Delayed Large Local Reactions to mRNA-1273 Vaccine against SARS-CoV-2.

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Abstract

To the Editor: Baden et al. 1 report on a phase 3 clinical trial of the mRNA-1273 vaccine against SARS-CoV-2, and they provide information on immediate injection-site reactions, which were observed in 84.2% of the participants after the first dose. The trial also showed that delayed injection-site reactions (defined in that trial as those with an onset on or after day 8) occurred in 244 of the 30,420 participants (0.8%) after the first dose and in 68 participants (0.2%) after the second dose. These reactions included erythema, induration, and tenderness. The reactions typically resolved over the following 4 to 5 days. However, these reactions were not further characterized, and links between reactions after the first dose and those after the second dose were not provided to inform clinical care. We have also observed delayed large local reactions to the mRNA-1273 vaccine, with a median onset on day 8 (range, 4 to 11) after the first dose. These reactions had a variable appearance (Figure 1). Here, we report on a series of 12 patients with these reactions, all of which appeared near the injection site after complete resolution of the initial local and systemic symptoms associated with vaccination. Five of the reactions were grade 3 plaques (≥10 cm in diameter) (Table 1). Some patients had concurrent systemic adverse effects, and among these patients, 2 had additional skin findings. Most patients received treatment for their symptoms (e.g., with ice and antihistamines). Some patients received glucocorticoids (topical, oral, or both), and 1 patient received antibiotic therapy for presumptive cellulitis. The symptoms resolved a median of 6 days after onset (range, 2 to 11). Our suspicion of delayed-type or T-cell–mediated hypersensitivity was supported by skin-biopsy specimens obtained from a patient with a delayed large local reaction who was not among the 12 patients described here. Those specimens showed superficial perivascular and perifollicular lymphocytic infiltrates with rare eosinophils and scattered mast cells (see Fig. S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). Given that neither local injection-site reactions nor delayed-type hypersensitivity reactions are contraindications to subsequent vaccination, 2 all 12 patients were encouraged to receive the second dose and completed their mRNA-1273 vaccination course. Although half the patients did not have a recurrence of large local reactions, three patients had recurrent reactions that were similar to those after the initial dose, and three patients had recurrent reactions that were of a lower grade than those after the initial dose. The median onset of cutaneous symptoms after the second dose (day 2; range, 1 to 3) was earlier than that after the first dose (Table 1). Clinicians may not be prepared to address delayed local reactions to the mRNA-1273 vaccine. Given the scale-up of mass vaccination campaigns across the world, these reactions are likely to generate concerns among patients and requests for evaluation. These reactions have not been consistently recognized, guidance regarding the second dose of vaccine has varied, and many patients have unnecessarily received antibiotic agents. We hope this letter encourages additional reporting and communication regarding the epidemiologic characteristics, causes, and implications of these delayed cutaneous reactions, since this information might allay the concerns of patients, encourage completion of vaccination, and minimize the unnecessary use of antibiotic agents.

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Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

Lindsey Baden, Hana El Sahly, Brandon Essink … (2020)

Abstract Background Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle–encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19. Methods This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2. Results The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups. Conclusions The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.)