Graphical abstract
Key words: booster, COVID-19, delayed hypersensitivity, delayed large local reaction, dermatology, injection site reaction, Moderna, Moderna arm, mRNA, Pfizer, SARS-CoV-2, vaccine, vaccine reaction
To the Editor: In the original phase 3 clinical trial of mRNA-1273 (Moderna) vaccine against SARS-CoV-2 reported in the New England Journal of Medicine, delayed injection site reactions were reported in 244 (0.8%) participants after the first dose and in 68 (0.2%) participants after the second dose.1 These reactions were characterized by erythema, induration, and tenderness; the onset was typically on or after day 8, with the resolution 4 to 5 days later. The first report of delayed large local reactions (DLLRs) in 12 patients who received the Moderna vaccine demonstrated a median onset on day 8 (range, 4-11) after dose 1, including 5 individuals with grade 3 (≥10 cm) plaques.2 Following dose 2 in all 12 patients, 50% had large local reaction recurrence of similar (n = 3) or lower (n = 3) grades, which were early in the onset (median day 2 [range, 1-3]). DLLRs have since been described with the Pfizer-BioNTech vaccine, albeit rarely.3 Although the etiology of this response is unknown, it is pathologically consistent with delayed-type hypersensitivity and potentially a response to the translated SARS-CoV-2 spike protein.2, 3, 4
Since the authorization of mRNA booster vaccines in September 2021, >95 million Americans have received a booster dose.5 We followed up with the same 12 patients who experienced DLLRs after their initial Moderna vaccination to investigate whether DLLRs recurred with their booster doses (Moderna [n = 10] and Pfizer-BioNTech [n = 2]), administered at a median duration of 9 months (range, 7-11 months) after dose 2 (Table I). Antihistamine premedication was used in 4 individuals, none of whom had a skin reaction recurrence. Injection site skin reactions were present in only 4 (33%) patients, one of whom received the Pfizer-BioNTech vaccine. Local reactions occurred with a median onset on day 2 (range, 1-5), and only 1 patient met the criterion of a delayed reaction (onset day 5). All 4 patients reported these reactions as either similar to or of a smaller magnitude than their previously experienced reaction(s). Local reactions resolved at a median duration of 4.5 days (range, 4-9 days) after the onset without the use of steroid treatment. Reaction images and descriptions for the 4 patients are presented in Fig 1. No patients received a skin biopsy.
Table I.
Patients who experienced DLLRs to mRNA-1273 COVID-19 vaccines∗
| Variable | Patient 1 | Patient 2 | Patient 3 | Patient 4 | Patient 5 | Patient 6 | Patient 7 | Patient 8 | Patient 9 | Patient 10 | Patient 11 | Patient 12 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Demographic characteristics/clinical history | ||||||||||||
| Age, y | 37 | 61 | 45 | 31 | 40 | 43 | 38 | 49 | 31 | 47 | 52 | 46 |
| Sex | F | F | F | F | F | M | F | F | F | M | F | F |
| Race and ethnicity | Asian, non-Hispanic | White, non-Hispanic | White, non-Hispanic | White, non-Hispanic | White, non-Hispanic | White, non-Hispanic | White, non-Hispanic | White, non-Hispanic | White, non-Hispanic | White, Black, Native American, Hispanic | White, non-Hispanic | White, non-Hispanic |
| Allergy or dermatology history | None | Anaphylaxis (from contrast) | None | Chronic urticaria, contact dermatitis | None | None | None | Chronic urticaria | None | None | Anaphylaxis | None |
| Previous COVID-19 infection | No | No | No | No | No | Yes, after dose 2 | No | No | No | No | No | No |
| Dose 1/Dose 2 details | ||||||||||||
| Dose 1 DLLR onset | Day 8 | Day 8 | Day 8 | Day 8 | Day 4 | Day 9 | Day 9 | Day 8 | Day 10 | Day 11 | Day 8 | Day 9 |
| Dose 1 DLLR maximum diameter/Grade | 9.0 cm/2 | 10.0 cm/3 | 14.0 cm/3 | 5.0 cm/1 | 13.0 cm/3 | 12.5 cm/3 | 7.0 cm/2 | Two separate lesions, each 3.0-4.0 cm/2 | 7.5 cm/2 | 7.0 cm/2 | 19.5 cm/3 | 7.0 cm/2 |
| Dose 2 large local recurrence | No | Yes, earlier in onset; lower grade | Yes, earlier in onset; similar grade | Yes, earlier in onset; similar grade | No, slight erythema at the injection site between days 0 and 1 | Yes, earlier in onset; lower grade | Yes, earlier in onset; lower grade | No, slight erythema between days 2 and 3 | No, small area of erythema between days 2 and 3 that self-resolved | Yes, earlier in onset; similar grade | No, slight erythema between days 2 and 3 | No |
| Dose 3 details | ||||||||||||
| Duration between dose 2 and dose 3 | 8 mos | 7 mos | 10 mos | 9 mos | 9 mos | 11 mos | 11 mos | 10 mos | 9 mos | 9 mos | 9 mos | 10 mos |
| Dose 3 manufacturer (dose) | Moderna (100 μg/0.5 mL) | Moderna (50 μg/0.25 mL) | Moderna (50 μg/0.25 mL) | Moderna (50 μg/0.25 mL) | Moderna (50 μg/0.25 mL) | Pfizer-BioNTech (0.3 mL) | Moderna (50 μg/0.25 mL) | Moderna (50 μg/0.25 mL) | Moderna (50 μg/0.25 mL) | Moderna (50 μg/0.25 mL) | Moderna (50 μg/0.25 mL) | Pfizer-BioNTech (0.3 mL) |
| Premedication | Cetirizine 10 mg (1 h before injection) | Cetirizine 10 mg | None | None | Cetirizine 10 mg, twice a day (starting 3 d before injection) | None | Loratadine 10 mg | None | None | None | None | None |
| Initial systemic symptoms after dose 3 | Fatigue | None | Headache, fever (Tmax 102.5 °F), myalgias, lymphadenitis | Fatigue, headache, myalgias, lymphadenitis | Fatigue, fever (Tmax 100.5 °F), myalgias | Elevated temperature (Tmax 99.9 °F) | Fatigue, myalgias | Fatigue, myalgias | Headache, myalgias | Myalgias | Fatigue, fever (Tmax 101.0 °F), myalgias, nausea | Headache, fever |
| Local injection site symptoms | None | None | Pain, swelling, rash, pruritus | Pain, swelling | None | Swelling, rash | Pain, swelling | None | Rash | Rash, pruritus | Pain | None |
| Skin reaction onset | -- | -- | Day 1 | -- | -- | Day 2 | -- | -- | Day 2 | Day 5 | -- | -- |
| Skin reaction resolution | -- | -- | Day 9 | -- | -- | Day 4 | -- | -- | Day 4 | Day 5 | -- | -- |
| Dose 3 diameter/Grade | -- | -- | 29.0 cm/3 | -- | -- | 11.5 cm/3 | -- | -- | 7.5 cm/2 | 6.5 cm/2 | -- | -- |
| Skin reaction size comparison between doses | -- | -- | Dose 2 = Dose 3 > Dose 1 |
-- | -- | Dose 1 = Dose 2 = Dose 3 |
-- | -- | Dose 2 > Dose 1 > Dose 3 |
Dose 1 > Dose 2 > Dose 3 |
-- | -- |
| Post vaccination treatment | None | None | Acetaminophen 325 mg (2 doses) | Naproxen 220 mg, twice a day (3 d) | Cetirizine 10 mg, twice a day (3 d); acetaminophen 1000 mg (2 doses) | Ibuprofen 200 mg (2 doses) | Acetaminophen 500 mg, 4 times a day | None | Acetaminophen 500 mg (2 doses) | None | None | Acetaminophen 1000 mg (1 dose) |
DLLR, Delayed large local reaction; Tmax, maximum temperature.
Clinical data are from patient self-report.
Fig 1.
Injection site reactions after mRNA-1273 COVID-19 vaccine. Of 12 patients with DLLRs after mRNA-1273 COVID-19 vaccine dose 1, 6 (50%) had injection site skin reactions with dose 2 that were not delayed in onset and 4 (33%) had injection site skin reactions with dose 3 (the booster dose). Although morphologies of dose 1 DLLRs to mRNA-1273 against SARS-CoV-2 were diverse and included annular, edematous (patient 6), and/or targetoid (patient 3) plaques near the site of injection for vaccination, most dose 2 and dose 3 injection site reactions were uniform erythematous plaques of similar or lower grade than those of dose 1. In addition to the injection site reaction, patient 6 developed urticarial plaques on the elbows from their initial vaccination course that did not reoccur after receiving the Pfizer-BioNTech booster. Some photographs may be inverted because of the way in which they were taken (eg, with a mirror or front-facing cameras). DLLR, Delayed large local reaction.
All patients in this series experienced remarkable DLLRs after their first Moderna vaccine dose, but subsequent doses were well-tolerated, and skin reactions were generally mild and early in onset. Given the low risk of DLLR recurrence, our results support that DLLRs are not a contraindication to subsequent vaccination and do not lead to systemic allergic reactions.2 Our results should be confirmed with larger cohort data that assess recurrence risk and whether antihistamine premedication should be recommended to potentially attenuate these reactions. To date, there is limited guidance for clinicians to manage patient expectations with subsequent doses, and further investigation on the mechanism of these reactions is warranted. Although pathologically consistent with delayed hypersensitivity, DLLRs after mRNA vaccination are not clinically consistent given that they are not predictably recurring and worsening with each exposure. As booster doses become increasingly recommended and/or required, patients with DLLRs should be counseled on reaction recurrence and may consider switching to an alternative mRNA vaccine.
Conflicts of interest
None disclosed.
Footnotes
Funding sources: Supported by MGHDOM Transformative Scholar Program and COVID Junior Investigator Support Initiative.
IRB approval status: Not applicable.
References
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