Study Shows Improved Tolerance with Second COVID-19 Vaccine


Research showed that the second dose of the COVID-19 vaccine was well tolerated by patients who experienced allergic reactions from their first dose.

Ever since the COVID-19 vaccines were approved for the public population, conversations have persisted regarding their efficacy, especially regarding people who had immediate allergic reactions with the first dose.

Despite this, a multicenter, retrospective study confirmed that most patients with immediate and potentially allergic reactions to the COVID-19 vaccines tolerated the 2nd dose.

In an interview with HCPLive, 2 of the leading authors of the study, Kimberly Blumenthal, MD, MSc, Quality and Safety Officer for Allergy, Massachusetts General Hospital, Co-Director, Clinical Epidemiology Program, Division of Rheumatology Allergy and Immunology and Matthew Krantz, MD, Clinical Fellow, Allergy/Immunology, Vanderbilt University Medical Center spoke of the genesis of the study as well as the data gathered on reactions from participants.

Prior to the study, the team targeted healthcare workers who had received some of the first doses of the Pfizer-BioNTech and Moderna vaccines.

“One of the unexpected observations early on after emergency use authorization in December of 2020 where we primarily targeted vaccinating healthcare workers was we did observe a higher rate of immediate potentially allergic reactions and anaphylaxis than with traditional vaccines,” Krantz said.

Krantz, Blumenthal and colleagues set out to find if participants in the study were truly allergic to the COVID-19 vaccines.

“If you're allergic to something, you have an IgE antibody, [so] you have to avoid it,” Blumenthal said. “That’s really important for mRNA vaccines: were people forming true, classic allergy to these vaccines?”

The Study

From January 1, 2021-March 31, 2021, the investigators enrolled 189 patients from participating centers, all of whom recorded an immediate reaction to their first Pfizer-BioNTech or Moderna vaccine.

Patient population demographics showed that the mean age of all patients was 43 years, and that most of the total population (86%) were women. Of the vaccine first-dose reactions, 130 (69%) were Moderna and 59 (31%) were Pfizer-BioNTech.

Allergic reactions were defined as symptom onset within 4 hours of dose 1, at least 1 allergic symptom, and referral for an allergy/immunology consultation with in-clinic or tele-heath assessment.

Anaphylaxis was scored using the Brighton and the National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network Criteria.

Blumenthal, Krantz and colleagues defined second dose tolerance as 1 of the following:

1. No immediate symptoms after second dose administration

2. Symptoms that were mild, self-limited and/or resolved with antihistamines

Phone calls regarding clinical details were made for individuals who did not have their second dose observed by allergy/immunology departments.


The investigators noted that the most frequently reported first-dose reactions in patients were flushing or erythema (28%), dizziness or lightheadedness (26%), tingling (24%), throat tightness (22%), and hives (21%), and 32 participants (21%) met the anaphylaxis criteria.

Encouragingly, 159 patients as well as 19 individuals who experienced first-dose anaphylaxis tolerated the second dose of the COVID-19 vaccine. Only 20% of participants reported immediate and potentially allergic symptoms associated with the second dose, which were either self-limited, mild, or resolved with antihistamines alone.

Additionally, most of the participants in the study (89%) received the second dose, and 47 patients (30%) were given an antihistamine premedication before the second dose.

“It's important to note that in terms of classic IgE allergy, we do not expect premedications to abort a reaction,” Krantz said. “But, in the case of a non-IgE mediated reaction, antihistamines can also blunt or make these reactions (milder).”

The effectiveness of the drugs on some patients supported the hypothesis that the participants did not have to avoid the COVID-19 vaccines, as they did not have what’s considered a “classic allergy” response.

Blumenthal also noted the effectiveness of the premedication and clarified that the study was not intended to recommend a specific medication, as each patient was treated with individual methods depending on what their allergist felt was appropriate.

“Everybody had a different [recommendation],” Blumenthal said. “This study wasn't designed to test how best to get from a dose 1 immediate reaction to safe dose 2 completion. But it gives us a hint that it's largely possible.”

Future Possibilities

Blumenthal noted that further research might explore the possibilities of a specific premedication or treatment methods for patients who had a reaction to the COVID-19 vaccines, especially considering the possibilities of COVID-19 vaccine boosters in the coming fall season.

“What we really need is a prospective study when it comes to the booster doses,” Blumenthal said. “So, prospective, meaning that we enroll people who had reactions before (and) who didn't have reactions, and we have them diary their medication so that we can piece out what premedication regimen might work.”

Blumenthal and Krantz both noted the potential for improvement in identifying allergic reactions in patients regarding the COVID-19 vaccines and general vaccines.

The study, “Safety Evaluation of the Second Dose of Messenger RNA COVID-19 Vaccines in Patients With Immediate Reactions to the First Dose,” was published online in JAMA Internal Medicine.

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