post‐COVID‐19 immunization mucocutaneous reactions. Therefore, the main objective of this qualitative systematic review is to recapitulate and categorize the clinical characteristics of mucocutaneous reactions following COVID vaccination, provide an update on the state of underlying mucocutaneous diseases after vaccination, their diagnoses and biopsies, therapeutic strategies, patients' outcomes, and further integrated guidance for approach to patients who have previously experienced these side effects or flares of underlying diseases with other vaccines. We have also tried to classify experts' recommendations and consensus guidelines on COVID‐19 vaccination in those with immune‐mediated dermatologic disorders, allergic disorders, along with systemic disorders with probable mucocutaneous presentations, for example, autoimmune inflammatory rheumatic diseases (AIIRD); as these disorders could be underlying factors that may affect vaccine immunogenicity, either by themselves, or indirectly, with the use of immunosuppressive and immunomodulatory treatment for their control. Being knowledgeable and updated on the non‐critical, critical or potentially life threatening mucocutaneous adverse effects of COVID‐19 vaccine and the mutual effects of vaccination and dermatologic disorders on each other is a must for dermatologic, as well as general medical practice today, and we hope the present article provides a stepping stone to that aim. This study is the first systematic review that thoroughly assesses all aspects of the various dermatological concerns regarding COVID‐19 vaccination, condensing the results of all study types with a detailed categorization of the results. 2. METHODS 2.1. Protocol and registration We followed the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines to conduct and report this review. 48 2.2. Search strategy A comprehensive electronic search was performed through the international databases including Medline (PubMed), Scopus, Cochrane, Web of science, and Google scholar from the beginning to July 12, 2021, and all articles regarding mucocutaneous manifestations and considerations after COVID‐19 vaccine administration were initially retrieved using the following major keywords and their MeSH terms: COVID‐19 vaccine, dermatology considerations and mucocutaneous manifestations. The search strategy is illustrated in Appendix S1 of supplement file. In addition, a manual search through the references of included reviews was conducted to identify any missing related studies. Two researchers separately performed the search and screening, and the details of each step in the search and screening process is provided in our PRISMA flow diagram, 49 depicted in Figure 1. 2.3. Eligibility criteria Our inclusion criteria were studies or reports on any dermatology‐related adverse events following the administration of COVID‐19 vaccines and vaccine related concerns and consideration for those with dermatologic disorders. Inclusion was not limited by the type of COVID‐19 vaccine. Exclusion criteria were in vitro studies, animal studies, basic science studies, studies on non‐dermatologic adverse events (AEs) of vaccines, COVID‐19 disease manifestations, and any non‐COVID‐19 vaccine study. 2.4. Screening and data extraction After duplication removal of the primary search results, two reviewers independently screened the title and abstract of retrieved articles based on the above eligibility criteria. They then separately studied the full‐text of the selected studies in detail, for evaluation of eligibility and data extraction. In case of disagreement, they discussed the subject and if they did not reach a consensus, another researcher expert in the field joined the discussion. The data extraction sheet contained the following information: first author name, patient characteristics in case reports, or number of patients, gender distribution and mean age in other studies, vaccine type, dose of vaccine, history of previous mucocutaneous conditions, constitutional symptoms after vaccine, characteristics and location of mucocutaneous reactions, mean time of onset, diagnosis, management of reactions, duration of reactions, and final outcomes. Studies regarding COVID‐19 vaccination considerations and recommendations among dermatologic patients were assessed separately. The study design, data reporting, and validity of included RCTs were assessed in accordance with the Consolidated Standards of Reporting Trials (CONSORT) statement. 3. RESULTS 3.1. Overview of the studies A total of 917 articles were retrieved from all databases and 248 duplicates were identified and removed. A total of 669 articles went through title and abstract screening. From those, 388 articles were excluded, including 7 animal studies, 16 trial protocols, 21 systematic reviews, 78 non‐recommendation narrative reviews, 109 non‐“vaccine related AEs” studies, and 157 non‐“dermatologic AEs” studies. The remaining281 articles were selected for full text screening. From those, 101 studies were excluded, including 7 trial protocols, 28 non‐“vaccine related AEs” studies, 30 non‐“dermatologic AEs” studies, 18 RCTs without specification of cutaneous AEs, and 18 recommendation narrative reviews with no consensus opinion or guideline. Also, references of 20 retrieved narrative and systematic reviews, comprised of 152 articles, were manually screened for any missing articles and 7 related articles from those were also added to our included papers. Finally, a total of 180 studies were included in our data extraction and descriptive synthesis, including 65 case reports, 10 case series, 41 RCTs, 27 analytical studies, and 37 recommendations or guidelines. 3.2. Case reports In total, 116 cases were included in the case reports table from a total of 65 articles, as depicted in Table 1. The mean age of participants was 47.37 years, with a female‐dominant gender distribution (F/M: 1.7, F = 73[62.9%] M = 43[37.1%]). The vaccines studied in order of number of participants having received them were BNT162b2 (n = 76, 65.5%), mRNA‐1273 (n = 19, 16.4%), ChAdOx1S nCoV‐19 (n = 9, 7.8%), CoronaVac (n = 7, 6%), Ad26.COV2.S (n = 3, 2.6%), and BBV152 (n = 2, 1.7%). TABLE 1. | Supplemental references a | First author | Case age | Case gender | Patients' mucocutaneous disease history | Patients' other comorbidity | Drug history at the time of vaccination | Vaccine dose | Any sign after vaccine | Description of mucocutaneous reactions | reactions onset | Skin or mucosal biopsy | Diagnosis | Resolution after (time) | Management of reactions | |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---| | 1. Injection site reactions, “Covid arm” (n = 12) | |||||||||||||| | With BNT162b2 | |||||||||||||| | 1 | Gyldenløve, M. | 33 | F | NM | DM, obesity | NM | 1 | Neg | Asymptomatic rash at the injection site | 12d | Perivascular, lymphocyte infiltration in the dermis | Reactions after incorrect subcutaneous administration | NM | Neg | | 2 | Tammaro, Antonella | 64 | F | Neg | Neg | Neg | 2 | Neg | A nodule surrounded by an erythematous halo, extremely painful and pruritic | 1d | NM | Localized reaction | 4d | Topical Corticosteroid cream | | 2 | Tammaro, Antonella | 56 | F | Neg | Neg | Neg | 2 | Neg | Small vesicular lesions surrounded by erythema | 1d | NM | Localized reaction | 7d | Topical Corticosteroid cream | | 2 | Tammaro, Antonella | 60 | F | Neg | Neg | Neg | 2 | Neg | Severe xerosis and pruritus in the area injected, extensive erythematous pruritic and painful rash, on the shoulder and chest | 7d | NM | Localized reaction | 7d | Topical Corticosteroid cream | | 3 | López‐Valle, A. | 27 | F | Neg | NM | NM | 1 & 2 | 1st: fever, 2nd: fatigue after 24 h of injection | 1st: pain at the injection site, erythematous–edematous firm plaque over the deltoid area, 2nd: pain and an erythematous–edematous plaque on the injection site | 1st:7d / 2nd:6 h | NM | NM | 1st: 2d | Paracetamol for 2nd dose symptoms (resolved after 2d) | | 4 | Baeck, M. | 38 | F | BNT | NM | NM | 1 | Pain at the injection site had completely resolved within 2 days, numbness of the fingers | Only after 1st dose: erythema of the upper arm | 6d | sparse, superficial, deep lymphohistiocytic infiltrates with CD3+ (including CD8+ and CD4+) T cells and some eosinophils and very rare CD20+ B cells | Delayed local reaction | 5d | Spontaneous resolution | | With mRNA‐1273 | |||||||||||||| | 5 | Sidlow, J. S. | 67 | F | NM | mild atopy | NM | 1 | NM | Only after 1stt: itchy 7‐cm erythematous red patch at the vaccine injection site of the upper portion of patient's left arm | 7d | Spongiosis perivascular, interstitial infiltrate, mixed cell type with rare eosinophils, occasional neutrophils within the reticular dermis | Localized reaction | 7d | Topical Corticosteroid use | | 5 | Sidlow, J. S. | 40 | F | NM | atopic family history | NM | 1 & 2 | NM | 1st: sharply demarcated warm urticarial oval patch, swelling and progressive erythema on the arm, 2nd: mild swelling at the injection site | 8d | Spongiosis perivascular, interstitial infiltrate, mixed cell type with rare eosinophils, occasional neutrophils within the reticular dermis | Localized reaction | NM | Erythromycin for presumed erysipelas | | 5 | Sidlow, J. S. | 53 | F | NM | mild atopic background | NM | 1 & 2 | 2nd: weakness, diarrhea, patient could not raise her arm above 90° angle | 1st: some mild sensitivity at the injection site and tenderness, 2nd: tender erythematous urticarial red ring on the injected arm | NM | Spongiosis perivascular, interstitial infiltrate, mixed cell type with rare eosinophils, occasional neutrophils | Localized reaction | 3d | Neg | | 6 | Lindgren, A. L. | 60 | F | NM | Neg | NM | 1 | Neg | Swollen, painful, extremely pruritic, erythematous plaque with minute papules in vaccination site | 6d | NM | Hypersensitivity reaction | 14 h | Clobetasol 0.05% cream twice | | 6 | Lindgren, A. L. | 44 | F | NM | Neg | NM | 1 | fever, chills, headache, and myalgias | Erythema, pain, pruritus, induration and swelling at the vaccination site on patient's left arm | 7d | NM | Hypersensitivity reaction | 2d | Triamcinolone 0.1% cream | | 6 | Lindgren, A. L. | 33 | F | NM | NM | NM | 1 | Neg | Redness, pain, itching, and swelling at the injection site | 7d | NM | Hypersensitivity reaction | 4d | 1% Hydrocortisone cream | | 2. Non‐injection site reactions (n = 104) | |||||||||||||| | 2.1. Hypersensitivity reaction type 1 (n = 14) | |||||||||||||| | 2.1.1. Urticaria (n = 5) | |||||||||||||| | With BNT162b2 | |||||||||||||| | 7 | Bianchi, L. | 24 | F | NM | Allergic rhinitis | NM | 1 | NM | Generalized acute urticaria | 5 min | NM | urticaria | NM | Betamethasone Sodium Phosphate IV | | 7 | Bianchi, L. | 28 | M | NM | Allergic rhinitis | NM | 1 | NM | Generalized acute urticaria | 5 min | NM | urticaria | NM | Neg | | 8 | Pitlick M. | 24 | F | NM | NM | NM | 1 | NM | Urticaria | 3 h | NM | NM | 4d | antihistamines | | 8 | Pitlick M. | 45 | F | NM | Food allergy | NM | 1 | Throat tightness | Urticaria | 8 h | NM | NM | NM | Neg | | 8 | Pitlick M. | 33 | F | NM | Asthma, venom anaphylaxis | NM | 1 | Tachycardia | Urticaria | 15 min | NM | NM | 12 h | antihistamines | | 2.1.2. Flushing (n = 3) | |||||||||||||| | With BNT162b2 | |||||||||||||| | 7 | Bianchi, L. | 58 | F | NM | Allergic rhinitis and asthma | NM | 1 | NM | Flushing of the face | 30 min | NM | Flushing | NM | Neg | | 7 | Bianchi, L. | 44 | F | NM | Allergic rhinitis | NM | 1 | NM | Flushing of the face | 20 min | NM | Flushing | NM | Neg | | 8 | Pitlick M. | 36 | F | NM | NM | NM | 1 | NM | Facial flushing | 5 min | NM | NM | 1 h | antihistamines | | 2.1.3. Angioedema(n = 3) | |||||||||||||| | With BNT162b2 | |||||||||||||| | 7 | Bianchi, L. | 31 | F | NM | Allergic rhinitis | NM | 1 | NM | Angioedema (tongue, gums) | 24 h | NM | Angioedema | NM | Neg | | 7 | Bianchi, L. | 54 | F | atopic dermatitis,contact allergy | Allergic rhinitis | NM | 1 | NM | Angioedema (tongue, lips) | 10 min | NM | Angioedema | NM | Neg | | With mRNA‐1273 | |||||||||||||| | 8 | Pitlick M. | 20 | M | NM | Vaccine allergy | NM | 1 | NM | Angioedema | 3 h | NM | NM | 1d | Steroids, Antihistamines | | 2.1.4. Anaphylaxis(n = 3) | |||||||||||||| | With BNT162b2 | |||||||||||||| | 9 | Daou, Christophe Abi Zeid | 30 | M | Allergies to Meperidine, Amocixillin‐Clavulonate Acid, pollen, and dust mites | NM | NM | 1 | Tachycardia, tachypnea, dysphagia, dyspnea, severe chills, dysphagia | Diffuse maculopapular rash + urticaria, diaphoresis, palate pruritis, rash, pruritus,diaphoresis, sudden onset of rash followed by urticaria, diaphoresis | a few minutes | NM | Biphasic anaphylaxis | 1d | Diphenhydramine, Prednisone, Dexamethasone, Hydrocortisone Sodium Succinate, Epinephrine | | 10 | Restivo, V. | 30 | F | Poly‐allergic subject, urticaria‐angioedema, immediate cutaneous reaction | NM | Prednisone, Chlorphenamine Maleate before vaccination | 1 | the feeling of a slurred mouth and hoarseness | erythematous spots on the face and neck | 5 h | NM | Severe allergic reaction | NM | Dexamethasone, Chlorphenamine Maleate, 0.9% NaCl, Oxygen | | With mRNA‐1273 | |||||||||||||| | 8 | Pitlick M. | 22 | F | NM | Allergic rhinitis | NM | 1 | wheezing, throat pruritus | Angioedema | 20 min | NM | Level 1 Anaphylaxis | 6 h | Antihistamines, Steroids | | 2.2. Generalized eruptions (n = 21) | |||||||||||||| | With BNT162b2 | |||||||||||||| | 11 | Edriss, Manar | 54 | M | NM | NM | NM | 1 | Neg | Clustered erythematous papules and nodules on posterior upper left arm that extended to left elbow and forearm | 5d | NM | erythematous papules and nodules | NM | Clobetasol BD | | 12 | Ackerman, M. | 55 | M | NM | Neg | NM | 1 | injection‐site soreness, slight hepatic cytolysis (ASAT and GGT 2 N) | Localized pruritic erythematous eruption, later spread on the face, trunk, upper extremities and thighs, 30% of body surface area involved | 3 h | slight lymphocytic perivascular infiltrate, compatible with non‐severe maculopapular toxidermia late biopsied | Persistent maculopapular exanthem | NM | one dose of Dermocorticoid Treatment, withholding of 2nd dose | | 13 | Akinosoglou, K. | 32 | F | Neg | NM | NM | 1 & 2 | Neg | Itchy annular granulomatous rash over both elbows | 2d | Cutaneous small cell vasculitis, possibly of leukocytoclastic origin | Annular rash | 3d | Neg | | 14 | Zafar, M. | 84 | M | NM | BPH | NM | 2 | Rise in D‐dimers and eosinophils | Widespread disseminated mildly itchy rash | 11d | NM | Rash with eosinophilia | NM | Oral Antihistamines, Topical Steroids | | 15 | Patruno, C. | 42 | F | Neg | NM | Neg | 1 | NM | Wheals (acute urticaria) on the trunk and limbs | 7d | NM | Acute urticaria | 7d | Antihistamine, Prednisone 25 mg | | 15 | Patruno, C. | 55 | M | NM | Neg | Neg | 1 | NM | Multiple itchy erythematous papules, vesicles, and blisters | 10d | spongiosis, epidermal exocytosis of lymphocytes, apoptotic keratinocytes, dermal edema | Erythema Multiforme‐like eruption | 10d | Systemic Prednisone 25 mg/day | | 16 | Lavery, M. J. | 58 | F | Erythema Multiforme (quiescent), recurrent episodes of herpes labialis | RA, Endometriosis, HTN, thyroid goiter | Abatacept, famciclovir | 1 & 2 | NM | A painful cutaneous eruption, erythematous concentric targetoid plaques on the palms of her hands and soles of the feet bilaterally | 1st: 12 h,2nd:1d | NM | Erythema Multiforme‐like eruption | NM | Topical Clobetasol | | 17 | Gambichler, T. | 74 | F | NM | Severe dementia syndrome | Pantoprazole | 1 | NM | Erythematous partly violaceous coalescing macules and papules with slightly indicated cocarde formation on the trunk and extremities | 1d | epidermal atrophy, vacuolar interface dermatitis, lymphocytic infiltrates, dyskeratoses of basal keratinocytes | Rowell's syndrome | NM | NM | | 18 | Ohsawa, R. | 55 | F | NM | Neg | NM | 1 | pain at the injection | d2: pruritic papules and erythematous lesions developed over the entire body except for the face d6: mild pruritic vesicopapular, erythematous macular and morbilliform eruption on the bilateral flanks and extremities | 2d | perivascular lymphocytic infiltrates, basal cell vacuolization and intraepidermal vesicle with mild spongiotic change containing collections of Langerhans cells and degenerated acantholysis‐like keratinocytes,microthrombi in small vessels in the mid‐ and deep dermis,perivascular and intraepidermal lymphocytic infiltrates with CD8+ > CD4+ cells | Morbilliform rash | 7d | 2d: topical betamethasone dipropionate and oral antihistamine: ineffective, 6d: 15 mg of oral predonisolone, withholding 2nd dose of vaccine | | 19 | Farinazzo, E. | 37 | F | NM | NM | NM | NM | NM | Morbilliform eruption | NM | NM | Morbilliform eruption | NM | NM | | 20 | Weinstock‐Guttman, B. | 31 | F | history of allergic reaction to cefixime | history of MOGSD and biopsy‐confirmed smoldering myeloma with monoclonal gammopathy | IV RTX for the last 2 years, monthly doses of IVIG (1st vaccination 12 weeks after the RTX infusion) | 1 | local warmth | 1st: multiple urticarial papules and plaques located on both lower extremities and gluteal area, primarily left side (unilateral side of the vaccination), local 2nd: lesions increased in size and became more evident Resolution: minimal hyperpigmentation residue | 1st:7d, 2nd: 2d | NM | Late onset erythema | NM | oral corticosteroids tapered within 3 weeks (15 mg/10 mg/5 mg prednisone) | | 19 | Farinazzo, E. | 44 | F | NM | NM | NM | 2 | NM | Purplish macule on the third finger of one hand | 10d | NM | Fixed Drug Eruption | NM | NM | | With mRNA‐1273 | |||||||||||||| | 5 | Sidlow, J. S. | 45 | M | NM | atopy and seasonal allergies | NM | 1 | Neg | Only after 1st: pruritic morbilliform rash with spread to the arms and abdomen | 8d | spongiosis and a superficial and deep, perivascular and interstitial infiltrate, mixed cell type with numerously abundant eosinophils and occasional neutrophils within the reticular dermis | Generalized reaction | 7d | Neg | | 5 | Sidlow, J. S. | 31 | F | History of guttate psoriasis | NM | NM | 1 & 2 | 2nd: low‐grade fever, generalized achiness, and malaise | Both doses: urticarial papular eruption on the contralateral aspect of the right arm | 3d | spongiosis and a superficial and deep, perivascular and interstitial infiltrate, mixed cell type with eosinophils and occasional neutrophils within the reticular dermis | Generalized reaction | 7d | Neg | | 5 | Sidlow, J. S. | 88 | F | NM | multiple drug allergies | NM | 1 | 1st: pins and needles sensation on the limbs and dysesthesia on the tongue | Only after 1st: generalized and progressing pruritus | 3d | spongiosis and a superficial and deep, perivascular and interstitial infiltrate, mixed cell type with eosinophils and occasional neutrophils within the reticular dermis | Generalized reaction | NM | Benadryl (Johnson and Johnson) and Sarna (Stiefel) lotion | | 21 | Kong, Joyce | 66 | M | NM | HTN, hyperlipidemia, DM, CKD, CAD, idiopathic hypothyroidism | Amlodipine, Aspirin, Brimonidine, Clopidogrel, Furosemide, Gabapentin, Insulin, Levothyroxine | 2 | fever, myalgias, malaise; After 5d: lower extremity muscle tenderness, stiffness with preserved strength | Painful blistering rash on torso, arms, legs, violaceous, poorly demarcated patches on trunk, arms, thighs, large flaccid bullae, erosion on buttocks, posterior shoulder, and scrotum | 1d | epidermal necrosis, with detachment from the underlying dermis forming a subepidermal blister, a very sparse lymphocytic inflammatory infiltrate and a sparse perivascular dermatitis | Extensive Bullous Fixed Drug Eruption | 5d | Ibuprofen, High‐dose Oral Prednisone, drainage of patient's bullae, Mupirocin Ointment with Vaseline | | With Ad26.COV2.S | |||||||||||||| | 22 | Lospinoso, K. | 74 | M | Known allergy to sulfa drugs and amoxicillin‐clavulanic acid, no prior vaccination‐related reactions | Panhypopituitarism, adrenal insufficiency, neurogenic bladder, obstructive sleep apnea | Prednisone (20 mg, daily) | 1 | ipsilateral arm discomfort, including the axilla, within 24 h of administration | Generalized distribution (50% of body) of erythematous plaques, numerous small, non‐follicular pustules, with sparing of the face, genitals, and mucosae; Significant acral swelling | 3d | epidermal spongiosis with focal, dermal neutrophilic inflammation and occasional eosinophils, scattered subcorneal neutrophilic pustules | Spongiotic and pustular eruption | 20d | Oral Prednisone (20 mg, daily), Topical Steroids | | 23 | Song, E. J. | 83 | F | Neg | HTN, hypothyroidism, breast cancer | Palbociclib, Letrozole, Vitamin D | 1 | Neg | pruritic erythematous annular patches with central clearing on the breast, abdomen, and axilla; scattered petechiae on previous sites of involvement | 2d | a mixed spongiotic and interface dermatitis with rare eosinophils and extravasated erythrocytes | Widespread annular eruption | 14d | Fexofenadine 360 mg daily, Cetirizine 20 mg daily, Triamcinolone 0.1% cream BD | | With ChAdOx1 nCoV‐ 19 | |||||||||||||| | 24 | Dash, S. | 60 | M | NM | DM, HTN | Teneligliptin, Metformin and Amlodipine | 1 | Fever, oral ulceration and skin rash | Multiple purpuric macules present all over the body with peri‐lesional erythema; lesions coalesced to form large sheets of necrosed skin over front and back of trunk, with bullae on few areas; Mucosal involvement: oral erosions, hemorrhagic crusting over the lips, eye congestion, erosions over the glans | 3d | Orthokeratosis, epidermal atrophy, infiltration of lymphocytes, neutrophils spongiosis, scattered degenerated apoptotic keratinocytes, basal cell degeneration, interface dermatitis, perivascular and peri‐adnexal inflammatory cell infiltrate, extravasation of erythrocytes in dermis | Steven‐Johnson syndrome | 7d | Oral Cyclosporine 300 mg | | 14 | Zafar, M. | 55 | F | stable psoriasis and scleroderma | NM | NM | 1 | NM | new‐onset non‐itchy rashes, with progressive worsening over the past month on hands and back | 2d | NM | Rash without eosinophilia | NM | oral antihistamines and topical steroid creams | | 25 | Tammaro, A. | 35 | F | NM | Prior COVID‐19 + | NM | 1 | fever, nausea, and pain on the site of injection for 2d | extended erythematous rash on the legs with pruritus and warmth 2d later: vesicular lesions on top of that rash Resolution: vesicular lesions were substituted by white discolorations | 6d | NM | Local nonspecific inflammatory reaction to vaccination | NM | ebastine 10 mg and 2 tablets of betamethasone 1 mg (tapered for 4d) | | 2.3. Chilblain‐like lesions (CBLL) (n = 9) | |||||||||||||| | With BNT162b2 | |||||||||||||| | 26 | Lesort, C | 82 | F | psoriasis | NM | Methotrexate for more than 10 years | 1 | Neg | slightly painful macular violaceous and erythematous lesions of the fingers and toes, suggestive of CBLL | 24 h | A partly necrotic epidermis, overlying a dense dermal lymphocytic infiltrate forming rather well‐circumscribed aggregates around blood vessels, eccrine sweat glands and occasionally nerves | CBLL | NM | NM | | 27 | Piccolo, V. | 41 | F | Neg | Neg | Neg | 2 | NM | CBLL on the volar aspects of, the second and the third fingertip of right hand along with an acrocyanosis of the hands | Soon after | NM | CBLL | NM | NM | | 28 | Pileri, A. | 42 | M | NM | NM | NM | 1 | NM | Nonpainful erythematous, purplish patches located on his distal phalanges and nail beds | 12d | NM | CBLL | NM | NM | | 29 | Davido, Benjamin | 41 | F | NM | Bipolar disorder | Valproate for more than 10 years | 1 | Sudden toe pain with walking impairment, otherwise asymptomatic | chilblain‐like skin changes on toes, itching at night; 10d after vaccination: non‐tender violaceous toes of the left foot, with no other dermatological lesion | 4d | NM | CBLL | 28d | NM | | 19 | Farinazzo, E. | 27 | F | NM | NM | NM | 1&2 | NM | 1st: Chilblain‐like rash on the first and third finger of one foot + urticarial rash 2nd: urticarial rash | 1st: 4d,2nd:1d | NM | Chilblain‐like rash | NM | NM | | With mRNA‐1273 | |||||||||||||| | 30 | Watad A. | 48 | F | NM | Neg | NM | 1 | NM | Painful chilblains like lesions on fingers; itchy urticarial‐type lesions (resembling urticarial multiforme)over volar aspect of both wrists and feet; evolving over thighs (asymptomatic) and extensor surfaces of both elbows; painful macular/nodular lesions over palmar surface of both hands | 10d | NM | CBLL and Urticarial‐type lesions | 7d | Hydrocortisone 0.5%, Naproxen 500 mg | | 31 | Kha, C. | 70 | M | NM | Pityriasis lichenoides chronica, clinically stable | clobetasol 0.05% ointment | 1 & 2 | erythema, swelling, and pain with movement of the right PIP joints of the 4th and 5th digits for 10d | few scattered pruritic red edematous papules on an erythematous/violaceous background on palmar and lateral aspects of the fingers on right hand | 1st: 2d, 2nd: 3d | dense and predominantly perivascular lymphocytic infiltrate (majority of CD31 T cells) within the superficial‐to‐deep reticular dermis, epidermis normal with no vacuolar changes at the epidermal‐dermal junction, notable papillary dermal edema, some slightly thickened vessels walls with trophism of lymphocytes within the superficial dermis | Chilblains | 1st: 14d, 2nd: 7d | 1st: Clobetasol 0.05% ointment applied twice daily 2nd: Topical Steroid therapy | | WithCoronaVac | |||||||||||||| | 32 | Selami Aykut Temiz | 44 | M | Neg, Prior COVID ‐ | Neg | Neg | NM | Neg | Mildly pruritic, edematous violaceous plaques and nodules on the dorsal hands | 7d | NM | Acral CBLL | 21d | Topical corticosteroids, Antihistamines | | 32 | Selami Aykut Temiz | 53 | M | Neg, Prior COVID ‐ | Neg | Neg | NM | Neg | Erythematous‐to‐violaceous, patches on the marginal side of the fingers of both hands | 7d | NM | Acral CBLL | 21d | Topical corticosteroids, Antihistamines | | 2.4. Pityriasis rosea (n = 9) | |||||||||||||| | With BNT162b2 | |||||||||||||| | 33 | Cyrenne, Benoit | 20 | F | Alopecia areata | NM | Neg | 1 & 2 | NM | 1st: large, pruritic, red and scaly plaque at the inoculation site, small, red, scaly lesions on the trunk, 2nd: increased pruritus and an increasing number of lesions, multiple oval pink‐to‐tan‐colored thin plaques with peripheral scale on the trunk and proximal extremities | 2d | Parakeratosis with minimal acanthosis and spongiosis of the epidermis, few scattered dyskeratotic keratinocytes in the lower epidermis, Melanin incontinence, perivascular lymphocytic infiltrate and rare scattered extravasated red blood cells in the papillary dermis | Pityriasis rosea‐like eruption | 14d | Topical corticosteroid therapy | | 33 | Cyrenne, Benoit | 40 | M | NM | NM | Neg | 2 | Neg | 2nd: red and scaly plaque on lateral left axilla, widespread eruption of pruritic, symmetrically distributed, smaller plaques with peripheral scale on the trunk and proximal extremities | 21d | NM | Pityriasis rosea | 21d | Doxycycline and Bilastine | | 34 | Busto‐Leis, J.M. | 29 | M | NM | NM | NM | 2 | NM | Herald patch, typical oval‐shaped macules, appeared along skin tension lines | 1d | Mild spongiosis with foci of parakeratosis and a lymphohistiocytic infiltrate around superficial vessels | Pityriasis rosea | NM | NM | | 34 | Busto‐Leis, J.M. | 26 | M | NM | NM | NM | 2 | NM | Herald patch, typical oval‐shaped macules appeared along skin tension lines | 7d | Mild spongiosis with foci of parakeratosis and a lymphohistiocytic infiltrate around superficial vessels | Pityriasis rosea | NM | NM | | 35 | Carballido Vazquez, A.M. | 35 | M | NM | NM | NM | 1 & 2 | NM | Extremely itchy exanthema, a single oval erythematous lesion on the thigh, papulo‐squamous rash on the trunk and proximal extremities | NM | NM | Pityriasis rosea like eruption | 14d | Antihistamines, Topical Betamethasone | | 19 | Farinazzo, E. | 42 | F | NM | NM | NM | 2 | NM | Pityriasis rosea‐like rash on the thighs and abdomen | 4d | NM | Pityriasis rosea‐like rash | NM | NM | | 19 | Farinazzo, E. | 64 | M | NM | NM | NM | 1 | NM | Pityriasis rosea‐like rash on the neck, upper limbs, and trunk | 5d | NM | Pityriasis rosea‐like rash | NM | NM | | 36 | Abdullah, Lina | 40 | M | NM | Neg | Neg | 2 | Neg | Rash, single larger erythematous patch with scale on the back, papules on the arms, thighs, chest, abdomen, and flanks in a Blaschkoid distribution | 7d | Neg | Pityriasis rosea | 21d | 0.1% Triamcinolone cream | | With CoronaVac | |||||||||||||| | 37 | Akdas, E. | 45 | F | Neg | Neg | Neg | 1 & 2 | NM | Plaques, with a peripheral collarette scaling, herald patch on the right scapula and the right breast, salmon‐colored plaques over the trunk and proximal extremities, many of which had peripheral scales; distribution of plaques: along cleavage lines reminiscent of a Christmas tree pattern on the patient's body | 1st& 2nd: 4d | Focal parakeratosis in mounds with exocytosis of lymphocytes, spongiosis in the epidermis and extravasated red blood cells in the dermis | Pityriasis rosea | 1st:21d | 1st: oral Antihistamine, Topical corticosteroid | | 2.5. Herpes zoster (n = 8) | |||||||||||||| | With BNT162b2 | |||||||||||||| | 38 | Tessas, Ioannis | 44 | M | Mild varicella during a stressful period in childhood | Dyslipidemia and active smoking | NM | 1 | 1st: neuropathic pain extending to the neck and the left hand, tiredness | Only after 1st: pain and redness, herpetiform vesicular and erythematous rash on the left upper back and lateral side and inner side of the left arm (C5–C6 dermatomes) | 7d | NM | Ipsilateral Herpes zoster | NM | Oral Valaciclovir TDS for 14d | | 39 | Burlando, Martina | 42 | M | NM | Neg | NM | 1 | NM | Unilateral small papulovesicular lesions, heralded by a burning sensation, on right hemithorax | 2d | NM | Herpes zoster | NM | Acyclovir 800 mg five times a day for 7d | | 40 | Nanova, Krassimira | 33 | F | Chickenpox in childhood | NM | NM | 1 | High‐grade fever | Widespread rash, Multiple vesicular lesions with an erythematous rim, observed on the trunk, scalp, and limbs | 7d | NM | Herpes zoster | NM | NM | | 19 | Farinazzo, E. | 34 | F | NM | NM | NM | 1 | NM | Herpes Zoster of the scalp | NM | NM | Herpes zoster | NM | NM | | 19 | Farinazzo, E. | 48 | F | NM | NM | NM | 1 | NM | Herpes Zoster | NM | NM | Herpes zoster | NM | NM | | With CoronaVac | |||||||||||||| | 41 | Bostan, E. | 78 | M | NM | CHD, CVA, HTN, COPD, radical cystectomy, prostatectomy | Neg | NM | Neg | Erythematous, painful, pruritic, stinging crusted, hemorrhagic vesicles upon an erythematous base involving the left mammary region (an area corresponding to T3‐ T4 dermatomes on the chest and the back) | 5d | NM | Herpes zoster | NM | Oral valacyclovir TDS for 7d | | With BBV152 | |||||||||||||| | 42 | Arora, P. | 60 | M | NM | DM, HTN | NM | NM | Neg | Multiple grouped vesicles on an erythematous base, present over the knee, and anterior aspect of right thigh | 4d | Intraepidermal spongiotic vesicle containing acantholytic cells with large vesicular nuclei neutrophils and dyskeratotic cells; Occasional multinucleate cell with ground‐glass chromatin and molded nuclei seen within the blister | Herpes zoster | 14d | Oral Valacyclovir 1 g TDS for 7d, Topical Fusidic Acid BD | | With ChAdOx1 nCoV‐ 19 | |||||||||||||| | 43 | Algaadi, S. A. | 65 | M | Chicken pox at childhood | CHD, HTN, DM | NM | 1 | NM | Painful grouped vesicles and ulcerations with a burning sensation on the right side of chest | 6d | NM | Herpes zoster | NM | 7d Acyclovir, Topical Fusidic Acid | | 2.6. Purpuric lesions (n = 16) | |||||||||||||| | 2.6.1. Immune thrombocytopenic purpura (ITP) (n = 14) | |||||||||||||| | With BNT162b2 | |||||||||||||| | 44 | Ganzel, C. | 53 | M | NM | Morbid obesity, DM, HTN | Lercanidipin, Losartan, Doxazocin, Hydrochlorothiazide, Aspirin | NM | Epistaxis and low PLT count | Wet purpura on palate and petechial and purpuric rash on the trunk and limbs | 14d | NM | ITP | NM | Dexamethasone 20 mg/d and IVIG, 1 g/kg, | | 45 | Tarawneh, O. | 22 | M | NM | Neg | Neg | NM | Neg | Widespread petechiae and gum bleeding | 3d | NM | ITP | 3d | Dexamethasone, PLT transfusion, IVIG at 1 g/kg | | 46 | Mazzatenta, C | 44 | F | NM | NM | NM | 2 | NM | Asymptomatic purpuric lesions on the right and left eyelid, circumscribed on the upper eyelid | 23d | NM | Purpuric lesions on the eyelids | 10d | Neg | | 46 | Mazzatenta, C | 63 | M | NM | NM | NM | 2 | NM | Asymptomatic purpuric lesions on the right and left eyelid, circumscribed on the upper eyelid | 14d | NM | Purpuric lesions on the eyelids | 15d | Neg | | 46 | Mazzatenta, C | 67 | F | NM | NM | NM | 1 | NM | Moderately itchy ecchymotic lesions on upper eyelids | 10d | NM | Purpuric lesions on the eyelids | 12d | Neg | | 47 | de Bruijn, S. | 38 | F | NM | previously TTP‐ naïve | Neg | 1 & 2 | blurred vision in the left eye (central serous chorioretinopathy) | Bruises after 1st dose, increased bruising and petechiae, diffuse ecchymosis after 2nd dose | 14d | NM | Immune‐ mediated TTP (iTTP) | NM | plasma exchange, methylprednisolone, Asprin, RTX, and caplacizumab | | With mRNA‐1273 | |||||||||||||| | 48 | Toom, S. | 36 | F | Allergy to acetaminophen | ITP | Etonogestrel‐Ethinyl Estradiol | 1 | A mild headache 7d post vaccination | Diffuse petechiae of the extremities and trunk, easy bruising, oral ecchymosis | 14d | NM | ITP | 3d | Dexamethasone 40 mg IV daily for 4d, IVIG 1 mg/kg for 3d, monitoring | | 49 | Julian, J. A. | 72 | F | Seasonal contact dermatitis | Gout, DM | Allopurinol, Sitagliptin | NM | NM | Diffuse petechiae across arms, legs, and abdomen and hemorrhagic bullae of the gingival mucosa | 1d | NM | ITP | NM | Dexamethasone, IVIG, aminocaproic acid, RTX, PLT transfusions | | 50 | Helms, J. M. | 74 | M | NM | HTN, gout, hyperlipidemia and nonischemic cardiomyopathy | NM | 1 | acute epistaxis | diffuse cutaneous purpura | Few hours | NM | Severe, Refractory Immune Thrombocytopenia | NM | High dose Dexamethasone, IVIG, PLT transfusions, RTX, Eltrombopag, plasma exchange, high dose Methylprednisolone, Romiplostim, Cefazolin | | With ChAdOx1 nCoV‐ 19 | |||||||||||||| | 51 | Candelli, M | 28 | M | NM | Neg | Neg | 1 | fatigue and headache for 10 days and fever for 2 days | oral bleeding and the appearance of petechiae over the trunk, arms, and legs for 3d purpura over the trunk, all four limbs, and bleeding lesions within the oral cavity | 19d | NM | ITP | NM | dexamethasone (40 mg/day) | | 52 | Ryan, E. | 35 | F | NM | migraine | Neg | 1 | general myalgia and extreme fatigue,headache (different from her known migraine headaches | onset of bruising and petechiae | 10d | Marrow aspirate revealed some reactivefeatures with no evidence of an underlying infiltrative disorder | VITT | NM | preemptively anticoagulated with apixaban | | 53 | Thaler, J. | 62 | F | NM | substituted hypothyroidism of unresolved genesis since age 20 | NM | 1 | flu‐ like symptoms including aching joints, moderate headache, and moderate dizziness, self‐ medicated with 1 g paracetamol, fever: 400 mg aspirin twice | unusually large hematoma after slight biting of lip, gum bleedings, an atraumatic hematoma at the right ankle, small hematomas and petechiae of the limbs | 8d | NM | VIPIT | NM | low dose fibrinogen concentrate (1 g for 2d), danaparoid‐ sodium 750 IE IV bolus + 1500 IE SC, followed by 1500 IESC every 8 h). high dose IVIG (1 g/kg),prednisolone (0.75 mg/kg)(2d) | | With Ad26.COV2.S | |||||||||||||| | 54 | Costello, A. | 40 | F | NM | migraines, obesity | NM | 1 | sudden headache (intermittent, worsening with sinus pressure, prescribed amoxicillin/clavulanate, methocarbamol, and methylprednisolone), body aches, fever, chills, bilateral lower‐extremity pain without edema, intermittent vertigo | swollen red cheeks, petechiae on her right cheek and bilateral breasts and spontaneous bruising in extremities | 10‐12d | NM | vaccine‐induced thrombotic thrombocytopenia | NM | Bivalirudin, Prednisone, (1 mg/kg/day), IVIG (1 g/kg/day), discharged on Rivaroxaban and a Prednisone taper | | With CoronaVac | |||||||||||||| | 55 | Cebeci, F. | 82 | F | NM | seronegative RA, HTN | Hydroxychloroquine 3 years, Olmesartan 2 years Prednisolone 5 mg 6 months (discontinued 3 weeks vaccination) | 1 | weakness, burning in the legs | 1st: diffuse petechial rash on both lower extremities 2nd: uneventful | 1d | NM | petechial rash as a vaccine‐ induced hypersensitivity reaction | 7d | Prednisolone restarted 1 week after complete remission of the rash | | 2.6.2. Vasculitis associated purpura (n = 2) | |||||||||||||| | With BNT162b2 | |||||||||||||| | 30 | Watad A. | 53 | M | NM | Neg | NM | 1 | Mild abdominal pain, arthralgia | Palpable purpura | 3d | Leukocytoclastic cutaneous vasculitis (IgA and C3 deposits in the vessel walls) | Henoch‐Schonlein purpura | NM | Dexamethasone 10 mg, Prednisone 60 mg thereafter | | With BBV152 | |||||||||||||| | 56 | Kharkar, V. | 31 | F | Neg | Neg | Neg | 2 | NM | painful palpable purpura on legs, predominantly on the left leg, Dermoscopy: irregularly arranged red blotches, with an orange–red background | 4d | Perivascular infiltrate comprised of eosinophils and lymphocytes with a few neutrophils, along with erythrocyte extravasation, perivascular fibrin and perivascular edema | Cutaneous small vessel vasculitis (cSVV) | 10d | Wait‐and‐watch policy | | 2.7.Inflammatory flare‐ups (n = 27) | |||||||||||||| | 2.7.1. Autoimmune inflammatory rheumatic diseases (n = 13) | |||||||||||||| | 2.7.1.1. Psoriasis (n = 3) | |||||||||||||| | With BNT162b2 | |||||||||||||| | 57 | Cohen, Stephanie R | 46 | F | Psoriasis (2 years in remission) | Psoriatic arthritis, IBS, leukocytoclastic vasculitis (biopsy‐proven) | Prednisone | 1 & 2 | Neg | 1st: mild exacerbation of palpable purpuric papules on the bilateral lower legs, 2nd: exacerbated again with significant exquisitely tender palpable purpuric papules distributed bilaterally on the lower legs, feet, upper extremities, lower back, and abdomen | 1st& 2nd: 2d | Perivascular mixed inflammatory infiltrate with numerous neutrophils, lymphocytes, occasional eosinophils, leukocytoclasia and erythrocyte extravasation, no fibrinoid necrosis of vessels | Small vessel vasculitis such as IgA vasculitis (Leukocytoclastic vasculitis flare) | NM | Topical steroids and a Prednisone taper | | With mRNA‐1273 | |||||||||||||| | 30 | Watad A. | 36 | F | Psoriasis since childhood (mild) | NM | NM | 1 | Dactylitis, stiffness and tightness, finger joint pain | Painful erythematous macules over palmar surfaceof several fingers on both hands, painful chilblains like lesions (CBLL) on fingers | 10d | NM | NM | NM | Ibuprofen 800 mg | | With CoronaVac | |||||||||||||| | 58 | Onsun, Nahide | 72 | M | Plaque psoriasis | Prerenal acute injury, HTN | Indapamide | 1 | Fever | Diffuse erythema, desquamation, and coalescing pustules over the entire body | 4d | Compatible with generalized pustular psoriasis | Generalized pustular psoriasis | NM | Acitretin (25 mg/d), IV infliximab 5 mg/kg | | 2.7.1.2. Lichen planus or lichenoid reactions (n = 2) | |||||||||||||| | With BNT162b2 | |||||||||||||| | 59 | Hiltun, I. | 56 | F | Lichen planus lesions 7 years prior (successfully treated with topical therapy) | NM | Neg | 2 | NM | Polygonal, well‐delimited, erythematous papules in the ankles, periumbilical area, flexural wrist and forearms and mammary and axillary folds, Dermoscopy: slight desquamation and Wickham's striae, no mucosal or nail involvement | 2d | Typical findings of lichen planus with epidermal hyperplasia forming a characteristic saw‐tooth appearance with wedge‐shaped hypergranulosis, vacuolar degeneration of basal layer and dense lymphocytic infiltrate in the superficial dermis | Lichen planus | NM | High‐potency Topical corticosteroids | | 39 | Burlando, Martina | 47 | M | Previously diagnosed with lichen planus located on both forearms | Neg | NM | 1 | NM | Sudden worsening of the preexisting papules, which spread to both arms and trunk | 1d | Refused by patient | Lichenoid reactions | NM | Topical corticotherapy BD for 10d | | 2.7.1.3. Behçet's (n = 4) | |||||||||||||| | With BNT162b2 | |||||||||||||| | 30 | Watad A. | 21 | M | Behcet's disease for 3 years | NM | Colchicine | 1 | NM | Oral aphthous ulcers | 5d | NM | Behcet's disease flare | NM | 20 mg Prednisone for 7d | | 30 | Watad A. | 55 | M | Behcet's disease for 20 years | Chronic lymphocytic leukemia | Apremilast | 2 | Synovitis of small joints | Oral aphthous ulcers(on the tongue) | 7d | NM | Behcet's disease flare | NM | Colchicine 0.5 mg BD, 5 mg Prednisone | | 30 | Watad A. | 20 | M | Behcet's disease for 2 years | NM | Colchicine | 1 | NM | Oral aphthous ulcers | 3d | NM | Behcet's disease flare | NM | Colchicine 2 mg daily | | 30 | Watad A. | 34 | M | Behcet's disease for 10 years | Neg | Colchicine, Humira | 1 | NM | Pustular skin lesions | 5d | NM | Behcet's disease flare | NM | NSAIDs, increase of Colchicine dose | | 2.7.1.4. Systemic lupus erythematosus (SLE) (n = 2) | |||||||||||||| | With BNT162b2 | |||||||||||||| | 30 | Watad A. | 78 | F | Laboratory SLE | NM | NM | 1 | Fever and arthritis | Erythematous rash (generalized acute cutaneous lupus), purpura, oral aphthous ulcers | 2d | Biopsy from purpura: leukocytoclastic vasculitis | Leukocytoclastic vasculitis | NM | Hydroxychloroquine | | With ChAdOx1 nCoV‐ 19 | |||||||||||||| | 30 | Watad A. | 50 | F | SLEwith arthritis, mucosal ulcers and hemolysis | NM | NM | 1 | Severe hemolysis and arthralgia | Oral and nasal ulceration | 14d | NM | SLE flare | NM | Prednisolone 60 mg daily, RTX | | 2.7.1.5. Other AIIRDs (n = 2) | |||||||||||||| | With BNT162b2 | |||||||||||||| | 30 | Watad A. | 62 | F | Dermatomyositis | NM | Methotrexate, Plaquenil | 1 | NM | Skin rash similar to the dermatomyositis rash | 7d | NM | Dermatomyositis flare | 7d | Local Steroid cream | | 30 | Watad A. | 42 | F | NM | Transient synovitis | NM | 1 | Migratory arthritis of small joints | Painless hemorrhagic rash on toes, erythema on small joints | 4d | NM | Florid clinical arthritis of the PIP joints | 7d | Prednisolone 10 mg, daily | | 2.7.3. Ulcerative colitis (UC) (n = 1) | |||||||||||||| | With BNT162b2 | |||||||||||||| | 30 | Watad A. | 28 | M | NM | UC for 10 years, HES for 5 years, (well controlled) | Vedolizumab, Cyclosporin | 1 | Hemorrhagic diarrhea | Vesicular skin rash, oral aphthosis | 4d | NM | Flare of HES and UC | NM | 1 gr of Sulomedrol daily for 3d, Prednisone 60 mg/day | | 2.7.4. BCG scar local skin inflammation (n = 2) | |||||||||||||| | With BNT162b2 | |||||||||||||| | 60 | Lopatynsky‐Reyes, E. Z. | 31 | F | NM | Neg | NM | 1 | headaches, chills, myalgias, pain at injection site, lymphadenopathies | Only after 2nd: inflammation area of 1.5 cm on the BCG scar site with erythema, induration, but painless to palpation (5 cm from the COVID vaccine injection site) | 2nd: 2d | NM | BCG Scar Local Skin Inflammation | 4d | 2nd: three doses of Oral Paracetamol | | With mRNA‐1273 | |||||||||||||| | 60 | Lopatynsky‐Reyes, E. Z. | 28 | F | NM | NM | NM | 1 & 2 | 1st: pain, redness at the injection site, myalgias, arthralgias, malaise, 2nd: headache, nausea, myalgias, arthralgias, and malaise | 1st: redness at injection site, 2nd erythematous reaction followed by pain, induration, and mild edema at BCG scar site (3 cm below COVID vaccine injection site) | 2nd: 36 h | NM | BCG Scar Local Skin Inflammation | 2d | 2nd: four doses of Oral Paracetamol | | 2.7.5. Radiation recall phenomenon (n = 3) | |||||||||||||| | With BNT162b2 | |||||||||||||| | 61 | Soyfer, V. | 68 | M | NM | Metastatic soft tissues sarcoma in the posterior chest wall and 1 lesion in the right lung | Preoperative radiation therapy, resection in the posterior chest wall | 2 | NM | pain, burning sensation, redness, and mild skin exfoliation in the area of the posterior chest wall electron field (the electron port shape closely resembles the erythematic area) | 5d | NM | Radiation Recall Phenomenon | a few days | Topical steroids and painkillers | | 61 | Soyfer, V. | 64 | M | NM | Metastatic solitary fibrous tumor | Radiation of lumbar vertebrae after spinal cord surgery | 2 | NM | Only after 2nd dose (14d after RT): skin redness and itching sensation, sparing the skin covering the lumbar spine | 6d | NM | Radiation Recall Phenomenon | 7d | Neg | | With CoronaVac | |||||||||||||| | 62 | Afacan, E | 60 | F | Melanoma | NM | Dabrafenib/Trametinib combination therapy | 1 | Sudden onset painful lesion on the medial side of the right leg | Well demarcated, erythematous, indurated plaque confined to an area of previous irradiation | 5d | Epidermal intercellular edema, lymphocyte exocytosis, and rare necrotic keratinocytes as well as increased dermal collagenization and fibrosis | Radiation Recall Phenomenon | NM | NM | | 2.7.6. Inflammatory reaction to hyaluronic acid (HA) soft tissue fillers (n = 2) | |||||||||||||| | With BNT162b2 | |||||||||||||| | 63 | Michon, A. | 39 | F | NM | Neg | Neg | 1 | flu‐ like illness symptoms (fatigue, headache, myalgias, and anorexia), which resolved within 4d | tender, erythematous swelling at the left tear trough area (areas previously treated with filler) | 2d | NM | Delayed inflammatory reaction to HA fillers | 5d | Spontaneous resolution | | 63 | Michon, A. | 61 | F | NM | intermittent benign vertigo | Neg | 1 | Flu‐like illness symptoms | intermittent facial swelling mostly on cheeks and undereye (areas previously treated with filler), lasting for almost 1d per episode, and once for 72 h | 1d | NM | Delayed inflammatory reaction to HA fillers | 2d after hyaloronidase | 75 units of hyaluronidase at a concentration of 150 units/mL | | 2.7.7. No Flare‐up in Autoimmune Disorders (n = 6) | |||||||||||||| | With BNT162b2 | |||||||||||||| | 64 | Iannone, Michela | 48 | F | HS for 6 years (vaccination was after 90D of treatment with a single HS flare), anti–TNF‐ α‐induced lupus syndrome | Concomitant endometriosis | Surgical drains, systemic Clindamycin/Rifampicin, Ixekizumab SC 160 mg | 1 & 2 | NM | No adverse events and no HS flares | NM | NM | NM | NM | Routine continuation of Ixekizumab | | 65 | Pacifico, A | 48 | M | Psoriasis, with flares of both PsO and PsA during asymptomatic COVID‐19 infection, spontaneous resolution 10 days after COVID‐19 remission | Psoriatic arthritis | Apremilast, achieving stable remission, maintained for 8 months | 1 & 2 | NM | No psoriasis flares with either dose | NM | NM | NM | NM | NM | | 65 | Pacifico, A | 36 | F | Plaque psoriasis, concurrent pustular palmoplantar psoriasis area | NM | Apremilast and narrowband UVB for 3 years | NM | Neg | No psoriasis flares with either dose | NM | NM | NM | NM | NM | | 66 | Rama, T. A. | 37 | F | Adult‐onset monomorphic maculopapular cutaneous mastocytosis lesions with generalized pruritus, flare up of lesions, and osteopenia | severe mast cells mediator‐related symptoms including abdominal colicky pain, bloating and diarrhea | Antihistamines, Montelukast | 1 | Neg | No mastocytosis flare | NM | NM | NM | NM | NM | | 66 | Rama, T. A. | 47 | F | monomorphic maculopapular cutaneous mastocytosis, anaphylaxis with multiple drugs, pruritus | MC mediator‐related symptoms including migraines, gastroesophageal reflux, and osteopenia | Antihistamines, montelukast | 1 | Myalgia | No mastocytosis flare | 1d | NM | NM | NM | NM | | With ChAdOx1 nCoV‐19 | |||||||||||||| | 65 | Pacifico, A | 76 | M | Psoriasis for 4 years: stable residual Psoriasis area severity index (PASI) of 3 | NM | Apremilast for 4 years | 1 | 1st: fever (38.5°C) and myalgia for 3 days | No psoriasis flares with either dose | NM | NM | NM | NM | NM | Abbreviations: 1st, after the first dose; 2nd, after the second dose; AIIRD, autoimmune inflammatory rheumatic diseases; ASAT, aspartate aminotransferase; BD, twice a day; BPH, benign prostatic hypertrophy; CAD, coronary artery disease; CBLL, chilblain‐like lesions; CHD, coronary heart disease; CKD, chronic kidney disease; CVA, cerebrovascular accident; d, days; GGT 2N, gamma‐glutamyl transferase twice normal upper limit; HA, hyaluronic acid; HES, hypereosinophilic syndrome; HS, hidradenitis suppurativa; HTN, hypertension; IBS, irritable bowel syndrome; ITP, immune thrombocytopenic purpura; IVIG, intravenous immunoglobulin; MC, mast cell; MOGSD, myelin oligodendrocyte glycoprotein spectrum disorder; Neg, negative; NM, not mentioned; PIP, proximal interphalangeal; PLT, platelet; PO, by mouth; PsA, psoriatic arthritis; PsO, plaque psoriasis; RT, radiation therapy; RTX, rituximab; SC, subcutaneously; SLE, systemic lupus erythematosus; SLE, systemic lupus erythematosus; TDS, three times a day; UVB, ultraviolet B. Supporting information Table S1. A total of 73 cases (62.9%) developed mucocutaneous reactions after receiving the 1st dose of the vaccines, 19 cases (16.4%) after the 2nd dose, and 15 cases (13%) after both doses. Nine reports (7.7%) had not specified the administered dose. Cases were further categorized into sections based on their clinical and pathological diagnosis: 3.2.1. Injection site reactions, “Covid arm” (n = 12) Injection site skin reaction (Covid arm) consisted of 12 cases (mean age: 47.9 years, 100% female). Three of them (25%) had atopic background (either themselves or their family). They developed symptoms including painful or pruritic erythematous swelling, urticarial oval patch, patch, vesicle, nodule, or induration at the vaccine injection site after 6.27 days (50% BNT162b2 and 50% mRNA‐1273; 50% after 1st dose, 25% after 2nd dose and 25% after both doses). Resolution of symptoms was achieved in an average of 4.15 days, mainly with the use of topical corticosteroid cream (58.3%). 3.2.2. Non‐injection site reactions (n = 104) Hypersensitivity reaction type 1 (n = 14) A total of 14 patients were incorporated in the section of type 1 hypersensitivity reaction. Urticaria (n = 5) Isolated urticaria occurred in 5 patients (mean age: 30.8 years, F/M: 4) in a range of 5 min to 8 h after inoculation (100% BNT162b2; 100% 1st dose), 80% had an allergic background and they were mainly treated by antihistamines and then oral corticosteroids. Flushing (n = 3) Three patients experienced Flushing of the face (mean age: 48 years, all female) in a range of 5–30 min after inoculation (100% BNT162b2; 100% 1st dose). Two had an allergic background and 1 was treated with antihistamines. Angioedema (n = 3) Three patients (mean age: 35 years, F/M:2) presented with angioedema within 10 min to 24 h of immunization (66.7% BNT162b2 and 33.3% mRNA‐1273; 100% 1st dose). For two patients, no treatment was conducted and for the other one antihistamines and corticosteroids were prescribed and symptom relief was achieved in 24 h. Anaphylaxis (n = 3) Three patients encountered anaphylaxis (mean age: 27.3 years, F/M:2) all of whom had an allergic background and developed symptoms pertaining to anaphylaxis, with systemic reactions such as tachycardia, tachypnea, dysphagia, dyspnea, severe chills, dysphagia, the feeling of a slurred mouth and hoarseness, wheezing and throat pruritus, along with mucocutaneous reactions such as diffuse maculopapular rash, urticaria, diaphoresis, palate pruritis, generalized rash and pruritus, sudden onset of rash followed by urticaria and angioedema in a span of a few minutes to 5 h after vaccination (66.7% BNT162b2 and 33.3% mRNA‐1273; 100% after 1st dose). They were diagnosed as Biphasic anaphylaxis, Severe allergic reaction and Level 1 Anaphylaxis. Resolution was achieved 6 h to 1 day after the onset of symptoms using steroids, antihistamines, one patient was treated with an Epinephrine injection and Sodium Succinate, and one was given oxygen. Generalized Eruptions (n = 21) In the generalized eruptions section, we considered patients with miscellaneous presentations and diagnoses who could not be further categorized in other groups. A total of 21 patients were included (mean age: 55.14 years, F/M:1.63)(57.1% BNT162b2, 19% mRNA‐1273, 14.3% ChAdOx1 nCoV‐19, 9.6% Ad26.COV2.S; 66.7% after 1st dose, 14.3% after 2nd dose, 14.3% after both doses and 4.7% dose not mentioned). Among the more distinguished presentations were: Steven‐Johnson syndrome was a diagnosis of a patient (male, 60‐year‐old) who presented with fever, oral ulceration, eye congestion, erosions over the glans, and multiple purpuric macules all over the body with perilesional erythema which progressed to necrosis after 3 days of immunization (ChAdOx1 nCoV‐19, 1st dose); resolution of his symptoms was achieved in 7 days on oral cyclosporine. Rowell's syndrome was diagnosed in a 74‐year‐old man with erythematous and partly violaceous coalescing macules and papules with slightly indicated cocarde formation on the trunk and extremities along with positive antinuclear autoantibodies (ANA) with 1:640 in a speckled pattern, anti‐Ro/SSA (60), anti‐Ro/SSA (52), and anti‐La/SSB antibodies within 1 day following vaccination (BNT162b2, 1st dose). Two patients (mean age: 56.5 years, F/M: 1) encountered Erythema multiforme (EM)‐like eruption following inoculation (100% BNT162b2; 50% 1st dose, 50% both doses); The first patient was a 55‐year‐old male without previous history of EM who developed symptoms within 10 days and treated with systemic corticosteroids within 10 days, but the second patient was a 58‐year‐old female with a past medical history of EM and recurrent episodes of herpes labialis, presented her symptoms in 12 h after first and 24 h after the second dose and was cured with topical corticosteroids. Two patients were diagnosed with Fixed Drug Eruption (FDE). One a 44‐year‐old female who developed purplish macule on the third finger of one hand 10 days after her 2nd dose of BNT162b2, and the other, a 66‐year‐old male who developed painful blistering rashes, violaceous, poorly demarcated patches, large flaccid bullae, and erosions all over his body along with fever, myalgias, malaise, muscle tenderness and stiffness in lower extremity with preserved strength, following his 2nd dose of mRNA‐1273 and was diagnosed with extensive bullous FDE. Resolution was achieved in 5 days using ibuprofen, high‐dose oral prednisone, along with drainage of patient's bullae, and administration of mupirocin ointment with Vaseline. Chilblain‐like lesions (CBLL) (n = 9) CBLLs were reported in 9 patients (mean age: 49.8 years, F/M: 1.25) with manifestations as violaceous/ erythematous lesions in the spectrum of macules, nodules to patches or plaques, located on the fingers and/or toes almost symmetrically which could be painful or to a lesser extent, pruritic. The patient's presentation onset was 5.22 days on average after injection (55.6% BNT162b2, 22.2% CoronaVac, and 22.2% mRNA‐1273; 44.5% after 1st dose, 11.1% after 2nd dose, 22.2% after both doses and 22.2% dose not mentioned) and their symptoms resolved in an average of 18.2 days, treated with topical corticosteroids (44.5%), antihistamines (22.2%) and NSAIDs (11.1%). Pityriasis rosea (n = 9) Nine patients (mean age: 37.9 years, F/M: 0.67) developed pityriasis rosea manifestations (herald patch, oval erythematous thin plaques with peripheral scale dominantly on the trunk and proximal extremities) without previous or relevant history after 6.38 days on average of immunization (88.9% BNT162b2 and 11.1% CoronaVac; 11.1% after 1st dose, 55.6% after 2nd dose and 33.3% after both doses), and resolution took place after 17.5 days on treatment with topical corticosteroids (44.4%) and antihistamines (33.3%) (either separately or in combination). Herpes zoster (n = 8) Eight patients (mean age: 50.5 years, F/M: 0.6) presented with painful (burning sensation) grouped vesicles on erythematous background in the various dermatomes and were diagnosed with herpes zoster. 37.5% of them reported a history of varicella infection in childhood, the patients became symptomatic following vaccination (62.5% BNT162b2, 12.5% CoronaVac, 12.5% ChAdOx1S nCoV‐19, 12.5% BBV152; 75% 1st dose and 25% doses not mentioned) after 5.17 days on average and mainly managed with Acyclovir. Purpuric lesions (n = 16) Immune thrombocytopenic purpura (ITP) (n = 14) A total of 14 patients (mean age: 51.14 years, F/M: 1.8) developed ITP with the presentation of widespread petechiae, purpura or ecchymosis (78.6%) or local purpuric lesions on the eyelids (21.4%) after 9.14 days on average of vaccination (33.3% BNT162b2, 25% mRNA‐1273, 25% ChAdOx1S nCoV‐19, 8% Ad26.COV2.S and 8% CoronaVac for diffuse lesions; and 100% BNT162b2 for local eyelid purpuric lesions; 57.1% after 1st dose, 14.4% after 2nd dose, 7.1% after both doses and 21.4% dose not mentioned). ITP was treated mostly by dexamethasone and IVIG and purpuric lesions on the eyelids were managed conservatively. Vasculitis associated purpura (n = 2) Two patients encountered vasculitis symptoms: A 31‐year‐old female without rheumatologic background developed painful palpable purpura on her legs after 4 days of injection (BBV152, dose 2). She was diagnosed with cutaneous small vessel vasculitis (biopsy proven) and her symptoms resolved within 10 days by wait & watch strategy. Another patient was a 53‐year‐old male who experienced abdominal pain, arthralgia, and palpable purpura after 3 days of vaccination (BNT162b2, 2nddose), received the diagnosis of Henoch Schoenlein Purpura and biopsy revealed leukocytoclastic vasculitis. He was managed with corticosteroids. Inflammatory flare‐ups (n = 27) Autoimmune inflammatory rheumatic diseases (AIIRD) (n = 13) A total of 13 patients with AIIRD had flare ups of their disease, including known cases of psoriasis (23%), lichen planus (15.33%), Behcet's disease (31%), SLE (15.33%) and other (dermatomyositis, arthritis)(15.33%), Psoriasis (n = 3) Three psoriatic patients (mean age: 51.3 years, F/M: 1.5) experienced disease flare after 4.5 days on average of inoculation (33.3% BNT162b2, 33.3% mRNA‐1273 and 33.3% CoronaVac, 75%after 1st dose and 25% after 2nd dose). One of them was a 46‐year‐old woman with in remission psoriasis (for 2 years, under prednisolone) and leukocytoclastic vasculitis who developed palpable purpuric papules after both BNT162b2 vaccine doses, and biopsy from the lesions revealed leukocytoclastic vasculitis flare, thereafter it was treated by topical and oral corticosteroids. Another patient was a 72‐year‐old man with a history of plaque psoriasis, who developed biopsy‐proven generalized pustular psoriasis after CoronaVac and was afterward treated by acitretin and infliximab. Lichen planus or lichenoid reactions (n = 2) Lichen planus was a medical history of 2 patients (mean age: 51.5 years, F/M:1) who encountered their disease relapse after 1.5 days on average of their immunization (100% BNT162b2, 50% after 1st dose, and 50% after 2nd dose). Behçet's (n = 4) In 4 patients with Behcet's disease (mean age: 32.5 years, 100% males), flare occurred with a presentation of aphthous ulcers (75%) and pustular lesions (25%) 5 days on average after injection (100% BNT162b2, 75% after 1st dose, 25% after 2nd dose) and their treatments were with colchicine, oral corticosteroids and NSAID either single or in combination. Systemic lupus erythematosus (SLE) (n = 2) Two patients experienced SLE flares. A 78‐year‐old woman with a past history of Systemic lupus erythematosus, presented with fever and arthritis, besides erythematous rash (generalized acute cutaneous lupus), purpura and oral aphthous ulcers after 2 days of inoculation with 1st dose of BNT162b2; biopsy from purpura showed leukocytoclastic vasculitis and consequently treatment was done with hydroxychloroquine. Another patient with SLE was a 50‐year‐old woman who received 1st dose of ChAdOx1S nCoV‐19 and presented with severe hemolysis and arthralgia in addition to oral and nasal ulceration 14 days post‐vaccination. Eventually, she was treated with oral corticosteroid and rituximab. Other AIIRDs (n = 2) A 62‐year‐old woman with a history of dermatomyositis, developed a characteristic rash of dermatomyositis (which she had experienced prior) after 7 days of receiving her 1st dose of BNT162b2 and was subsequently treated by topical corticosteroids leading to the resolution in 1 day. A 42‐year‐old woman with history of transient synovitis developed a painless hemorrhagic rash on toes and erythema along with migratory arthritis on small joints 4 days after her 1stdose of BNT162b2, leading to a diagnosis of florid clinical arthritis of the PIP joints. She was treated with daily prednisolone 10 mg, and the symptoms resolved within 7 days. Ulcerative colitis (UC) (n = 1) A 28‐year‐old male with history of UC for 10 years, and hyper eosinophilic syndrome (HES) for 5 years (which were both well controlled under vedolizumab and cyclosporin), experienced vesicular skin rash, oral aphthosis and hemorrhagic diarrhea 4 days following his 1st dose of BNT162b2, which was treated with daily 1 gr of sulomedrol for 3 days and prednisone 60 mg/day. BCG scar local skin inflammation (n = 2) Two patients (mean age: 29.5 years, both female) experienced BCG scar local skin inflammation after 1.75 days of their 2nd injection (50% BNT162b2 and 50% mRNA‐1273; 50% after 1st dose, 50% after both doses) and it resolved within 3 days on average with paracetamol use. Radiation recall phenomenon (n = 3) Three patients with a medical history of malignancy (mean age: 64 years, F/M: 0.5) who had undergone radiotherapy, experienced Radiation Recall Phenomenon 5.3 days on average following injection (66.7% BNT162b2 and 33.3% CoronaVac, 66.7% after 1st dose, 33.3% after 2nd dose). Inflammatory reaction to hyaluronic acid (HA) soft tissue fillers (n = 2) Two women, one 39 and the other 61 years old, experienced delayed inflammatory reaction to HA fillers after their 1st doses of BNT162b2, presenting with flu‐like symptoms such as headache, fatigue, myalgias, and anorexia, along with tender, erythematous swelling at areas previously treated with filler. One resolved spontaneously after 5 days, but the other was administered 75 units of hyaluronidase (at a concentration of 150 units/mL), as her swelling was intermittent and lasted for 1–3 days at a time, and she had a larger volume of filler injected in her face; her symptoms subsided 2 days after administration of the hyaluronidase. No flare‐up in autoimmune disorders (n = 6) In the “No flare‐up” group, three patients (mean age: 53.3 years, F/M: 0.5) with a history of psoriasis, under control with apremilast (and narrowband type B ultraviolet [UVB] therapy in one of them), did not experience any flare‐ups after vaccination (66.7% BNT162b2 and 33.3% ChAdOx1S nCoV‐19, either dose). Two patients (mean age: 42 years, both female) with history of mastocytosis and also one patient with a history of hidradenitis suppurativa (HS) did not suffer from a flare‐up following inoculation (BNT162b2, 1st dose in patients with mastocytosis and both doses in the one with HS). In the viewpoint of comparing side‐effects following the three most administered vaccine groups, the most common mucocutaneous eruptions among mRNA vaccine recipients presented in case reports (n = 90) were generalized eruptions (17.7%), hypersensitivity reactions (15.5%), injection site reactions (14%), purpuric lesions (11%), Pityriasis Rosea (8%), Chilblain‐like lesions (7.7%), and inflammatory flare‐ups (20%). Among Adenovirus viral vector vaccines (n = 11), generalized Eruptions (45%) and purpuric lesions (36%) were most common. Considering inactivated virus vaccines (n = 9), Chilblain‐like lesions (22%), Herpes Zoster (22%), and purpuric lesions (22%) were more prevalent. 3.3. Case series A total of 10 case series were identified, comprised of 314 cases (mean age: 44.49 years; 83.76% F), as depicted in Table 2. History of previous allergy or allergic reaction was present in 42% to 90% of patients. 63.4% and 36.3% of patients received BNT162b2 and mRNA‐1273 vaccines, respectively, and one participant's (3%) vaccine was unknown. The mucocutaneous reactions appeared on first or both doses. - 1. Injection site reaction (n = 17, 5.4%) TABLE 2. | Supplemental references a | First author | Number of patients | Women percentage | Mean of Age (year) | Patients' mucocutaneous disease history | Dose | Any symptoms after vaccine | Mucocutaneous lesions characteristic | Mean time of onset reaction | Location of mucocutaneous reaction | Duration of reaction | Treatment | Outcome | |---|---|---|---|---|---|---|---|---|---|---|---|---|---| | 1. Injection site reaction (n = 17) | ||||||||||||| | With BNT162b2 | ||||||||||||| | 1 | Farinazzo, E. | 17 | 82.4 | 47 | NM | 1 or 2 | Fever (24%) | Erythema (30%), wheals (some burning, itchy, painful, with axillary lymphadenopathy [n = 2]) (24%), swelling (18%), nodules (painful and itchy erythematous subcutaneous nodule, Painful hardening)(18%), Itching (10%) | 1.7d (of those reported) | Injection site | NM | NM | NM | | 2. Generalized reaction (n = 33) | ||||||||||||| | With BNT162b2 | ||||||||||||| | 2 | Corbeddu, M. | 11 | 64 | 50 | Allergy or allergic diathesis (72.7%) | 1 & 2 | Extracutaneous manifestations (36.3%), such as laryngospasm | Erythematous reactions, morbilliform rash, mild erythema, positive dermographism, urticarial rash, periorbital edema, angioedema, an atopic dermatitis flare up | 1.66 d | Diffuse (27.5%), Injection site (27.5%), face (9%), chest, trunk (18%), legs (9%), dorsum of foot (9%) | 2–3 d | Short oral steroids course | Mostly spontaneous remission | | 1 | Farinazzo, E. | 22 | 95.5 | 43 | NM | 1 &/or 2 | Fever (4.5%) | Erythema (some itching) (23%), urticarial rash (23%), diffuse urticaria (14%), generalized itching (14%), swelling (eyelids, face, with mandibular lymphadenopathy)(14%), Rash (erythematous macular)(7.5%), Dermatitis (itchy)(4.5%) | 5.2 d | Generalized, localized other than injection site | NM | NM | NM | | 3. Delayed localized hypersensitivity reactions (n = 32) | ||||||||||||| | With BNT162b2 | ||||||||||||| | 3 | Coto‐Segura, P. | 4 | 0 | 81.5 | NM | 1 | Neg | Bullous drug‐induced reactions with severe pruritus Patients 1–3: urticated and erythematous plaques and tense bullae on erythematous base (1–3 cm in diameter), Patient 4: small vesicles‐bullae/bleb, some in a rosette‐like pattern; (Biopsy: subepidermal/subcorneal blisters, positivity in DEJ for IgG and C3) (Mucous membranes and eyes spared) | 3–17 d | Patients 1–3: trunk, forearms and thighs Patient 4: limited to forearms | NM | NM | NM | | With mRNA‐1273 | ||||||||||||| | 4 | Blumenthal, K. G. | 12 | 83.3 | 43.3 | Allergy (42%), rhinitis (20%) | 1 & 2 | 1st: Fatigue (33%), myalgias (17%), headache, chills, lymphadenopathy, fever, Postural tachycardia, HTN 2nd: Fever (67%), myalgias (58%), chills (75%), fatigue (25%), headache (50%), lymphadenitis (17%), lymphadenopathy (9%), nausea (9%) | 1st: Pruritus, warmth, burning, swelling, rash, erythema, induration, hyperpigmentation (9%) 2nd:(in 50% of those with 1st dose reactions, either similar or lower grade) rash (50%), erythema (50%), itching (9%), urticaria (9%) Biopsy: Large T‐cell–mediated | 1st: 8.3 d | Near the injection site, palmar, near elbow | 6d | Amoxicillin (875 mg), clavulanic acid (125 mg), cetirizine 10 mg, loratadine 10 mg, diphenhydramine 25–50 mg, triamcinolone 0.1% topical, prednisone, famotidine 20 mg, clobetasol propionate 0.05% topical, hydrocortisone 1% topical | 58%resolution, 25% Hyperpigmentation, 17% Pain, Itching | | 5 | Johnston, M. S. | 16 | 81 | 48.1 | NM | 1 & 2 | 1st: Fevers, chills, arthralgias, myalgias, headache, fatigue (19%),Sore arm (38%) 2nd:Nausea, chills (38%), myalgias (31%), headache (63%), sore arm (31%), fatigue (44%),decreased appetite, arthralgias (13%), Lethargy, rigors | 1st: (94% skin reaction) pruritic and variably painful erythematous reactions,typically homogenous,less commonly annular 2nd: (75% skin reaction, 73% similar to 1st dose reactions), pruritic, painful, and edematous pink plaques | 1st: 7d 2nd: 2.3 d | at or near the injection site | 1st: 8.2 d 2nd: 3d | Topical steroids (clobetasol ointment,hydrocortisone cream), oral antihistamines, cool compresses, cephalexin | NM | | 4. Anaphylaxis (n = 66) (those in the preceding reports are counted once) | ||||||||||||| | With BNT162b2 | ||||||||||||| | 6 | Shimabukuro, T. | 21(first report) | 90 | 40.5 | Allergic reactions (81%), anaphylactic episode (33%) | 1 | Swollen airway, swollen lips (19%) and tongue (10%), wheezing (20%), stridor, nausea (14%), hoarseness (10%), difficulty swallowing, cough (10%) | Diffuse erythematous rash (35%), urticaria (50%), diffuse pruritic rash (10%), pruritus (5%) (of 95% of all patients) | 46 min | Generalized | NM | Epi in 90% of patients | recovery | | 7 | Shimabukuro, T. | 47(updated) | 94 | 39 | allergy or allergic reactions (77%), anaphylaxis (34%) | 1 & 2 | respiratory and airway obstruction symptoms, and nausea | Generalized urticaria, diffuse erythematous rash; facial, tongue, or laryngeal angioedema | 10 min | Generalized | NM | Epi (92%), endotracheal intubation (11%), corticosteroids (86%), antihistamines (72%) | 92% recovery | | With mRNA‐1273 | ||||||||||||| | 8 | Shimabukuro, T. | 10(first report) | 100 | 46.2 | allergy or allergic reaction (90%), previous anaphylactic episode (50%) | 1 | Respiratory failure, vomiting, decreased peripheral perfusion, persistent dry cough, nausea, hypotension, wheezing | (of 50% of all patients): Diffuse erythematous rash (80%),Generalized urticarial rash (20%); Tongue swelling (40%), throat swelling (10%), periorbital edema (20%) | 10.8 min | Generalized | NM | Epi in 100% of patients | 80% recovery | | 7 | Shimabukuro, T. | 19(updated) | 100 | 42.3 | allergy or allergic reactions (84%), prior anaphylaxis (26%) | 1 & 2 | Respiratory and airway obstruction symptoms, nausea | Generalized urticaria, Diffuse erythematous rash Facial, tongue, or laryngeal angioedema | 16.8 min | Generalized | NM | Epi (92%), endotracheal intubation (11%), Corticosteroids (86%), Antihistamines (72%) | 92% recovery | | 5. Non‐anaphylaxis allergic reaction (n = 126) | ||||||||||||| | With BNT162b2 | ||||||||||||| | 6 | Shimabukuro, T. | 83 | 90 | 43 | allergies or allergic reactions (67%) | 1 | mild respiratory symptoms | Rash, pruritus, itchy and scratchy sensations in the throat | 12 min | Generalized, throat | NM | NM | NM | | With mRNA‐1273 | ||||||||||||| | 8 | Shimabukuro, T. | 43 | 91 | 43 | allergies or allergic reactions (67%) | 1 | sensations of throat closure | Rash, pruritus, itchy sensations in the mouth and throat | 15 min | Generalized, mouth, throat | NM | NM | NM | | 6. Herpes zoster (n = 20) | ||||||||||||| | 6 with BNT162b2 and 14 with mRNA‐1273 | ||||||||||||| | 9 | Lee, C. | 20 | 50 | 55.9 | Psoriasis, Atopic Eczema, Melanoma, Shingles, Chickenpox Actinic keratosis, BCC, SCC, previous vaccination with Zostavax and Shingrix, rubella, measles | NM | Deep painat injection site and body aches | Unilateral dermatomal herpetiform skin eruption, injection site itchiness | 6.85 d (itching, burning), 10.2 d (herpetiform eruption) | Generalized | NM | Valacyclovir, gabapentin, LMX, terrasil, shingles cream,prednisone,mupirocin,tramadol,hydrocodone/acetaminophen,acyclovir, desonide cream | NM | | 7. Immune thrombocytopenic purpura (ITP) (n = 20) | ||||||||||||| | 9 with BNT162b2, 11 with mRNA‐1273, 1 unknown | ||||||||||||| | 10 | Lee, E. J. | 20 | 58 (of 19 reports) | 44.4(of 19 reports) | ITP in remission (2%), mild–moderate thrombocytopenia (10%), inherited thrombocytopenia (2%), autoimmune conditions (hypothyroidism, Crohn's disease, or anti‐tg Ab +) (15%) | 1 & 2 | Thrombocytopenia | Petechiae, bruising or mucosal bleeding (gingival, vaginal, epistaxis) | 8.7 d | Generalized | NM | Corticosteroids (70%), IVIG (60%), PLT transfusions (40%), rituximab (10%), romiplostim, vincristine, aminocaproic acid | 88% improvement, 6% death, 6% no improvement | Abbreviations: 1st, after the first dose; 2nd, after the second dose; anti‐tg Ab, anti‐thyroglobulin antibodies; BCC, basal cell carcinoma; d, days; DEJ, dermo‐epidermal junction; Epi, epinephrine injection; HF, heart failure; HTN, hypertension; ITP, immune thrombocytopenic purpura; IVIG, intravenous immunoglobulin; KF, kidney failure; NM, not mentioned; PLT, platelet; SCC, squamous cell carcinoma. Supporting information Table S2. Injection site reactions, including erythema, wheals (some burning, itchy, painful, with axillary lymphadenopathy), swelling, painful and itchy erythematous subcutaneous nodule, painful hardening and itching were present among 17 patients (5.4%)(100% BNT162b2), appearing after an average of 1.7 days (for whom a day of onset was reported). - 2. Generalized reaction (n = 33, 10.5%) (100% BNT162b2) Other nonspecific cutaneous reactions were reported in 33 patients (10.5%). They included generalized urticaria, morbilliform rash and widespread erythematous lesions, appearing after an average of almost 4 days (for whom a day of onset was reported). - 3. Delayed localized hypersensitivity reactions (n = 32, 10.2%) (12.5% BNT162b2 and 87.5% mRNA‐1273) Delayed reactions were reported in 32 patients (10.2%) occurring almost a week after injection. From these, 12 patients developed Delayed large T‐cell mediated hypersensitivity presented with rash and pruritis in extremities which persisted for 6 days and left hyperpigmentation in 17% of the patients. A total of 16 patients showed delayed localized hypersensitivity reactions at injection site, characterized with painful erythematous lesions which disappeared within 8.2 days after the 1st dose and in 3 days after the 2nd dose. Four patients developed bullous drug‐induced reactions with severe pruritus. Delayed reactions were managed with topical steroids, oral antihistamines and oral antibiotics. - 4. Anaphylaxis (n = 66, 21%) (71% BNT162b2 and 29% mRNA‐1273) Three articles by Shimabukuro, et al. report anaphylaxis after mRNA vaccines in different time frames. 50 , 51 , 52 The patients in the preceding reports are only counted once, together with the ones reported in the updated article. Anaphylaxis was reported in 66 patients (21%), developed an average of about 13 min (10–16.8 min) after the injections; presenting with respiratory distress, wheezing and nausea, along with generalized urticaria, diffuse erythematous rash and angioedema (facial, tongue, or laryngeal), and they were treated with epinephrine (92%), endotracheal intubation (11%), corticosteroids (86%) and antihistamines (72%). History of prior allergy or allergic reactions was present in 80% of patients, and 30% had a history of prior anaphylaxis. Either vaccine was associated with anaphylaxis and no deaths from anaphylaxis were reported. - 5. Non‐anaphylaxis allergic reaction (n = 126, 40.1%) (65.9% BNT162b2 and 34.1% mRNA‐1273) A total of 126 patients developed rash, pruritus, itchy and scratchy sensations in the throat and mild respiratory symptoms onset 12–15 min, indicative of an allergic reaction, but not to the degree of anaphylaxis. 67% of these people had prior history of allergies or allergic reactions. - 6. Herpes zoster (n = 20, 5.8%) (30% BNT162b2 and 70% mRNA‐1273) A total of 20 patients (5.8%) developed Herpes Zoster after 10 days of injection, which were treated with antivirals, local or systemic corticosteroids and analgesics. - 7. Immune thrombocytopenic purpura (ITP) (n = 20, 5.8%) (45% BNT162b2 and 55% mRNA‐1273) A total of 20 patients (5.8%) developed Idiopathic thrombocytopenic purpura (ITP) presented with diffuse petechia and bruising, 8.7 days after injection which were managed with corticosteroids, platelet transfusions, and rituximab so that 88% had improvements and 6% were deceased. 3.4. RCTs We included a total of 41 RCTs as depicted in Table 3, having enrolled a cumulative number of 160,464 participants who received vaccines, with a cumulative mean age of 38.28 years (weighted average age from 40 studies), 51.53% of them being women. TABLE 3. | Supplemental references a | First author | Phase of RCT | Number of participants (n) | Women percentage | Mean of Age (year) | Participants' comorbidity and (age group in study) | Vaccine dose | Days between doses | Dose number | Any symptoms after vaccine | Percentage of mucocutaneous reaction | Time of onset the reactions (days) | |---|---|---|---|---|---|---|---|---|---|---|---|---| | 1. mRNA vaccines | |||||||||||| | 1.1. BNT162b2 (n = 39,144) | |||||||||||| | 1 | Walsh, E. E. | Phase 1 | 36 | 39 | 36.7 | NM (18–55 years) | 10, 20, and 30 μg | 21 | 1 | Injection site pain, fever, fatigue, chills, small numbers of severe systemic events (fatigue, headache, chills, muscle pain, and joint pain) | Injection site redness: (20 μg:0%, 30 μg:8%) Injection site swelling (10 μg:17%) | Peak at d2 | | 2 | Sahin, U. | Phase 1/2 (extended) | 12 | 66.7 | 34.8 | NM | 10 μg | 21 | 1&2 | Injection site pain, fever, chills, headache, fatigue, muscle pain, joint pain, diarrhea | Injection site: swelling (8%) | 0–7, 22–28 | | 2 | Sahin, U. | Phase 1/2 (extended) | 12 | 33.3 | 46.7 | NM | 30 μg | 21 | 1&2 | Injection site pain, chills, headache, fatigue, muscle pain, joint pain, diarrhea | Injection site: swelling (58.3%),redness(8%) | 0–7, 22–28 | | 3 | Polack | Phase 2/3 | 18,860 | 48.9 | 51.2 | Obesity (34.8%) | 30 μg | 21 | 1 | Injection site pain, fever, fatigue, headache, chills, vomiting, diarrhea, muscle pain, jointpain, severe systemic events (<2%) | Injection site: redness (16‐55 years:5%, ≥55 years: 5%), swelling (16‐55 years:6%, ≥55 years: 7%, lymphadenopathy (0.3%), | NM | | 3 | Polack | Phase 2/3 | 18,556 | 48.9 | 51.2 | Obesity (34.8%) | 30 μg | 21 | 2 | Injection site pain, fever, fatigue, headache, chills, vomiting, diarrhea, muscle pain, jointpain, severe systemic events: <2% except for fatigue (3.8%) and headache (2.0%) | Injection site: redness (16‐55 years:6%, ≥55 years: 7%), swelling (16‐55 years:6%, ≥55 years: 7%) | NM | | 4 | Frenck, R. W., Jr. | Phase 3 | 1131 | 49.9 | 13.6 | Baseline COVID +(4.1%) (12–15 years) | 30 μg | 21 | 1&2 | Injection site pain, fatigue, headache, chills, vomiting, diarrhea, muscle pain, joint pain,fever | Injection site: redness(1st:6%, 2nd:5%), swelling(1st:7%, 2nd:5%) | 0–7 | | 4 | Frenck, R. W., Jr. | Phase 3 | 537 | 52.5 | 19.4 | Baseline COVID +(5.6%) (16–25 years) | 30 μg | 21 | 1&2 | Injection site pain, fatigue, headache, chills, vomiting, diarrhea, muscle pain, joint pain,fever | Injection site: redness(1st:6%, 2nd:6%), swelling(1st:8%, 2nd:7%) | 0–7 | | 1.2. BNT162b2 booster in ChAdOx1‐S‐primed participants (CombiVacS) (n = 450) | |||||||||||| | 5 | Borobia, A. M. | Phase 2 | 450 | 57 | 43.93 | Hypothyroidism, Allergies, Asthma, HTN, Hypercholesterolaemia, Psychiatric, Migraine, Insomnia, Arthralgia, Back pain, Drug hypersensitivity, baseline COVID + (0%) | 30 μg | 50–84 | 2 | Injection site pain and discomfort, malaise, pyrexia, headache, myalgia, arthralgia, chills, cough, nausea | Injection site: erythema(31%), pruritus(10.9%), urticaria(15%), hardness(35.5%), pustule(0.2%), general pruritus (2%), rash (1.3%) (among 448 subjects) | 0–7 | | 1.3. BNT162b1 (n = 324) | |||||||||||| | 6 | Li, J. | Phase 1 | 24 | 50 | 37.9 | Cardiac Ischemia,Sinus Bradycardia,Hyperuricemia, Nasopharyngitis, Increasedblood uric acid,HTN (18–55 years) | 10 μg | 21 | 1&2 | Injection site pain, fever, headache, fatigue, malaise, joint pain, muscle pain, chills, nausea, anorexia, diarrhea, | Injection site: redness (1st:12.5%, 2nd:16.7%), swelling(1st: 12.5%, 2nd:8.3%) | 0–7 | | 6 | Li, J. | Phase 1 | 24 | 50 | 70.5 | Hyperuricemia, HTN, DM (65–85 years) | 10 μg | 21 | 1&2 | Injection site pain, fever, headache, fatigue, malaise, chills | Injection site: redness (1st:12.5%) | 0–7 | | 6 | Li, J. | Phase 1 | 24 | 50 | 39.7 | Sinus Bradycardia, Hyperuricemia, Blood uric acid increased (18–55 years) | 30 μg | 21 | 1&2 | Injection site pain, fever, headache, fatigue, malaise, joint pain, muscle pain, chills, nausea, anorexia, diarrhea, vomiting | Injection site: redness (1st:25% 2nd:20.9%), swelling(1st:20.8%, 2nd:16.7%), induration(1st:8.3%, 2nd:4.2%) | 0–7 | | 6 | Li, J. | Phase 1 | 24 | 50 | 68.5 | Hyperuricemia, HTN, DM (65–85 years) | 30 μg | 21 | 1&2 | Injection site pain, fever, headache, fatigue, malaise, joint pain, muscle pain, chills, anorexia | Injection site: redness (1st: 16.6%),swelling(2nd: 21.7%), induration(1st: 4.2%) | 0–7 | | 1 | Walsh, E. E. | Phase 1 | 36 | 39 | 36.7 | NM (18–55 years) | 10 μg, 20 μg, 30 μg | 21 | 1 | Injection site pain, fever, fatigue, chills | Injection site redness: (30 μg:17%) Injection site swelling: (10 μg:25%, 20 μg:17%) | Peak at d2 | | 1 | Walsh, E. E. | Phase 1 | 36 | 39 | 36.7 | NM (18–55 years) | 10 μg, 20 μg, 30 μg | 21 | 2 | Injection site pain, fever, fatigue, chills *dose‐dependent (greater after the 2nd dose than after the 1st dose, both systemic and local reactions) | Injection site redness: (30 μg:17%) Injection site swelling: (20 μg:8%, 30 μg:25%) | Peak at d2 | | 1 | Walsh, E. E. | Phase 1 | 36 | 67 | 70.1 | NM (65–85 years) | 10 μg, 20 μg, 30 μg | 21 | 1 | Injection site pain, fever, fatigue, chills (systemic events milder than in the younger participants) | Injection site swelling: (10 μg:8%, 20 μg:8%, 30 μg:17%) | Peak at d2 | | 1 | Walsh, E. E. | Phase 1 | 36 | 67 | 70.1 | NM (65–85 years) | 10 μg, 20 μg, 30 μg | 21 | 2 | Injection site pain, fever (33% after the 2nd dose, 1 severe), fatigue, chills | Injection site redness: (20 μg:8%, 30 μg:8%) Injection site swelling: (10 μg:8%, 20 μg:17%, 30 μg:25%) | Peak at d2 | | 7 | Sahin, U. | Phase 1/2 | 12 | 58.3 | 38.21 | NM | 1 μg | 21 | 1&2 | Injection site pain, fever, chills, headache, fatigue, muscle pain, joint pain, diarrhea | Injection site: swelling(17%) | 0–7, 22–28 | | 7 | Sahin, U. | Phase 1/2 | 12 | 66.7 | 43.62 | NM | 10 μg | 21 | 1&2 | Injection site pain, fever, chills, headache, fatigue, muscle pain, joint pain, diarrhea | Injection site: swelling(4%) | 0–7, 22–28 | | 7 | Sahin, U. | Phase 1/2 | 12 | 33.3 | 35.74 | NM | 30 μg | 21 | 1&2 | Injection site pain, fever, chills, headache, fatigue, muscle pain, joint pain, diarrhea | Injection site: redness(54.1%), swelling(41.6%) | 0–7, 22–28 | | 7 | Sahin, U. | Phase 1/2 | 12 | 50 | 33.88 | NM | 50 μg | 21 | 1&2 | Injection site pain, fever, chills, headache, fatigue, muscle pain, joint pain, diarrhea, vomiting | Injection site: redness(62.5%), swelling(50%) | 0–7, 22–28 | | 7 | Sahin, U. | Phase 1/2 | 12 | 41.7 | 35.81 | NM | 60 μg | 21 | 1 | Injection site pain, fever, chills, headache, fatigue, muscle pain, joint pain, diarrhea, vomiting | Injection site: swelling(33%) | 0–7, 22–28 | | 8 | Mulligan, M. J. | Phase 1&2 | 12 | 50 | 35.8 | NM | 30 μg | 21 | 1&2 | Injection site pain, fever, fatigue, headache, chills, diarrhea, muscle pain, joint pain Severe adverse events: (8.3%) | Injection site redness:(both doses: <20%) Injection site swelling: (1st:<20%, 2nd:<30%) | 0–7, Peak at d2 | | 8 | Mulligan, M. J. | Phase 1&2 | 12 | 58.3 | 38.3 | NM | 100 μg | 21 | 1 | Injection site pain, fever, fatigue, headache, chills, diarrhea, muscle pain, joint pain Severe adverse events: (8.3%) | Injection site redness(<40%), Injection site swelling(<50%) | 0–7, Peak atd2 | | 1.4. mRNA‐1273 (n = 30,359) | |||||||||||| | 9 | Anderson, E. J. | Phase 1 | 10 | 70 | 65.8 | NM (56–70 years) | 25 μg | 28 | 1&2 | Injection site pain, fever, headache, fatigue, arthralgia, myalgia, chills, nausea, | Injection site erythema/redness(2nd ≤ 10%), swelling/induration(1st ≤ 10% and 2nd ≤ 20%) | 0–1 | | 9 | Anderson, E. J. | Phase 1 | 10 | 20 | 72.8 | NM (≥71 years) | 25 μg | 28 | 1&2 | Injection site pain, headache, fatigue, arthralgia, myalgia | Injection site erythema/redness (2nd ≤ 20%), swelling/induration(2nd ≤ 20%), skin and subcutaneous tissue disorders (collective n = 3 in age group) | 0–1 | | 9 | Anderson, E. J. | Phase 1 | 10 | 50 | 63.8 | NM (56–70 years) | 100 μg | 28 | 1&2 | Injection site pain, fever, headache, fatigue, arthralgia, myalgia, chills, nausea, | Injection site erythema/redness(2nd ≤ 10%), swelling/induration(2nd ≤ 20%) | 0–1 | | 9 | Anderson, E. J. | Phase 1 | 10 | 70 | 72.6 | NM (≥71 years) | 100 μg | 28 | 1&2 | Injection site pain, fever, headache, fatigue, arthralgia, myalgia, chills, nausea, | Injection site erythema/redness(2nd ≤ 20%), swelling/induration(2nd ≤ 30%), skin and subcutaneous tissue disorders(collective n = 3 in age group) | 0–1 | | 10 | Jackson, L. A. | Phase 1 | 15 | 51 | 33 | NM | 25 μg | 28 | 1 | Injection site pain, fatigue, headache, myalgia, nausea | Transient urticaria on both legs in one participant | 5 | | 10 | Jackson, L. A. | Phase 1 | 15 | 51 | 33 | NM | 100 μg | 28 | 1 | Injection site pain, arthralgia, fatigue, chills, headache, myalgia, | Erythema/redness (13.4%), induration/swelling (13.3%) | NM | | 10 | Jackson, L. A. | Phase 1 | 15 | 51 | 33 | NM | 100 μg | 28 | 2 | Injection site pain, fever, nausea, arthralgia, fatigue, chills, headache, myalgia | Erythema/redness (13.4%), induration/swelling (6.7%) | NM | | 10 | Jackson, L. A. | Phase 1 | 15 | 51 | 33 | NM | 250 μg | 28 | 1 | Injection site pain, arthralgia, fatigue, chills, headache, myalgia, nausea | Erythema/redness (6.7%), induration/swelling (13.4%) | NM | | 10 | Jackson, L. A. | Phase 1 | 14 | 51 | 33 | NM | 250 μg | 28 | 2 | Injection site pain, fever, arthralgia, fatigue, chills, headache, myalgia, nausea | Erythema/redness (21.4%), induration/swelling (21.4%) | NM | | 11 | Chu, L. | Phase 2 | 100 | 64 | 36.6 | NM (≥18 ‐ < 55 years) | 50 μg | 28 | 1&2 | Injection site pain,headache,fatigue,myalgia,arthralgia,nausea/vomiting,chills | Local: erythema(1st:2%, 2nd:5%), swelling(1st:5%, 2nd:6%), axillary swelling /tenderness(1st:7%, 2nd:7%), generalized rash(1st:4%, 2nd:7%) | 0–7 | | 11 | Chu, L. | Phase 2 | 100 | 73 | 64.6 | NM (≥55 years) | 50 μg | 28 | 1&2 | Injection site pain,headache,fatigue,myalgia,arthralgia,nausea/vomiting,chills | Local: erythema (1st:3%, 2nd:5%), swelling(1st:3%, 2nd:6%), axillary swelling /tenderness(1st:3%, 2nd:12%), generalized rash(1st:2%, 2nd:3%) | 0–7 | | 11 | Chu, L. | Phase 2 | 100 | 53 | 38.3 | NM (≥18 ‐ < 55 years) | 100 μg | 28 | 1&2 | Injection site pain,headache,fatigue,myalgia,arthralgia,nausea/vomiting,chills | Local: erythema (1st:3%, 2nd:8%), swelling(1st:5%, 2nd:11%), axillary swelling /tenderness(1st:15%, 2nd:10%), generalized rash(1st:4%, 2nd:4%) | 0–7 | | 11 | Chu, L. | Phase 2 | 100 | 71 | 63.9 | NM (≥55 years) | 100 μg | 28 | 1&2 | Injection site pain, fever, headache, fatigue, myalgia, arthralgia, nausea/vomiting, chills | Local: erythema(1st:2%, 2nd:7%), swelling(1st:3%, 2nd:10%), axillary swelling /tenderness(1st:3%, 2nd:10%), generalized rash(1st:1%, 2nd:2%) | 0–7 | | 12 | Baden, L. R. | Phase 3 | 15,168 | 47.8 | 51.4 | CLD, Cardiac disease, Obesity, DM, Liver disease, HIV | 100 μg | 28 | 1 | Injection site pain, fever, headache, fatigue, myalgia, arthralgia, nausea or vomiting, chills, serious adverse events: (<0.1%) | Erythema (2.8%), swelling (6.1%), lymphadenopathy (10.2%), hypersensitivity (1.1%), urticaria (0.2%), rash (0.2%), contact dermatitis (0.2%) | 2.6 | | 12 | Baden, L. R. | Phase 3 | 14,677 | 47.8 | 51.4 | CLD, Cardiac disease, Obesity, DM, Liver disease, HIV | 100 μg | 28 | 2 | Injection site pain, fever, headache, fatigue, myalgia, arthralgia, nausea or vomiting, chills, serious adverse events: (<0.1%) | Erythema (8.6%), swelling (12.2%), lymphadenopathy(14.2%), hypersensitivity (1.1%), urticaria (0.2%), rash (0.2%), contact dermatitis (0.2%) | 3.2 | | 2. Adenovirus viral vector vaccines | |||||||||||| | 2.1. ChAdOx1 nCoV‐19 (n = 13,995) (SD: 3.5–6.5 [mostly 5] × 1010 virus particles, LD: 2.2 × 1010 viral particles) | |||||||||||| | 13 | Barrett, J. R. | Phase 1/2 | 20 | 70 | 36 | NM | SD/SD | 56 | 1&2 | Injection site pain, chills, fatigue, fever, feverish, headache, joint pain, malaise, muscle ache, nausea | Itch(1st& 2nd), tenderness(1st&2nd), warmth(1st& 2nd) | 0–7 | | 13 | Barrett, J. R. | Phase 1/2 | 32 | 52 | 44 | NM | SD/LD | 56 | 1&2 | Injection site pain, chills, fatigue, fever, feverish, headache, joint pain, malaise, muscle ache, nausea | Induration(1st), itch(1st& 2nd), redness(1st& 2nd), swelling(2nd), tenderness(1st& 2nd), warmth(1st& 2nd) | 0–7 | | 14 | Folegatti, P. M. | Phase 1/2 | 487 | 49 | 34 | NM | SD | single | 1 | Injection site pain, feverishness,fever, chills,joint pain,muscle ache,fatigue,headache,malaise,nausea | Local: redness(3%), warmth(25%), itch(7%), swelling(4%), induration(3%), tenderness(83%) | 0‐7 peak at d1 | | 14 | Folegatti, P. M. | Phase 1/2 | 56 | 49 | 34 | NM | SD + prophylactic paracetamol | single | 1 | Injection site pain, feverishness,fever, chills,joint pain,muscle ache,fatigue,headache,malaise,nausea | Local: redness(2%), warmth (20%), itch(12%), swelling(2%), tenderness(77%) | 0–7 peak at d1 | | 14 | Folegatti, P. M. | Phase 1/2 | 10 | 49 | 34 | NM | SD | single | 1&2 | Injection site pain, feverishness,fever, chills,joint pain,muscle ache,fatigue,headache,malaise,nausea | Local: warmth(20%), itch(10%), tenderness(50%) (after both doses) | 0–7 peak at d1 | | 15 | Madhi, S. A. | Phase 1b–2 | 1011 | 43.2 | 31 | Obesity(18.8%), current smoker (42.9%), HTN (3.1%), Chronic respiratory condition (3.5%), DM (0.4%) | SD | 21–35 | 1&2 | Cough, feverish, headache, joint pain, muscle pain, sweating, tenderness, weakness | Injection site: redness, swelling, bruising, hardness,mild itching, epidermal and dermal conditions(0.9%), skin appendage conditions(0.5%), angioedema and urticaria(0.2%), dental and gingival conditions(0.2%), oral soft tissue conditions(0.4%), allergic conditions(0.2%) | 0–6 | | 16 | Frater, J., | Phase 2/3 | 54 | 0 | 42.5 | HIV + | NM | 28–56 | 1&2 | Injection site pain,feverish, fever, chills, joint pain, muscle ache, fatigue, headache, malaise, nausea | Local: warmth(1st:11.3%, 2nd:5.9%), itch(1st:3.8%, 2nd:2%), swelling(1st:1.9%), induration(1st:1.9%), tenderness(1st:62.3%, 2nd:43.1%) | 0–7 | | 16 | Frater, J., | Phase 2/3 | 50 | 48 | 38.5 | HIV ‐ | NM | 28–56 | 1&2 | Injection site pain,feverish, fever, chills, joint pain, muscle ache, fatigue, headache, malaise, nausea | Local: redness(2nd:2.0%), warmth(1st:16%, 2nd:12.2%), itch(1st:4.0%, 2nd:12.2%), tenderness(1st:76.0%, 2nd:61.2%) | 0–7 | | 17 | Ramasamy, M. N. | Phase 2/3 | 50 | 70 | 44.5 | NM (18–55 years) | SD/SD | 28 | 1&2 | Injection site pain,tenderness, feverish, fever, chills, joint pain, muscle ache, fatigue, headache, malaise, nausea | Injection site: redness(2nd:2%), warmth(1st:14%, 2nd:12%), itch(1st:4%, 2nd:12%) | 0–7 | | 17 | Ramasamy, M. N. | Phase 2/3 | 30 | 33 | 60.4 | NM (56–69 years) | SD/SD | 28 | 1&2 | Injection site pain,tenderness, feverish, chills, joint pain, muscle ache, fatigue, headache, malaise, nausea | Injection site: warmth(1st:7%, 2nd:14%), itch(1st:7%, 2nd:3%) | 0–7 | | 17 | Ramasamy, M. N. | Phase 2/3 | 46 | 35 | 73 | NM (≥70 years) | SD/SD | 28 | 1&2 | Injection site pain,tenderness, feverish, chills, joint pain, muscle ache, fatigue, headache, malaise, nausea | Injection site: redness(1st:2%, 2nd:2%), warmth(1st:14%, 2nd:4%), itch(1st:4%, 2nd:2%), swelling(1st:4%, 2nd:4%), induration(1st:2%, 2nd:2%) | 0–7 | | 17 | Ramasamy, M. N. | Phase 2/3 | 49 | 47 | 39 | NM (18–55 years) | LD/LD | 28 | 1&2 | Injection site pain,tenderness, feverish, chills, joint pain, muscle ache, fatigue, headache, malaise, nausea | Injection site: redness(2nd:2%), warmth(1st:18%, 2nd:6%), itch(1st:4%, 2nd:2%) | 0–7 | | 17 | Ramasamy, M. N. | Phase 2/3 | 30 | 53 | 59.5 | NM (56–69 years) | LD/LD | 28 | 1&2 | Injection site pain,tenderness, feverish, fever, chills, joint pain, muscle ache, fatigue, headache, malaise, nausea | Injection site: warmth(1st:3%), itch(1st: 7%) | 0–7 | | 17 | Ramasamy, M. N. | Phase 2/3 | 49 | 43 | 73 | NM (≥70 years) | LD/LD | 28 | 1&2 | Injection site pain,tenderness, feverish, fever, chills, joint pain, muscle ache, fatigue, headache, malaise, nausea | Injection site: redness(1st:2%, 2nd:4%), warmth(1st:2%, 2nd:2%), itch(1st:2%), swelling(1st:2%, 2nd:4%), induration(1st:2%, 2nd:4%) | 0–7 | | 18 | Voysey, M. | Different phases (1,2,3) | 12,021 | 56 | NM | CVD, Respiratory disease, DM, some Baseline COVID + (18–55 years, 56–69 years, 70+ years) | SD/SD or LD/SD | 28 | 1&2 | Cardiac, sensory, GI, general and injection site, procedural complications, infections and infestations, neoplasms, nervous system, renal and urinary, musculoskeletal and connective tissue, reproductive, respiratory side effects | Cellulitis1 (<0.1%),anaphylactic reaction1 (<0.1%),psoriasis 1 (<0.1%), rosacea 1 (<0.1%), vitiligo 1 (<0.1%), Raynaud's phenomenon 1 (<0.1%), uveitis 2 (<0.1%) | any time during study | | 2.2.Gam‐COVID‐Vac (n = 15,011) (all 1 × 1011 viral particles) | |||||||||||| | 19 | Logunov, D. Y. | Phase 1/2 | 9 | 78 | 27 | NM | LyophilisedrAd5‐S | 21 | 1&2 | Injection site pain, hyperthermia,headache,muscle and joint pain,changes in laboratory variables | Local: edema(11%), hyperthermia(11%),mucosal abnormality | 0–28 | | 19 | Logunov, D. Y. | Phase 1/2 | 9 | 0 | 27.8 | NM | rAd26‐S | 21 | 1&2 | Injection site pain, hyperthermia,headache,asthenia,muscle and joint pain,heartbeat (subjective palpitation),diarrhea,loss of appetite,changes in laboratory variables | Local: itch(11%), generalized: hives(11%) | 0–28 | | 19 | Logunov, D. Y. | Phase 1/2 | 9 | 44 | 31.4 | NM | LyophilisedrAd26‐S | 21 | 1&2 | Injection site pain, hyperthermia,headache,muscle and joint pain,changes in laboratory variables | Local: edema(22%) | 0–28 | | 19 | Logunov, D. Y. | Phase 1/2 | 20 | 30 | 26.4 | NM | rAd26‐S plus rAd5‐S (heterologous prime‐boost) | 21 | 1&2 | Injection site pain, hyperthermia,headache,asthenia,muscle and joint pain,diarrhea,rhinorrhea,loss of appetite,pain in the oropharynx, malaise,sore throat, nasal congestion, cough, sneezing, changes in laboratory variables | Local: hyperthermia(10%), swelling(5%) | 0–28 | | 20 | Logunov, D. Y. | Phase 3 | 14,964 | 38.9 | 45.3 | DM, HTN, IHD, Obesity | rAd26‐S plus rAd5‐S (heterologous prime‐boost) | 21 | 1&2 | Vascular disorders, infections and invasions, reproductive, heart disorders, injury, intoxication and complications of procedures, GI, renal, liver and biliary tract, muscle, skeletal and connective tissue and nervous system side effects | Hypersensitivity (0.01%), acne‐form dermatitis (0.01%), allergic skin reaction(0.01%), allergic rash(0.05%), alopecia(0.02%), itching (0.04%), skin rash (0.1%), petechial rash(0.01%), rash(0.03%), eczema (0.01%), keratoconjunctivitis(0.01%),chalazion (0.01%), allergic reaction (0.15%), herpes (0.09%), benign neoplasm of the eyelid (0.01%), axillary lymphadenitis (0.07%) | any time during study | | 2.3. Ad5‐nCoV (n = 490) (LD: 5 × 1010 viral particles, MD: 1 × 1011 viral particles, HD: 1.5 × 1011 viral particles) | |||||||||||| | 21 | Zhu, F. C. | Phase 1 | 36 of 108 | 49 | 36.3 | Baseline COVID + (0%) | LD | single | 1 | Injection site pain, fever, headache, fatigue, vomiting, diarrhea, muscle pain, joint pain, throat pain, cough, nausea, impaired appetite, functional gi disorder,dizziness | Injection site: induration(6%), redness(6%), swelling(11%), itch (6%), general pruritis: (3%) | 0–7 | | 21 | Zhu, F. C. | Phase 1 | 36 of 108 | 49 | 36.3 | Baseline COVID + (0%) | MD | single | 1 | Injection site pain, fever, headache, fatigue, diarrhea, muscle pain, joint pain, throat pain, cough, nausea, impaired appetite | Injection site: induration(3%), redness(3%), swelling(11%), itch(8%), general pruritis:(3%) | 0–7 | | 21 | Zhu, F. C. | Phase 1 | 36 of 108 | 49 | 36.3 | Baseline COVID + (0%) | HD | single | 1 | Injection site pain, fever, headache, fatigue (6% grade 3), vomiting, diarrhea, muscle pain (3% grade 3), joint pain (3% grade 3), muscular weakness, throat pain, cough, nausea, impaired appetite, dyspnoea (3% grade 3), dizziness | Injection site: induration(3%), redness(3%), general pruritis:(3%), mucosal abnormality (3%) | 0–7 | | 22 | Zhu, F. C. | Phase 2 | 253 | 50 | 40 | Underlying diseases (3%), Baseline COVID + (0%) | MD | single | 1 | Injection site pain, fever, headache, fatigue, vomiting, diarrhea, muscle pain, joint pain, oropharyngeal pain, cough, nausea, dyspnoea, appetite impaired, syncope | Injection site reactions: induration (5%), redness (2%), swelling (4%), itching (6%), general: pruritus (2%) | 0–14 | | 22 | Zhu, F. C. | Phase 2 | 129 | 50 | 39.7 | Underlying diseases (6%), Baseline COVID + (0%) | LD | single | 1 | Injection site pain, fever, headache, fatigue, vomiting, diarrhea, muscle pain, joint pain, oropharyngeal pain, cough, nausea, dyspnoea, appetite impaired, syncope | Injection site reactions: induration (2%), redness (1%), swelling (4%), itching (2%), general: pruritus (3%) mucosal abnormality | 0–14 | | 2.4. Ad26.COV2.S (n = 22,537) (LD: 5 × 1010 viral particles, HD: 1 × 1011 viral particles) | |||||||||||| | 23 | Sadoff, J., | Phase 1–2a | 162 | 52 | 36.1 | NM 18–55 years | LD | 56 | 1&2 | Injection site pain, fatigue, headache, myalgia, nausea, pyrexia | Local: erythema (<5%), swelling(<5%) | 0–28 | | 23 | Sadoff, J., | Phase 1–2a | 158 | 54 | 34.8 | NM 18–55 years | HD | 56 | 1&2 | Injection site pain, fatigue, headache, myalgia, nausea, pyrexia | Local: erythema(<5%), swelling(<5%) | 0–28 | | 23 | Sadoff, J., | Phase 1–2a | 161 | 48 | 69.6 | NM ≥ 65 years | LD | 56 | 1&2 | Injection site pain, fatigue, headache, myalgia, nausea, pyrexia | Local: erythema(<10%), swelling(<10%) | 0–28 | | 23 | Sadoff, J., | Phase 1–2a | 161 | 51 | 70 | NM ≥ 65 years | HD | 56 | 1&2 | Injection site pain, fatigue, headache, myalgia, nausea, pyrexia | Local: erythema(<10%), swelling(<10%) | 0–28 | | 24 | Sadoff, J. | Phase 3 | 21,895 | 44.9 | 52 | Baseline COVID + (9.8%), Obesity (28.6%) | LD | 56 | 1 | Injection site pain, headache, fatigue, myalgia, nausea, fever | Local: erythema (0.23%), swelling(0.2%), urticaria (n = 8), hypersensitivity(n = 9) | 0–7 | | 3. Protein subunit vaccines | |||||||||||| | 3.1. NVX‐CoV2373 (n = 1060) (Ad: Adjuvant 50 μg Matrix‐M1) | |||||||||||| | 25 | Shinde, V. | Phase 1 | 334 | 43.1 (all 2199) | 31.9 (all 2199) | HTN, DM, HIV, Baseline COVID + (0%) | 5 μg + Ad | 21 | 1 | Injection site pain and tenderness, fever, headache, fatigue, malaise, joint pain, muscle pain,nausea or vomiting | Injection site: erythema(1.5%), swelling(1.2%) | 0–6 | | 25 | Shinde, V. | Phase 1 | 329 | 43.1 (all 2199) | 31.9 (all 2199) | HTN, DM, HIV, Baseline COVID + (0%) | 5 μg + Ad | 21 | 2 | Injection site pain and tenderness, fever, headache, fatigue, malaise, joint pain, muscle pain,nausea or vomiting | Injection site: erythema(1.8%), swelling(2.7%) | 21–27 | | 25 | Shinde, V. | Phase 1 | 150 | 43.1 (all 2199) | 31.9 (all 2199) | HTN, DM, HIV, Baseline COVID +(100%) | 5 μg + Ad | 21 | 1 | Injection site pain and tenderness, fever, headache, fatigue, malaise, joint pain, muscle pain,nausea or vomiting | Injection site: erythema(1.3%), swelling(4%) | 0–6 | | 25 | Shinde, V. | Phase 1 | 142 | 43.1 (all 2199) | 31.9 (all 2199) | HTN, DM, HIV, Baseline COVID +(100%) | 5 μg + Ad | 21 | 2 | Injection site pain and tenderness, fever, headache, fatigue, malaise, joint pain, muscle pain,nausea or vomiting | Injection site: swelling(0.7%) | 21–27 | | 26 | Keech, C. | Phase 1/2 | 25 | 52 | 27.2 | NM | 25 μg, Un‐adjuvanted | 21 | 1&2 | Injection site pain, arthralgia,fatigue,malaise,headache,myalgia,nausea or vomiting | Local: erythema or redness(2nd:4%), induration or swelling(2nd:4%) | 0–7 | | 26 | Keech, C. | Phase 1/2 | 26 | 50 | 29.5 | NM | 5 μg + Ad | 21 | 1&2 | Injection site pain, arthralgia,fatigue,malaise,headache,myalgia,nausea or vomiting | Local: erythema or redness(2nd:7.6%), induration or swelling(2nd:3.8%),skin and subcutaneous tissue disorders(3.8%) | 0–7 | | 26 | Keech, C. | Phase 1/2 | 3 | 33.3 | 23.7 | NM | 5 μg + Ad | 21 | 1&2 | Injection site pain, fatigue,malaise,headache,myalgia | Local: erythema or redness(1st:33.3%,2nd:33.3%) | 0–7 | | 26 | Keech, C. | Phase 1/2 | 25 | 32 | 35.6 | NM | 25 μg + Ad | 21 | 1&2 | Injection site pain, arthralgia,fatigue,malaise,fever,headache,myalgia,nausea or vomiting | Local: induration or swelling(2nd:8.3%)skin and subcutaneous tissue disorders(4%), rash(4%) | 0–7 | | 26 | Keech, C. | Phase 1/2 | 26 | 65.4 | 33 | NM | 1st: 25 μg + Ad 2nd: placebo | 21 | 1&2 | Injection site pain, arthralgia,fatigue,malaise,headache,myalgia,nausea or vomiting | Local: erythema or redness(1st:3.8%,2nd:3.8%)skin and subcutaneous tissue disorders(7.7%) | 0–7 | | 3.2. MF59‐adjuvanted sclamp (n = 96) | |||||||||||| | 27 | Chappell, K. J. | Phase 1 | 24 | 54 | 34.1 | NM | 5 μg | 28 | 1&2 | Injection site pain, chills, nausea, vomiting, fever, headache, fatigue/somnolence, myalgia, arthralgia, malaise | Local: tenderness(1st:50.0%, 2nd:62.5%), induration/swelling(1st:8.3%); Alopecia (4.2%), pruritis (4.2%) | 0–7 | | 27 | Chappell, K. J. | Phase 1 | 24 | 54 | 31 | NM | 15 μg | 28 | 1&2 | Injection site pain, nausea, vomiting, headache, fatigue/somnolence, diarrhea, myalgia, arthralgia, malaise | Local: tenderness(1st:54.2%, 2nd:58.3%), induration/swelling(1st:8.3%) | 0–7 | | 27 | Chappell, K. J. | Phase 1 | 1st: n = 48 2nd: n = 24 | 33.5 | 32.3 | NM | 45 μg | 28 | 1&2 | Injection site pain, chills, nausea, vomiting, headache, fatigue/somnolence, diarrhea, myalgia, arthralgia, malaise | Local: tenderness(1st:47.9%, 2nd:58.3%), erythema/redness (1st:2.1%), induration/swelling(1st:4.2%); Macular rash(4.2%), contact dermatitis(4.2%) | 0–7 | | 3.3. SCB‐2019 (n = 88) | |||||||||||| | 28 | Richmond, P. | Phase 1 | 8 | 38 | 35.8 | NM (18–54 years) | 3 μg + AS03 | 21 | 1&2 | Injection site pain, fever, headache, myalgia, nausea, vomiting, fatigue | Local: erythema (12.5%) | 0–7 | | 28 | Richmond, P. | Phase 1 | 8 | 38 | 62.8 | NM (55–75 years) | 3 μg + AS03 | 21 | 1&2 | Injection site pain, headache, fatigue | Local: erythema (6.25%), swelling(6.25%) | 0–7 | | 28 | Richmond, P. | Phase 1 | 8 | 100 | 41.9 | NM (18–54 years) | 3 μg + CpG/Alum | 21 | 1&2 | Injection site pain, headache, myalgia, nausea, fatigue | Local: erythema (6.25%), swelling(6.25%) | 0–7 | | 28 | Richmond, P. | Phase 1 | 8 | 50 | 37 | NM (18–54 years) | 9 μg + AS03 | 21 | 1&2 | Injection site pain, fever, headache, myalgia, fatigue | Local: erythema (6.25%), swelling (18.75%) | 0–7 | | 28 | Richmond, P. | Phase 1 | 8 | 38 | 59.1 | NM (55–75 years) | 9 μg + AS03 | 21 | 1&2 | Injection site pain fever headache myalgia fatigue | Local: erythema (25%), swelling(18.75%) | 0–7 | | 28 | Richmond, P. | Phase 1 | 8 | 50 | 36.1 | NM (18–54 years) | 9 μg + CpG/Alum | 21 | 1&2 | Injection site pain, headache, myalgia, fatigue | Local: erythema (12.5%), swelling(6.25%) | 0–7 | | 28 | Richmond, P. | Phase 1 | 8 | 38 | 60.3 | NM (55–75 years) | 9 μg + CpG/Alum | 21 | 1&2 | Injection site pain, fever, headache, myalgia, fatigue | Local: erythema (6.7%), swelling(6.7%) | 0–7 | | 28 | Richmond, P. | Phase 1 | 8 | 75 | 31.3 | NM (18–54 years) | 30 μg + AS03 | 21 | 1&2 | Injection site pain, fever, headache, myalgia, diarrhea, nausea, vomiting, fatigue | Local: erythema (6.25%), swelling(18.75%) | 0–7 | | 28 | Richmond, P. | Phase 1 | 8 | 75 | 59.8 | NM (55–75 years) | 30 μg + AS03 | 21 | 1&2 | Injection site pain, headache, myalgia, diarrhea nausea, vomiting | Local: erythema (6.25%), swelling(6.25%) | 0–7 | | 28 | Richmond, P. | Phase 1 | 8 | 75 | 39.1 | NM (18–54 years) | 30 μg + CpG/Alum | 21 | 1&2 | Injection site pain, headache, fatigue | Local: erythema (18.75%), swelling(6.25%) | 0–7 | | 28 | Richmond, P. | Phase 1 | 8 | 50 | 61.5 | NM (55–75 years) | 30 μg + CpG/Alum | 21 | 1&2 | Injection site pain, myalgia, fatigue | Local: swelling(6.25%) | 0–7 | | 3.4. CoV2 preS dTM (n = 336) (LD: 1.3 μg, HD: 2.6 μg) | |||||||||||| | 29 | Goepfert, P. A. | Phase 1/2 | 18 | 50 | 35.3 | NM (18–49 years) | LD + AF03 | 21 | 1&2 | Injection site pain, fever, headache, malaise, myalgia | 1st: injection site: erythema(6.3%) 2nd: injection site: erythema(12.5%), swelling(18.8%) | 0–7 | | 29 | Goepfert, P. A. | Phase 1/2 | 54 | 46 | 33.7 | NM (18–49 years) | LD + AS03 | 21 | 1&2 | Injection site pain, fever, headache, malaise, myalgia | 1st: injection site:swelling(2%) 2nd: injection site: erythema(19.6%), swelling(15.7%) | 0–7 | | 29 | Goepfert, P. A. | Phase 1/2 | 28 | 39 | 59.8 | NM (≥50 years) | LD + AS03 | 21 | 1&2 | Injection site pain, fever, headache, malaise, myalgia | 1st: injection site: erythema(3.6%) 2nd: injection site: erythema(32.1%),swelling(25%) | 0–7 | | 29 | Goepfert, P. A. | Phase 1/2 | 17 | 65 | 32.5 | NM (18–49 years) | HD + AF03 | 21 | 1&2 | Injection site pain, fever, headache, malaise, myalgia | 2nd: injection site: erythema(17.6%), swelling(17.6%) | 0–7 | | 29 | Goepfert, P. A. | Phase 1/2 | 10 | 70 | 58.7 | NM (≥50 years) | HD + AF03 | 21 | 1&2 | Injection site pain, headache, malaise, myalgia | 1st: injection site: erythema(11.1%) 2nd: injection site: erythema(11.1%),swelling(11.1%) | 0–7 | | 29 | Goepfert, P. A. | Phase 1/2 | 54 | 43 | 34.9 | NM (18–49 years) | HD + AS03 | 21 | 1&2 | Injection site pain, fever, headache, malaise, myalgia | 1st: injection site: erythema(3.7%),swelling(7.4%) 2nd: injection site: erythema(50%),swelling(33.3%) | 0–7 | | 29 | Goepfert, P. A. | Phase 1/2 | 31 | 68 | 61.7 | NM (≥50 years) | HD + AS03 | 21 | 1&2 | Injection site pain, fever, headache, malaise, myalgia | 1st: injection site: erythema(6.5%),swelling(3.2%) 2nd: injection site: erythema(32.3%),swelling(25.8%) | 0–7 | | 29 | Goepfert, P. A. | Phase 1/2 | 18 | 56 | 34.8 | NM (18–49 years) | HD Un‐adjuvanted | 21 | 1&2 | Injection site pain, headache, malaise, myalgia | 2nd: injection site: erythema(5.9%),swelling(5.9%) | 0–7 | | 29 | Goepfert, P. A. | Phase 1/2 | 24 | 58 | 36 | NM (18–49 years) | LD + AF03 | single | 1 | Injection site pain, headache, malaise, myalgia | Injection site: erythema(3.8%), swelling(3.8%) | 0–7 | | 29 | Goepfert, P. A. | Phase 1/2 | 10 | 80 | 59.3 | NM (≥50 years) | LD + AF03 | single | 1 | Injection site pain, headache, malaise, myalgia | Injection site: erythema(10%) | 0–7 | | 29 | Goepfert, P. A. | Phase 1/2 | 24 | 38 | 35.4 | NM (18–49 years) | LD + AS03 | single | 1 | Injection site pain, headache, malaise, myalgia | Injection site: swelling(7.7%) | 0–7 | | 29 | Goepfert, P. A. | Phase 1/2 | 24 | 54 | 32 | NM (18–49 years) | HD + AF03 | single | 1 | Injection site pain, headache, malaise, myalgia | Injection site: swelling(4.3%) | 0–7 | | 29 | Goepfert, P. A. | Phase 1/2 | 24 | 58 | 29.7 | NM (18–49 years) | HD + AS03 | single | 1 | Injection site pain, headache, malaise, myalgia | Injection site: erythema(12.5%), swelling(8.3%) | 0–7 | | 3.5. ZF2001(n = 640) | |||||||||||| | 30 | Yang, S. | Phase 1 | 20 | 30 | 31.7 | NM | 25 μg | 30 | 1&2&3 | Injection site pain, fever, headache, cough, muscle pain | Swelling(5%), induration(10%), redness(20%), itch(20%) | 0–7 | | 30 | Yang, S. | Phase 1 | 20 | 45 | 33.6 | NM | 50 μg | 30 | 1&2&3 | Injection site pain, headache, fatigue, weakness, cough, nausea | Swelling(15%), induration(25%), redness(20%, 5% grade ≥3), rash(5%), itch(35%) | 0–7 | | 30 | Yang, S. | Phase 2 | 150 | 57 | 43.04 | NM | 25 μg | 30 | 1&2 | Injection site pain, fever, headache, fatigue, cough, nausea, muscle pain | Swelling(4%), induration(3%), redness(8%), rash(2%), itch(6%) | 0–7 | | 30 | Yang, S. | Phase 2 | 150 | 62 | 44.4 | NM | 50 μg | 30 | 1&2 | Injection site pain, fever, headache, fatigue, cough | Swelling(6%), induration(5%), redness(8%, 1% grade ≥3), rash(3%), itch(9%) | 0–7 | | 30 | Yang, S. | Phase 2 | 150 | 53 | 42.7 | NM | 25 μg | 30 | 1&2&3 | Injection site pain, fever, headache, cough, muscle pain | Swelling(14%), induration(9%), redness(16%, 1% grade ≥3), rash(1%), itch(19%) | 0–7 | | 30 | Yang, S. | Phase 2 | 150 | 58 | 43.2 | NM | 50 μg | 30 | 1&2&3 | Injection‐site pain, fever, nausea | Swelling(13%, 2% grade ≥3), induration(7%, 1% grade ≥3), redness(14%, 3% grade ≥3), rash(1%, grade ≥3), itch(17%) | 0–7 | | 3.6. V‐01 (n = 24) | |||||||||||| | 31 | Zhang, J. | Phase 1 | 24 | 75 | 40 | NM | 10 μg | 21 | 1&2 | Injection site pain, fever, anorexia, vomiting, nausea, headache, fatigue | Local: pruritus(4.17%) | 0–30 | | 4. Inactivated virus vaccines | |||||||||||| | 4.1. CoronaVac (n = 7497) | |||||||||||| | 32 | Wu, Z. | Phase 1 | 24 | 54 | 65.6 | NM | 3 μg | 28 | 1&2 | Injection site pain, muscle pain, fatigue, nausea, fever, abdominal distention | Injection site pruritus(4.2%), hypersensitivity(4.2%) | 0–28 | | 32 | Wu, Z. | Phase 1 | 24 | 46 | 67.5 | NM | 6 μg | 28 | 1&2 | Injection site pain, muscle pain, fatigue,headache, decreased appetite, cough | Injection site pruritus(4.2%),mucocutaneous eruption(8.3%), rash(4.2%) | 0–28 | | 32 | Wu, Z. | Phase 2 | 100 | 51 | 66.8 | NM | 1.5 μg | 28 | 1&2 | Injection site pain,fever, fatigue, diarrhea, cough | Injection site: erythema(2%), pruritus(1%) | 0–28 | | 32 | Wu, Z. | Phase 2 | 100 | 51 | 66.5 | NM | 3 μg | 28 | 1&2 | Injection site pain, fever, fatigue, diarrhea, cough | Injection site: swelling(1%) | 0–28 | | 32 | Wu, Z. | Phase 2 | 99 | 55 | 66.2 | NM | 6 μg | 28 | 1&2 | Injection site pain | Injection site: erythema(1%), swelling(1%) | 0–28 | | 33 | Zhang, Y. | Phase 1 | 24 | 58.3 | 45 | NM | 6 μg | 14 | 1&2 | Injection site pain, fatigue, diarrhea, fever, abdominal pain | Injection site discoloration(4.2%), acute hypersensitivity with manifestation of urticaria (1st dose, one case, 4% of 24), general hypersensitivity(4.2%) | Mostly 0–2 | | 33 | Zhang, Y. | Phase 2 | 120 | 55 | 42 | NM | 3 μg | 14 | 1&2 | Injection site pain, fatigue, fever, diarrhea, nausea, headache, muscle pain,vomiting, chest pain,dizziness, decreased appetite | Injection site: swelling(1.7%), redness(0.8%)hypoaesthesia(0.8%),pruritus(0.8%),induration(0.8%) | Mostly 0–2 | | 33 | Zhang, Y. | Phase 2 | 120 | 60 | 42.4 | NM | 6 μg | 14 | 1&2 | Injection site pain, fatigue, fever, diarrhea, nausea, headache, muscle pain,cough,chest pain, drowsiness,palpitations | Injection site: swelling (2.5%), redness (1.7%), hypoaesthesia (0.8%), discoloration (0.8%), pruritus (0.8%), general hypersensitivity (0.8%) | Mostly 0–2 | | 33 | Zhang, Y. | Phase 2 | 120 | 47.5 | 41.5 | NM | 3 μg | 28 | 1&2 | Injection site pain, fatigue, fever, diarrhea,headache, muscle pain,cough | General hypersensitivity (0.8%) | Mostly 0–2 | | 33 | Zhang, Y. | Phase 2 | 120 | 47.5 | 40.6 | NM | 6 μg | 28 | 1&2 | Injection site pain, fatigue, fever, diarrhea,headache, muscle pain,decreased appetite | Injection site: swelling (0.8%), redness (0.8%), discoloration (0.8%), pruritus (0.8%) | Mostly 0–2 | | 34 | Tanriover, M. D. | Phase 3 | 6646 | 42.6 | 45 | HTN, CVD, Chronic respiratory disease, DM, Malignancy, Autoimmune | 3 μg | 14 | 1&2 | Injection site: pain and paraesthesia, fatigue, headache, myalgia, chill, fever, diarrhea, cough, arthralgia, nausea, vomiting, seizure(n = 1),encephalitis(n = 1) | Injection site: erythema(0.18%), swelling(0.06%), induration(0.05%), pruritus(0.03%), generalized: rash(0.11%), allergic reaction(0.08%), pruritis and swelling (<0.0%), redness and swelling in the mouth(n = 1) | 0‐unblinding | | 4.2. WIBP‐CorV (n = 132) | |||||||||||| | 35 | Xia, S. | Phase 1 | 24 | 54.2 | 36 | Baseline COVID + (0%) | 2.5 μg | 28 | 1&2&3 | Injection site pain | Local: swelling(4.2%) | 0–28 | | 35 | Xia, S. | Phase 1 | 24 | 54.2 | 43.1 | Baseline COVID + (0%) | 10 μg | 28 | 1&2&3 | Injection site pain,fever,nausea and vomiting, anorexia | Local: redness(4.2%), swelling(4.2%) | 0–28 | | 35 | Xia, S. | Phase 2 | 84 | 61.9 | 43.8 | Baseline COVID + (0%) | 5 μg | 21 | 1&2 | Injection site pain, diarrhea, fever, nausea and vomiting | Local: itching(1.2%), swelling(1.2%) | 0–28 | | 4.3. BBIBP‐CorV (n = 27,367) | |||||||||||| | 36 | Xia, S. | Phase 1 | 24 | 66 | 42.7 | NM (18–59 years) | 2 μg, HB02 strain | 28 | 1&2 | Injection site pain, fever,fatigue,headache | Injection site: redness(4%), mucocutaneous abnormalities(4%),itch (non‐injection site)(4%) | 0–7 | | 36 | Xia, S. | Phase 1 | 24 | 50 | 37.7 | NM (18–59 years) | 4 μg, HB02 strain | 28 | 1&2 | Injection site pain, fever, vomiting | Injection site: itch (4%) | 0–7 | | 36 | Xia, S. | Phase 1 | 24 | 47 | 40.1 | NM (18–59 years) | 8 μg, HB02 strain | 28 | 1&2 | Injection site pain, fever, inappetence, nausea, constipation | Injection site: swelling (8%) | 0–7 | | 36 | Xia, S. | Phase 1 | 24 | 72 | 67.5 | NM (≥60 years) | 8 μg, HB02 strain | 28 | 1&2 | Injection site pain, fever, fatigue,headache | Injection site: induration (8%) | 0–7 | | 36 | Xia, S. | Phase 2 | 84 | 54 | 40.8 | NM (18–59 years) | 8 μg, HB02 strain | single | 1 | Injection site pain, fever, fatigue,headache, diarrhea, muscle pain, dizziness, anaphylaxis(1%) | Injection site: swelling(2%),itch(2%),redness(1%),rash(1%) | 0–7 | | 36 | Xia, S. | Phase 2 | 84 | 55 | 41 | NM (18–59 years) | 4 μg, HB02 strain | 14 | 1&2 | Injection site pain, fever, fatigue,headache, diarrhea, muscle pain | Injection site:itch(1%),itch (non‐injection site)(2%) | 0–7 | | 36 | Xia, S. | Phase 2 | 84 | 53 | 41.7 | NM (18–59 years) | 4 μg, HB02 strain | 21 | 1&2 | Injection site pain, fever, fatigue,nausea,headache, drowsiness | Injection site: swelling(4%),redness(1%) | 0–7 | | 36 | Xia, S. | Phase 2 | 84 | 57 | 43.7 | NM (18–59 years) | 4 μg, HB02 strain | 28 | 1&2 | Injection site pain, fever fatigueheadache, cough | Injection site: swelling(1%),itch(1%),redness(1%), itch (non‐injection site)(1%) | 0–7 | | 37 | Al Kaabi, N. | Phase 3 | 13,464 | 15.9 | 36.2 | Baseline COVID PCR + (0.2%), Baseline IgG +(5.0%) | 5 μg, WIV04 strain | 21 | 1&2 | Injection site pain, headache, fatigue, myalgia, diarrhea, coughing, fever, dyspnea, arthralgia, constipation, nausea, vomiting, dysphagia, anorexia | Injection site: induration(1.0%), swelling(1.5%), rash(0.7%), redness (1.1%), itching(0.4%), pruritus (non‐inoculated site)(1.3%), skin and mucosal abnormalities(0.2%), acute allergic reactions(0.3%) | 0–7 | | 37 | Al Kaabi, N. | Phase 3 | 13,471 | 15.4 | 36.2 | Baseline COVID PCR + (0.2%), Baseline IgG +(5.2%) | 4 μg, HB02 strain | 21 | 1&2 | Injection site pain, headache, fatigue, myalgia, diarrhea, coughing, fever, dyspnea, arthralgia, constipation, nausea, vomiting, dysphagia, anorexia | Injection site: induration(0.6%), swelling(0.8%), rash(0.7%), redness(0.9%), itching(0.5%), pruritus (non‐inoculated site)(1.5%), skin and mucosal abnormalities(0.2%), acute allergic reactions(0.3%) | 0–7 | | 4.4. BBV152 (n = 380) | |||||||||||| | 38 | Ella, R. | Phase 1/2 | 190 | 26 | 34 | NM | 3 μg + Algel‐IMDG | 14 | 1&2 | Injection site pain, body ache, fever, headache, malaise | Redness at injection site (1st:1%), itching (1st:1%), stiffness in upper arm(1st:1%) | 0–7 | | 38 | Ella, R. | Phase 1/2 | 190 | 24 | 35 | NM | 6 μg + Algel‐IMDG | 14 | 1&2 | Injection site pain, weakness in injection arm, body ache, fever, headache, malaise, weakness | Redness at injection site (1st:1%), itching(1st:1%, 2nd:1%),rashes(1st:1%) | 0–7 | | 4.5. KCONVAC (n = 424) | |||||||||||| | 39 | Pan, H. X. | Phase 1 | 24 | 50 | 38 | NM | 5 μg | 14 | 1&2 | Injection site pain,myalgia, fatigue | Injection site:induration(4%), erythema(8%) | 0–28 | | 39 | Pan, H. X. | Phase 2 | 100 | 47 | 45.5 | NM | 5 μg | 14 | 1&2 | Injection site pain,fever, inappetence, myalgia, headache, fatigue | Injection site:induration(2%), erythema(1%), pruritus(2%) | 0–28 | | 39 | Pan, H. X. | Phase 2 | 100 | 55 | 44.9 | NM | 10 μg | 14 | 1&2 | Injection site pain,fever, diarrhea, inappetence, vomiting, myalgia, headache, cough, dyspnea, fatigue | Injection site:pruritus(1%), skin or mucosa abnormality(1%) | 0–28 | | 39 | Pan, H. X. | Phase 2 | 100 | 62 | 42.4 | NM | 5 μg | 28 | 1&2 | Injection site pain,fever, diarrhea, myalgia, headache, cough, fatigue | Injection site:erythema(1%), pruritus(1%) | 0–28 | | 39 | Pan, H. X. | Phase 2 | 100 | 54 | 44.5 | NM | 10 μg | 28 | 1&2 | Injection site pain,fever, diarrhea, nausea, cough, fatigue | Injection site:induration(%3), swelling(2%), erythema(5%), pruritus(2%) | 0–28 | | 4.6. IBMCAMS vaccine (n = 96) (LD: 50EU, MD: 100EU) | |||||||||||| | 40 | Pu,J. | Phase 1 | 24 | 54 | 37 | NM | LD | 14 | 1 | Injection site pain, fatigue, fever, serious adverse events (8.3%) | Injection site itching (8.3%), rash (4.2%) | 0–7 | | 40 | Pu,J. | Phase 1 | 24 | 54 | 37 | NM | LD | 14 | 2 | Injection site pain, fatigue | Injection site redness (4.2%) | 0–7 | | 40 | Pu,J. | Phase 1 | 24 | 67 | 38.2 | NM | MD | 14 | 2 | Injection site pain, fatigue, diarrhea | Injection site itching (4.2%) | 0–7 | | 40 | Pu,J. | Phase 1 | 24 | 50 | 40.1 | NM | MD | 28 | 2 | Injection site pain, fatigue, fever, serious adverse events (8.3%) | Injection site swelling (4.2%) | 0–7 | | 5. Virus‐like particle vaccines | |||||||||||| | 5.1. CoVLP (n = 180) | |||||||||||| | 41 | Ward, B. J. | Phase 1 | 20 | 55 | 34.9 | NM | 3.75 μgUn‐adjuvanted | 21 | 1&2 | Injection site pain, headache, fatigue, chills, discomfort or uneasiness | Injection site: redness (5%), swelling(5%), swelling in neck(5%) 0‐21d: allergicconjunctivitis (5%), maculo‐papular rash (5%) | 0–7 | | 41 | Ward, B. J. | Phase 1 | 20 | 50 | 35.3 | NM | 3.75 μg + CpG | 21 | 1&2 | Injection site pain, fever, headache, muscle aches fatigue, chills, discomfort or uneasiness | Injection site: redness (5%), swelling(1st:5%, 2nd: 15%) swelling in neck(1st:20%, 2nd: 5%), chest wall (5%); 0‐21d: hordeolum(5%), plantar fasciitis(5%) | 0–7 | | 41 | Ward, B. J. | Phase 1 | 20 | 75 | 34.7 | NM | 3.75 μg + AS03 | 21 | 1&2 | Injection site pain, fever, headache, muscle aches, joint aches, fatigue, chills, discomfort or uneasiness | Injection site: redness (1st:5%, 2nd:31.6%), swelling(1st:15%, 2nd: 31.6%), swelling in neck(5.3%); 0‐21d: bacterial vaginosis(5%), vaginal infection (5%) | 0–7 | | 41 | Ward, B. J. | Phase 1 | 20 | 50 | 35.6 | NM | 7.5 μg Un‐adjuvant | 21 | 1&2 | Injection site pain, headache, muscle aches, joint aches fatigue, chills | Injection site: swelling(5%); swelling in neck (5%), axilla (5%), groin(5%); 0‐21d: rash(5%) | 0–7 | | 41 | Ward, B. J. | Phase 1 | 20 | 60 | 32.4 | NM | 7.5 μg + CpG | 21 | 1&2 | Injection site pain, fever, headache, muscle aches, fatigue, chills, discomfort or uneasiness | Injection site: redness (5%), swelling(1st:20%, 2nd:15%), swelling in neck (5%) 0‐21d: vulvovaginal pruritus(5%), contact dermatitis (5%), erythema(5%) | 0–7 | | 41 | Ward, B. J. | Phase 1 | 20 | 60 | 37.2 | NM | 7.5 μg + AS03 | 21 | 1&2 | Injection site pain, fever, headache, muscle aches, joint aches, fatigue, chills, discomfort or uneasiness | Injection site: redness(35%), swelling(1st:30%, 2nd:40%); swelling in neck(1st:5, 2nd:10), axilla(5%), groin(5%), chest wall(5%); 0‐21d: lymphadenopathy(5%), injection site papule(5%) | 0–7 | | 41 | Ward, B. J. | Phase 1 | 20 | 65 | 34.1 | NM | 15 μg Un‐adjuvanted | 21 | 1&2 | Injection site pain, headache, muscle aches, fatigue | Swelling in neck (10%); 0‐21d: oral herpes(5%), dyshidrotic eczema(5%) | 0–7 | | 41 | Ward, B. J. | Phase 1 | 20 | 50 | 32 | NM | 15 μg + CpG | 21 | 1&2 | Injection site pain, fever, headache, muscle aches, joint aches, fatigue, chills, discomfort or uneasiness | Injection site: swelling(1st:10%, 2nd:5.3%); swelling in neck(1st:5%, 2nd:5.3%), axilla(5.3%), chest wall (5%); 0‐21d:hot flush(5%) | 0–7 | | 41 | Ward, B. J. | Phase 1 | 20 | 45 | 32.7 | NM | 15 μg + AS03 | 21 | 1&2 | Injection site pain, fever, headache, muscle aches, joint aches, fatigue, chills, discomfort or uneasiness | Injection site: redness (1st:5%, 2nd:20%), swelling(1st:20%, 2nd:25%); swelling in neck(1st:10%, 2nd:15%), axilla(1st:10%, 2nd:10%); 0–21 d:injection sitebruising(5%), erythema(5%), warmth(5%), swelling(5%) | 0–7 | Abbreviations: 1st, after the first dose; 2nd, after the second dose; CLD, chronic lung disease; CVD, cardiovascular disease; d, days; DM, diabetes mellitus; GI, gastrointestinal; HIV, human immunodeficiency virus positive; HTN, hypertension; IHD, ischemic heart disease; NM, not mentioned. Supporting information Table S3. The included articles consist of phase 1 (n = 11), phase 2 (n = 3), phase 1/2 (n = 17), phase 2/3 (n = 3) and phase 3 (n = 6) trials, along with 1 study on all three phases. The candidate vaccines in order of number of studies on them are ChAdOx1 nCoV‐19 (6 studies), BNT162b2 (5 studies), BNT162b1 (4 studies), mRNA‐1273 (4 studies), CoronaVac (3 studies), 5 candidate vaccines with 2 studies each and 10 candidate vaccines with one study each. Among the vaccinated participant groups we included in our study, most had received BNT162b2 (n = 39,144), mRNA‐1273 (n = 30,359), BBIBP‐CorV (n = 27,367), Ad26.COV2.S (n = 22,537), Gam‐COVID‐Vac (n = 15,011), and ChAdOx1 nCoV‐19 (n = 13,995), in descending order. For intervals between the two (or three) doses, studies on BNT162b2, BNT162b1, Gam‐COVID‐Vac, NVX‐CoV2373, SCB‐2019, V‐01 and CoVLP used an interval of 21 days; studies on mRNA‐1273 and MF59‐adjuvanted sclamp used 28 days; and studies on Ad26.COV2.S used 56‐day intervals or single doses. Other trials also tested different regimens or single doses, sometimes comparing the two. For example, studies on ChAdOx1 nCoV‐19 tested day 0–21, 0–28, 0–56 regimens or intervals anywhere between 21 to 35 days (the rest are noted in the table). Most of these trials used the same candidate vaccines for both the primer and booster doses, some using different doses of the same vaccine for each dose. Three of the studies had administered heterologous primer‐booster vaccines; rAd26 with rAd5 (making up the Gam‐COVID‐Vac), 15 , 16 and ChAdOx1‐S with BNT162b2 (named the CombiVacS). 53 Among our included groups, only one study which was on BNT162b2 had individuals under the age of 18, set in two groups, 12 to 15‐year‐olds and 16 to 25‐year‐olds. 4 The rest had only included individuals above the age of 18, some extending their age groups up to 85‐year‐olds. Also, the trials often had groups with different age ranges, measuring the side effects in each age group, which are all noted in Table 3. We must bear in mind that the earlier expeditious vaccination with mRNA vaccines and their larger number of RCT participants is also reflected in the net number of observed side‐effects, as the number of participants in RCTs on mRNA vaccines (70,277), is almost comparable to the number of participants in the collective rest of the vaccine RCTs (90,353). This earlier jumpstart in mRNA vaccination also warrants more time for researchers to observe the side effects. We believe that these reasons have led to the larger number of studies on mRNA vaccines and therefore when evaluating the different vaccine categories, the relative risk of side‐effects should be compared between the groups, not the number of reported cases or articles. 3.5. Analytical observational studies A total of 27 observational articles, consisting of case‐control, cohort and cross‐sectional studies were included, with a total population of 467,577 participants, as illustrated in Table 4. The studies came from different countries such as United States, the UK, Italy, Poland, Czech Republic, Jordan, Spain, South Korea, Malta, Scotland, Argentina, China and international registries. The administered candidate vaccines in these studies in order of number of collective number participants having received them were Ad26.COV2.S (n = 338,765), 54 mRNA‐1273 (n = 55,944), 47 , 55 BNT162b2 (n = 33,539), 45 , 47 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ChAdOx1 nCoV‐19 (n = 26,862), 56 , 60 , 62 , 63 , 66 , 67 , 68 CoronaVac (n = 1855), 69 , 70 Gam‐COVID‐Vac (n = 683), 71 and BBIBP‐CorV (n = 89). 56 In addition, seven studies reported combined results on more than one vaccine, collectively comprised of 9851 participants. Five of these studies were on BNT162b2 and mRNA‐1273, 72 , 73 , 74 , 75 , 76 one study with the addition of ChAdOx1 nCoV‐19 to the two previous vaccines, 77 and one study with BNT162b2 and ChAdOx1 nCoV‐19. 78 We categorized the studies base on the vaccines administered in Table 4. TABLE 4. | Supplemental references a | Patients No | Woman ratio | Mean of Age (year) | Participants' characteristics or comorbidities | Dose | Any symptoms after vaccine | Mucocutaneous lesions characteristic | Time of onset the reactions | Location of mucocutaneous reaction | Duration of reaction | |---|---|---|---|---|---|---|---|---|---|---| | With BNT162b2 | |||||||||| | 1 | 141 | 70.7 | 34.99 | NM | 1 | Fever(6.4%), fatigue(31.9%), myalgia(21.3%), bone pain(7.1%), joint pain (13.5%), headache(27.7%), injection site pain(75.9%), arm numbness (12.1%), diarrhea(1.4%), shortness of breath(1.4%) | Herpes zoster (0.7%), redness and swelling (0.7%) | NM | Injection site | 1.39 days | | 2 | 803 | 86.55 | 43 | NM | 1 & 2 | Injection site pain(88.04%), weakness(58.9%), myalgia(45.7%), headache(44.83%), chills(35.99%), fever(22.04%), joint pain(16.56%), nausea(15.94%), spasm(9.59%), sweating(9.22%), dizziness(8.34%), musculoskeletal (53.3%), GI (21.42%), neurological (12.7%), cardiovascular (5.98%), respiratory(2.61%), allergy(1.24%) lymphadenopathy(3.36%) | Swelling(5.48%), itching(5.35%), rash(2.49%), skin discoloration(1.25%), hives(0.62%), bleeding(0.37%), mouth/throat swelling(0.37%), atopic eczema(0.25%), Hair loss(0.12%), Swelling of the lips(0.12%), Flushing(7.1%) | NM | Injection site, Mouth, Lips | NM | | 3 | 877 | 88.5 | 42.56 | Allergy(5.9%), baseline COVID + (19.3%), HTN(36.9%), thyroid disease(25.6%), asthma(21.8%), DM(9.6%), CVD(5.9%), RA(4.8%), bowel disease(4.4%), Neurologic disease(4.1%), Psychological distress(3%), Renal disease(2.2%), COPD(1.8%), Cancer(1.5%), Hepatologic disease(0.7%), Ophthalmologic disease(0.4%) | 1 & 2 | Injection site pain(89.8%), fatigue(62.2%), headache(45.6%), muscle pain(37.1%), chills(33.9%), fever(21.7%), lymphadenopathy(16.2%), nausea(13%), taste disturbance(3.5%) | At least one skin‐related side effect(5.2%):swelling(25.6%), redness(23%), rash(62.2%), urticaria(22.2%); At least one oral side effect(13%): blisters(36%), halitosis(25.4%), ulcers(14%), bleeding gingiva(11.4%), white/red plaque(10.5%), burning gingiva(8.8%), angular cheilitis(4.4%), tongue tingling(4.4%), vesicles(3.5%), swollen lips(3.5%), xerostomia(2.6%) | 1–3 days (26.8%), 1st week (28.6%), 2nd week (16.1%), 3rd week (18.8%), 4th week (9.8%) | Upper limb (60%), chest/trunk(33.3%), lower limb(22.2%), face(20%), back (17.8%), lips(74.1%), labial/buccal(14.8%), tongue(13%), palate(9.3%), gingiva(9.3%) | 1 day (45.1%), 3 days (35.8%), 5 days (9.4%), 1 week (5.3%), >1 week (3.0%), >4 week (1.4%) | | 4 | 103 | 88.3 | 40.4 | NM | 1 & 2 | (47.6%) of reactions After 1st dose, (52.4%) of reactions after 2nd dose, (18.4%) of participants had reactions after both doses | Delayed injection‐site reaction (COVID‐arm) (100%), itching (68%), disseminated lesions(4.9%), slightly indurated erythematous targetoid patch(1%) | NM | Injection site, Generalized | 72 h(13.6%) | | 4 | 4775 | 83.4 | 43.2 | NM | 1 & 2 | NM | Vaccine‐related urticaria (0.04%) | NM | NM | <7d | | 5 | 57 | 71 | 48.9 | Psoriatic arthritis(17.5%), Spondylo‐arthritis(5%), RA(10%), systemic sclerosis(8.7%), SLE(1.5%), Sjogren syndrome(1.7%), HTN(15.7%), obesity(8.7%), DM(3.5%) | 1 & 2 | 1st: injection site pain(29%), fatigue(8.7%), headache(28%), fever(5.2%), tachycardia(3.5%), paresthesia(3.5%), 2nd: injection site pain(41%), fatigue(58%), headache(58%), fever(58%), paresthesia(5.8%), itchy scratchy throat(5.8%), diarrhea(23.5%), lymphadenopathy(5.8%) | 2nd: cutaneous vasculitis(5.8%) | NM | NM | NM | | 6 | 282,103 | 61·6 | 62 | NM | 1 | Headache(7.8%), fatigue(8.4%), chills(2.5%), diarrhea(1.4%), fever(1.5%), arthralgia(3.2%), myalgia(2.3%), nausea(2.1%) | Local side‐effects(71.9%), rash(0.2%), skin burning(0.7%) | 0–8 days | NM | NM | | 28,207 | 69·6 | 61 | 2 | Headache(13.2%), fatigue(14.4%), chills(6.4%), diarrhea(1.5%), fever(3.8%), arthralgia(7%), myalgia(5%), nausea(3.5%) | Local side‐effects(68.5%), Rash(0.4%), Skin burning(1.1%) | 0–8 d | NM | NM | || | 7 | 131 | 85.5 | 47 | CVD(21.4%), respiratory disease(26%),autoimmunity(16%), chronic skin conditions(2.2%), anaphylaxis(92.4%), asthma(34.4%), chronic urticaria(5.3%), contact dermatitis(9.9%) | 1 | Mild immediate reaction in (0.7%) with history of severe asthma, Nasal obstruction, Rhinolalia | Pruriginous erythematous macules (0.7%) | 10 min | Neck and upper thorax | 1 h | | 8 | 34 | 85 85% | 42 42 | Atopic dermatitis(7%), contact dermatitis(2.8%), psoriasis(4.2%), urticaria(2.8%), acne vulgaris(2.8%), HTN(11%), COPD(2.8%), morbid obesity(4.2%), DM(1.4%), CVD(2.8%), rheumatologic disease(5.6%), malignancy(4.2%) | 1 | Fatigue(32%), Myalgia(29%), Headache(26%), Fever(12%), Arthralgia(15%), Nausea(12%), Chills(12%), Lymphadenopathy(5.9%), Diarrheal(2.9%), Injection site pain(24%) | Delayed large local reaction(15%), Local injection site reaction(24%), swelling(18%), erythema(18%), urticaria(26%), morbilliform(18%), erythromelalgia(2.9%), Flare of existing dermatologic condition (2.4%), vesicular(8.8%), pernio/chilblains(8.8%), VZV(2.9%), pityriasis rosea(5.9%), vasculitis(2.9%), reaction in breastfed infant(5.9%), petechiae(2.9%) | Urticarial:3d, morbilliform:3d, Erythromelalgia:7d | Urticaria: arms (68%), trunk(57%), legs(46%), morbilliform: arms(62%), trunk (42%), legs(27%), erythromelalgia: arms(69%), face(31%), hands(23%), feet(15%) | Urticaria:5 days, Morbilliform:4.5 days, Erythromelalgia:5.5 days | | 40 | 2 | Fatigue(33%), myalgia(25%), headache(15%), fever(10%), arthralgia(20%), nausea(7.5%), chills(13%), lymphadenopathy(7.5%), injection site pain(18%) | Delayed large local reaction(18%), local injection site reaction(25%), swelling(15%), erythema(20%), urticaria(20.5%), morbilliform(7.5%), erythromelalgia(5%), flare of existing dermatologic condition(7.5%), vesicular(5%), pernio/chilblains(5%), VZV(10%), angioedema(2.5%), pityriasis rosea(2.5%), filler reaction(2.5%), contact dermatitis(5%), reaction in breastfed infant(2.5%), onset of new dermatologic condition(5%) | Urticarial:2 days, morbilliform: 2 days, Erythromelalgia: 1 day | Urticaria: arms(68%), trunk(57%), legs(46%); morbilliform: arms (62%), trunk (42%), legs 27%); erythromelalgia: arms(69%), face(31%), hands(23%), feet(15%) | Urticaria: 3 days, Morbilliform: 2.5 days, Erythromelalgia:3 days | |||| | 9 | 277 | 66.8 | NM | NM | 1 | Injection site pain(70.0%), fever(6.9%), chills(15.9%), muscle ache(33.6%), joint pain(9.4%), headache(24.2%), dizziness(14.4%), confused mentality(3.6%), anxiety(4.7%), dyspepsia(6.1%), abdominal pain(4.7%), vomiting(6.1%), diarrhea(5.8%), fatigue(37.5%), palpitation(4.3%), HTN(3.6%), hypotension(3.6%), paralysis(3.6%), paraesthesia(4.3%), nasal obstruction(5.8%), parageusia(1.4%), foreign body sensation in the throat(9.7%), hoarseness(2.2%), odynophagia(2.5%), wheezing(0.7%), chest discomfort(0.4%) | Injection site: redness(2.5%), swelling(5.1%), itch(6.1%), angioedema(4.3%), tongue edema(3.6%), throat swelling and tightness(5.8%), urticaria(0.7%), skin rash(1.8%) | 3 days | Injection site, diffuse | NM | | 10 | 93 | 74.1 | 29 | NM | 1&2 | Injection site pain, fatigue, muscle pain, headache, diarrhea, headache, chills, joint pain, fever (only after 2nd dose) | Injection site: redness (<10%),swelling (<10%) | 0–7 days | Injection site | NM | | 11 | 1480 | 66.69 | NM | NM | 1&2 | Pain at injection site(49.85%), fever(10.11%), chills(10.20%), fatigue(21.79%), muscle pain(24.16%), joint pain(11.00%), headache(21.91%), vomiting(12.90%), diarrhea(13.75%) | Injection site: redness(31.07%),swelling(36.44%) | Peak 1–2d | Injection site | NM | | 12 | 151 | 48 | 73 | CVD(41%), DM(15%), underlying lung pathology(8%), malignancy (100%: solid cancer [63%], hematological cancer [37%]) | 1&2 | Injection‐site pain, flu‐like symptoms, headaches, chills, fatigue, arthralgia, nausea/vomiting, fever, diarrhea, deranged liver function tests | Injection site: erythema (<10%), swelling(<10%) | 0–30 days | Injection site | NM | | 13 | 10,445 | 85 | 41 | (Study only on cutaneous reactions after mRNA COVID‐19 vaccination) | 1 | NM | Dose 1 reaction: cutaneous reaction(1.4%), itching or rash(1.2%), hives/urticaria(0.2%), swelling/angioedema(0.2%) | 0–3 days | Injection site, diffuse | NM | | 124 | 2 | Recurrent dose 2 reaction: cutaneous reaction(16%), Itching or rash(14%), hives/urticaria(2.4%), swelling/angioedema(2.4%) | |||||||| | 9055 | 2 | New dose 2 reaction: cutaneous reaction(1.4%), itching or rash(1.1%), hives/urticaria(0.3%), swelling/angioedema(0.2%) | |||||||| | 14 | 4953 reports | NM | NM | NM | 1 | Thrombocytopenia (excluding ITP)(0.003%), venous thromboembolic events (including CVST)(0.03%), Arterial thromboembolic events)(0.03%), hemorrhagic events)(0.01%) | ITP (<0.001%) | 0–27 days | NM | NM | | With mRNA‐1273 | |||||||||| | 8 | 267 | 92 92% | 45 45 | Atopic dermatitis(3.5%), contact dermatitis(2.9%), psoriasis(1.7%), urticaria1.5%), acne vulgaris(1.2%), HTN(16%), COPD(5.2%), morbid obesity(4.1%), DM(4.1%), CVD(2.3%), rheumatologic disease(1.7%), malignancy(1.5%) | 1 | Fatigue(22%), myalgia(21%), headache(17%), fever(6.7%), arthralgia6%), nausea(5.6%), chills(5.2%), lymphadenopathy(4.9%), diarrheal(3.4%), injection site pain(35%) | Delayed large local reaction(66%), injection site reaction(54%), swelling(44%), erythema (49%), urticaria(5.9%), morbilliform(4.1%), erythromelalgia(1.9%), flare of existing dermatologic condition(1.1%), vesicular(1.5%), pernio/chilblains(1.1%), VZV(1.9%), angioedema(1.9%), pityriasis rosea(0.4%), erythema multiforme (1.1%), filler reaction (1.1%), vasculitis (0.7%), contact dermatitis (1.1%), onset of new dermatologic condition (0.7%), petechiae(0.4%) | Urticarial:3 days, morbilliform:3 days, Erythromelalgia:7 days, delayed large local reactions:7 days | Urticaria: arms(68%), trunk(57%), legs(46%), morbilliform: arms(62%), trunk(42%), legs(27%), erythromelalgia: arms(69%), face(31%), hands(23%), feet (15%) | Urticaria: 5 days, morbilliform: 4.5 days, delayed large local reaction: 4 days, erythromelalgia: 5.5 days | | 102 | 2 | Fatigue(62%), myalgia(62%), headache53%), fever(41%), arthralgia(27%), nausea(27%), chills(46%), lymphadenopathy(8.8%), diarrheal(3.9%), injection site pain(59%) | Delayed large local reaction (30%), Local injection site reaction(70%), swelling(68%), erythema(67%), urticaria(6.9%), morbilliform(6.9%), erythromelalgia(5.9%), Flare of existing dermatologic condition(1%), vesicular(1%), filler reaction(4.9%), contact dermatitis(1%), petechiae(2%) | Urticarial:2 days, Morbilliform:2 days, Erythromelalgia:1 day, Delayed large local reactions:2 days | Urticaria:arms(68%), trunk(57%), legs(46%); morbilliform: arms(62%), trunk(42%), legs(27%); erythromelalgia: arms(69%), face(31%), hands(23%), feet(15%) | Urticaria: 3 days, morbilliform: 2.5 days, erythromelalgia: 3 days | |||| | 13 | 30,195 | 85 | 41 | (Study only on cutaneous reactions after mRNA COVID‐19 vaccination) | 1 | NM | Dose 1 reaction: cutaneous reaction(2.1%), itching or rash(1.6%), hives/urticaria(0.5%), swelling/angioedema(0.3%) | 0–3 days | Injection site, diffuse | NM | | 485 | 2 | Recurrent dose 2 reaction: cutaneous reaction(17%), itching or rash(13%), hives/urticaria (3.5%), swelling/angioedema(2.7%) | |||||||| | 24,884 | 2 | New dose 2 reaction: Cutaneous reaction(2.6%), Itching or rash(1.8%), Hives/urticaria(0.7%), Swelling/angioedema(0.4%) | |||||||| | With ChAdOx1 nCoV‐19 | |||||||||| | 1 | 179 409 409 | 70.7 70.7% | 34.99 34.99 | NM | 1 | Fever(73.7%), fatigue(84.9%), myalgia(79.9%), bone pain(44.1%), joint pain (57.0%), headache(68.7%), injection site pain(91.1%), arm numbness(22.9%), diarrhea(9.5%), shortness of breath(9.5%), dizziness (3.4%), vomiting(3.4%), nausea(6.1%) | Urticaria (0.6%) | NM | NM | 1.39 d | | 15 | 92 | 77.2 | 35.37 | Allergy(1.1%), Baseline COVID + (8.7%), thyroid disease(5.4%), asthma (4.3%), neurologic disease(3.3%), psychologic distress(2.2%), RA(1.1%), bone disease(1.1%), HTN(1.1%) | 1 & 2 | Injection site pain(72.8%), fatigue(73.9%), muscle pain(55.4%), chills(48.9%), feeling unwell (46.7%), nausea(45.7%), headache(29.3%), fever(15.2%),lymphadenopathy(5.4%), taste alterations (5.4%) | Injection site: swelling(10.9%), redness(10.9%); skin rash(4.3%); oral: oral ulcers/blisters/vesicles(7.6%), halitosis(3.3%), bleeding gingiva(3.3%), white/red plaque(1.1%), Swollen lips(1.1%) | 1–3 days (82.6%), 1st week (13%), 4th week (4.3%) | Injection site, lips (1.1%), labial/buccal mucosa (4.3%), tongue (2.2%) | 1–3 days | | 6 | 345,280 | 57·7 | 63·3 | NM | 1 | Headache (22.8%), fatigue(21.1%), chills(14.7%), diarrhea(2.2%), fever(8.2%), arthralgia(11.5%), myalgia(7%), nausea(5.7%) | Local side‐effects (58.7%), Rash (0.4%), Skin burning (1.7%) | 0–8 days | NM | NM | | 16 | 994 | 76.7 | 35.7 | NM | 1 | Injection site: tenderness(94.5%) resting pain(88%); fatigue(92.9%), headache(77.7%), malaise(83.8%), arthralgia(61.5%), chills(67.2%), fever(27.6%), nausea/vomiting(36.4%), diarrhea(19.9%) | Injection site: redness(34.1%), swelling(48.7%); reports of urticaria at both arms, both legs, itching sense or warmth at the injection site | 2.2 days, peak at 4 days | Injection site, diffuse | 1 day, for many | | 9 | 5589 | 77 | NM | NM | 1 | Injection site pain(81.2%), fever(51.3%), chills(65.8%), muscle ache(79.9%), joint pain(48.6%), headache(69.5%), dizziness(46.8%), confused mentality(19.1%), anxiety(22.4%), dyspepsia(30.9%), abdominal pain (24.3%), vomiting (22.8%), diarrhea (24.1%), fatigue (76.5%), palpitation(28.3%), HTN (18.1%), hypotension(18.0%), paralysis(17.7%), paraesthesia (19.3%), nasal obstruction (27.2%), parageusia (8.1%), foreign body sensation in the throat(24.3%), hoarseness(10.4%), odynophagia(11.0%), wheezing(6.4%), chest discomfort(6.3%) | Injection site: redness (7.0%), swelling (9.6%), itch (22.2%), angioedema (19.1%), tongue edema (18.0%), throat swelling and tightness (21.1%), urticaria (5.8%), skin rash(5.7%) | 3 days | Injection site, diffuse | NM | | 10 | 42 | 90.5 | 36 | NM | 1 | Injection site pain (93%), fatigue (81%), muscle pain (79%), headache (62%), vomiting (<20%), diarrhea (<20%), headache (~60%), chills (~60%), joint pain (~30%), fever (<40%) | Injection site: redness (<20%), swelling (<20%) | 0–7 days | Injection site | NM | | 14 | 19,148 reports | NM | NM | NM | 1 | Thrombocytopenia (excluding ITP) (0.002%), Venous thromboembolic events (including CVST) (0.02%), Arterial thromboembolic events (0.07%), Hemorrhagic events (0.01%) | ITP (0.001%) | 0–27 days | NM | NM | | With Ad26.COV2.S | |||||||||| | 17 | 13,725 | 66.2 | 42 | (Percentages are among all 338,765 participants receiving the vaccine, 13,725 of which experienced adverse events) | 1 | Fatigue (59.1%), injection site pain (57.9%), headache (52.2%), myalgia (47.8%), fever (34.7%), chills (34.2%), joint pain (26.1%), nausea (18.7%), diarrhea (9.4%), abdominal pain (7.4%), vomiting (2.1%) | Swelling (9.3%), redness (7.4%) itching (7.1%) rash (1.9%) (serious adverse reactions: 3%, including 3 reports of non‐CVST TTS)cerebral venous sinus thrombosis thrombocytopenia syndrome | 0–7 days | Injection site, diffuse | NM | | With BBIBP‐CorV | |||||||||| | 1 | 89 | 65.6 | 39.27 | NM | 2 | Headache (12.4%), fever (4.5%), fatigue (16.9%), myalgia1 (4.6%), injection site pain (37.1%), injection site numbness (5.6%), joint pain (3.4%), diarrhea (1.1%), shortness of breath (2.2%), bone pain (4.5%) | Herpes zoster (1.1%) | NM | NM | NM | | With CoronaVac | |||||||||| | 18 | 329 | 48.5 | 35.77 | NM | 2 | Injection site pain, headache (16.8%), fever (3.6%), state of sleep/fatigue (13.8%), nausea/vomiting (10.8%), myalgia (3.9%), (tachycardia, loss of taste, feeling of throat swelling, vertigo) (5.1%) | Injection site: redness/swelling/pain (9.0%), allergy (0.9%), extensive itchiness (0.6%) (serious adverse reactions: 33.2%) | 1.14 days (for serious events) | Injection site, diffuse | 1.68 days (for serious events) | | 19 | 1526 | 79.3 | 35.4 | Allergic history (6.3%), adverse reactions to other vaccines (5.6%), BMI ≥ 28 (5.1%) | 1 | Fatigue (8.3%), Muscle pain (8.1%), headache/dizziness(6%), fever(2.9%), vomiting/diarrhea(1.6%), appetite impaired/nausea (1.4%), cough/throat pain(1.2%), stuffy runny nose(0.9%), non‐solicited adverse reactions (menstruation, chest pain, numbness of limbs): (0.6%) | Injection site adverse reactions (pain, induration, redness, swelling, or itch): (9.6%), allergic reaction/urticaria/rash(1%), lymphadenopathy(0.7%) | NM | Injection site, diffuse | NM | | 2 | Fatigue (6.5%), muscle pain (7.8%), headache/dizziness (3.4%), fever (1%), vomiting/diarrhea (0.9%), appetite impaired/nausea (0.9%), cough/throat pain (0.5%), stuffy runny nose (0.4%), non‐solicited adverse reactions (menstruation, chest pain, numbness of limbs): (0.3%) | Injection site adverse reactions (pain, induration, redness, swelling, or itch): (10.7%), lymphadenopathy (0.3%) (129 did not receive the 2nd dose, 16.3% of which had an adverse reaction after the 1st dose) | NM | Injection site, diffuse | NM | ||||| | With Gam‐COVID‐Vac | |||||||||| | 20 | 683 | 68.2 | 35 | Allergies (5.3%), DM (0.9%), hepatic disease (0.6%), renal failure (0.1%), corticosteroid treatment (0.1%), autoimmune disease (1.6%), baseline COVID‐19 + (5.0%), any vaccinations 4 months prior (1.5%), family history of reaction to vaccines (0.9%) | 1 | New or worsened muscle pain (58%, 10% severe, 1% grade 4), pain at injection site (57%, 2% severe), fever (40%), headache (33%), diarrhea (5%, n = 1 severe), vomiting (3%, n = 2 severe), breathing difficulty (2%) | Local redness or swelling (11%), swelling of face or throat (1%) 33% of all reported adverse events were local (serious adverse events: 5%) | 0–3 days | Injection site, diffuse | NM | | Results on more than one vaccine in a study (received by noted percentage of participants) | |||||||||| | With BNT162b2 (54%), mRNA‐1273 (46%) | |||||||||| | 21 | 741 | 57 | 60 | Study conducted only on solid organ transplant recipients, kidney (49%), liver (19%), heart (15%), lung (11%), pancreas (1%), multiple organs (5%) (median 7 [Refs. 3–14] years since transplant, on maintenance immunosuppression) Prior COVID +(2%) | 1&2 | Pain at the injection site (80%), fatigue (46%) (severe:2.5%), headache (49%), myalgia, chills, fever, diarrhea, vomiting | Local swelling and erythema <20% | 0–7 days | Injection site | NM | | With BNT162b2 (93%), mRNA‐1273 (7%) | |||||||||| | 22 | 708 | 65 | 44 | (Study conducted only on nephrologists) Prior COVID +(17%) | 1&2 | Local reaction (68%), followed by myalgia (44%), tiredness (39%) and headache (34%) chills (28%), Low‐grade fever (21%)(75% of all included) (69%) after the first dose (57%) after the second dose | Lymphadenopathy (6%), rash (<1%) | 0–7 days | Diffuse | NM | | With BNT162b2 (51%), mRNA‐1273 (49%) | |||||||||| | 23 | 325 | 96 | 43 | Only on patients with rheumatic and musculoskeletal diseases (RMD): inflammatory arthritis (38%), SLE (28%), overlap connective tissue disease (19%) Treated with: non‐biologic disease modifying antirheumatic drugs (44%), biologic therapy (19%) and combination therapy (37%) | 1 | Systemic symptoms (69%), fatigue: the most common systemic event, 7.4% severe), headache, myalgia, chills, fever, diarrhea, vomiting | Local symptoms (89%) including pain (<90%), swelling (<30%), and erythema (~20%) | 0–7 days | Injection site | NM | | With BNT162b2 (95.16%), mRNA‐1273 (4.81%), unknown (0.03%) | |||||||||| | 24 | 3908 | 80.33 | 42.75 | NM | 1&2 | (79.68%) reported after the first dose, general disorders (48.80%), such as fatigue, pain, and chills nervous system disorders (46.39%) headache (46.39%), dizziness (38.67%), and paraesthesia (25.48%) syncope (2.04%), facial nerve paralysis (0.99%), and seizure (0.66%) Gastrointestinal disorders (25.54%) nausea (56.41%), vomiting (14.73%), and diarrhea (14.13%) anaphylactic or anaphylactoid reactions (~4.15%) | Skin and subcutaneous tissue disorders: 24.08% (rash: 40.28%) | 3 days | Diffuse | NM | | With mRNA‐1273 (90%), BNT162b2 (7%), other or unknown (3%) | |||||||||| | 25 | 510 | 93 | 50 | (Results only on Black, Indigenous, or People of Color [BIPOC]) | 1&2 | (96%) after 1st dose and (85%) after mRNA‐1273 | Delayed large local reactions (100%, 11% reported in BIPOC patients), diffuse itching, hives or other rash, or angioedema (20%) | 8 days | Injection site, diffuse | NM | | With BNT162b2 (94.9%), ChAdOx1 nCoV‐19 (3.9%) and mRNA‐1273 (1.2%) | |||||||||| | 26 | 1657 | 79 | NM | NM | 1 | Soreness (78%), limb pain (46.6%), fatigue (30%), malaise (21.3%), headache (16.65%), muscle and joint pain (15%), fever (17.3%), chills (11.5%), lymphadenopathy (4.2%), seizures (1.6%), insomnia (4.3%), nausea (3.9%), vomiting (0.8%), allergic reactions (0.6%), migraine (2.6%), diarrhea (1.3%), cough (0.9%) | Swelling (24.5%), redness (18.3%), hair loss (0.8%) | NM | Injection site | NM | | 2 | Soreness (64.7%), fatigue (45.7%), malaise (43%), pain in the limb (38.7%), muscle and joints pain (33%), chills (31%), headache (30%), fever (42.3%), lymphadenopathy (9.5%), insomnia (7%), nausea (6.8%), migraine (3.6%), seizures (3.2%), cough (1.9%), diarrhea (1.7%), fainting (1.2%), vomiting (1.1%), allergic reaction (0.5%) | Swelling (20%), redness (16.6%), pruritus (4.8%), hair loss (0.9%) | NM | Injection site | NM | ||||| | A comparison of mRNA and viral vector vaccines: BNT162b2 (83.6%), ChAdOx1 nCoV‐19 (14.1%), other or unknown (2.3%) | |||||||||| | 27 | 2002 | 72.1 | 45 | Prior COVID‐19 + (26.6%) | 1 1 | More common in viral vector vaccines: Fever, flu‐like illness, shortness of breath, fatigue or tiredness | More common in viral vector vaccines: Skin rash, tingling, face and mouth swelling, generalized swelling, anaphylaxis (less common among those without a prior COVID infection) | 0–7 days | Injection site, diffuse | NM | | More common in mRNA vaccines: Any side effect | More common in mRNA vaccines: Localized reaction (mostly mild in mRNA vaccines) | Abbreviations: 1st, after the first dose; 2nd, after the second dose; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular disease; DM, diabetes mellitus; GI, gastrointestinal; HTN, hypertension; NM, not mentioned; RA, rheumatoid arthritis; SLE, systemic lupus erythematous; VZV, Varicella‐zoster virus. Supporting information Table S4. 3.6. Recommendations and guidelines for vaccination in specific groups A total of 37 articles regarding recommendations, guidelines and consensus opinion of experts on COVID vaccination in specific groups, such as those with underlying dermatologic or autoimmune disorders (with worries of potential flare‐ups 79 , 80 ), those with allergies, and those on immunosuppressive, immunomodulatory or biologic therapies (with worries of inefficient immunization 79 , 81 ), along with articles on certain precautions to be taken with regard to possible anaphylaxis or vaccine‐induced thrombotic thrombocytopenia (VITT) were found and their key points were extracted, as highlighted in Table 5. TABLE 5. | Supplemental references a | FA | Recommendations | Reason for recommendation | Drug dose adjustments | Any added drugs or monitoring | |---|---|---|---|---|---| | 1. For patients with autoimmune disorders | ||||| | 1.1. Autoimmune inflammatory rheumatic diseases | ||||| | 1 | Curtis, J.R. | Vaccinate AIIRD patients with stable, low‐activity disease, and those receiving immunomodulatory treatments, with either vaccine available to them (suggest the 2nd dose of the same vaccine) Vaccinate AIIRD patients with life‐threatening disease, only after controlling their disease Consider patients with SLE receiving cytotoxic therapy and higher‐dose glucocorticoids, or patients receiving RTX therapy as high risk AIIRD patients and advised to get vaccinated | AIIRD patients are at a higher risk for incident viral infections hospitalization due to COVID‐ 19 compared to the general population | Withhold MTX and JAK inhibitors 1 week after each vaccine dose, for those with controlled disease Withhold ABT SC both 1 week prior to and 1 week after only the 1st dose of vaccination Schedule ABT IV infusion 4 weeks only before the 1st vaccination, and postpone the subsequent ABT infusion by 1 week (5 week interval in total) (no adjustments needed for 2nd vaccine dose) Schedule CP administration 1 week after each vaccine dose Delay RTX 2–4 weeks after 2nd vaccine dose if disease activity allows | Prophylaxis with Acetaminophen or NSAIDs to prevent post‐vaccination symptoms is not recommended | | 2 | Park, J.K. | Suggest patients with AIIRD and their family members to receive a COVID‐19 vaccine Administer the vaccination, ideally when the patient's AIIRD is in a quiescent state, and before beginning immunosuppressive therapy Continue DMARDs during vaccination; and to improve vaccine efficacy, adjust the timing of RTX, MTX, and ABT administration Consider immediate, severe allergic reaction to a previous COVID‐19 vaccine or its components, the only contraindication to COVID‐19 vaccination | Patients with AIIRD are immunocompromised due to underlying immune dysfunction and concomitant immunosuppressive treatment | Continue DMARDs during vaccination since withholding DMARDs can increase disease activity, which is associated with worse COVID‐19 infection severity and outcomes Temporarily discontinue MTX for 1–2 weeks after each dose Start the next cycle of RTX 4 weeks after the 2nd vaccine dose Schedule ABT 1 week after the 1st vaccine dose and continue after the 2nd vaccine dose Schedule CP IV 1 week after each vaccine dose Withhold JAK inhibitors 1 week after each vaccine dose | Monitor patients for at least 15 min after being vaccinated for signs of anaphylaxis Patients should continue general public health measures against COVID‐19, such as wearing masks, hand hygiene, and social distancing, even after vaccination | | 3 | Moutsopoulos, H.M. Moutsopoulos | Delay initiation of immunosuppressive therapy until vaccination is completed Vaccinate patients on monthly IV pulse CP/methyl prednisone therapy either prior to therapeutic scheme or 1 month after the completion of 6 months pulse therapy Perform immunization after the anti‐cytokine drug therapy has reached baseline sera levels Vaccinate reluctant patients without withholding their immunoregulatory/immunosuppressive therapy Check antibody titers against SARS‐CoV‐2, 2–4 weeks after the final vaccination dose and at 3 and 6 months thereafter, in all of the mentioned cases | Serum antibodies against PF‐4 in patients with SLE and APS display an association with thrombotic events | Hold anti‐metabolites, calcineurin and JAK inhibitors for 10 days before and 10 days after each vaccine dose Decrease Prednisone dosage (of >0.5 mg/kg body weight or an equivalent synthetic steroid dose) to <10 mg/daily for 10 days before and after each vaccine dose Vaccinate patients on RTX therapy either 1 month prior to initiation of the therapeutic scheme or 6–8 months after the RTX infusion Continue anti‐cytokine therapies, AZA and calcineurin inhibitor therapy in patients Temporarily hold MTX and JAK inhibitors only after and not prior to administration of each vaccine dose | Suggest a constant vigilance following vaccination in patients with SLE and APS due to possible thrombotic events | | 4 | Tam, L.S. | For rheumatic and musculoskeletal diseases (RMD) (including SLE):Vaccinate RMD patients with normal or altered immunocompetence as soon as it becomes available to them based on current country, regional and/or international guidelines Initiate immunosuppressive therapies in patients with newly diagnosed RMD at least 2 weeks after the completion of COVID‐19 vaccination (with 2nd dose administered after minimum interval), if disease activity allows | To allow an adequate immune response to the vaccine and also to minimize the delay in the administration of immunosuppressive therapy | Consider a temporary discontinuation of MTX for 2 weeks post‐vaccination in well‐controlled rheumatoid arthritis patients | NM | | 5 | Santosa, A. | For connective tissue disorders, Psoriatic arthritis, SLE, Immune mediated inflammatory myositis, Sjogren's syndrome, Systemic sclerosis:Making individualized decisions is suggested If possible, administer the vaccine when the disease is quiescent Continue immunomodulatory drugs, other than RTX, alongside COVID‐19 vaccination Vaccinate household contacts | B cell depleting therapy with RTX is associated with significant reduction in immunogenicity. | Administer the vaccine a minimum of 6 months after the last dose, and/or 4 weeks prior to the next dose of RTX Do not delay vaccination in patients on or planned for RTX, with an ideal interval of vaccination 4–8 weeks after the last dose of RTX or 2 weeks prior to a planned dose of RTX, if possible | NM | | 6 | Bechman, K. | For immunosuppressed patients with rheumatic disordersIf immunosuppressive treatment has not been started, administer the 1st dose at least 2 weeks prior to initiation of the therapy course and administer 2nd dose before starting the treatment with a minimum interval of 3–4 weeks after 1st dose If patients are already on immune modulation, vaccinate at least 6 months after administration and 4 weeks before the next course of B cell–depleting therapy No universal decision on DMARD interruption has been made yet | To have a more adequate immune response | Adjust conventional synthetic DMARD therapy on an individual basis | NM | | 1.1.1 Psoriasis | ||||| | 7 | Gelfand, J.M. | Recommend an mRNA‐based COVID‐19 vaccine to patients without contraindications, as soon as possible | Comorbidities leading to more severe COVID‐19 are more frequent among patients with psoriasis | Continue the biologic or oral therapies for psoriasis and/or psoriatic arthritis during the vaccination period | NM | | 8 | Mease, P. J. | Consensus opinion from rheumatologists, dermatologists, infectious disease specialists, and patient research partners:Data does not suggest that having psoriatic diseases or being under treatment significantly increases the risk of COVID infection, or a more severe disease course The telehealth experience for patients with psoriatic diseases has been a success overall | Concerns of more severe outcomes of COVID‐19 among those with psoriatic diseases | Before getting the chance to vaccinate, treatment should continue without concerns of a more severe COVID course. | NM | | 1.2. Hidradenitis Suppurativa (HS) | ||||| | 9 | Giamarellos‐Bourboulis, E.J. | Vaccinate HS patients without specific contraindications Consider HS patients with metabolic diseases as a priority group to get vaccinated Patients treated with biologics should not be given vaccines containing living microorganisms Serological confirmation of adequate immune response is still not recommended as routine practice Treatment of HS with ADA and antibiotics seems not to increase the chance of contraction or a more severe course of COVID‐19 | Metabolic diseases, which are more common in HS, may induce an increased risk of a severe course of COVID‐19 and possible fatalities. Biological drugs reduce the hyperactivity of the immune system which might result in suboptimal immunization. | Treatment with ADA should not be interrupted especially in moderate‐to‐severe HS, and patients can be vaccinated with non‐living virus vaccines, but ADA may be suspended around the vaccination periodat the discretion of the responsible physician, who knows the patient's clinical situation best | Initiation of HS treatment with therapies other than ADA and antibiotics should be carefully evaluated at an individual level Recommend self‐protection with masks, even after vaccination | | 1.3. Patients with pemphigus on RTX | ||||| | 10 | Waldman, R. A. | Individuals who have not initiated RTX therapy: - Typically vaccinated at least 4 weeks before RTX infusion. Individuals who are actively receiving RTX: - Often vaccinated 12–20 weeks after completion of a treatment cycle,so there is a 4‐week or longer period prior to next their infusion (assuming dosing every 6 months) to mount an immune response (this is the common pattern for influenza vaccines and could be used for COVID vaccination as well) | Concerns of the effect of RTX on immune response after vaccination | Before getting the change to vaccinate, encourage careful use of anti‐CD20 (RTX) therapy for skin diseases. When vaccines are available, consider vaccination 12–20 weeks after the completion of a treatment cycle, or extending RTX dosing intervals Extending RTX dosing intervals to enhance the immune response after vaccination should be weighed against the risk of disease recurrence. | Although vaccine response may be attenuated, and may have lower rates in RTX recipients, it can be quantified with titers, which may then be helpful for further decisions to revaccinate patients. | | 1.4. Inflammatory bowel diseases | ||||| | 11 | Siegel, C. A. | Patients with IBD should be vaccinated against COVID as soon as possible. Patients with IBD are at the same risk of COVID as the general population. Patients with IBD, whether or not receiving immune‐modifying therapies, can safely receive all non‐live vaccinations for any vaccine‐preventable illness. If on immune they should not receive live virus vaccines. Do not defer vaccination for a patient with IBD receiving immune‐modifying therapies. Inform patients that they will mount an immune response to vaccination, however, vaccine efficacy may be blunted when receiving systemic corticosteroids. | Concerns of inefficient immunization | Patients with IBD receiving Infliximab infusions can receive non‐live vaccinations: - on the day of their infusion - or in mid‐cycle Patients can be vaccinated during induction or maintenance of biologic therapies irrespective of timing within their treatment cycle. | NM | | 2. For patients with allergic or atopic disorders | ||||| | 2.1. Atopic dermatitis | ||||| | 12 | Pfaar, O. | Vaccination is possible at any time No increased risk of allergic reactions, only short‐term aggravation of eczema is possible after vaccination Suggest vaccination of patients receiving systemic therapy with CYSP, MTX, Systemic Steroids and/or CYSP, AZA, or Baricitinib at any time, but a temporary interruption of treatment or a reduced dosage of the medication is recommended | General immune stimulation in AD, and immune suppression under drugs | Vaccination is recommended between two injections of biologics with 1 week interval between vaccination and the treatment; however, vaccination can be done at any time under dupilumab | Apply topical anti‐inflammatory locally, using both steroids and calcineurin inhibitors | | 13 | Ring | Vaccinate according to their local or national vaccination plan Suggest to do a diagnostic work‐up for allergy prior to vaccination in patients with a history of anaphylaxis to drugs in general or vaccinations, and in patients with systemic mastocytosis or idiopathic anaphylaxis | The protein or the vector, one possible elicitor of anaphylaxis could be other ingredients such as PEG, present both in the BNT162b1 and the mRNA‐1273 vaccines | NM | NM | | 14 | Thyssen, J.P. | AD is not a contraindication to vaccinationrecommend a case‐by‐case approach considering the specific drug and vaccine product recommend to strictly follow guidelines and decisions issued by the local and national health authorities in each country Suggest at least 3 weeks between the two COVID‐19 vaccine doses | AD worsening is unlikely after vaccination, as the vaccination response is mainly skewed toward T helper cell 1. The risk of AD flares and loss of AD control increases if the systemic AD therapy is withheld or reduced in dose for longer than 3 weeks. | Most clinicians pause these therapies as follows:JAK‐inhibitors and CYSP from the vaccination day until 1 week after MTX and AZA until 2 weeks after vaccination (to possibly improve chances or appropriate vaccination response) - suggest using the lowest dose possible: 2.5 mg/kg/day CYSP,1 mg/kg/day AZA and 7.5 mg/week MTX | NM | | 2.2. Mastocytosis | ||||| | 15 | Bonadonna, P. | Mastocytosis alone is not a contraindication to vaccines but some patients have a high risk of anaphylaxis:Uncontrolled MC‐mediator induced symptoms (intense flushing, episodes of hypotension, other uncontrolled symptoms from cardiovascular, respiratory, gastrointestinal, neurological systems): first treat symptoms accordingly, and vaccination should be delayed until treatment and proper control of symptoms Unstable mastocytosis and severe uncontrolled MCAS symptoms should first be treated until the symptoms are well controlled before receiving vaccination. known or suspected allergy to PEG or polysorbate 80/20 previous anaphylaxis to vaccination Brighton consensus anaphylactic reaction grade 1 and 2 to the 1st dose of COVID ‐19 vaccine | NM | Continue anti‐mediator‐based treatment, like omalizumab, during the time of vaccination | Allergy evaluation prior to vaccination Skin test to PEG and polysorbate 80/20 and vaccine H1‐antihistamines 30 to 60 min before vaccination (also consider corticosteroids, H2‐antihistamines, and montelukast) Supervision for 60 min after vaccination | | 16 | Stingeni, L. | For cutaneous and systemic mastocytosis in general, the following criteria are suggested as contraindications for vaccination:Severe anaphylaxis on 1st administration of SARS‐cov‐2 vaccine History of severe immediate reactions (urticaria‐angioedema syndrome, anaphylaxis) and/or delayed reactions (maculo‐papular eruptions, severe adverse drug reactions) to drugs containing PEG, polysorbate 80/20, and tromethamine Documented immediate and/or delayed allergy to PEG, polysorbate 80/20, and tromethamine | Excipients with known sensitizing potential in COVID‐19 vaccines:PEG‐2000 in BNT162b2 PEG‐2000 tromethamine in mRNA‐1273 polysorbate 80 in ChAdOx1S/nCoV‐19 | NM | Evaluate individually Premedicate with antihistamine (cetirizine oral drops 10 mg: 24 h before the vaccination day, on the vaccination day, and on the following 5 days) | | 2.3. Urticaria | ||||| | 12 | Pfaar, O. | For chronic spontaneous urticaria:Vaccination is possible at any time No increased risk of allergic reactions; but vaccination may result in transient aggravation Patients on systemic steroids and/or CYSP can be vaccinated at any timeHowever, if applicable, adequate immunological response to vaccination should be verified by serum antibody levels | Effect of vaccination may be reduced by systemic immunosuppression | Vaccination is recommended between two injections of biologics with 1 week interval between vaccination and the treatment; however, vaccination can be done at any time under Omalizumab | Systemic antihistamines can be used during vaccination and do not impact the effect of the vaccination | | 13 | Ring, J. | - Groups that should undergo a drug allergy diagnostic work‐up before vaccination: - Patients with a history of anaphylaxis to drugs in general, especially to vaccines - Patients with systemic mastocytosis or idiopathic anaphylaxis Consider severe allergic reactions to ingredients of the vaccine as contraindication | Systemic allergic reactions to vaccines are rare, and are due to hypersensitivity to components of the formulation of the vaccine | - For patients with urticaria, acute flare of eczema, and other allergic diseases, do not delay vaccination, but they should be actively treated for their disease | Consider anti‐allergic medication such as combined histamine H1 and H2 receptor antagonists + oral glucocorticoids prior to vaccination Observe for 30 min after vaccination In the case of anaphylaxis: main acute treatment includes IM Epinephrine | | 2.4. Allergic diseases (general) | ||||| | 17 | Klimek, L. | Consider common allergies due to medications, food, inhalants, venoms and latex as general public Consider patients with history of allergy to oral medications or family history of severe allergic reaction as general public Vaccinate in a healthcare setting with appropriate equipment Do not vaccinate if a patient has a history of severe reaction to the 1st dose or to the vaccine's component (PEG) Recommend to use non‐live vaccines in chronic rhinosinusitis with nasal polyps or AD patients whom are under immunomodulator medications | No evidence of immunosuppressive effects in dupilumab and omalizumab | Defer vaccination for 90 days after receiving convalescent plasma or monoclonal antibody treatment for COVID‐19 Administer any other vaccines with a minimum interval of 14 days before and after mRNA COVID‐19 vaccines No need to hold allergen immunotherapy and biologics Do not administer SC immunotherapy injections or biologics on the same day as mRNA vaccine No need to adjust the dose for sublingual forms of immunotherapy | Monitor patients with history of severe allergic reaction for 30 min and others for 15 min | | 18 | Peter, J. | Consider following conditions as contraindications to vaccinationin allergic or immune‐based diseases:Patients with inborn errors of immunity, malignancies (hematological cancers with immunoparesis), hematopoietic stem cell and solid organ transplant Patients with a prior anaphylactic reaction to either the 1st dose of COVID‐19 vaccine or an ingredient in the vaccine formulation, like PEG | Increased risk for severe COVID‐19 disease is considered in contraindicated conditions. The majority of drug‐ or vaccine‐induced anaphylactic reactions occur within the first 30 min following vaccination. | Suggest a case‐by‐case risk assessment | Observe patients with prior anaphylaxis or severe allergic disorders for 30 min after vaccination Suggest an allergy assessment and review by a specialist in patients with prior vaccine‐associated anaphylaxis suggest vaccination in a fully equipped setting with experienced staff to manage | | 19 | Murphy, K.R. | Known history of a severe allergic reaction to any component of the vaccine (e.g., polysorbate, PEG) is a contraindication for vaccination In case of immediate allergic reaction of any severity happening within 4 h of receiving the 1st dose, do not vaccinate with 2nd dose State that there is an experimental option for vaccine administration in patients with higher risk for developing serious or fatal COVID‐19 infections and who have previously experienced a suspected or confirmed severe allergic reaction to a COVID‐19 vaccine (explained in the adjustment column) | Adjuvants and other excipients/components in the vaccine are generally responsible for allergic reactions | The graded vaccine administration protocol as an experimental protocol: administer 0.05 ml of 1:10 dilution, and 10%, 20%, 30%, and 40% of the full dose in ascending order, in alternate arms at 15‐min intervals, followed by a minimum 30‐min observation period | Screen patients by asking several questions to determine the possible risk for an allergic reaction to the mRNA COVID‐19 vaccines Observe patients with a history of systemic reactions to food, drugs, or venoms for 30 min, others for 15 min | | 20 | Kleine‐Tebbe, J. | For atopic and/or eosinophilic airway diseases with type 2 inflammation:Consider a 1–2 week interval between vaccination and allergen immunotherapy injections, on manufacturer's recommendations Continue sublingual immunotherapy as usual | NM | Do not interrupt biologics such as Benralizumab, Dupilumab, Mepolizumab, Omalizumab, Reslizumab; continue as planned Schedule vaccination approximately midway through the treatment interval | NM | | 21 | Tanno, L.K. | Consider following conditions as contraindication for COVID‐19 vaccination: - History of allergy to one of the components of the vaccine (PEG) - History of immediate reaction to first injection of a COVID‐19 mRNA vaccine or another vaccine or unidentified drug Vaccinate with precaution in following conditions: - Possible Mast Cell Activation Syndrome (MCAS)/mastocytosis - History of immediate allergic reaction to multiple drug classes, with the trigger unidentified - History of “immediate allergy” or anaphylaxis to a vaccine or a parenteral biological therapy, an injected corticosteroid, colonoscopy preparation, or laxatives - History of idiopathic anaphylaxis, latex allergy or topical disinfectant allergy, bradykinin related angioedema or inhibitor angiotensin agent induced anaphylaxis | Concerns of allergies | NM | Observe patients for 15–30 min In local reactions: use local treatment and carry on In systemic mild reaction (like acute urticaria): treat accordingly, take precise clinical history, and refer immediately to the allergist/immunologist (count them as contraindicated patients for 2nd injection until allergy work up) In anaphylaxis: measure tryptasemia between 30 min to 2 h after the onset of reaction, then >24 h after the onset of reaction, to exclude other diagnosis like mast cell activation | | 22 | Untersmayr, E. | Recommendation clearly speaks in favor of COVID‐19 vaccination In times of vaccine shortage, high‐risk patients as well as patients under immunosuppressive therapy should be prioritized. Although further detailed assessment of the protective effect of vaccination is warranted, especially for patients receiving immunomodulatory or immunosuppressive therapy, vaccination is expected to be beneficial. Patients should be clearly informed that vaccination reactions are to be expected. | Concerns of vaccination among patients under immunomodulatory and immunosuppressive therapy or those with immunodeficiencies | Prophylactic paracetamol (in not contraindicated), about 6 h after vaccination can attenuate reactions to vaccination. If necessary, paracetamol can be continued every 6 h for 24 to 48 h. | | | 2.5. Precautions for anaphylaxis | ||||| | 23 | Turner, P.J. | Recommend special precaution for following conditions: - history of immediate allergic reaction like anaphylaxis to multiple different drug classes, with the trigger unidentified (which may indicate PEG allergy) - history of anaphylaxis to a vaccination or parenteral monoclonal antibody preparation - Mast cell disease (systematic mastocytosis) Vaccination contraindications: - prior allergic reaction to the vaccine itself or to its components such as PEG In these cases, vaccination should be proceeded as normal: - Local (non‐systemic) reaction to prior vaccination, stable asthma on biologics, hypersensitivity to NSAIDs, prior history of allergy to an identified food, venom or a defined group of medication | Adjuvants and other excipients/components in the vaccine are generally responsible for allergic reactions | NM | Assessment of possible risk of PEG‐allergy, and referral to allergist‐immunologist 30 min observation after vaccine injection No pretreatment with antihistamine, as it may mask initial symptoms of a reaction Consider obtaining venous access prior to skin testing with PEGs Recommend a blood sample for evaluation of mast cell tryptase to diagnose vaccine‐associated anaphylaxis after a reaction | | 24 | Kim, M. A. | Those excluded from or candidates for a delayin vaccination: - Current COVID‐19 infection or fever ≥37.5°C - Pregnant - ≤18 years old Special considerations: - Patients with chronic illness or immunocompromised conditions - Breast‐feeding mothers Past history of COVID‐19 infection: vaccinate at least 4 weeks after recovery In asymptomatic cases: vaccinate 4 weeks after first PCR test Patient on systemic steroids for more than 2 weeks: - vaccinate at least 4 weeks after stopping systemic steroids - If patients cannot stop steroids due to underlying diseases, vaccinate based on the risk‐to‐benefit ratio. | Concerns of vaccination after a COVID infection or in special groups | Subjects treated with monoclonal antibodies or therapeutic plasma exchange for COVID‐19 infection: defer vaccination for at least 90 days, to avoid the potential interference of immune responses | - Patients with inherited coagulopathy: factor replacement on the day of vaccination is necessary | | 25 | Klimek, L. | Contra‐indications to vaccination: - Immediate‐ or late‐type allergy, or anaphylaxis to one or more ingredients of the vaccine or to substances that are cross‐reactive to them - Patients with an anaphylactic reaction to the first dose of vaccine - Previous anaphylaxis of unclear cause - Known mastocytosis or anaphylaxis to different drugs or other vaccines No allergy sufferer should be excluded from COVID‐19 vaccination without sufficient reason, except those with contra‐indications or high‐risk groups. High risk patients should undergo an “allergological evaluation” prior to COVID vaccination. | Concerns of allergies in vaccination | Provide an interval of 7 days between allergologically relevant biologics and vaccination | Monitor patients with allergies or those who belong to a defined risk groups for 30 min after vaccination. Vaccinators and vaccination staff must be prepared and have the appropriate expertisefor the recognition and treatment of anaphylaxis and severe allergic reactions and vaccination sites must have a minimum equipment of drugs and instruments. In case of (supposed) allergic reactions to vaccination, an allergological work‐up in a specialized center is indicated. | | 26 | Klimek, L. | Regularly inform patients about possible severe allergic/anaphylactic reactions Ask patients about such incidents in the past, including allergic reactions to additives, in particular PEG and cross‐reactive PEG analogues In suspected cases, perform an allergological clarification (skin prick test, laboratory diagnostics) and consult an allergist More precise definitions of the type, cause, and severity of severe allergic reactions are needed not over‐exclude people from vaccination and possibly damage the achievement of herd immunity | Concerns of allergies in vaccination | NM | Vaccination personnel must always be prepared for the possibility and treatment of severe allergic/anaphylactic reactions and anaphylaxis | | 27 | Worm, M. | A recommended set of questions for the assessment of the “allergological riskpotential” for COVID‐19 vaccination should be asked, finding details onPrevious (possibly repeated) severe allergic reactions to medications, vaccines, or PEG‐macrogol or polysorbate‐containing drugs (e.g., macrogol or cold medications) (Repeated) severe general reactions during medical procedures such as colonoscopies or operations under general anesthesia Severe general reaction to an unknown trigger Known mastocytosis in patients with previous severe immediate drug reactions or anaphylaxis to an unknown trigger For the second dose: possible a = severe general reaction after the first dose | Concerns of allergies prior to vaccination | NM | NM | | 3. For dermatology patients on immunosuppressive, immunomodulatory or biologic therapies | ||||| | 28 | Ferretti, F. | Consider patients with systemic comorbidities related to immune‐mediated chronic skin diseases, such as cardiovascular diseases, diabetes and obesity, and those under treatment with conventional therapy or biologics as a priority group to get vaccinated A case‐by‐case approach to any therapeutic decision is recommended, but it is suggested to withdraw or delay immunosuppressant drugs or biologics in case of COVID‐19 diagnosis up to infection recovery, except for patients on systemic corticosteroids therapy | Due to high risk of severe COVID‐19 or hospitalization | Taper systemic corticosteroids to ≤20 mg/day of prednisone or equivalent to administer live vaccines Withhold MTX and JAK inhibitors 1 week after each vaccine dose For patients with an autoimmune bullous disease treated with RTX; if RTX is not started, patient needs to be vaccinated ≥4 weeks prior to RTX infusion, otherwise they need to be vaccinated 12–20 weeks after completion of a cycle of therapy | NM | | 29 | Gresham, L.M. | Advise to check antibody titers after vaccination, and use additional vaccinations if needed, to boost the level of protective antibodies Consider nonviral or inactivated SARS‐CoV‐2 vaccine subtypes before, during, or after receiving systemic immunosuppressant, immune‐targeting therapy and biologic therapy without significant modification of ongoing treatments | Concerns of immune therapies | NM | Consider anti‐IL‐17 biologics, anti‐IL‐12/23 biologics, Omalizumab, MTX and JAK inhibitors as safe therapies during the COVID‐19 pandemic | | 30 | Wang, C. | Consider atopic dermatitis, immune‐bullous disorders, vasculitis and cutaneous drug eruptions as high‐risk patients and advise to get vaccinated if immunomodulator or biologic therapy have not been started, vaccinate prior to initiation of the therapy course Advise to administer vaccines other than those against COVID at least 7 days either before or after the completion of the two‐dose COVID‐19 vaccine regimen | To maximize vaccine response and decrease the frequency of local and systemic reactions | if patient is already on a biologic or immunomodulatory agent:administer the vaccine (non‐live COVID‐19 vaccines strongly recommended) at least 7 days on either side of biologic or immunomodulator dose, and at a different anatomical location | NM | | 31 | Hauptman, M. | For patients on biologic therapies (including patients with psoriasis):Administer an inactivated vaccine if it is a possible option Consider discontinuation of biologics prior to receiving an inactivated vaccine in patients who prioritize high titer immunity over potential skin flare Discontinue the biologic therapy, if only live attenuated vaccines are available | Concerns of immune therapies | NM | NM | | 32 | Chakravarthy, K. | - There is no evidence that patients receiving epiduralsteroid therapy for pain management are more at risk of adverse reactions to COVID vaccination - There is no evidence that bolus steroids in theepidural space will impact the immune response to vaccination | Concerns of those receiving steroids | There is no need to defer neuraxial steroid injections when indicated in the context of COVID‐19 vaccination There is no specific guidance suggesting withholding NSAIDs or other anti‐inflammatories before vaccination | NM | | 4. Precautions for vaccine‐induced thrombotic thrombocytopenia | ||||| | 33 | Elalamy, I. | Rapidly vaccinate those under 60 years of age with comorbidities (like cancer, CVD, kidney or liver impairment, immunosuppressant use, obesity, DM) and patients on long‐term anticoagulant treatment for APS or other reasons IM injection should be done correctly at the appropriate lower site of deltoid muscle and not intravascularly Minimal systemic signs, low‐grade fever, or muscular pain are expected in varying degrees for each individual and should decrease in 48 to 72 h Check for extensive ecchymotic or purpuric local reaction that is particularly painful In case of thrombocytopenia (PLT < 120 G/L): investigate for HIT by screening for heparin‐PF4 antibodies Do not take these steps for everyone systematically: management of vaccination with thromboprophylaxis (LMWH or direct oral anticoagulant or aspirin, screening for thrombophilia before vaccination, measuring of anti‐PF4 antibodies after vaccination, monitoring of D‐dimer changes before and after vaccination, venous ultrasound before and after vaccination; use a case‐by‐case basis Do not contraindicate vaccination in case of history of thrombosis, autoimmune disease, history of HIT (but mRNA vaccines are preferable), history of allergy (except for allergy after 1st dose of any vaccine), immune thrombocytopenia | on a Principle of Precaution | Recommended labs after physical exam:CBC with PLT count, D‐dimers (>1000 ng/mL), and schistocytes to rule out a hypercoagulable state with PLT consumption (PLT < 120 G/L) or DIC with a decrease in fibrinogen (<2 g/L), and other tests depending on the clinical state Use imaging to detect thrombosis in various sites (venous ultrasound, MRI, CTA) Patients presenting more than 4 days (4–28 days) after the vaccination with symptoms suggestive of thrombosis and thrombocytopenia should be admitted with a low threshold so an immediate and thorough work‐up is possible Symptoms include: intense and persistent headaches, dizziness, visual disorders, impaired speech, acute pain or worsening muscular pain, edema of a limb suggestive of phlebitis, significant changes in a limb temperature (heat or cold), difficulty breathing, sudden heart rate acceleration, unusual bleeding signs, especially petechiae) | In the event of major thrombotic events, infuse immunoglobulins (1 g/kg) + antithrombotics for 48 h Steroids and plasma exchange are also options to reduce the autoantibodies inhibitors of Bruton's tyrosine kinase (like Ibrutinib), can be another potential option in treatment of VITT Implement an effective non‐heparin antithrombotic treatment without delay: By injectable anticoagulant (Fondaparinux, Danaparoid, Argatroban), and depending on the clinical evolution, switching to direct oral anticoagulant (dabigatran, rivaroxaban, apixaban) can be an option In case of flu‐like symptoms, it is advisable for the patient to drink lots of fluids and take Paracetamol | | 34 | Oldenburg, J. | The positive effects of vaccination with ChAdOx1 nCoV‐19 outweigh the negative effects, so its administration is welcome to be resumed in Germany. Considering the immunogenesis of thrombosis in intracranial veins or other atypical locations, patientswith a history of thrombosis and/or known thrombophilia do not have a higher risk for this specific and very rare complication with ChAdOx1 nCoV‐19. Flu‐like symptoms (joint and muscle pain or headache) persisting for 1 to 2 days after vaccination are a common side effect and not a cause for concern If side effects persist or recur more than 3 days after vaccination (dizziness, headache, visual disturbances, nausea, vomiting, shortness of breath, acute pain in chest, abdomen, or extremities), further medical diagnostics should be carried out to clarify a thrombosis Anticoagulation is necessary to treat the thrombosis. While heparins are contraindicated in (autoimmune) HIT, IV anticoagulation with heparins is likely possible in confirmed VIPIT. Diagnostics for HIT/VIPIT should be ordered before administering IVIG, since high‐dose IVIGs may lead to false‐negative test results. There is no indication for routine thromboprophylaxis with anticoagulants or antiplatelet agents following vaccination with ChAdOx1 nCoV‐19. Regardless of (autoimmune) HIT/VIPIT test results, alternative causes of thrombocytopenia and/or thrombosis must be considered and further clarified, including: thrombotic microangiopathies ITTP or atypical HUS, APS, paroxysmal nocturnal hemoglobinuria, and underlying hematological malignancies | Concerns of thromboses after ChAdOx1 nCoV‐19 | Labs: CBC with PLT count, blood smear, D‐dimers, further imaging in indicated (cranial MRI, ultrasound, chest and abdomen CT).In the case of thrombocytopenia and/or evidence of thrombosis (regardless of previous exposure to heparin): antibodies against the PF4/heparin complex In case of a negative screening test: an HIT‐like cause of thrombosis/thrombocytopenia can be ruled out. In case of a positive screening test for PF4/heparin antibodies: order classical HIPA assayor SRA, as a functional confirmatory test; if positive: establishment of the diagnosis of autoimmune HIT (in the absence of previous heparin exposure) if negative: order a modified HIPA assay; if positive: establishes the diagnosis of VIPIT Patients receiving oral anticoagulation (e.g., for AF, VTE): continue treatment during and after vaccination. Patients with no indication for oral anticoagulation at significant risk of VTE: thromboprophylaxis over several days may be indicated individually, in case of severe flu‐like symptoms with fever and immobilization | - Until (autoimmune) HIT is ruled out: anticoagulation with heparins should be avoided, alternated to danaparoid, argatroban, direct oral anticoagulants, and possibly fondaparinux (with very specific considerations) - The authors of this guidance document advise against the use of LMWH or fondaparinux for thromboprophylaxis, as it cannot be safely ruled out that these IV anticoagulants foster the production of platelet‐activating antibodies. - As an off‐label alternative, general measures (exercise, fluid replacement, compression stockings) + prophylactic doses of direct oral anticoagulants (rivaroxaban 10 mg once daily or apixaban 2.5 mg BD), maybe be considered. - In case of confirmed (autoimmune) HIT/VIPIT and critical thromboses such as sinus/cerebral or splanchnic vein thrombosis: high dose IVIG is very likely to interrupt the prothrombotic pathomechanism. | | 5. For delayed reactions to hyaluronic acid soft tissue fillers | ||||| | 35 | Gotkin, R. H. | Collected data does not support the concern for a higher risk of adverse reactions following soft tissue filler injections associated with COVID vaccination, compared to other previously described triggers or the default of adverse reactions following soft tissue filler injections | Concerns of reactions to fillers | NM | NM | | 36 | Rice, S. M. | - Emerging reports of delayed‐type hypersensitivity reactions (DTRs) to facial fillers after COVID vaccination may cause patients to become confused by potential side effects and possibly postpone vaccination as a result. - Vaccination must be encouraged and patients should be informed about the temporary and treatable nature of these side effects. - Do not discourage patients with a history of treatment with dermal fillers from vaccination A time frame should be suggested: - longer than 2 weeks between vaccination and filler procedures, dental procedures or for with recent infections, - potentially longer windows for those with risk factors such as prior sensitivity to dermal fillers, autoimmune disorders, or those on immunomodulatory medications | Concerns of DTRs to fillers | Dilution of fillers with saline or lidocaine or use of non‐HA fillers around the time of vaccination may also be suggested to minimize the risk of DTRs | In case of facial swelling lasting longer than 48 h: treat with antihistamines, steroids, and/or hyaluronidase, with resolution both alone or in combination, without altering the vaccine efficacy ACE‐Is(lisinopril) have been recommended (not strongly) for the treatment of facial edema following COVID‐19 vaccination In case of symptoms after first vaccine dose, manage the side effects, reassure the patient and advise them to obtain their second dose, with pretreatment considerations (including antihistamines), and instruct them to present to the emergency department if a more severe reaction is suspected | | 37 | Rice, S. M. | Pre‐vaccine counseling in cosmetic patients seeking fillers:Patients with allergies, history of injection site reactions, or urticaria may benefit from antihistamines and topical medications. COVID‐19 vaccine–related planning (procedures could be planned with a time window to minimize the risk of reactions), along with screening for dental procedures and the herpes simplex virus Cutaneous implications of both COVID‐19 infection and vaccination may become part of standard medical counseling prior to aesthetic procedures Patients seeking filler injection may be counseled regarding vaccine options not associated with adverse reactions; especially for patients with risk factors discussed | Concerns of DTRs to fillers | In cases of facial swelling: short courses of oral steroids (<2 weeks) can achieve resolution, and do not appear to alter vaccine effectivity In case of residual or prolonged edema: hyaluronidase Consider a 4 –8 week window between filler injections and vaccination for the general population, and potentially longer for those with risk factors: autoimmune or immunologic disorders, chemotherapy or immunomodulatory medications, history of sensitivity to dermal fillers (more pronounced and delayed swelling than expected for a given filler) | Inform patients to contact their physicians for treatment if facial swelling or nodules develop, or present to the emergency room in case of more serious reactions. Fillers containing HA and polymethylmethacrylate may be more likely to cause reactions, so other filler options (e.g., calcium hydroxyapatite, polylactic acid, or laser resurfacing) may be prioritized, especially during the months surrounding vaccination Dilution of filler is another reasonable consideration, for both polylactic acid and HA with saline, sterile water, or lidocaine can decrease the risk of adverse reactions and DTRs | Abbreviations: ABT, abatacept; ACE‐I, angiotensin converting enzyme inhibitors; AD, atopic dermatitis; ADA, adalimumab; AF, atrial fibrillation; AIIRD, autoimmune inflammatory rheumatic diseases; APS, antiphospholipid syndrome; AZA, azathioprine; CBC, complete blood count; CP, cyclophosphamide; CT, computed tomography; CTA, computed tomography angiography; CVD, cardiovascular disease; CYSP, cyclosporine; DIC, disseminated intravascular coagulation; DM, diabetes mellitus; DMARD, disease‐modifying anti‐rheumatic drugs; DTRs, delayed‐type hypersensitivity reactions; FA, first author; HIPA, heparin‐induced platelet activation; HIT, heparin‐induced thrombocytopenia; HUS, hemolytic uremic syndrome; IM, intramuscular; ITTP, immune thrombotic thrombocytopenic purpura; IV, intravenous; Lab, laboratory investigations; LMWH, low‐molecular‐weight heparin; MC, mast cell; MCAS, mast cell activation syndrome; MRI, magnetic resonance imaging; MTX, methotrexate; NM, not mentioned; NSIAD, non‐steroidal anti‐inflammatory drugs; PEG, polyethylene glycol; PF4, platelet factor 4; PLT, platelet; RMD, rheumatic and musculoskeletal diseases; RTX, rituximab; SC, subcutaneous; SLE, systemic lupus erythematosus; SRA, serotonin‐release assay; VTE, venous thromboembolism. Supporting information Table S5. These points have been categorized in the table as depicted below: 4. DISCUSSION With the emerging knowledge of the adverse events following COVID‐19 immunization, an arising demand has been put on clinicians to be updated on the various mild to severe or potentially life‐ threatening manifestations of COVID vaccines, and whether or not certain patient groups can be vaccinated, or what precautions are to be taken with regard to their medical status. Much attention has been focused on hot topics regarding COVID‐19 prognostic and therapeutic options during the pandemic, with special focus on dermatologic concerns, 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 and now with the wide distribution of the COVID vaccines, a comprehensive assessment of the mucocutaneous eruptions associated with COVID‐19 immunization is an issue of great importance, so that with concrete knowledge, vaccination is not hindered by hesitancy through false beliefs about the extension or prevalence of adverse events or worries of flare‐ups or inefficient immunization, and that critical or potentially fatal adverse reactions are safely avoided. We extracted any side effects of COVID‐19 vaccines reported in these studies with a special emphasis on mucocutaneous manifestations, comorbidities, lesion characteristics, time of onset, location, and duration of reactions, along with vaccine types, and further details regarding dosage, conjugated materials and age groups for the RCTs. It is important to mention that studies with no mucocutaneous manifestations were not included in our systematic review. Also, among the studies we did include, we did not extract the data on groups or subgroups that had no mucocutaneous reactions to the vaccines, so the results and numbers presented here are only on groups with mucocutaneous side effects. Regarding the case reports and case series, we would like to also emphasize the importance of reporting registries and helping the medical community gather data on more unsolicited adverse events related to vaccination, that were perhaps less commonly observed in the initial trials, and through this cumulative international effort to report these events, many less solicited adverse reactions are now well‐known and clinicians are well aware of their potential emergence, and as expressed earlier, many guidelines, consensus recommendations and position papers have been written since. Regarding the RCTs, the most common side effect among all trials was injection site pain, present in 95% of studies. Among the common systemic reactions were fatigue, fever, headache, chills, malaise, arthralgia, myalgia, nausea, vomiting and diarrhea. Among the common local (injection site) reactions reported in the RCTs were redness, swelling, induration, pruritis and warmth. Generalized pruritis, rash, hypersensitivity and lymphadenopathy (axillary) were also among the solicited general side effects. Less solicited or unsolicited mucocutaneous adverse events reported in the RCTs were mucocutaneous eruptions like pustules (at injection site or elsewhere), macular or maculo‐papular allergic rashes, petechial rash, urticaria, injection site discoloration or bruising, alopecia, contact dermatitis, acne‐form dermatitis, allergic conjunctivitis, hordeolum, chalazion, keratoconjunctivitis, uveitis, benign neoplasm of the eyelid, plantar fasciitis, swelling in the neck, chest wall or groin, oral herpes, dyshidrotic eczema, bacterial vaginosis, vaginal infection, vulvovaginal pruritus, anaphylactic reactions, cellulitis, psoriasis, rosacea, vitiligo, Raynaud's phenomenon, among other epidermal and dermal conditions, skin appendage conditions, dental and gingival conditions and oral soft tissue conditions. These side effects were sometimes more common in lower dose groups or younger age groups, which is an interesting observation. There was the same pattern with the primer and booster doses where sometimes side effects were more common after the booster doses and sometimes after the primers, so the trials' results were not all in the same direction on this matter. Among patients' comorbidities were obesity, hypertension, diabetes, history of or current COVID‐19, metabolic and endocrine conditions, allergies and hypersensitivities, asthma, cardiac and pulmonary conditions, psychiatric disorders, joint and back pain, positive HIV, malignancy and autoimmune illnesses. Moving on to safety assessments, most studies had observed the side effects within 7 days after vaccination, others extending the watch period to 14, 21, 28, or more days. Regarding the analytical observational studies, a wide range of side effects after vaccination were reported in the studies. Among these studies, the most common reaction after COVID‐19 vaccination was local adverse events such as injection site pain and numbness. Apart from local events, systematic reactions such as fatigue followed by fever, myalgia, headache, bone pain, joint pain represented as the most common symptoms. Other mild adverse effects such as nausea, sweating, dizziness, diarrhea, vomiting, taste disturbance, itchy scratchy throat, insomnia, spasm, migraine, nasal obstruction, and rhinolalia were also observed in the reported results. To further categorize the reported adverse events, they mostly fell into seven groups; musculoskeletal, gastrointestinal, cardiovascular, neurological, respiratory, allergic reactions, and mucocutaneous symptoms. The mucocutaneous reactions ranged a broad spectrum from mild local reactions including swelling, redness, pruritus, rash, urticaria, and burning sensation of the skin, to more rare reactions such as erythromelalgia, morbilliform rash, contact dermatitis, oral ulcers, blisters and vesicles, bleeding and burning gingiva, angular cheilitis, swollen lips, xerostomia, flare of existing dermatologic conditions such as varicella‐zoster or herpes simplex flares, and pityriasis rosea‐like reactions. The rare mucocutaneous effects were efficiently controlled with steroids, antihistamines, and pain‐relievers. The side effects were most frequently reported within the first 3 days after vaccination, but there were also some studies reporting delayed adverse reactions, up to 4 weeks after vaccination. Duration of reactions varied from most frequently almost 1 day to as long as 4 weeks or more. The most common location of mucocutaneous lesions was upper limbs (injection site), trunk and face. Almost half of these studies reported participants' comorbidities. The most commonly reported comorbidities were hypertension, prior COVID‐19, diabetes mellitus, cardiovascular disorders, autoimmune, rheumatologic or allergic disorders, malignancies, obesity, and anaphylaxis. 47 , 57 , 59 , 65 , 67 , 70 , 71 , 72 , 73 , 74 , 78 , 118 , 136 , 137 , 138 , 139 In addition, less common co‐morbidities including asthma, thyroid disorder, psychological distress, hepatologic disease, and ophthalmologic disease were also mentioned in these studies. Regarding the recommendations and guidelines for vaccination in specific groups, a generally positive view toward vaccination was expressed, inviting most groups to vaccinate, while having the necessary precautions in mind, and clarifying the contra‐indications so those with higher risks could safely avoid any severe adverse reactions or modify their vaccination and/or treatment schedules to achieve peak immunization, all the while having their underlying diseases under control. In some cases, a true causality between proposed adverse events and vaccination was not concluded. In these situations, we relied on the authors' original statement, while considering patient's past medical history, notably previous allergic/hypersensitivity reactions to other vaccines or drugs, and the temporal course between vaccine administration and onset of the eurptions. Based on provided evidence, in patients with no alternative underlying source for the adverse eurptions, and in case the onset of reactions were compatible with our experience and current literature, usually occurring from 2–3 days to 3–4 weeks, a vaccine induced adverse reaction was ascertained. The authors of this study have worked on various clinical aspects of COVID‐19, COVID‐19 vaccination and dermatology 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 140 , 141 and it seems that this hot topic could answer some questions and concerns about the most encountered specific disorder in the field of dermatology. We hope the present article provides its audience with the state‐of‐the‐art knowledge that is essential in today's standard of care regarding the mucocutaneous adverse reactions following COVID‐19 vaccination. 5. CONCLUSION Mild, moderate, severe, and potentially life‐threatening adverse events have been reported following immunization with COVID‐19 vaccines. It appears that although in the assessment of the pros and cons of vaccination, mucocutaneous adverse events could be one of the causes of vaccine hesitancy, they are nonetheless mostly non‐significant, self‐limiting reactions, and for the more uncommon moderate to severe reactions, guidelines and consensus position papers can be of great importance to provide those at higher risks and those with specific worries of flare‐ups or inefficient immunization, with sufficient recommendations to safely schedule their vaccine doses, or avoid vaccination if they have the discussed contra‐indications. CONFLICT OF INTEREST The authors declare no conflicts of interest. AUTHORS CONTRIBUTION All authors contributed to the preparation and finalization of this article. Supporting information ACKNOWLEDGMENTS The authors would like to express their gratitude to the staff of the Rasool Akram Medical Complex Clinical Research Development Center (RCRDC) for their technical and editorial assistance. Seirafianpour F, Pourriyahi H, Gholizadeh Mesgarha M, Pour Mohammad A, Shaka Z, Goodarzi A. A systematic review on mucocutaneous presentations after COVID‐19 vaccination and expert recommendations about vaccination of important immune‐mediated dermatologic disorders. Dermatologic Therapy. 2022;35(6):e15461. doi: 10.1111/dth.15461 Farnoosh Seirafianpour, Homa Pourriyahi, and Milad Gholizadeh Mesgarha contributed equally to this study. DATA AVAILABILITY STATEMENT The data that support the findings of this study are available from the corresponding author upon reasonable request.

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