Clinical Phenotypes of Immediate First-Dose Reactions to mRNA COVID-19: A Multicenter Latent Class Analysis.

BACKGROUND: Although immediate potentially allergic reactions have been reported after dose 1 of mRNA coronavirus disease 2019 (COVID-19) vaccines, comprehensively defined subtypes have not been clearly distinguished. OBJECTIVE: To define distinct clinical phenotypes of immediate reactions after dose 1 of mRNA COVID-19 vaccination, and to assess the relation of clinical phenotype to mRNA COVID-19 vaccine second dose tolerance. METHODS: This retrospective study included patients with 1 or more potentially allergic symptoms or signs within 4 hours of receiving dose 1 of an mRNA COVID-19 vaccine and assessed by allergy/immunology specialists from 5 U.S. academic medical centers (January-June 2021). We used latent class analysis-an unbiased, machine-learning modeling method-to define novel clinical phenotypes. We assessed demographic, clinical, and reaction characteristics associated with phenotype membership. Using log-binomial regression, we assessed the relation between phenotype membership and second dose tolerance, defined as either no symptoms or mild, self-limited symptoms resolving with antihistamines alone. A sensitivity analysis considered second dose tolerance as objective signs only. RESULTS: We identified 265 patients with dose-1 immediate reactions with 3 phenotype clusters: (1) Limited or Predominantly Cutaneous, (2) Sensory, and (3) Systemic. A total of 223 patients (84%) received a second dose and 200 (90%) tolerated their second dose. Sensory cluster (all patients had the symptom of numbness or tingling) was associated with a higher likelihood of second dose intolerance, but this finding did not persist when accounting for objective signs. CONCLUSIONS: Three novel clinical phenotypes of immediate-onset reactions after dose 1 of mRNA COVID-19 vaccines were identified using latent class analysis: (1) Limited or Predominantly Cutaneous, (2) Sensory, and (3) Systemic. Whereas these clinical phenotypes may indicate differential mechanistic etiologies or associations with subsequent dose tolerance, most individuals proceeding to their second dose tolerated it.

Diagnostic accuracy of vaccine and vaccine excipient testing in the setting of allergic reactions to COVID-19 vaccines: A systematic review and meta-analysis.

For persons with immediate allergic reactions to mRNA COVID-19 vaccines, skin testing (ST) to the vaccine/excipients (polyethylene glycol[PEG] and polysorbate 80 [PS]) has been recommended, but has unknown accuracy. To assess vaccine/excipient ST accuracy in predicting all-severity immediate allergic reactions upon re-vaccination, systematic review was performed searching Medline, EMBASE, Web of Science, and the WHO global coronavirus database (inception-Oct 4, 2021) for studies addressing immediate (≤4 h post-vaccination) all-severity allergic reactions to 2nd mRNA COVID-19 vaccination in persons with 1st dose immediate allergic reactions. Cases evaluating delayed reactions, change of vaccine platform, or revaccination without vaccine/excipient ST were excluded. Meta-analysis of diagnostic testing accuracy was performed using Bayesian methods. The GRADE approach evaluated certainty of the evidence, and QUADAS-2 assessed risk of bias. Among 20 studies of mRNA COVID-19 first dose vaccine reactions, 317 individuals underwent 578 ST to any one or combination of vaccine, PEG, or PS, and were re-vaccinated with the same vaccine. Test sensitivity for either mRNA vaccine was 0.2 (95%CrI 0.01-0.52) and specificity 0.97 (95%CrI 0.9-1). PEG test sensitivity was 0.02 (95%CrI 0.00-0.07) and specificity 0.99 (95%CrI 0.96-1). PS test sensitivity was 0.03 (95%CrI 0.00-0.0.11) and specificity 0.97 (95%CrI 0.91-1). Combined for use of any of the 3 testing agents, sensitivity was 0.03 (95%CrI 0.00-0.08) and specificity was 0.98 (95%CrI 0.95-1.00). Certainty of evidence was moderate. ST has low sensitivity but high specificity in predicting all-severity repeat immediate allergic reactions to the same agent, among persons with 1st dose immediate allergic reactions to mRNA COVID-19 vaccines. mRNA COVID-19 vaccine or excipient ST has limited risk assessment utility.

Identifying Modifiable Predictors of COVID-19 Vaccine Side Effects: A Machine Learning Approach.

Side effects of COVID-19 or other vaccinations may affect an individual's safety, ability to work or care for self or others, and/or willingness to be vaccinated. Identifying modifiable factors that influence these side effects may increase the number of people vaccinated. In this observational study, data were from individuals who received an mRNA COVID-19 vaccine between December 2020 and April 2021 and responded to at least one post-vaccination symptoms survey that was sent daily for three days after each vaccination. We excluded those with a COVID-19 diagnosis or positive SARS-CoV2 test within one week after their vaccination because of the overlap of symptoms. We used machine learning techniques to analyze the data after the first vaccination. Data from 50,484 individuals (73% female, 18 to 95 years old) were included in the primary analysis. Demographics, history of an epinephrine autoinjector prescription, allergy history category (e.g., food, vaccine, medication, insect sting, seasonal), prior COVID-19 diagnosis or positive test, and vaccine manufacturer were identified as factors associated with allergic and non-allergic side effects; vaccination time 6:00-10:59 was associated with more non-allergic side effects. Randomized controlled trials should be conducted to quantify the relative effect of modifiable factors, such as time of vaccination.

Successful Treatment of Delayed Localized Necrotizing Inflammatory Myositis After Severe Acute Respiratory Syndrome Coronavirus 2 mRNA-1273 Vaccine: A Case Report.

Reported adverse reactions to the mRNA-1273 vaccine (Spikevax, Moderna Inc) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) range from mild, local delayed cutaneous reactions to rarer, more serious reactions such as myocarditis. Here, we describe the presentation and successful treatment of delayed, localized necrotizing inflammatory myositis following a third dose of the mRNA-1273 SARS-CoV-2 vaccine. To our knowledge, this is the first report of biopsy-confirmed, delayed inflammatory myositis after administration of an mRNA-1273 SARS-CoV-2 vaccine booster.

Differential Severe Acute Respiratory Syndrome Coronavirus 2 Antibody Profiles After Allergic Reactions to Messenger RNA Coronavirus Disease 2019 Vaccine.

Allergic symptoms after messenger RNA (mRNA) coronavirus disease 2019 (COVID-19) vaccines occur in up to 2% of recipients. Compared to nonallergic controls (n = 18), individuals with immediate allergic reactions to mRNA COVID-19 vaccines (n = 8) mounted lower immunoglobulin G1 (IgG1) to multiple antigenic targets in severe acute respiratory syndrome coronavirus 2 spike following vaccination, with significantly lower IgG1 to full-length spike (P = .04). Individuals with immediate allergic reactions to mRNA COVID-19 vaccines bound Fcγ receptors similarly to nonallergic controls. Although there was a trend toward an overall reduction in opsonophagocytic function in individuals with immediate allergic reactions compared to nonallergic controls, allergic patients produced functional antibodies exhibiting a high ratio of opsonophagocytic function to IgG1 titer.

Rapid progress in our understanding of COVID-19 vaccine allergy: A cause for optimism, not hesitancy.

Anaphylaxis is a life-threatening condition and when associated with vaccination, leads to vaccine hesitancy. The concerns around vaccine-related anaphylaxis have become even more important during the coronavirus disease 2019 (COVID-19) pandemic where the COVID-19 vaccines remain one of our most important tools. Although rates of anaphylaxis to COVID-19 vaccines are not significantly different from those to other vaccines, Centers for Disease Control and Prevention guidance recommends avoidance of the same COVID-19 vaccine in individuals who had an allergic reaction or are allergic to a COVID-19 vaccine component. Fortunately, our understanding of COVID-19 vaccine allergic reactions has improved dramatically in the past year in large part due to important research efforts from individuals in the allergy community. Initially, researchers published algorithmic approaches using risk stratification and excipient skin testing. However, as our experience and knowledge improved with ongoing research, we have better data showing safety of repeat vaccination despite an initial reaction. We review our progress starting in December 2020 when the Food and Drug Administration approved the first COVID-19 vaccine in the United States through early 2022, highlighting our success in understanding COVID-19 vaccine reactions.

Risk of Second Allergic Reaction to SARS-CoV-2 Vaccines: A Systematic Review and Meta-analysis.

IMPORTANCE: Vaccination against SARS-CoV-2 is a highly effective strategy to prevent infection and severe COVID-19 outcomes. The best strategy for a second dose of vaccine among persons who had an immediate allergic reaction to their first SARS CoV-2 vaccination is unclear. OBJECTIVE: To assess the risk of severe immediate allergic reactions (eg, anaphylaxis) to a second dose of SARS-CoV-2 mRNA vaccine among persons with immediate allergic reactions to their first vaccine dose. DATA SOURCES: MEDLINE, Embase, Web of Science, and the World Health Organization Global Coronavirus database were searched from inception through October 4, 2021. STUDY SELECTION: Included studies addressed immediate allergic reactions of any severity to a second SARS-CoV-2 vaccine dose in persons with a known or suspected immediate allergic reaction (<4 hours after vaccination) after their first SARS-CoV-2 vaccine dose. Studies describing a second vaccine dose among persons reporting delayed reactions (>4 hours after vaccination) were excluded. DATA EXTRACTION AND SYNTHESIS: Paired reviewers independently selected studies, extracted data, and assessed risk of bias. Random-effects models were used for meta-analysis. The GRADE (Grading of Recommendation, Assessment, Development, and Evaluation) approach evaluated certainty of the evidence. MAIN OUTCOMES AND MEASURES: Risk of severe immediate allergic reaction and repeated severe immediate allergic reactions with a second vaccine dose. Reaction severity was defined by the reporting investigator, using Brighton Collaboration Criteria, Ring and Messmer criteria, World Allergy Organization criteria, or National Institute of Allergy and Infectious Diseases criteria. RESULTS: Among 22 studies of SARS-CoV-2 mRNA vaccines, 1366 individuals (87.8% women; mean age, 46.1 years) had immediate allergic reactions to their first vaccination. Analysis using the pooled random-effects model found that 6 patients developed severe immediate allergic reactions after their second vaccination (absolute risk, 0.16% [95% CI, 0.01%-2.94%]), 232 developed mild symptoms (13.65% [95% CI, 7.76%-22.9%]), and, conversely, 1360 tolerated the dose (99.84% [95% CI, 97.09%-99.99%]). Among 78 persons with severe immediate allergic reactions to their first SARS-CoV-2 mRNA vaccination, 4 people (4.94% [95% CI, 0.93%-22.28%]) had a second severe immediate reaction, and 15 had nonsevere symptoms (9.54% [95% CI, 2.18%-33.34%]). There were no deaths. Graded vaccine dosing, skin testing, and premedication as risk-stratification strategies did not alter the findings. Certainty of evidence was moderate for those with any allergic reaction to the first dose and low for those with severe allergic reactions to the first dose. CONCLUSIONS AND RELEVANCE: In this systematic review and meta-analysis of case studies and case reports, the risk of immediate allergic reactions and severe immediate reactions or anaphylaxis associated with a second dose of an SARS-CoV-2 mRNA vaccine was low among persons who experienced an immediate allergic reaction to their first dose. These findings suggest that revaccination of individuals with an immediate allergic reaction to a first SARS-CoV-2 mRNA vaccine dose in a supervised setting equipped to manage severe allergic reactions can be safe.

Humoral and cellular immunogenicity of SARS-CoV-2 vaccines in chronic lymphocytic leukemia: a prospective cohort study.

Chronic lymphocytic leukemia (CLL), the most common leukemia worldwide, is associated with increased COVID-19 mortality. Previous studies suggest only a portion of vaccinated CLL patients develop severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antibodies. Whether the elicited antibodies are functional and/or accompanied by functional T-cell responses is unknown. This prospective cohort study included patients with CLL who received SARS-CoV-2 and PCV13 vaccines (not concurrently). The primary cohort included adults with CLL off therapy. Coprimary outcomes were serologic response to SARS-CoV-2 (receptor binding domain [RBD] immunoassay) and PCV13 vaccines (23-serotype IgG assay). Characterization of SARS-CoV-2 antibodies and their functional activity and assessment of functional T-cell responses was performed. Sixty percent (18/30) of patients demonstrated serologic responses to SARS-CoV-2 vaccination, appearing more frequent among treatment-naïve patients (72%). Among treatment-naïve patients, an absolute lymphocyte count ≤24 000/µL was associated with serologic response (94% vs 14%; P < .001). On interferon-γ release assays, 80% (16/20) of patients had functional spike-specific T-cell responses, including 78% (7/9) with a negative RBD immunoassay, a group enriched for prior B-cell-depleting therapies. A bead-based multiplex immunoassay identified antibodies against wild-type and variant SARS-CoV-2 (α, ß, γ, and δ) in all tested patients and confirmed Fc-receptor binding and effector functions of these antibodies. Of 11 patients with negative RBD immunoassay after vaccination, 6 (55%) responded to an additional mRNA-based vaccine dose. The PCV13 serologic response rate was 29% (8/28). Our data demonstrate that SARS-CoV-2 vaccination induces functional T-cell and antibody responses in patients with CLL and provides the framework for investigating the molecular mechanisms and clinical benefit of these responses. This trial was registered at www.clinicaltrials.gov as #NCT05007860.

Symptom monitoring after coronavirus disease 2019 (COVID-19) vaccination in a large integrated healthcare system: Separating symptoms from severe acute respiratory coronavirus virus 2 (SARS-CoV-2) infection.

OBJECTIVE: To describe the incidence of systemic overlap and typical coronavirus disease 2019 (COVID-19) symptoms in healthcare personnel (HCP) following COVID-19 vaccination and association of reported symptoms with diagnosis of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) infection in the context of public health recommendations regarding work exclusion. DESIGN: This prospective cohort study was conducted between December 16, 2020, and March 14, 2021, with HCP who had received at least 1 dose of either the Pfizer-BioNTech or Moderna COVID-19 vaccine. SETTING: Large healthcare system in New England. INTERVENTIONS: HCP were prompted to complete a symptom survey for 3 days after each vaccination. Reported symptoms generated automated guidance regarding symptom management, SARS-CoV-2 testing requirements, and work restrictions. Overlap symptoms (ie, fever, fatigue, myalgias, arthralgias, or headache) were categorized as either lower or higher severity. Typical COVID-19 symptoms included sore throat, cough, nasal congestion or rhinorrhea, shortness of breath, ageusia and anosmia. RESULTS: Among 64,187 HCP, a postvaccination electronic survey had response rates of 83% after dose 1 and 77% after dose 2. Report of ≥3 lower-severity overlap symptoms, ≥1 higher-severity overlap symptoms, or at least 1 typical COVID-19 symptom after dose 1 was associated with increased likelihood of testing positive. HCP with prior COVID-19 infection were significantly more likely to report severe overlap symptoms after dose 1. CONCLUSIONS: Reported overlap symptoms were common; however, only report of ≥3 low-severity overlap symptoms, at least 1 higher-severity overlap symptom, or any typical COVID-19 symptom were associated with infection. Work-related restrictions for overlap symptoms should be reconsidered.