key: cord-0726960-t4mt475m
authors: Shaker, Marcus; Abrams, Elissa M.; Greenhawt, Matthew
title: A Cost-Effectiveness Evaluation of Hospitalizations, Fatalities, and Economic Outcomes Associated With Universal Versus Anaphylaxis Risk-Stratified COVID-19 Vaccination Strategies
date: 2021-03-09
journal: J Allergy Clin Immunol Pract
DOI: 10.1016/j.jaip.2021.02.054
sha: 70e091ea9f7d1642bd7e65da8e1e6f2f6c110bba
doc_id: 726960
cord_uid: t4mt475m

Background Vaccine-associated anaphylaxis is a rare event (1.34 events/million doses; 0.00017% occurrence over 26 years). Several reports of allergic reactions concerning for anaphylaxis have been reported early into the Pfizer-BioNTech and Moderna COVID-19 vaccine campaign in the United States, Canada, and United Kingdom. Objective To perform a cost-effectiveness analysis characterizing the risks of COVID-19 versus vaccine anaphylaxis, comparing universal COVID-19 vaccination vs. risk-stratified vaccination approaches. Methods Cohort analysis models were created to evaluate the cost-effectiveness of universal vaccination vs. risk-stratified vaccination (e.g., contraindicated in persons with a history of any prior episode of anaphylaxis) with a threshold for cost-effective care at $10,000,000 per death prevented. In the base case, risk of anaphylaxis was estimated at 0.1% with case-fatality estimated at 0.3%. Results On a population level (n=300,000,000 simulated persons), universal vaccination was associated with a cost-savings of $503,596,316 and saved 7,607 lives, but the cost-savings was sensitive to increasing rates of vaccine-associated anaphylaxis. The universal strategy dominated at higher rates of COVID-19 infection and low rates of vaccine-associated anaphylaxis in both the healthcare and societal perspectives. When the risk of vaccine-associated anaphylaxis exceeded 0.8%, the risk-stratified approach to vaccination was the most cost-effective strategy. There was also an interaction between anaphylaxis risk and anaphylaxis fatality, with a risk-stratified approach becoming cost-effective as each risk increased concurrently. Stratified observation time by anaphylaxis history (15 minutes vs 30 minutes) was not cost-effective until a 1% anaphylaxis case-fatality was assumed and risk of vaccine anaphylaxis exceeded 6%. Conclusion This study demonstrates that unless vaccine anaphylaxis rates exceed 0.8% a universal vaccination approach dominates a risk-stratified approach where persons with any history of anaphylaxis would be contraindicated from vaccination, with lower cost and superior health outcomes.

As of December 13, 2020 the novel coronavirus COVID-19, caused by the pathogen SARS-127

CoV-2, had infected over 72 million people internationally with over 1.6 million global 128 deaths.(1) On December 11, 2020, the U.S Food and Drug Administration (FDA) issued its first 129 emergency use authorization for the Pfizer-BioNTech COVID-19 vaccine to be distributed in the on data from 30,420 participants followed for 14 days post 2 nd vaccination, which noted a 0.4% 146 excess rate of hypersensitivity of any severity, and no attributable increase in anaphylaxis. (3, 9) 147

However, on the first day of Pfizer-BioNTech vaccine administration in the United Kingdom 148 J o u r n a l P r e -p r o o f (UK), there were two reports of reactions suspicious for anaphylaxis among two recipients, both 149 with a prior history of a severe allergic reaction (one to food, one to a drug) and both of whom 150 carried epinephrine autoinjectors.(7) Both of these healthcare workers recovered with standard 151 treatment for a presumed allergic reaction. There have since been reports of reactions concerning 152 for potential anaphylaxis among five vaccine recipients in the United States (US) within the first 153 two weeks both the Pfizer-BioNTech and Moderna vaccines were available, including events 154 occurring in persons both with and without a history of prior allergic disease.(10, 11) Given the 155 vaccine distribution patterns to date, the overwhelming majority of cases have occurred in 156 healthcare workers, with vaccine administration in a healthcare setting. In January 2021, the 157 Notably, an approach of vaccine deferral in patients with history of non-COVID-19 vaccine 182 anaphylaxis was quickly revised in the UK, and in the US a history of anaphylaxis (unrelated to a All costs were expressed in 2020 dollars and, because the time horizon was one year, discounting 215 and all-cause age-adjusted mortality was not applied. The threshold for cost-effective care was 216 set at $10,000,000 per death prevented. Model assumptions are shown in Table 1 . 241 242

Deterministic sensitivity analyses were performed for higher COVID-19 / lower anaphylaxis 244 risk, lower COVID-19 / higher anaphylaxis risk, lower vaccine effectiveness (floor rate of 50%), 245 and for each variable across specified ranges (Table 1) ($9,999,656) was greater when compared with risk-stratification ($9,999,400), with risk-278 stratification dominated (e.g., lower cost, higher benefit) by a universal approach (ICER, -279 $66,201 per death prevented, please refer to the methods for an interpretation of the negative 280 ICER) ( Table 2) . 281 282

From a healthcare perspective, when higher COVID-19 infection risk was assumed along with a 284 lower vaccine-associated anaphylaxis risk, a risk-stratified approach was even more dominated 285 (ICER, -$299,899 per death prevented) with larger differences in net monetary benefit between 286 strategies (individual NMB $9,981,450 for the universal vs $9,963,847 risk-stratified strategies), 287

with the universal approach resulting in 1,510,427 fewer hospitalizations on a population level 288 (Table 2) . Conversely, under assumptions of lower COVID-19 infection risk combined with a 289 higher vaccine-associated anaphylaxis risk, a universal approach became dominated by the risk-290 stratified approach (ICER, -$1,527,990 per death prevented). 291

The universal vaccination cost-effectiveness exceeded $10,000,000 per death prevented with 293 increasing rates of vaccine-associated anaphylaxis. When risk of vaccine-associated anaphylaxis 294 exceeded 0.8%, the risk-stratified approach was the most cost-effective strategy ( Figure 2 ). An 295 interaction was noted between anaphylaxis risk and anaphylaxis fatality, with a risk-stratified 296 approach becoming cost-effective as each risk increased concurrently (Figure 3 ). In addition, as 297 risk of COVID-19 increased, cost-effectiveness of a risk-stratified required vaccine deferral at 298 uncertain. This analysis demonstrates a universal vaccination approach is cost-saving and 342 provides superior health outcomes compared to a risk-stratified approach that, in our analysis, 343 broadly excluded anyone with a history of self-reported anaphylaxis from being vaccinated. 344

However, in situations characterized by low COVID-19 infection risk together with significant 345 rates of vaccine-associated anaphylaxis a risk-stratified approach (assuming risk-stratification 346 can prevent 95% of vaccine-related anaphylaxis) becomes cost-effective (i.e., as risk of 347 anaphylaxis from the vaccine increased above 0.8%). While stratified observation time by with no attributable anaphylaxis) were low.(7-9, 47) However, even if the mRNA vaccines were 385 associated with an excess 0.1% anaphylaxis rate (e.g., equivalent to a rate of 1000 cases per 386 million vaccine doses), this would be much higher than typical rates of vaccine anaphylaxis 387 (given the aforementioned historical rate of 1.3 cases of anaphylaxis per million vaccine doses). 388

For perspective, our threshold for when the strategies flip in this analysis to support restricting 389 the opportunity to offer vaccination to someone with a history of prior anaphylaxis occurs when 390 the rate reaches 7600-8000 cases per million doses (and this assumes risk-stratification can 391 effectively mitigate this rate, which is unproven). It should be understood how even further 392 disproportionately high this threshold rate of vaccine-associated anaphylaxis would be compared 393 to historical estimates, to reinforce how exaggerated the margins of the analysis are to the reader, 394

given numeracy with risk reporting can be difficult to accurately translate. Readers should also 395 keep in mind that over a 26 year period in which several new vaccines were brought to market 396 were never as restrictive), there is still concern that a patient reporting a history of a prior episode 423 of anaphylaxis (from any source) may be perceived at higher risk, and this perception could act 424 as a deterrent to vaccination efforts either through prolonged wait times or fear. (18, 20) The 425 only standing contraindication at the time of each vaccine EUA release was a history of prior 426 reaction to this vaccine's components, which is considerably narrower than what we are 427 simulating. However, there is distinct advantage for being broadly over-inclusive for Figure E1 . Decision tree. Decision tree depicting health states and transitions in a risk-stratification vs a universal vaccination strategy. cAnaAdmit: cost of anaphylaxis hospitalization; cCOVIDAdmit: cost of COVD-19 hospitalization. Figure E2 . Two-way sensitivity analysis of anaphylaxis risk and COVID-19 risk. As risk of COVID-19

increased, cost-effectiveness of a risk-stratified required vaccine deferral at higher anaphylaxis risk thresholds Figure E3 . Two-way sensitivity analysis of risk-stratification by time. Evaluating risk stratification of anaphylaxis risk by observation time, a universal approach of 15 minute observation was preferred until risk of anaphylaxis and anaphylaxis case-fatality rates rose significantly. However, if a 1% anaphylaxis case-fatality was assumed, a risk-stratified approach of 30 minute (vs 15 minute) observation became cost-effective when vaccine anaphylaxis exceeded 6% (WTP = 10,000,000 per death prevented).

Fact sheet for healthcare providers administering vaccine(vaccination providers) 451 emergency use authorization (eua) of the moderna covid-19 vaccine to prevent coronavirus 452 disease 2019 (covid-19) 2020

FDA Takes Key Action in Fight Against COVID-19 By 458 Issuing Emergency Use Authorization for First COVID-19 Vaccine

Covid-19: People with history of significant allergic reactions should not 462 receive Pfizer vaccine, says regulator

US Food and Drug Administration. Vaccines and Related Biological Products Advisory 464 Committee Meeting December 10

The New York Times. 2 Alaska Health Workers Got Emergency Treatment After 469 Receiving Pfizer's Vaccine

Allergic reactions 475 including anaphylaxis after receipt of the first dose of Pfizer-BioNTech COVID-19 vaccine -476 United States

Time to revisit 483 the definition and clinical criteria for anaphylaxis?

Anaphylaxis-a 2020 practice parameter update, systematic review, and Grading of 486

Development and Evaluation (GRADE) analysis

494 managing-allergic-reactions-following-covid-19-vaccination-with-the-pfizer-biontech-vaccine. 495 18. Centers for Disease Control and Prvention. Interim Clinical Considerations for Use of 496 mRNA COVID-19 Vaccines Currently Authorized in the United States

Update on MHRA decision re: Pfizer COVID-19 Vaccination 30

TEMPORARY 507 REMOVAL:mRNA Vaccines to Prevent COVID-19 Disease and Reported Allergic Reactions: 508 Current Evidence and Approach

Journal of Allergy and Clinical Immunology in Practice. 2021. 512 23. Global preparedness monitoring board. A world in disorder

Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement

Recommendations for Conduct, Methodological Practices, and Reporting of Cost-effectiveness 522 Analyses: Second Panel on Cost-Effectiveness in Health and Medicine

Anaphylaxis in America: the prevalence and characteristics of anaphylaxis in the United States

Risk factors for severe anaphylaxis in 534 patients receiving anaphylaxis treatment in US emergency departments and hospitals. The 535

Case fatality and population mortality associated with 537 anaphylaxis in the United States

Recent Trends in Anaphylaxis-Related Hospitalization in the United 539 States

Risk factors for severe anaphylaxis in 545 patients receiving anaphylaxis treatment in US emergency departments and hospitals

Administering 548 influenza vaccine to egg allergic recipients: a focused practice parameter update

Administration of influenza vaccines to egg allergic 551 recipients: A practice parameter update 2017

Adverse 554 reactions to vaccines practice parameter 2012 update

Immediate 557 Hypersensitivity to Polyethylene Glycols and Polysorbates: More Common Than We Have 558 Recognized

Immediate-type hypersensitivity to polyethylene glycols: a 560 review

Activation of mast cells by double-562 stranded RNA: evidence for activation through Toll-like receptor 3

Recognition of 565 single-stranded RNA viruses by Toll-like receptor 7. Proceedings of the National Academy of 566 Sciences of the United States of America

568 Evaluation of hypersensitivity reactions to cancer chemotherapeutic agents in pediatric 569 patients

mRNA Vaccines 571 to Prevent COVID-19 Disease and Reported Allergic Reactions: Current Evidence and Suggested 572 Approach

American College of Allergy, Asthma, and Immunology COVID-19 Vaccine Task Force: Allergic 575 Reactions to mRNA SARS-CoV-2 Vaccines

Vaccines and Related Biological Products Advisory Committee Meeting

Safety and 580 Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

COVID-19 vaccination 582 intention in the UK: results from the COVID-19 vaccination acceptability study (CoVAccS), a 583 nationally representative cross-sectional survey

Caregiver 586 willingness to vaccinate their children against COVID-19: Cross sectional survey

J o u r n a l P r e -p r o o f