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In this large prospective study of health care employees in the US, 97.6% of the cohort successfully completed the recommended 2-dose mRNA COVID-19 vaccine series. We found that a self-reported history of high-risk allergy was associated with a 2.5-fold higher risk for self-reported allergic reactions in the 3 days after vaccination and an approximately 4-fold higher risk of hives and angioedema specifically. Although reporting of severe allergic reactions to an mRNA COVID-19 vaccine was rare (0.3%), those with a history of high-risk allergy were at a nearly 5-fold increased risk of these reactions, and such reactions were verified by specialists in most individuals who sought clinical care for their symptoms within the Mass General Brigham system. These identified associations were not sensitive to covariate adjustment and persisted across subgroups that were stratified by these factors.

Severe allergic reactions to vaccines are rare, with a reported incidence of 1.31 to 7.91 cases per million vaccine doses.9,28 However, a recent study of 429 highly allergic individuals who received the Pfizer-BioNTech vaccine under medical observation identified a much higher rate of minor allergic reactions (1.4%) and anaphylaxis (0.7%).29 Past vaccine reactions have largely been attributed to excipients rather than to vaccine active ingredients.13,30 The cohort in the present study included 217 employees with a history of a severe allergic reaction to an injectable medication or a vaccine and 9 employees with a history of severe allergic reaction to PEG. By reported history alone, many of these individuals may have been ineligible for an mRNA COVID-19 vaccine, according to many international guidelines. However, following the CDC guidelines, with allergist consultation, risk stratification, and shared decision-making, all employees were able to complete the 2-dose vaccine series.27 For the rare individuals with a history of severe allergic reactions to PEG, consultation with an allergist or immunologist is recommended because the mRNA vaccine may not be an absolute contraindication for such individuals.

Lessons may also be learned from previous restrictions of vaccine based on excipient allergy. For example, concerns were raised regarding the safety of administering egg-containing immunizations to individuals with an egg allergy during the H1N1 influenza A pandemic from 2009 to 2010 and played a role in global vaccine hesitancy. A large body of evidence subsequently emerged that indicated inactivated influenza vaccine to be safe for those with an egg allergy, and current national and international guidelines now recommend the administration of influenza vaccine to individuals with an egg allergy of any severity.31 Future studies involving diverse populations are needed to help address ongoing questions regarding the safety of mRNA COVID-19 vaccines in individuals with suspected or confirmed PEG allergy. Moreover, the emergence of allergy symptoms on first exposure, as was more commonly observed in this study, is atypical for IgE-mediated reactions,1 and an investigation of other mechanisms (eg, non-IgE-mediated mast cell activation or complement activation) underlying these reactions is warranted.

Of individuals with allergist-confirmed severe allergic reactions to mRNA COVID-19 vaccine to date, roughly one-third reported a history of anaphylaxis and most were women.4,7 Cutaneous findings about Moderna arm, a delayed-onset localized skin reaction, have been described largely in female patients.32 In a study of more than 400 dermatological reactions after COVID-19 vaccination, 90% of participants were women in an international dermatology registry.33 Similarly, we found female sex to be an independent factor in self-reported allergic reactions after mRNA COVID-19 vaccination in an adjusted multivariable model. This prospective study design vastly reduces the impact of reporter bias that is observed in case series and registry studies. Further studies are needed to better understand the risk factors, including sex, for allergic reactions after receipt of an mRNA COVID-19 vaccine. A multicenter, phase 2 randomized clinical trial is currently being conducted to assess COVID-19 vaccination reactions in individuals with a history of high-risk allergy and control participants with no atopic history.34

Assessment of allergy symptoms after vaccination was based on self-reported reactions. Of the 175 possible severe allergic reactions in a CDC report, 86 (49%) were ultimately deemed nonanaphylactic allergic reactions.7 The true incidence of postvaccination allergic reactions may therefore be lower than that reported in this study. Given the scale of the national mass vaccination efforts and the volume of employees who were vaccinated in a short time frame, manual review of all reported allergy symptoms was not feasible. However, allergic reactions were validated in more than 60% of those who reported severe reactions and who had a specialist visit, and in a subgroup analysis of clinical professionals with medical knowledge and training, allowing for high-quality self-reported health data,35 we observed a stronger association between high-risk allergy and risk of allergy symptoms after vaccination, suggesting less random misclassification of the outcome. Although additional prospective studies are needed to further examine the risk factors for confirmed allergic reactions after COVID-19 vaccination, perceived (ie, self-reported) allergy symptoms are also critical to study because of their equivalent association with public perception and vaccine hesitancy.

Recent data indicated that, even for individuals who reported immediate and potentially allergic reactions after the first dose of an mRNA COVID-19 vaccine, the second dose can be safely administered.36 Similarly, in this cohort, few individuals did not complete the 2-dose vaccine regimen, raising the possibility that not all first-dose reactions are truly allergic or may occur through non–IgE-mediated mechanisms. Reasons for incomplete vaccination vary and may include ineligibility for dose 2 after an allergy evaluation, scheduling factors, or other personal reasons for vaccine hesitancy. Future work directed at better understanding the reasons for delaying or not completing COVID-19 vaccination is warranted.

Strengths and Limitations

This study has some strengths. First, it included a large sample size; used comprehensive, prospectively collected data on allergy history (given that reporting was a requirement for vaccine eligibility); and captured more than 88% of the entire Mass General Brigham employee population with postvaccination symptom surveys. Second, we performed subgroup analyses of clinical health care practitioners and manual EHR reviews for employees who met the definition of experiencing a severe allergic reaction.

This study also has some limitations. First, the cohort consisted only of health care employees in the northeastern US, and thus the study findings may not be generalizable to health care employees in other parts of the country or to international populations.37 However, given the thousands of individuals who were included in this study, the findings remain informative and highly relevant as mRNA booster vaccinations begin. Second, comorbidity information may be incomplete for some individuals because they may have medical practitioners outside of the Mass General Brigham system and therefore their medical history may not be fully recorded in the EHR. However, this problem is inherent in the use of EHR data for clinical research; before comorbidity ascertainment, we identified that more than 89% of employees had at least 1 encounter that allowed for the near-complete capture of comorbidity data in the year before COVID-19 vaccination. Moreover, because self-reporting a history of high-risk allergy was required for vaccine eligibility and scheduling, per institutional protocols, exposure data were complete for all study participants. Third, adjustment for potential confounders in the multivariable models did not substantially change the effect size estimates, suggesting that any residual confounding is unlikely to jeopardize the internal validity of the findings.


This cohort study found that a self-reported history of high-risk allergy was associated with an increased risk of self-reported allergic reactions after mRNA COVID-19 vaccination, but most of the reported allergy symptoms did not impede the completion of the 2-dose mRNA COVID-19 vaccine series. Risks were higher after dose 1, and the reactions with the highest risk were hives and angioedema. Severe allergic reactions were rare. This study not only highlighted that high-risk allergy history was associated with allergy symptoms after COVID-19 vaccination but also supported the overall safety of mRNA vaccines in all eligible individuals.

Source: Association of allergy history with allergy symptoms after COVID-19 vaccination

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