In the Vaxzevria clinical trials, a delayed local large reaction to the vaccine has not been described. In the phase 1/2 trial of Vaxzevria, local site reactions were only recorded for 7 days following vaccination [3]. It is therefore possible that the observation period was too short to report the delayed injection site reactions. Likewise, in the interim primary efficacy analysis of four phase 3 randomized controlled trials of ChAdOx1-S, no case with delayed cutaneous reaction was reported [4].

On the other hand, a similar phenomenon as in our patient has been described multiple times for the mRNA-based Moderna (mRNA-1273) vaccine and to a lesser extent for Comirnaty (Pfizer/BioNTech, BNT162b2) [5,6,7,8]. In the Moderna phase 3 trial, delayed injection site reaction occurred in 244 participants (0.8%) after the first dose of Moderna vaccine and in 68 participants (0.2%) after the second dose [5]. The delayed injection site reaction was defined as reaction on or after day 8.

The International COVID-19 Dermatology Registry started capturing skin reactions to COVID-19 vaccines in January 2021 and just recently published 414 cases with skin reactions to Comirnaty and Moderna vaccines [7]. They defined delayed large local reactions as occurrence after 4 or more days after vaccination. The most common cutaneous reaction to Moderna vaccination was delayed large local reaction (n = 175 first dose, n = 31 second dose). Interestingly, they also reported cases with local large reaction after administration of Comirnaty (n = 5 first dose, n = 7 second dose). Of note, no cases of anaphylaxis or other serious adverse events after subsequent vaccination following delayed major local reactions to Moderna or Comirnaty vaccines were described [7].

The time course and clinical symptoms of delayed major skin reaction after vaccination with Moderna or Comirnaty have a similar pattern that we recognized in our patient after Vaxzevria vaccination. To the best of our knowledge, this is the first description of a patient with delayed large local reaction to the vector-based Vaxzevria vaccine.

We suspect a delayed-type or T cell-mediated hypersensitivity reaction as it was proposed for the mRNA vaccines [6]. A skin-biopsy specimen obtained from a patient with delayed large local reaction after Moderna vaccination showed findings consistent with delayed-type or T cell-mediated hypersensitivity, supporting this hypothesis [6]. Although the aetiology of these reactions is unclear, delayed-type hypersensitivity reactions to excipient ingredients of vaccines have been reported previously [7].

While polysorbate 80 is the excipient in Vaxzevria and Johnson & Johnson (Janssen) vaccines, polyethylene glycol (PEG) 2000 is used in Moderna and Comirnaty vaccines. Polysorbate 80 is structurally similar to PEGs, and cross-reactivity of PEGs with polysorbate 80 has been described [9]. PEG 2000 is a substance not used before in vaccine development [10], and it is hypothesized that delayed localized cutaneous reactions to Moderna and Comirnaty vaccines may be associated with T cell responses to the new vaccine excipient [11]. For polysorbate 80, delayed cutaneous reactions have long been described after intramuscular injections [12] and may be the culprit antigen in this case.

Thousands of medications contain either PEGs or polysorbates [9]. Our patient is taking 5 mg olmesartan (ALIUD Pharma GmbH) once daily. This drug contains PEG 400, but neither polysorbate 80 nor PEG 2000. Therefore, amplification of hypersensitivity reaction due to concomitant drug intake is unlikely. However, cross-reactive hypersensitivity cannot be ruled out without allergy skin testing.