Assessing Safety of COVID-19 mRNA Vaccine Administration in the Setting of a Previous Adverse Reaction
Phase: PHASE4
Conditions: COVID-19, Corona Virus Infection
Sponsor: University of Michigan

Assessing safety of COVID-19 mRNA vaccine administration in 
the setting of a previous adverse reaction 
 
NCT05212610 
 
Date of IRB Approval: October 1, 2024 

Assessing safety of COVID-19 mRNA vaccine administration in the setting of a 
previous adverse reaction  
 
Protocol V6.0 
November 2024 
 
 
Title: Assessing safety of COVID-19 mRNA vaccine administration in the setting of a 
previous adverse reaction  
 
Principal Investigator: James R. Baker Jr., MD; Allergy and Immunology 
 
Co-Investigators:  
Charles F. Schuler, MD; Allergy and Immunology 
Kelly M. O’Shea, MD; Allergy and Immunology 
Ian F. Slack, MD; Allergy and Immunology 
 
 
1. Objective 
 
This study will evaluate the safety of administering an additional dose of a 
currently FDA approved mRNA COVID-19 vaccine to individuals who have had 
adverse reactions to a previous dose of a COVID-19 vaccination. In addition, this 
study will evaluate the safety of administering an additional dose of  the currently 
FDA approved mRNA COVID-19 vaccine to individuals experiencing an adverse 
reaction to a natural COVID-19 infection (“long COVID”).  
 
We hypothesize that individuals who have had adverse reactions to a previous 
dose of an mRNA COVID-19 vaccine will tolerate an additional dose of the 
current FDA recommended vaccine, as indicated, and those with a personal 
history of allergic reaction will tolerate an initial dose of this vaccine as well. We 
also hypothesize that those individuals experiencing an adverse reaction to a 
natural COVID-19 infection will tolerate an additional dose of the current FDA 
recommended vaccine, as indicated. 
 
2. Endpoints 
 
Primary Endpoint 1: Determine the safety of administering an additional dose of 
an mRNA COVID-19 vaccine to individuals who have had adverse reactions to a 
previous  dose of an mRNA vaccine and the safety of administering an additional 
dose of an mRNA COVID-19 vaccine to individuals experiencing an adverse 
reaction to a natural COVID-19 infection (“long COVID”).  
Primary Endpoint 2: Determine the reaction rate in this population. 
Secondary Endpoint: Define clinical reaction type when they occur. 
 
3. 
Background  
 
The RNA based COVID-19 vaccines have been remarkably effective in preventing 
infection, severe disease, and death even with the advent of more contagious variants 
(1). The side effects have been relatively minimal; however, one concern has been 
adverse reactions that are potentially immune mediated, hypersensitivity or allergic in 
nature. (2) There are many of these reactions after the first dose of the vaccine, and 
most have not been fully evaluated. (3) As a result, individuals have been told simply to 
avoid the second dose of the vaccine. This approach has been reinforced by CDC 
recommendations issued at the beginning of the vaccine campaign. (4)  
 
In addition, many individuals with a personal history of allergic reaction were advised 
early in the vaccination campaign to avoid mRNA COVID-19 vaccination due to widely 

Assessing safety of COVID-19 mRNA vaccine administration in the setting of a 
previous adverse reaction  
 
Protocol V6.0 
November 2024 
 
 
publicized anecdotal reports of individuals with a personal history of allergic reaction 
experiencing adverse reactions to the mRNA vaccines.  
Initially, avoiding a second shot of RNA based COVID-19 vaccine appeared to be the 
safer alternative to receiving a second dose as a single dose seemed to provide 
significant protection from infection. Recent events, unfortunately, have changed the 
risks and benefits of incomplete vaccination. It appears that two full doses of vaccine are 
necessary to protect against infection with the delta variant. (5) In addition, the immunity 
provided by these vaccines appears to wane to some degree over time. (1) This 
diminution is greater in individuals who receive only a single dose of vaccine. (6) More 
recently, the Omicron variant demonstrated that additional booster doses of the mRNA 
COVID-19 vaccines significantly enhanced the protection provided by these vaccines 
against infection, hospitalization, and death from COVID-19. (13) Together, these 
emerging problems have raised concerns of COVID-19 morbidity, mortality, and 
transmissibility for those individuals who do not get a second dose of vaccine or who 
were advised against receiving a booster dose following an adverse reaction to the 
second dose in the primary vaccine series.(14) Though the initial suggestion that these 
individuals should avoid mRNA COVID-19 vaccination was revised (15), many 
individuals avoided vaccination because of the initial concerns raised during the early 
vaccination campaign. What literature is available on first dose reactions to COVID 
vaccines have suggested that most individuals with reactions do not have events that 
preclude receiving a second dose. A study out of Harvard examined their health care 
providers reactions to the RNA vaccines and found out that 1,365 individuals (2.1% of 
those vaccinated) felt that they had an adverse allergic reaction to the first dose of 
vaccine. (2) Despite this, when reviewing the clinical records of these reactions it 
appeared that only 14 had symptoms resembling a hypersensitivity reaction that would 
preclude a second dose. Unfortunately, this hypothesis was not tested as these 
individuals did not receive a second dose of vaccine. 
 
A recent study from Denmark also suggested that most individuals with first dose 
vaccine reactions could safely receive a second dose. (7) But again, this was not 
prospectively tested in a controlled manner and all allergic individuals were excluded 
from vaccine re-challenge.  
 
Previously, the CDC added recommendations that increasing the time between first and 
second doses of the mRNA COVID-19 vaccines may be optimal and should be 
considered. (9) This follows several recent studies reporting enhanced immune 
response following a delayed dosing interval between the first and second doses of 
mRNA COVID-19 vaccines. (10)(11)(12) 
 
Recently, on September 3rd, 2024, the FDA announced the release of an updated 
COVID-19 vaccine. The updated mRNA vaccines (manufactured by ModernaTX Inc. and 
Pfizer Inc.) formulas work to target the circulating variant strains of COVID-19 more 
accurately. This 2024-2025 formula includes a monovalent (single) component that 
corresponds to the Omicron variant KP.2 strain of SARS-CoV-S. The timeline for 
administering an additional dose to individuals that receive a previous dose is at least 
two months after the last dose. (18) 
 
In addition, the Omicron variant raised additional concerns about the waning of vaccine 
efficacy over time requiring the need for booster doses of the mRNA COVID-19 vaccines 
for optimal protection. This followed evidence of waning vaccine effectiveness and 

Assessing safety of COVID-19 mRNA vaccine administration in the setting of a 
previous adverse reaction  
 
Protocol V6.0 
November 2024 
 
 
increased breakthrough infections observed during the Delta variant surge. (13)  Those 
individuals who have experienced an adverse reaction to a second dose of an mRNA 
vaccine have faced uncertainty regarding the safety of booster doses, with many vaccine 
providers advising against additional doses of mRNA vaccine.  Determining the safety of 
administering additional doses to individuals following an adverse reaction to either dose 
of mRNA COVID-19 vaccine is essential as public health officials anticipate the need for 
additional doses in the future as variants continue to emerge and annual mRNA-based 
vaccinations for COVID-19 and influenza are developed for future use. 
 
Finally, as the COVID-19 pandemic has continued, a growing population of individuals 
who have experienced adverse reaction to natural COVID-19 infection (“long COVID”) 
has flooded the healthcare system.  Many of these individuals have avoided initiating or 
completing vaccination.  Available research suggests that not only is it safe to vaccinate 
these individuals (16), but that many long COVID patients report improved symptoms 
after administration of a COVID-19 vaccine (17).  As the potential for re-infection with 
newer variants continues to be a concern for those previously infected, fully vaccinating 
this population provides significant personal and societal benefit.  
 
 
 
1) Delahoy MJ, Ujamaa D, Whitaker M, et al. Hospitalizations Associated with COVID-19 
Among Children and Adolescents — COVID-NET, 14 States, March 1, 2020–August 14, 
2021. MMWR Morb Mortal Wkly Rep 2021;70:1255–1260.  
2) Blumenthal KG, Robinson LB, Camargo CA, et al. Acute Allergic Reactions to mRNA 
COVID-19 Vaccines. JAMA. 2021;325(15):1562–1565. 
3) Shavit R, Maoz-Segal R, Iancovici-Kidon M, et al. Prevalence of Allergic Reactions 
After Pfizer-BioNTech COVID-19 Vaccination Among Adults with High Allergy 
Risk. JAMA Netw Open. 2021;4(8):e2122255. 
doi:10.1001/jamanetworkopen.2021.22255 
4) https://www.cdc.gov/vaccines/covid-19/downloads/summary-interim-clinical-
considerations.pdf 
5) Planas, D., Veyer, D., Baidaliuk, A. et al. Reduced sensitivity of SARS-CoV-2 variant 
Delta to antibody neutralization. Nature 596, 276–280 (2021).  
https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment
_data/file/1001354/Variants_of_Concern_VOC_Technical_Briefing_17.pdf 
6) Hamady A, Lee J, Loboda ZA. Waning antibody responses in COVID-19: what can we 
learn from the analysis of other coronaviruses? Infection. 2021 Jul 29:1–15. doi: 
10.1007/s15010-021-01664-z. Epub ahead of print. PMID: 34324165; PMCID: 
PMC8319587. 
7) Rasmussen, TH,  Mortz, CG,  Georgsen, TK,  Rasmussen, HM,  Kjaer, HF,  Bindslev-
Jensen, C.  Patients with suspected allergic reactions to COVID-19 vaccines can be 
safely revaccinated after diagnostic work-up. Clin Transl Allergy.  2021;e12044. 
8) https://investors.modernatx.com/news-releases/news-release-details/moderna-
announces-significant-advances-across-industry-leading 
9) https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-
us.html 
10) Hall, VG, Ferreira, VH, Wood, H et al. Delayed-interval BNT162b2 mRNA COVID-19 
vaccination enhances humoral immunity and induces robust T cell responses.  Nat 
Immunol (2022). https://doi.org/10.1038/s41590-021-01126-6 

Assessing safety of COVID-19 mRNA vaccine administration in the setting of a 
previous adverse reaction  
 
Protocol V6.0 
November 2024 
 
 
11) Payne RP, Longet S, Austin JA et al. Immunogenicity of standard and extended 
dosing intervals of BNT162b2 mRNA vaccine. Cell. (2021); 184(23);5699-5714.e11. doi: 
10.10.1016/j.cell.2021.10.011 
12) Tauzin, A, Gong, SY, Beaudoin-Bussieres, G et al. Strong humoral immune 
responses against SARS-CoV-2 Spike after BNT 162b2 mRNA vaccination with a 16-
week interval between doses. Cell Host & Microbe. 2022; 30(1), 97-109. doi: 
https://doi.org/10.1016/j.chom.2021.12.004  
13) Khan, NA, Al-Thani, H, El-Menyar, A.  The emergence of new SARS-CoV-2 variant 
(Omicron) and increasing calls for COVID-19 vaccine boosters- The debate continues. 
Travel Med Infect Dis. 2022 Jan-Feb; 45: 102246. doi: 10.1016/j.tmaid.2021.102246 
14) NHS told not to give Covid vaccine to those with history of allergic reactions | 
Coronavirus | The Guardian 
15) CDC says people with history of severe allergic reactions can get COVID-19 vaccine 
| PBS NewsHour 
16) Arnold, DT, Milne, A, Samms, E et al. Are vaccines safe in patients with Long 
COVID? A prospective observational study.  medRxiv. doi: 
https://doi.org/10.1101/2021.03.11.21253225 
17) Ayoubkhani, D, Bermingham, C, Pouwels, KB et al. Trajectory of long covid 
symptoms after covid-19 vaccination: community based cohort study.  BMJ. 2022; 377. 
doi: https://doi.org/10.1136/bmj-2021-069676  
18) COVID-19 Vaccines for 2024-2025 | FDA   
 
4. 
Study Team Expertise  
 
Dr. Baker is the Ruth Dow Doan Professor of Internal Medicine in Allergy/Clinical 
Immunology, has a history of NIH and other funded laboratory work, has served as CEO 
of FARE (the national food allergy nonprofit), and SVP of vaccine development for 
Merck.  He is currently a protocol co-chair on the NIAID national clinical trial ‘Systemic 
Allergic Reactions to SARS-CoV-2 Vaccination’ Dr. Schuler is a Clinical Assistant 
Professor in Allergy/Clinical Immunology, has an expertise in respiratory virus 
immunopathology and clinical allergy/immunology, and has served as PI on clinical data 
and sample collection studies. Dr. Slack is a Clinical Assistant Professor in 
Allergy/Clinical Immunology, has an expertise in food allergy desensitization and clinical 
allergy/immunology, and has served as a sub-investigator on several clinical trials. Dr. 
O’Shea is a Clinical Assistant Professor in Allergy/Clinical Immunology, has an expertise 
in mast cell biology and has served as a co-investigator on clinical data and sample 
collection studies. Together, the study team has the expertise in study design, sample 
collection, subject recruitment, sample analysis, data management, analysis, and 
interpretation to successfully execute this proposed study. 
 
5. Methodology  
a. Inclusion/Exclusion Criteria 
 
Inclusion Criteria 
1. Age over 18.  
2. Participant must be able to understand and provide informed 
consent 
3. No evidence of infectious illness (defined as fever >38⁰C, 
vomiting, diarrhea, new cough, new shortness of breath, new 

Assessing safety of COVID-19 mRNA vaccine administration in the setting of a 
previous adverse reaction  
 
Protocol V6.0 
November 2024 
 
 
congestion, new runny nose, new headache or sore throat) within 
14 days of vaccine administration.  
4. Subjects must have a history of adverse reaction to either the 
Pfizer-BioNTech mRNA COVID vaccination or the Moderna 
mRNA COVID vaccination, a personal history of allergic reaction 
without prior mRNA COVID vaccination, or a history of adverse 
reaction to natural COVID infection.  
5. Females of childbearing potential must have a negative pregnancy 
test prior to vaccination. 
 
Exclusion Criteria 
1. Under age 18 
2. Inability or unwillingness of a participant to give written informed 
consent  
3. Evidence of COVID-19 infection within 21 days of vaccination visit 
4. History of antibody agent or convalescent plasma for treatment or 
prevention of COVID-19 within 90 days 
5. Individuals with known history of a severe allergic reaction (e.g., 
anaphylaxis) to any component of the Pfizer-BioNTech mRNA 
COVID-19 vaccination or the Moderna mRNA COVID-19 
vaccination. 
6. History of underlying immune disorder.  
• 
Pregnancy 
• 
Immunocompromised  
o Persons with primary or acquired immunodeficiency 
o Persons on anti-rejection therapy following solid 
organ transplant or bone marrow transplant 
o Persons on biologic therapeutic agents 
o Persons with malignancy and ongoing or recent 
chemotherapy 
o Persons receiving systemic immunosuppressive 
therapy, including corticosteroids equivalent to 20 
mg/day of prednisone for 2 weeks 
• 
Persons with chronic kidney disease stage 3 or higher 
• 
Persons with history of significant pulmonary compromise 
 
 
b. Recruitment Plan and Study Design 
i. Number of Subjects 
N=200 individuals 
 
ii. Method of Contact 
We will screen and recruit individuals that have been identified either as 
having a personal history of allergic reaction without prior mRNA COVID-19 
vaccination, having a history of adverse reaction to natural COVID-19 
infection, or as having possibly had an adverse reaction to either the Pfizer 
mRNA COVID vaccine or the Moderna mRNA COVID vaccine by medical 
chart review following healthcare provider referral or Data Direct database 
identification or from a response to a study advertisement.  Individuals will be 
contacted initially by a member of the study team in person or over the phone 

Assessing safety of COVID-19 mRNA vaccine administration in the setting of a 
previous adverse reaction  
 
Protocol V6.0 
November 2024 
 
 
following identification as a possible subject by healthcare provider referral, 
Data Direct database identification and chart review, or self-referral from 
study advertisement.   
 
iii. Method of Consent 
Individuals will be contacted as above. Individuals approached for the 
study will be provided the consent document for review, offered background on 
the study, and asked to provide verbal permission for pre-screening questions. 
If a participant provides verbal permission for pre-screening, a set of pre-
defined questions will be used to confirm eligibility.  This process may take 
place in person during a clinical visit or over the phone by a member of the 
study team.  Eligible participants will be provided the informed consent 
document and a thorough review of the document will take place.  Participants 
will have as much time as needed to ask questions and decide if they’d like to 
participate in the study.  In most cases, consent will be provided to the 
participant electronically and they will be asked to sign using the University of 
Michigan’s FDA 21 CFR Part 11 compliant e-signature service 
(“SignNow”).  This service automatically provides a copy of the fully signed 
document to all parties and a copy will be placed in the participant’s medical 
record.  There may be circumstances where a participant is able to complete 
the consent process in person during a clinical visit; sufficient time for review 
and questions will be provided for in person consenting as well.  Rarely, 
consents may send via postal mail for ink signatures.  In this case no study 
procedures will take place until the consent has been signed by all parties and 
a copy of the fully signed document is provided to the participant.  The method, 
location, and individuals involved in the consent process will be fully 
documented in the study records.  
 
iv. Method of Interaction/Procedure/Intervention 
Pre-Vaccination Visit 
1. Obtain written informed consent 
2. Collect demographics from the electronic medical record 
3. Review medical history and prior physical exam within the 
electronic medical record by a study physician or other 
qualified medical professional 
4. Assessment of concomitant medications 
5. Blood and urine sample collections for assessments to be 
obtained within 2 weeks of vaccination visit 
o Blood sample collections 
 
CBC with differential 
 
Serum tryptase 
 
ESR 
 
Comprehensive metabolic panel 
 
COVID-19 spike antibody level 
 
COVID-19 nucleocapsid antibody level 
o Urine sample collections 
 
Urinalysis 
 
Urine pregnancy test in all female participants 
The timeframe of scheduled vaccination visits: 
1. Participant will then be scheduled for a vaccination visit. 

Assessing safety of COVID-19 mRNA vaccine administration in the setting of a 
previous adverse reaction  
 
Protocol V6.0 
November 2024 
 
 
2. Subjects with a history of receipt of one previous dose of 
monovalent Moderna COVID-19 Vaccine (SpikeVax),one 
previous dose of monovalent Pfizer-BioNTech COVID-19 
Vaccine (Comirnaty), or history of a previous bivalent booster 
will be given an additional dose of the current FDA 
recommended COVID-19 vaccine. The timeline for 
administering an additional dose to individuals that have 
received a previous dose is at least 2 months after the last 
dose.  
3. Subjects who have received both of their primary doses of an 
approved, monovalent mRNA vaccine and want a booster 
dose of the current FDA recommended COVID-19  mRNA 
vaccine), will receive this additional dose at least 2 months 
after their last dose. 
4. Enrolled subjects who have received a primary dose in the 
study can receive a booster dose as well (i.e. at least three 
doses of mRNA COVID-19 vaccine) but must wait at least 2 
months after last dose before receiving an additional FDA 
recommended COVID-19 booster dose. 
5. Subjects will have booster vaccination with the current FDA 
recommended vaccine (i.e. Moderna COVID-19 Vaccine or 
Pfizer-BioNTech COVID-19 Vaccine). Regardless of whether 
the last dose was a monovalent primary or monovalent 
booster dose, subjects will be required to wait at least 2 
months before the receiving the current  FDA recommended 
booster dose in this study.  
6. It is possible that subjects might receive multiple COVID-19 
vaccine doses) within this study if they meet relevant 
enrollment criteria and desire to receive multiple doses within 
the context of this study.  
 
Vaccination Visit 
1. The participant will undergo an abbreviated medical history 
and targeted physical exam by a study physician. 
2. Assessment of concomitant medications. 
3. Vital signs (temperature, pulse rate, respiratory rate, O2 
saturation, blood pressure) will be obtained. 
4. Participants will then receive a Pfizer-BioNTech COVID mRNA 
vaccination, or Moderna COVID-19 Vaccine as indicated by 
the FDA and CDC guidelines.  They will receive the same 
vaccination as their initial reaction, if applicable. 
5. Following vaccination, the study participant will be observed 
for adverse events (AEs) for 30 minutes, including examination 
of the vaccination site, and have vital sign measurements 30 
minutes post-vaccination and/or after the onset of an adverse 
reaction.  
6. During the 30-minute observation period, all AEs will be 
recorded, and AEs judged by an investigator to constitute an 
allergic reaction, even if not severe, will be documented.  

Assessing safety of COVID-19 mRNA vaccine administration in the setting of a 
previous adverse reaction  
 
Protocol V6.0 
November 2024 
 
 
7. In the event of a systemic allergic reaction, participants will be 
treated with rescue medications as appropriate. The site 
investigators for this trial are allergists, trained to recognize, 
and familiar with the treatment of anaphylaxis, and will be 
available within 60 seconds in the event of a reaction. 
Emergency medications, oxygen, and equipment will be 
available to treat any allergic reactions. Vital signs will be 
monitored during a systemic allergic reaction. 
• 
The following medications may be used to treat an 
allergic reaction: 
i. Epinephrine 1 mg/mL; 0.3 – 0.5mg IM 
ii. β-adrenergic agonist inhaler or nebulizer 
(e.g. albuterol) 
iii. Antihistamines 
iv. Steroids 
v. IV fluids 
vi. Oxygen 
8. To assist study participants in the identification of and steps to 
take in the event of an allergic reaction after they leave the 
study site, each participant that has evidence of a systemic 
allergic reaction within 30 minutes of vaccination will be 
provided with epinephrine auto-injectors (2-pack) as well as an 
Anaphylaxis Emergency Care Plan. The PI or designee shall 
review the symptoms and steps to take in the event of an 
allergic reaction, including training on how to use the 
epinephrine auto-injector, with the participant prior to 
discharge. 
 
Post-Vaccination 
1. Participants without evidence of an adverse reaction within 30 
minutes of vaccination will receive a follow-up phone call after 
7 days to assess for development or lack of symptoms post-
vaccination.   
2. Participants that had a suspected reaction within 30 minutes of 
vaccination will be scheduled for a follow-up in-person visit 
within 7 days to assess for additional symptoms or resolution 
of symptoms.  
 
 
 
c. Subject Withdrawal 
i. Under what conditions will a subject be withdrawn prior to completion  
ii. If a subject withdraws prior to completion, what is the plan for the use of their 
data 
 
Any subject may withdraw at any time for any reason. These reasons 
may include but are not limited to: 
• 
Subject’s request, no reason needed 
• 
Adverse event – at Investigator’s request 
• 
Other 

Assessing safety of COVID-19 mRNA vaccine administration in the setting of a 
previous adverse reaction  
 
Protocol V6.0 
November 2024 
 
 
 
The data for any subject who withdraws prior to completion will be 
flagged as incomplete data in our data set. We will delete data if the 
subject requests this. 
 
d. Data Retention and/or Data Destruction Plan 
i. How long will you keep subject data? 
ii. If you plan to destroy the data, how will you destroy it? 
 
Data collected will be retained for study record keeping purposes 
and for future research use for up to 5 years. No data will be 
destroyed.  
 
Risks & Benefits 
a. What are the risks and what will be done to monitor the risks? 
b. What is the likelihood of each risk (common, likely, infrequent, or rare)? 
 
Potential Risks 
• 
Adverse reactions following the Pfizer-BioNTech COVID-19 Vaccine  that 
have been reported in clinical trials include injection site pain, fatigue, 
headache, muscle pain, chills, joint pain, fever, injection site swelling, 
injection site redness, nausea, malaise, and lymphadenopathy. LIKELY 
• 
Severe allergic reactions, including anaphylaxis, other hypersensitivity 
reactions (e.g., rash, pruritus, urticaria, angioedema), myocarditis, 
pericarditis, diarrhea, vomiting, and pain in extremity (arm) have been 
reported following the Pfizer-BioNTech COVID-19 Vaccine during mass 
vaccination outside of clinical trials. RARE 
• 
Adverse reactions reported in a clinical trial following administration of the 
Moderna COVID-19 Vaccine include pain at the injection site, fatigue, 
headache, myalgia, arthralgia, chills, nausea/vomiting, axillary 
swelling/tenderness, fever, swelling at the injection site, and erythema at the 
injection site. LIKELY 
• 
Severe allergic reactions, including anaphylaxis, myocarditis, and pericarditis 
have been reported following the Moderna COVID-19 Vaccine during mass 
vaccination outside of clinical trials. RARE 
• 
Allergic reactions have been reported to occur after vaccination with the 
Pfizer-BioNTechCOVID-19 Vaccine and Moderna COVID-19 Vaccine. 
Allergic reactions range from mild to severe and include life threatening 
anaphylactic reactions, although no deaths have been reported with either 
vaccine. If a participant experiences a systemic allergic reaction within 30 
minutes of vaccination, the site will provide the participant with an 
epinephrine auto-injector 2-pack. In addition, participants who experience a 
systemic allergic reaction will receive an Anaphylaxis Emergency Care Plan 
at the vaccination visit. The PI or designee will review the plan including 
symptoms of an allergic reaction and steps to take in the event of an allergic 
reaction, including training on how to use the epinephrine auto-injector, with 
the participant prior to discharge. If a participant has an allergic reaction, 
he/she may need oral, IM, or IV medications. The site investigators for this 
trial are allergists, trained to recognize, and familiar with the treatment of 
anaphylaxis, and will be available within 60 seconds in the event of a 

Assessing safety of COVID-19 mRNA vaccine administration in the setting of a 
previous adverse reaction  
 
Protocol V6.0 
November 2024 
 
 
reaction. Emergency medications, oxygen, and equipment will be available to 
treat any allergic reactions.  RARE 
• 
Treatment of individual acute allergic reactions during the conduct of the 
study should be with epinephrine, IV fluids, β-adrenergic agonists (e.g., 
albuterol), oxygen, antihistamines, and steroids, as indicated for the severity 
of the reaction.  RARE 
o Risks of these common medications are summarized below:  
 
Antihistamines: drowsiness, dizziness, constipation, 
stomach upset, blurred vision, or dry mouth/nose/throat 
 
Epinephrine: tachycardia, palpitations, nervousness, 
sweating, nausea, vomiting, trouble breathing, headache, 
dizziness, anxiety, tremors, or pale skin 
 
β-adrenergic agonists: nervousness, shaking (tremor), 
headache, or dizziness 
 
Steroids: nausea, vomiting, loss of appetite, heartburn, 
trouble sleeping, increased sweating, or acne 
• 
Participation in this study poses a risk for breach of confidentiality.  RARE 
• 
Subjects may experience discomfort during the blood draw, as well as 
bleeding, bruising and/or infection at the puncture site. However, this should 
be no greater than that experienced at the time of a routine blood draw. 
LIKELY   
• 
Taking part in more than one research study may be harmful to the subject.  
If subjects are already taking part in another study, we ask that they let us 
know. Subjects should not take part in more than one study at the same time, 
unless the subject and the investigators agree that the subject is not likely to 
be harmed, and the outcome of the study will not be disturbed.  RARE 
• 
As with any research study, though, there may be additional risks of 
participating that are unforeseeable or hard to predict. RARE 
 
What will be done to reduce or monitor these risks? 
• 
To minimize the breach of confidentiality risk, information shared outside of 
the University of Michigan will not use the subject’s name or hospital number, 
but rather a unique study number.  
• 
The site investigators for this trial are allergists, trained to recognize, and 
familiar with the treatment of anaphylaxis, and will be available within 60 
seconds in the event of a reaction. Emergency medications, oxygen, and 
equipment will be available to treat any allergic reactions.   
• 
The clinical team will provide prescriptions for epinephrine auto-injectors for 
participants that experience systemic allergic reactions within 30 minutes of 
vaccination. In addition, participants will receive an Anaphylaxis Emergency 
Care Plan at the vaccination visit. The PI or designee will review the plan 
including symptoms of an allergic reaction and steps to take in the event of 
an allergic reaction, including training on how to use the epinephrine auto-
injector, with the participant prior to discharge. 
 
c. What are the benefits?   
iii. To the individual 
• 
Participants receive an additional dose of a highly protective 
COVID-19 mRNA vaccine for the SARS-CoV-2 virus in an 
environment where the investigators and staff are experienced 

Assessing safety of COVID-19 mRNA vaccine administration in the setting of a 
previous adverse reaction  
 
Protocol V6.0 
November 2024 
 
 
in the care of patients with allergic reactions. Two full doses of 
a COVID-19 mRNA vaccine are necessary to protect against 
infection with the delta variant. In addition, the immunity 
provided by these vaccines appears to wane to some degree 
over time, with additional booster doses recommended after 
completion of the primary vaccination series for optimal 
protection against emerging variants. This diminution is 
greater in individuals who receive only a single dose of 
vaccine. 
• 
Participants will be compensated for their loss of time with a 
$75 VISA giftcard that they will receive at the completion of 
their vaccination visit.  
iv. To society  
This data is valuable for childhood and booster immunizations with 
mRNA vaccines to COVID-19 which are in planning stages. These 
findings will also be important for other vaccines based on RNA 
technology. Vaccines for influenza, respiratory syncytial virus and 
cancer are all being theorized using this technology.  
 
Data & Safety Monitoring 
a. Will there be a board your study will report adverse events and other 
problems to? 
 
Yes 
 
b. Adverse Events 
Adverse Events (AEs): Any untoward medical occurrence associated with the 
use of an intervention in humans, whether or not considered intervention-
related. AEs include expected and unexpected harmful effects, and 
unexpected risks of an interaction or an intervention. 
 
Serious Adverse Event (SAE): An adverse event or suspected adverse 
reaction is considered “serious” if, in the view of the investigator:  
1. Death. 
2. A life-threatening event: An AE is considered “life-threatening” if, in the 
view of the investigator, its occurrence places the subject at immediate 
risk of death. It does not include an AE that, had it occurred in a more 
severe form, might have caused death.  
3. Inpatient hospitalization.  
4. Persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions.  
5. Congenital anomaly or birth defect.  
6. Important medical events that may not result in death, be life 
threatening, or require hospitalization may be considered serious when, 
based upon appropriate medical judgment, they may jeopardize the 
subject and may require medical or surgical intervention to prevent one of 
the outcomes listed above. 
 
The investigator must report adverse events regardless of relationship to 
study therapy regimen or study mandated procedures.  

Assessing safety of COVID-19 mRNA vaccine administration in the setting of a 
previous adverse reaction  
 
Protocol V6.0 
November 2024 
 
 
 
 
i. Method of Identifying, Recording, Monitoring and Reporting Adverse 
Events 
 
Identifying:  
For this study, an adverse event will include the following associated 
with the vaccination administration: 
• All AEs occurring within 7 days after vaccination administration 
• All local reactions, except for injection site reactions of 
erythema/redness and induration/swelling measuring <2.5 cm, will be 
reported as AEs 
 
Collecting Adverse Events: Adverse events may be discovered 
through any of these methods:  
• Observing the participant 
• Receiving an unsolicited complaint from the participant 
 
Grading of Adverse Events Other than Systemic Allergic Reactions: 
The study sites will grade the severity of non-allergic adverse events 
experienced by the study participants according to the criteria set forth 
in the FDA Guidance for Industry Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials (September 2007); hereafter, referred to as the FDA 
Toxicity Grading Scale. Adverse events will be graded on a scale from 
1 to 5 according to the following standards in the FDA Toxicity 
Grading Scale: 
Grade 1 = Mild  
Grade 2 = Moderate  
Grade 3 = Severe  
Grade 4 = Life-threatening  
Grade 5 = Death 
 
Grading of Systemic Allergic Reactions:  
 
The investigator will grade severity of systemic allergic reactions on a 
scale of 1 to 5 according to criteria set forth in the CoFAR Grading 
Scale modified for use in adults only.  
 
CoFAR Grading Scale for Systemic Allergic Reactions Version 3.0: 
 
Grade 1: Reaction involving one of the following organ systems in 
which the symptoms are mild:  
• 
Cutaneous: Generalized pruritus, generalized urticaria, 
flushing, angioedema  
• 
Upper respiratory: Rhinitis, cough unrelated to laryngeal 
edema or bronchospasm  
• 
Conjunctival: Injection/redness, itching, tearing  
• 
GI: Nausea, abdominal pain (no change in activity level), 
single episode of vomiting and/or single episode of diarrhea 

Assessing safety of COVID-19 mRNA vaccine administration in the setting of a 
previous adverse reaction  
 
Protocol V6.0 
November 2024 
 
 
 
Grade 2: Reaction involving two or more of the following organ 
systems in which the symptoms are mild:  
• 
Cutaneous: Generalized pruritus, generalized urticaria, 
flushing, angioedema  
• 
Upper respiratory: Rhinitis, cough unrelated to laryngeal 
edema or bronchospasm  
• 
Conjunctival: Injection/redness, itching, tearing GI Nausea, 
abdominal pain (no change in activity level), single episode of 
vomiting, and/or single episode of diarrhea  
OR  
Reaction involving at least one of the following organ systems in 
which the symptoms are moderate:  
• 
Cutaneous: Generalized pruritus, generalized urticaria, 
flushing, angioedema  
• 
Upper respiratory: Rhinitis, cough unrelated to laryngeal 
edema or bronchospasm  
• 
Conjunctival: Injection/redness, itching, tearing  
• 
GI: Nausea, abdominal pain (with change in activity level), two 
episodes of vomiting and/or diarrhea 
 
Grade 3: Reaction involving one or more of the following organ 
systems:  
• 
Lower respiratory: Throat tightness, wheezing, chest tightness, 
dyspnea, cough that respond to short acting bronchodilator 
treatment (including IM epinephrine) with or without 
supplemental oxygen  
• 
GI: Severe abdominal pain, more than two episodes of 
vomiting and/or diarrhea  
• 
Cardiovascular: Reduced BP with lightheadedness, 
presyncope or tachycardia 
 
Grade 4: Life-threatening reaction involving one or more of the 
following organ systems with or without other symptoms listed in 
Grades 1 to 3:  
• 
Lower respiratory: Throat tightness with stridor, wheezing, 
chest tightness, dyspnea, or cough associated with a 
requirement for supplemental oxygen and refractoriness to 
short-acting bronchodilator treatment (including IM 
epinephrine)1  
OR  
• 
Respiratory compromise requiring mechanical support  
• 
Cardiovascular: Reduced BP with associated symptoms of 
end-organ dysfunction (e.g., hypotonia [collapse], syncope) 
defined as: systolic BP of less than 90 mmHg or >30% 
decrease from baseline 
 
Grade 5: Death  
 

Assessing safety of COVID-19 mRNA vaccine administration in the setting of a 
previous adverse reaction  
 
Protocol V6.0 
November 2024 
 
 
1. Examples of refractoriness could include continuous albuterol 
nebulizer or epinephrine IV infusion or more than three IM epinephrine 
injections 
 
The investigator will also grade the diagnostic certainty of anaphylaxis 
according to criteria set forth by the Brighton Collaboration case 
definition and guidelines for anaphylaxis. Please see attached 
supporting documents in Section 44.   
 
Recording/Monitoring: 
Throughout the study, the investigator will record adverse events and 
serious adverse events on the appropriate AE/SAE electronic Case 
Report Form (eCRF) regardless of the relationship to study vaccine or 
study procedure. Once recorded, an AE/SAE will be followed until it 
resolves with or without sequelae, or the AE/SAE stabilizes, or until 7 
days after the participant’s vaccine dose, whichever occurs first.  
 
Attribution of Adverse Events Code Descriptor Relationship 
RELATED CATEGORIES  
1. Definitely Related 
2. Probably Related 
3. Possibly Related  
NOT RELATED CATEGORY  
4. Unlikely to be Related 
5. Definitely not Related 
 
Reporting: 
We will report any adverse events and other reportable incidences 
and occurrences (ORIO) to the IRB.  Any adverse event or ORIO will 
be documented of that event including a description, subject number, 
date, outcome, and follow-up. Reporting of adverse events and 
ORIOs will follow IRBMED’s reporting timetable and will occur at least 
yearly.    
 
Statistical Design  
Descriptive characteristics of the samples will be described using means and 
standard deviations for normal-distributed continuous variables (medians and 
interquartile ranges for non-normal) and frequencies and percentages for 
categorical variables.  
 
To achieve 90% power with two-sided alpha=0.05 to detect a 2% allergic reaction 
rate and a 2% febrile reaction rate in the study population each vs a 0% null 
hypothesis rate using a t-test, 172 minimum total subjects would be needed for 
this study. To account for potential drop-out or follow-up failure of 20%, we will 
seek to enroll 200 total subjects.