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Principal Investigator: Pamela Frischmeyer-Guerrerio
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2023
Award: $754,258
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <2019-nCoV vaccine><Abdominal Pain><Acute><Aeroseb-HC><Age><Airway Resistance><Allergic><Allergic Reaction><Ambulatory Care Facilities><Anaphylactic Reaction><Anaphylactic Shock><Anaphylaxis><Anxiety><BNT 162b2><BNT162b2><Blinded><Blood Plasma><Blood Serum><C5 a><C5a><COVID><COVID-19><COVID-19 vaccine><COVID19><COVID19 vaccine><CV-19><CV19><Cardiac Chronotropism><Cetacort><Chest><Chronic><Classification><Clinical><CoV disease><Complement 5a><Complement Activation><Complement C5a><Cort-Dome><Cortef><Cortenema><Cortisol><Cortispray><Cortril><Dermacort><Disease><Disorder><Distress><Dizziness><Dose><Eldecort><Event><Excipients><Female><Goals><Heart Rate><Histamine><History><Hour><Hydrocortisone><Hydrocortone><Hypersensitivity skin testing><Hypophysis><Hypophysis Cerebri><Hypothalamic structure><Hypothalamus><Hytone><IgE><Immunization><Immunoglobulin E><Individual><Injections><Intensive Care Units><Investigators><LTE4><Leukotriene E-4><Leukotriene E4><Macrogols><Marrow Mast Cell><Mediating><Messenger RNA><Meta-Analysis><Metadrenaline><Metanephrine><NIH><National Institutes of Health><Neurologic><Neurologic Manifestations><Neurologic Signs and Symptoms><Neurologic Symptoms><Neurological><Neurological Manifestations><Neurological Signs and Symptoms><Nutracort><Organ><Out-patients><Outcome><Outpatient Clinics><Outpatients><Paresthesia><Participant><Pathway interactions><Patients><Pfizer-BioNTech COVID-19 vaccine><Pfizer-BioNTech coronavirus disease 2019 vaccine><Pharyngeal structure><Pharynx><Phase><Pituitary><Pituitary Gland><Pituitary Nervous System><Placebos><Plasma><Plasma Serum><Polyethylene Glycols><Polyethylene Oxide><Polyethyleneoxide><Polyoxyethylenes><Process><Proctocort><Public Health><RNA vaccine><RNA-based vaccine><Randomized><Reaction><Recombinant C5a><Recording of previous events><Recurrence><Recurrent><Reporting><Research Personnel><Researchers><Reticuloendothelial System, Serum, Plasma><Risk><SARS-CoV-2 vaccine><SARS-CoV2 vaccine><SARS-coronavirus-2 vaccine><Safety><Saline><Saline Solution><Screening procedure><Sensory><Serum><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe acute respiratory syndrome coronavirus 2 vaccine><Severities><Sham Treatment><Site><Skin Tests><Stress><Sympathetic Nervous System><Symptoms><System><Systematics><Thorace><Thoracic><Thorax><Throat><Tissue Basophils><Tryptase><United States National Institutes of Health><Urine><Vaccination><Vaccines><Visit><ages><allergen response><allergic response><allergy response><blood pressure elevation><booster dose><booster shot><booster vaccine><clinical center><cohort><complement pathway regulation><corona virus disease><corona virus disease 2019><corona virus disease 2019 vaccine><coronavirus disease><coronavirus disease 2019><coronavirus disease 2019 vaccine><coronavirus disease-19><coronavirus disease-19 vaccine><coronavirus infectious disease-19><detection method><detection procedure><detection technique><double-blind placebo control trial><double-blind placebo controlled trial><double-masked controlled trial><elevated blood pressure><experience><high risk><histories><hypersensitivity test><hypothalamic><immunologic skin test><increase in blood pressure><increased blood pressure><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><lung tryptase><mRNA><mRNA vaccine><mRNA-based vaccine><mast cell><mast cell protease II><mast cell tryptase><mastocyte><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><neural manifestation><novel><open label><open label study><pathway><prevent><preventing><randomisation><randomization><randomly assigned><response><screening tools><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><sham therapy><skin tryptase><trend><vaccine against 2019-nCov><vaccine against SARS-CoV-2><vaccine against SARS-CoV2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine for novel coronavirus>