COVID vaccine-associated allergic reactions

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

In FY23, we completed all study visits for our phase 2 randomized, double-blinded, placebo-controlled trial (COvid-19 Vaccine Associated Allergic Reactions trial; COVAAR) where 16 participants who previously reported a systemic allergic reaction (SAR) to their first dose of a COVID-19 mRNA vaccine were randomly assigned to receive their second dose of Pfizer-BioNTech vaccine and placebo (saline) on consecutive days in a 1:1 blinded cross-over fashion in the Intensive Care Unit in the NIH Clinical Center. All participants received an open-label Pfizer-BioNTech booster in an outpatient clinic 5 months later. In FY23, we have begun to analyze both the clinical and mechanistic outcomes from this trial. Median participant age was 45.5 years and all but one was female, consistent with the female predominance in reported anaphylactic reactions to COVID-19 vaccines. All reported a positive allergic history. SARs recurred in only 2 (12.5%) subjects following both second and booster doses. Only one participant experienced a severe SAR, which was easily treated in an outpatient setting. No SARs occurred after placebo. While SARs were uncommon, clinical reactions following both placebo and vaccine doses were frequent. However, these reactions did not meet SAR criteria but rather were consistent with Immunization Stress-Related Response (ISRR), a non-allergic rapid onset clinical reaction due to the immunization process and not vaccine components. ISRRs occurred after 62.5% of blinded vaccine, 75% of blinded placebo, and 75% of open-label booster doses. Overall, ISRRs occurred 5.5 times more often than SARs following placebo and vaccine doses. ISRRs had overlapping symptoms with allergic reactions including dizziness, throat and chest tightness, and abdominal pain. Both had rapid onset (within minutes) after injection. However, the triad of neurological symptoms (most commonly paresthesias), acute heart rate and systolic blood pressure elevation, and absence of physical signs strongly suggested ISRR. Due to their heterogeneous presentation, we devised a novel ISRR classification system, including severity grades based on patient-reported symptom severity and investigator-observed distress level as well as duration and symptom distribution. Moderate-severe ISRRs tended to be prolonged (single episode lasting 30 minutes), episodic (>1 episode), and/or chronic (lasting >48 hours) with neurologic (e.g. sensory abnormalities) or other organ symptoms. Although the small number of SAR events limited power, we observed modest trends of mast cell activation suggested by acute post-dose increases in urine leukotriene E4 (LTE4), plasma histamine, and serum tryptase. Forced oscillation technique detected acute post-vaccine increases in small (R5-19) and total airway resistance in SARs as would be expected during an allergic response. These changes were not observed during ISRRs, which were associated with rapid post-dose elevation in metanephrine, cortisol, and C5a, indicating stress-induced sympathetic nervous system, hypothalamus-pituitary-axis and complement activation. Furthermore, a single question assessing vaccine-associated pre-dose anxiety on a 0-10 scale appeared to predict high risk of ISRR in our cohort. Based on our findings, a score 2 may serve as a convenient ISRR-risk screening tool at vaccination sites. Notably, skin testing with Pfizer-BioNTech vaccine provided limited predictability, and excipient skin testing offered no value.