In December 2020, an Emergency Use Authorization was issued for Pfizer-BioNTech and Moderna coronavirus disease 2019 (COVID-19) vaccines. Shortly thereafter, allergic reactions including anaphylaxis to vaccination were described.1 Initial rates of anaphylaxis were reported at 11.1 cases per million doses administered.2 Since then, continued safety monitoring through the Vaccine Adverse Event Reporting System has shown lower rates of anaphylaxis.3 Although rare, systemic reactions have occurred, making the administration of subsequent doses problematic in some patients, resulting in vaccine hesitancy. The single dose administration of a second vaccination has been reported to be safe in patients who had an immediate reaction to the first dose; however, some patients decline this option.4 Therefore, shared decision making about additional options for subsequent vaccination in these patients is needed. In this study, we report a pilot study showing that graded COVID-19 messenger RNA (mRNA) vaccination is safe in patients with previous immediate allergic reactions, and results in antibody titers comparable with those of healthy controls who received full-dose vaccination.
We present data on 8 patients with immediate reactions to first dose Pfizer-BioNTech and Moderna COVID-19 vaccines (4 from each vaccine) who underwent a graded second dose vaccination. This subset of patients represented approximately 15% of patients evaluated for COVID-19 vaccine reaction at a University Allergy-Immunology clinic from December 2020 to February 2021. Patient-reported symptoms after initial COVID-19 mRNA vaccination included cutaneous, oropharyngeal, respiratory, gastrointestinal, and hemodynamic changes (Table 1 ). Symptom onset occurred within 5 to 60 minutes of receiving the vaccination. Four of 8 patients met the diagnostic criteria for anaphylaxis based on the Brighton Collaboration case definition (3 patients met Brighton level 3, and 1 patient met level 2).5 Although the remaining 4 patients had nonanaphylactic hypersensitivity reactions, 3 of these 4 patients were evaluated in the emergency department. Furthermore, 3 of 8 patients met the criteria for anaphylaxis based on the National Institute for Allergy and Infectious Disease definition.6
Table 1.
Characteristics of Subjects Who Underwent COVID-19 mRNA Vaccine Graded Dosing and Matched Healthy Controls
| Sex | Age, y | COVID-19 vaccine | Symptoms after first vaccination | Time in between first and second vaccination, d | Time in between second vaccination and COVID-19 ab testing, d | COVID-19 AB test | COVID-19 AB category (reactive, nonreactive) | COVID-19 AB value |
|---|---|---|---|---|---|---|---|---|
| F | 31 | Moderna | Dizziness, palpitations, throat swelling and tightness, abdominal cramping (within 10 min)a,b | 33 | 183 | SARS-COV2 AB (IgG), spike, semi-quantitative | Reactive | >20 |
| F | 33 | Moderna | None (Healthy control) | 28 | 259 | SARS-COV2 IgG AB spike protein | Reactive | 7.19 |
| M | 37 | Pfizer | Tachycardia, hypertension, chest tightness, cough, dizziness (within 10 min) | 52 | 232 | COVID-19 SARS-CoV-2 total AB, spike, semi-quantitative | Reactive | 231.7 |
| M | 37 | Pfizer | None (Healthy control) | 22 | 265 | SARS-CoV-2 IgG AB spike protein | Reactive | 2.04 |
| M | 55 | Pfizer | Throat swelling, lightheadedness, vomiting (within 5 min)a,b | 49 | 212 | COVID-19 SARS-CoV-2 total AB, spike, semi-quantitative | Reactive | 11.8 |
| M | 48 | Pfizer | None (Healthy control) | 23 | 164 | SARS-COV-2 IgG AB spike protein | Reactive | 2.65 |
| F | 57 | Moderna | Diffuse hives, throat swelling (within 60 min)a | 50 | 218 | SARS-COV-2 AB (IgG), spike, semi-quantitative | Reactive | 18.12 |
| F | 65 | Moderna | None (Healthy control) | 25 | 202 | SARS-COV-2 IgG AB spike protein | Reactive | 3.1 |
| F | 51 | Moderna |
Diffuse hives, lip tingling (within 40 min) | 30 | 190 | SARS-COV-2 AB (IgG), spike, semi-quantitative | Reactive | 4.85 |
| F | 34 | Moderna | None (Healthy control) | 27 | 210 | SARS-COV-2 IgG AB spike protein | Reactive | 2.56 |
| F | 51 | Pfizer | Diffuse hives (within 5 min) | 41 | 187 | SARS-COV-2 AB (IgG), spike, semi-quantitative | Reactive | >20 |
| F | 56 | Pfizer | None (Healthy control) | 21 | 244 | SARS-COV-2 IgG AB spike protein | Nonreactive | 0.58 |
| F | 34 | Pfizer | Throat itching and swelling, nausea (within 5 min)a,b | 52 | ||||
| F | 59 | Moderna | Mental fogginess, throat itching, diffuse erythematous rash (within 15 min) | 30 |
Abbreviations: AB, antibody; COVID-19, coronavirus disease 2019; IgG, immunoglobulin G; SARS-COV-2, severe acute respiratory syndrome coronavirus 2.
Met Brighton Collaboration Case Definition of Anaphylaxis.
Met National Institute for Allergy and Infectious Disease Criteria for Anaphylaxis.
All 8 patients had negative results in COVID-19 vaccine component skin testing to polyethylene glycol and polysorbate 20 and polysorbate 80.7 Patients were counseled about the low risk of second dose vaccination, and the full second dose was recommended. However, despite negative testing and counseling, all patients declined to receive the second full vaccine dose. To facilitate complete vaccination dosing, patients were offered a graded and monitored vaccine dosing administration.
All 8 patients consented to undergo a second dose graded-vaccine administration, which occurred 30 to 52 days after the initial vaccination. For the Moderna vaccine graded dosing, patients received 0.05 mL, 0.1 mL, 0.15 mL, and 0.2 mL intramuscularly, every 15 minutes. For the Pfizer vaccine graded dosing, patients received 0.05 mL, 0.1 mL, and 0.15 mL intramuscularly, every 15 minutes. For both vaccine-graded–dosing regimens, patients were observed for 60 minutes after the last dose. All patients tolerated the graded dosing without evidence of allergic reaction.
Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) spike protein antibody levels were obtained approximately 6 months after graded dosing in 6 of the 8 patients, and the antibody levels were compared with a healthy control group matched by sex, age, and vaccine type (Table 1). The study and control patients were tested through enzyme-linked immunosorbent assay measuring immunoglobulin G to SARS-COV2 spike protein, using 2 different laboratories. Study patient assays were performed through Quest Diagnostic, and control patient assays were performed through Beckman Coulter. Statistical analysis was performed using JMP software (Cary, North Carolina). Spike protein antibody levels were evaluated both qualitatively and quantitatively. There was no difference in qualitative assessment of response between the 2 groups (all 6 had reactive antibody levels in the graded-dosing group vs 5 in the control group; P = .30). There was a statistically significant difference in quantitative antibody levels, with the graded-dosing group having a higher level (median [interquartile range] 19.6 [10.1-73.7] vs 2.6 [1.7-4.1]; P = .008). There was a significantly longer time between the first and second vaccine doses for the graded-dosing patients than there was for the healthy controls (median [interquartile range] 45 [32-51] vs 24 [22-27] days; P = .005). However, in the graded-dosing group, the time between the second vaccination and the time when the spike protein antibody levels were obtained did not differ from the healthy controls (median [interquartile range] 201 [186-222] vs 227 [193-261] days; P = .38). It is plausible that a longer time between first and second vaccine doses in the graded-dosing patients accounts for a better antibody response, as has been suggested by previous studies.
In some patients, vaccine hesitancy may be because of hypersensitivity reactions resulting from the first dose of the COVID-19 vaccine. Here, in this small pilot study, we show that graded-dosing administration with COVID-19 mRNA vaccines is safe and provides a reactive SARS-COV2 spike protein antibody response at least 6 months after completion of the initial COVID-19 vaccination series. Furthermore, when compared with age, sex, and the vaccine-matched healthy control population who received the full-dose vaccination, the graded dosing provides comparable antibody responses. Previous published studies have assessed graded vaccine dosing.8 Patel et al9 published their 2-step protocol for the Pfizer vaccine only but did not evaluate antibody response to graded dosing. Tuong et al10 presented data on their longer graded-dosing protocol (4-step for Pfizer and 5-step for Moderna) in a women-only population. Unlike our matched healthy control population, Tuong et al10 reported comparisons in unmatched healthy controls. The authors of the study presented data as a log2 antibody response, and antibody levels were checked at a minimum of 2 weeks after vaccination, unlike our study, where antibody response was checked at a minimum of 6 months after vaccination.10
The limitations of our study include that the laboratory assays used were different between the 2 cohorts, and antibody values may not be used interchangeably as per the expanded authorization of semiquantitative tests of the US Food and Drug Administration.
All patients with an immediate hypersensitivity reaction to COVID-19 vaccine should be referred to an allergy-immunology specialist. In patients hesitant to receive a subsequent COVID-19 vaccine owing to a history of immediate allergic reaction, a graded-dosing vaccine administration should be considered and may provide protection like a standard full-dose vaccination.
Footnotes
Disclosures: Dr Petrov received consultancy funding within the last 12 months from Blueprint Medicines. Dr Domsic received consultancy funding within the last 12 months from CSL Behring and Aisa Pharmaceuticals. The other authors have no conflicts of interest to report.
Funding: The research reported in the manuscript was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under award number R01 AR080356.
References
- 1.Blumenthal KG, Robinson LB, Camargo CA, Shenoy ES, Banerji A, Landman AB, et al. Acute allergic reactions to mRNA COVID-19 vaccines. JAMA. 2021;325(15):1562–1565. doi: 10.1001/jama.2021.3976. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.CDC COVID-19 Response Team, Food and Drug Administration Allergic reactions including anaphylaxis after receipt of the first dose of moderna COVID-19 vaccine - United States, December 21, 2020-January 10, 2021. MMWR Morb Mortal Wkly Rep. 2021;70:125–129. doi: 10.15585/mmwr.mm7004e1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Shimabukuro T, Nair N. Allergic reactions including anaphylaxis after receipt of the first dose of Pfizer-BioNTech COVID-19 vaccine. JAMA. 2021;325(8):780–781. doi: 10.1001/jama.2021.0600. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Chu DK, Abrams EM, Golden DBK, Blumenthal KG, Wolfson AR, Stone CA, Jr, et al. Risk of second allergic reaction to SARS-CoV-2 vaccines: a systematic review and meta-analysis. JAMA Intern Med. 2022;182(4):376–385. doi: 10.1001/jamainternmed.2021.8515. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Rüggeberg JU, Gold MS, Bayas JM, Blum MD, Bonhoeffer J, Friedlander S, et al. Anaphylaxis: case definition and guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2007;25(31):5675–5684. doi: 10.1016/j.vaccine.2007.02.064. [DOI] [PubMed] [Google Scholar]
- 6.Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF, Jr, Bock SA, Branum A, et al. Second symposium on the definition and management of anaphylaxis: summary report–Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006;117(2):391–397. doi: 10.1016/j.jaci.2005.12.1303. [DOI] [PubMed] [Google Scholar]
- 7.Banerji A, Wolfson AR, Wickner PG, Cogan AS, McMahon AE, Saff R, et al. COVID-19 vaccination in patients with reported allergic reactions: updated evidence and suggested approach. J Allergy Clin Immunol Pract. 2021;9(6):2135–2138. doi: 10.1016/j.jaip.2021.03.053. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Pitlick MM, Gonzalez-Estrada A, Park MA. Graded coronavirus disease 2019 vaccine administration: a safe alternative to vaccine avoidance. Ann Allergy Asthma Immunol. 2022;128(6):731–733. doi: 10.1016/j.anai.2022.02.024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Patel GB, Chhiba KD, Chen MM, Guo A, Watts MM, Cullen J, et al. COVID-19 vaccinerelated presumed allergic reactions and second dose administration by using a two-step graded protocol. Allergy Asthma Proc. 2021;42(6):515–521. doi: 10.2500/aap.2021.42.210075. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Tuong LC, Capucilli P, Staicu M, Ramsey A, Walsh EE, Mustafa SS. Graded administration of second dose of Moderna and Pfizer-BioNTech COVID-19 mRNA vaccines in patients with hypersensitivity to first dose. Open Forum Infect Dis. 2021;8(12):ofab507. doi: 10.1093/ofid/ofab507. [DOI] [PMC free article] [PubMed] [Google Scholar]