PROmotion of COVID-19 BOOSTer VA(X)Ccination in the Emergency Department - PROBOOSTVAXED
Phase: NA
Conditions: COVID-19
Sponsor: University of California, San Francisco

 
1 
 
 
 
Project Title: PROmotion of COVID-19 BOOSTer 
VA(X)ccination 
in 
the 
Emergency 
Department 
– 
PROBOOSTVAXED 
R01 AI166967-01 
NCT06156215 
Sub-study: RTC for COVID-19 booster vaccine 
messaging platforms 
Date of Document: October 28, 2023 
 
 
 
 
 
 
 
 
 
 

 
2 
 
Study Procedures Manual for PROBOOSTVAXED  – A Cluster 
Randomized Trial:  
 
Contents 
 
I. 
Overview ........................................................................................................................................ 3 
II. 
IRB ................................................................................................................................................... 5 
III. 
Deposition of Protocol into ClinicalTrials.Gov .................................................................... 5 
IV. 
Setting and Sites .......................................................................................................................... 5 
V. 
Randomization ............................................................................................................................. 5 
VI. 
Site Orientation and Training ................................................................................................... 6 
VII. 
Study Hotline and Quality Assurance .................................................................................... 6 
VIII. 
Recruitment, Inclusions, Exclusions, and Consent ........................................................... 6 
IX. 
Study Procedures: Intervention Blocks ................................................................................. 7 
X. 
Study Procedures: Control Blocks ....................................................................................... 10 
XI. 
Research Staff Informing ED Providers When Participants Will Accept COVID-19 
Booster Vaccine for Intervention M and Intervention Q Arms ................................................... 11 
XII. 
Consents and Rationale ........................................................................................................... 12 
XIII. 
Primary Outcomes and Ascertainment ................................................................................ 12 
XIV. 
Data Recording and Entry ....................................................................................................... 14 
XV. 
Data Analysis .............................................................................................................................. 14 
XVI. 
Data Management Plan ............................................................................................................ 16 
XVII. Sample Size Considerations ................................................................................................... 17 
 
 
 
 
 

 
3 
 
I. 
Overview 
On January 22, 2020, Acting Health and Human Services Secretary Norris Cochran declared 
COVID-19 a national public health emergency, an action that eventually enabled emergency 
authorization for free COVID-19 vaccines, testing and treatments. This public health declaration 
has been renewed seven times for 90-day intervals, as required under section 319 of the Public 
Health Service (PHS) Act. Under this declaration over the past two years, the US government 
has provided full support and distribution of COVID-19 vaccines and therapeutics (antibody 
therapies, remdesivir, and nirmatrelvir/ritonavir), such that they have been widely available and 
free of charge to all Americans. Although these measures have not, by any means, ended the 
pandemic, it is clear from multiple epidemiologic modeling studies that they have decreased 
hospitalizations and saved hundreds of thousands of lives. They have also led to a narrowing of 
the profound morbidity and mortality disparities gap that was seen in minority populations in the 
first two waves of the pandemic.   
 
The PROCOVAXED trial was a multicenter study that sought to decrease COVID-19 vaccine 
hesitancy and increase COVID-19 vaccine uptake through the use of vaccine messaging 
platforms in the emergency department (ED). In this trial, we found that implementation of our 
COVID-19 messaging platforms (videos, information sheets and scripted, direct messaging) 
were associated with greater COVID-19 vaccine acceptance and uptake among unvaccinated 
ED patients (Rodriguez RM, Nichol G, Eucker SA, et al. Effect of COVID-19 Vaccine Messaging 
Platforms in Emergency Departments on Vaccine Acceptance and Uptake: A Cluster 
Randomized Clinical Trial. JAMA Intern Med. 2023;183(2):115–123. 
doi:10.1001/jamainternmed.2022.5909).  
 
In January 2022, we extended PROCOVAXED by shifting the focus to vaccinated ED patients 
to examine the timely and critically important topic of booster vaccine hesitancy in underserved 
ED populations. To better characterize COVID-19 booster hesitancy, we performed a cross-
sectional study at five high-volume, safety-net hospital EDs in four cities (San Francisco, 
Philadelphia, Seattle, and Durham, NC) using survey tools to gather quantitative data on 
vaccination status, demographic variables, usual source of care, and attitudes toward booster 
vaccination. Of 771 participants who had completed their full initial series, 316 (41%) had not 
received any booster vaccine. Among these 316 non-boosted participants, 179 (57%, 95% CI 
51-62) stated they would decline or were unsure whether they would accept a booster vaccine if 
it was offered to them (i.e., booster-hesitant). We found the following associations with booster 
vaccine hesitancy: age 35-49 years vs age 18-34 years (OR 1.16, 95% CI 0.99-1.36); Asian vs 
White race (OR 0.21, 95% CI 0.05-0.93); Hispanic/Latino vs White ethnicity (OR 1.59, 95% CI 
0.82-3.09); primary language non-English vs English (OR 2.35, 95% CI 1.49-3.71); and 
Republican vs Democrat party affiliation (OR 6.07, 95% CI 4.21-8.75). The three most common 
reasons for booster vaccine hesitancy were a preference to wait for more information (25%), 
concerns about side effects and safety (24%), and “I don’t need one because I’m fully 
vaccinated” (20%). 
 
Recognizing the ED as a unique opportunity to address COVID-19 booster vaccine hesitancy in 
underserved populations, we will launch the PROmotion of COVID-19 BOOSTer VA(X)ccination 
in the Emergency Department (PROBOOSTVAXED) trial as an extension of the 
PROCOVAXED trial, seeking to increase COVID-19 booster vaccine acceptance and uptake 
among vaccinated ED patients. Because of Omicron variant-associated surges during the 
COVID-19 pandemic with corresponding research staff illness and ED overcrowding, we found 

 
4 
wide week-to-week fluctuations in enrollment in the PROCOVAXED study. To reduce this 
variability of enrollment, we have changed the unit of randomization from 1-week to 1-day in the 
PROBOOSTVAXED trial.  
 
IMPORTANT CHANGE: Under intense political pressure and in response to Congress’ 
reluctance to spend more on COVID-19 pandemic relief, the Biden administration recently made 
two announcements: 1) the national public health emergency declaration regarding the COVID-
19 pandemic will be left to expire as of January 11, 2023, and 2) the administration will end their 
provision of free COVID-19 vaccines, testing and therapeutics, shifting the costs for vaccines, 
testing and treatments to health insurers and patients via commercial payment mechanisms. 
Because of these changes in reimbursement, we have been informed that only some of the 
PROBOOSTVAXED study sites will have COVID-19 vaccines available for distribution in the 
ED, whereas others will not. Nevertheless, we will proceed with the same research protocol, 
however, we will be performing additional subgroup analyses that compare 30-day vaccine 
uptake in sites with available COVID-19 vaccine to those without for the intervention and control 
arms.  
 
Specific Aim I: To determine whether implementation of COVID-19 booster vaccine 
trusted messaging platforms is associated with increased booster vaccine uptake in 
vaccinated ED patients. At five EDs (Zuckerberg San Francisco General, UCSF Parnassus 
Medical Center [San Francisco, CA], Thomas Jefferson University Hospital [Philadelphia, PA], 
Ben Taub Hospital [Houston, TX], Duke University Medical Center [Durham, NC]), we will 
conduct a cluster-randomized controlled trial of the implementation of PROBOOSTVAXED 
trusted messaging platforms, with 30-day booster vaccine uptake as the primary outcome and 
booster vaccine uptake in the ED as a secondary outcome. Hypothesis: Implementation of 
PROBOOSTVAXED trusted messaging platforms in EDs will be associated with increased 30-
day booster vaccine uptake in vaccinated ED patients. 
Specific Aim II: To determine whether implementation of COVID-19 booster vaccine 
trusted messaging platforms in EDs is associated with increased booster vaccine 
acceptance in vaccinated ED patients. For this specific aim, booster vaccine acceptance in 
the ED assessed via ED survey will be the primary outcome. Hypothesis: Implementation of 
PROBOOSTVAXED trusted messaging platforms in EDs will be associated with increased 
booster vaccine acceptance in vaccinated ED patients. 
Specific Aim III: To determine whether implementation of a protocol in which ED patients 
are asked whether they will accept a COVID-19 booster vaccine in the ED is associated 
with increased booster vaccine uptake in vaccinated ED patients.  Hypothesis: 
Implementation of an ED protocol in which patients are asked whether they will accept a 
COVID-19 booster vaccine will be associated with increased 30-day booster vaccine uptake in 
vaccinated ED patients. 
General Design: This is a three-arm cluster-randomized controlled trial (CRCT) to accomplish 
Specific Aims I, II, and III. 
Study arms 
PROBOOSTVAXED Intervention M 
(Messaging + Vaccine Question) 
Intervention Q (Vaccine Question, 
No Messaging) 
Control (No Messaging, No 
Vaccine Question)  

 
5 
• 
Vaccine messaging given 
• 
Vaccine acceptance 
question asked 
• 
No vaccine messaging  
• 
Vaccine acceptance 
question asked 
• 
No vaccine messaging 
• 
No vaccine acceptance 
question  
 
Primary Outcome for Specific Aims I and III: Booster Vaccine Uptake in the ED 
The primary outcome for Specific Aims I and III is 30-Day COVID-19 Booster Vaccine Uptake, 
which will be ascertained by review of ED electronic health records (EHRs) at 30 days and 
follow-up phone calls. For Specific Aim I, this primary outcome will be compared between the 
Intervention M arm (Messaging + Vaccine Acceptance Question) and the Control arm (No 
Messaging, No Vaccine Acceptance Question). For Specific Aim III, this primary outcome will be 
compared between the Intervention Q arm (Vaccine Acceptance Question, No Messaging) and 
the Control arm (No Messaging, No Vaccine Acceptance Question). 
Primary Outcome for Specific Aim II: Booster Vaccine Acceptance in the ED 
The primary outcome of Specific Aim II is COVID-19 Booster Vaccine Acceptance in the ED, 
which will be ascertained by a survey question of study participants in the ED. This outcome will 
be compared between the Intervention M arm (Messaging + Vaccine Acceptance Question) and 
the Intervention Q arm (Vaccine Acceptance Question, No Messaging). 
II. 
IRB  
We will submit our protocol to the UCSF Committee on Human Research as a modification. We 
will continue with multi-site reliance mechanism for the PROCOVAXED study as per NIH 
guidelines for randomized trials.  
III. 
Deposition of Protocol into ClinicalTrials.Gov 
As per federal regulations, we will deposit our full study protocol into the repository 
https://clinicaltrials.gov/.  
IV. 
Setting and Sites 
We will conduct this over six months (mid-September 2023 to February 28, 2024) at five high-
volume EDs in four cities: (Zuckerberg San Francisco General, UCSF Parnassus Medical 
Center [San Francisco, CA], Thomas Jefferson University Hospital [Philadelphia, PA], Ben Taub 
Hospital [Houston, TX], Duke University Medical Center [Durham, NC]). We have chosen this 
time-period to coincide with typical waves of the COVID-19 pandemic.  
V. 
Randomization 
Sites will be assigned be assigned to a condition for a day. Randomization within each of the 
site uses pseudorandom number to permute blocks of time. The blocks consist of 15 days 
duration during which each condition appears for 5 days. Hence, in any 15 day period there will 
be a balance of interventions within each of the sites. The particular days of each week 
(Monday, Tuesday, Wednesday, Thursday and Friday) for each of the study arms will thus vary 
randomly. This randomization scheme will minimize secular trends (changes in perceptions 
about the booster vaccine that may occur through the course of various pandemic waves). We 

 
6 
will generate a full study calendar based on this randomization scheme. To try to maintain 
masking of allocation, sites will be given a blacked-out study calendar and will be instructed to 
open the calendar for a particular study day the morning of that study day (other than that study 
day, the rest of the calendar will remain blacked out). 
VI. 
Site Orientation and Training  
The Core UCSF Site will develop orientation materials to familiarize the ED Sites with the study 
protocol. Each site will employ one or more Clinical Research Coordinators (CRCs), who will 
report to the Site PI and be responsible for day-to-day study implementation. We will develop 
and disseminate a manual of operating procedures (MOP) with standard personnel training 
methods, including education kits with scripts, summary cards, and PowerPoint presentations to 
assist coordinators in the orientation of site clinicians and other staff to our study protocol. We 
will convene ZOOM conference calls to review this summary and develop plans for optimization 
of PROBOOSTVAXED messaging platforms to improve usability and workflow. We will refine 
procedures with updates delivered to the site PIs during weekly ZOOM conferences.  
VII. 
Study Hotline and Quality Assurance 
We will maintain a study hotline and encourage study personnel to contact the PI and Central 
Study Coordinator for all issues and queries. Hotline hours will be during primary study hours 
(weekday 8 a.m. to 5 p.m. PST).  
We will enact rigorous methods for clinical trial quality assurance and performance 
improvement, including: 1) systematic review of enrollment logs, 2) weekly audits of random 
samples of data for accuracy and missing elements, and 3) structured review of protocol 
deviations or violations. The Central Study Coordinator will prepare monthly summary report 
cards, tabulating individual site quality assurance metrics for review during scheduled Steering 
Committee calls. The overall study PI (Dr. Rodriguez) will discuss site-specific data with site PIs 
individually and summarize these data collectively during Steering Committee calls, with prompt 
dissemination of plans for process improvement. 
VIII. 
Recruitment, Inclusions, Exclusions, and Consent 
Practical budget considerations and limits on research personnel in patient care areas during 
the COVID-19 pandemic, preclude 24/7 delivery of the PROBOOSTVAXED trusted messaging 
platforms and enrollment in this study. We will use a convenience sample technique to 
approach all eligible adult patients who present to our study EDs during 8-hour (one-day) 
blocks, typically beginning at approximately 9 a.m. and continuing to approximately 5 pm. Sites 
will be given leeway to vary their particular study time hours, as long as these study hours 
remain consistent from week to week.  
Inclusions will be: 
1) Age > 18 years 
2) Presenting to ED  
3) No receipt of COVID-19 booster within prior 6 months 
4) Able to provide informed consent 
5) Fluent in English or Spanish  

 
7 
6) Anticipated ability to complete study intervention in ED i.e., able to watch a 3-minute 
videoclip 
Reviewing ED triage information, we will exclude patients with the following characteristics:  
1) Major trauma such that it will preclude survey  
2) Inability to participate in a survey because of intoxication, altered mental status, or 
critical illness 
3) Incarceration 
4) Psychiatric hold 
5) Patients who state that they have already received a bivalent COVID-19 booster vaccine 
or other COVID-19 vaccine within the prior 6 months 
6) Patients who are in the ED for suspected acute COVID-19   
NOTE: For all three study arms, study procedures should be performed in patient waiting 
times and not interfere or disrupt patient care in any way. 
IX. 
Study Procedures: Intervention Blocks 
 
Procedures and workflow during PROBOOSTVAXED Intervention M Study Arm 
The anticipated flow of the study during the Intervention M study blocks is summarized in Figure 
1. CRCs and research personnel will begin by setting up their home base of consents and 
platforms (video clips, printed materials, and scripts for messaging).   
Figure 1: Intervention M Arm Study Flow  
 
Introduction to ED Staff:  Clinical Research Coordinators (CRCs) will set up their workstation 
in the ED and introduce themselves to ED staff (nurses, physicians, and mid-levels), informing 
them that they will be doing the PROBOOSTVAXED study that day. They will avoid telling 
providers whether this is an intervention versus control arm.  
Initial Screening and Scripted Consent for Surveys: CRCs will review ED dashboards for 
inclusion and exclusion information. When an eligible patient is identified, the CRC will ask the 
nurse or doctor caring for the patient whether it is okay for them to approach the patient about 
the study. For provider approved patients: CRCs will approach eligible patients and deliver a 
scripted consent for two short surveys: the (Pre-intervention) Intake Survey and the (Post-
Intervention) Vaccine Acceptance Survey. See Scripted Consent for the Intervention M period. 

 
8 
They will also get written HIPAA authorization for review of their ED EHR. If the patient 
does not agree to this HIPAA review of their EHR, they will be excluded from the study. 
Participants will not be compensated for participation. 
CRCs will complete screening and enrollment log indicating whether they agreed to participate. 
If they agreed to participate, the CRC will assign a Study ID#. 
Intake Survey:  We will administer the INTAKE SURVEY to participants. CRCs will have the 
option of inputting surveys to REDCap on iPads in real time or using paper surveys (and later 
inputting into REDCap). These surveys are to be delivered orally (CRC asks questions), not via 
handing them out. The Intake Surveys are the same for all three arms of the study.  
Intervention M (messaging):  The intervention will consist of three messaging platforms that 
were developed specifically to reduce booster vaccine hesitancy. All platforms have been 
reviewed by the UCSF Committee on Human Research. 
1) Video clips – short (approximately 3-minute) Public Service Announcement type videos 
to be viewed by participant using a QR code on their smartphone. If no smartphone is 
available, the video will be shown to the participant on an iPad. 
2) Printed materials – one page information sheets handed to subjects by CRCs. 
3) Face to face messaging – short (< 1 minute), scripted message from the patient’s 
providers in the ED (nurse or provider) 
 
Each site will maintain a library of  
A. 5 versions of the videos – the version used in any participant will be tailored to that 
participant’s stated race/ethnicity. See *** below 
B. 5 versions of printed flyers – likewise, the version will be tailored to the participant’s stated 
race/ethnicity. See *** below 
C. 1 version of scripted message to be delivered in English or Spanish. 
 
COVID-19 Booster Vaccine Flyer, Videos, and Telling Provider to Deliver Message: 
Interventions will be delivered in real-time patient visits in site EDs, during waiting times such 
that they will not interfere with patient care. At the end of the survey, the CRC will deliver the 
booster vaccine information flyer and ask the patient if they will watch a short video about 
booster vaccines. If they agree to watch the video, the CRC will give them a QR code to view 
the video on their smartphone. If they do not have a smartphone, they will show them video on 
an iPad. After finishing with the video, the CRC will tell the subject that they will be back in about 
an hour for the Vaccine Acceptance survey. The CRC will then leave the room and ask the 
patient’s primary provider (doctor, mid-level practitioner, or nurse) to deliver the booster vaccine 
message (hand them the scripted message). This message is short and should not significantly 
impact provider workflow. Notably, vaccine messaging is recommended in the ED by the 
American College of Emergency Physicians and other health care organizations (Centers for 
Disease Control).  
 
***We will deliver messaging from our platform libraries in patients’ preferred language (English, 
Spanish). To the extent possible, we will follow recommendations to choose platforms from site 
libraries that match video clip and printed material messengers with subjects’ likely preferences 
for race, ethnicity, age, and gender (e.g., Latinx messenger on video clip with Latinx participant).  
 

 
9 
Vaccine Acceptance Survey (Post-Intervention) in the ED: We will administer the Vaccine 
Acceptance Survey: INTERVENTION GROUP at some time (generally 30 minutes but up to 3 
hours) after the Intake Survey.   
Primary and Other Outcome Ascertainment: Primary outcome ascertainment of 30-day 
uptake of booster vaccine will occur in three ways:  
1) Ascertainment of vaccination in the ED by direct questioning and review of EHR records. 
2) Blinded review of EHR at 30-days 
3) For participants who have not received a booster vaccine upon questioning in the ED, staff 
will ask whether they will agree to phone follow-up at 30 days. For those agreeing to follow-
up, we will obtain written consent for phone follow-up (phone follow-up consent form). We 
will then ask participants for their best phone number(s) to reach them for a follow-up phone 
call. Sites will maintain a separate password protected database of subject IDs and follow-
up phone numbers.  
This method will assure that all study participants, even those who refuse phone follow-up, will 
have at least two ways of study outcome ascertainment (1 and 2 above).  
Secondary outcome ascertainment of booster vaccination in the ED will occur in two ways: 
1) Direct questioning of participants and their providers in the ED: Research staff will ask 
participants and their ED providers whether the participant received a booster vaccine in the 
ED one hour but up to 6-hours after the Vaccine Acceptance Survey. Notably, ED patient 
visits are variable such that not all patients have stays lasting greater than an hour and a 
half. Research staff should endeavor to complete this ascertainment prior to discharge, even 
if that ascertainment occurs before an hour after the Vaccine Acceptance survey.  
2) Review of each participant’s ED EHR by research staff on the next workday after their index 
ED visit to confirm receipt (or non-receipt) of a booster vaccine in the ED. This EHR review 
will be conducted in a blinded fashion – the research staff person reviewing the EHR 
will be unaware of participant’s study group assignment.  
Procedures and workflow during PROBOOSTVAXED Intervention Q Study Arm 
 
The workflow during this arm is identical to the Intervention M Arm except there will be no 
messaging platforms delivered. The anticipated flow of the study during Intervention Q Blocks 
is summarized in Figure 2. 
Figure 2: Intervention Q Arm Study Flow  

 
10 
 
Introduction to ED Staff: Clinical Research Coordinators (CRCs) will set up their workstation in 
the ED and introduce themselves to ED staff (nurses, physicians, and mid-levels), informing 
them that they will be doing the PROBOOSTVAXED study that day. They will avoid telling 
providers whether this is an intervention versus control arm.   
Initial Screening and Scripted Consent for Surveys: CRCs will review ED dashboards for 
inclusion and exclusion information. When an eligible patient is identified, the CRC will ask the 
nurse or doctor caring for the patient whether it is okay for them to approach the patient about 
the study. For provider approved patients: CRCs will approach eligible patients and deliver a 
scripted consent for two short surveys: the (Pre-intervention) Intake Survey and the (Post-
Intervention) Vaccine Acceptance Survey. See Scripted Consent for the No Messaging arm 
period.  
CRCs will complete screening and enrollment log indicating whether they agreed to participate. 
If they agreed to participate, the CRC will assign a Study ID#. 
Intake Survey:  We will administer the INTAKE SURVEY to participants. CRCs will have the 
option of inputting surveys to REDCap on iPads in real time or using paper surveys (and later 
inputting into REDCap). These surveys are to be delivered orally (CRC asks questions), not via 
handing them out. The Intake Surveys are the same for all three arms of the study.  
Vaccine Acceptance Survey: We will administer the Vaccine Acceptance Survey at some time 
(generally 30 minutes but up to 3 hours) after the Intake Survey. The surveys in the control 
group retain the same key primary and secondary outcome questions as in the intervention 
group Vaccine Acceptance surveys. See Vaccine Acceptance Survey: No Messaging arm.  
Primary and Other Outcome Ascertainment: Ascertainment of primary and secondary 
outcomes will occur in the same manner as in the Intervention M arm.  
X. 
Study Procedures: Control Blocks 
The workflow during this arm is identical to the Intervention Q arm except there will be no 
Vaccine Acceptance Question survey. The anticipated flow of the study during control blocks is 
summarized in Figure 3. 

 
11 
Figure 3: Control Arm Study Flow 
 
Introduction to ED Staff:  Clinical Research Coordinators (CRCs) will set up their workstation 
in the ED and introduce themselves to ED staff (nurses, physicians, and mid-levels), informing 
them that they will be doing the PROBOOSTVAXED study that day. They will avoid telling 
providers whether this is an intervention versus control arm.  
Initial Screening and Scripted Consent for Surveys: CRCs will review ED dashboards for 
inclusion and exclusion information. When an eligible patient is identified, the CRC will ask the 
nurse or doctor caring for the patient whether it is okay for them to approach the patient about 
the study. For provider approved patients:  CRCs will approach eligible patients and deliver a 
scripted consent for two short surveys – the Intake Survey and the (Post-Intervention) Vaccine 
Acceptance Survey. See Scripted Consent for the No Messaging arm period. 
CRCs will complete screening and enrollment log indicating whether or not they agreed to 
participate. If they agreed to participate, the CRC will assign a Study ID#. 
Intake Survey:  We will administer the INTAKE SURVEY to participants. CRCs will have the 
option of inputting surveys to REDCap on iPads in real time or using paper surveys (and later 
inputting into REDCap). These surveys are to be delivered orally (CRC asks questions), not via 
handing them out. The Intake Surveys are the same for all three arms of the study.  
Primary and Other Outcome Ascertainment: Ascertainment of primary and secondary 
outcomes will occur in the same manner as in the intervention arms.  
XI. 
Research Staff Informing ED Providers When Participants Will Accept COVID-19 
Booster Vaccine for Intervention M and Intervention Q Arms 
Only some study site EDs will have the capability of administering COVID-19 booster vaccines 
during the initial ED visit. The last question in the Vaccine Acceptance Survey in both the 
Intervention M and Intervention Q arms of the study is “Would you accept the COVID-19 
booster vaccine in the emergency department today if your doctor asked you?” For study site 
EDs capable of administering the COVID-19 vaccine, when a participant says they will accept 
the vaccine, the CRC or research staff will ask the participant if it is okay to notify that 
participant’s ED provider(s) – nurse and/or physician that they said they will accept the vaccine 

 
12 
and confirm whether or not they receive it in the ED. Research staff will not tell patients that they 
qualify for the booster vaccine and will not advise them in any manner. They will, however, 
inform the patient that if they choose to accept the vaccine, they may be liable for the vaccine’s 
cost, depending on their medical insurance coverage. If participants agree to notification of the 
ED provider, research staff will notify the ED provider that they stated they will accept the 
vaccine. They will not tell the provider that they meet criteria for the booster vaccine and will not 
push that they get vaccinated. 
XII. 
Consents and Rationale 
We will obtain scripted verbal consent for Intake surveys in the same manner that we have 
conducted with the PROCOVAXED study, which is nearly identical in design and scope. We will 
obtain written HIPAA consent for EHR review and separate written consent for 30-day follow-up 
phone calls.  
With regards to consent for delivery of the messaging intervention, we must emphasize that 
messaging for vaccine hesitancy is firmly a part of standard best-practice emergency 
department care (messaging of this type is currently be enacted in EDs across the US). Delivery 
of the vaccine messaging platforms is therefore an accepted common best practice not 
requiring consent. To add an extra layer of consent could lead to even greater vaccine 
hesitancy. We therefore plan the following processes with verbal assent for the Intervention: 
1) At the end of the Intake Survey, asking patients if they are willing to watch a booster vaccine 
messaging video(s). If the patient says Yes, then we will play the video. If the patient says 
No, we will not play the video.  
2) Asking participants whether they are willing to read an informational flyer about booster 
vaccines. If the patient says Yes, then we will give them the flyer. If the patient says No, we 
will not give them the flyer. 
3) Handing the participant’s ED provider(s) the scripted message about booster vaccines to 
deliver to the participant. Research staff will not mandate or check with providers whether 
they deliver the message.  
XIII. 
Primary Outcomes and Ascertainment  
Primary Outcome and Ascertainment of Specific Aim I  
Our primary outcome for Specific Aim I is 30-day booster vaccine uptake, comparing the 
Intervention M arm versus the Control (No Messaging, No Vaccine Acceptance Question) 
arm.  
Primary and Other Outcome Ascertainment: Primary outcome for Specific Aim I is booster 
vaccine uptake (at any vaccination location) within 30 days after participants’ index ED visit, 
comparing the Intervention M arm versus the Control arm. For ascertainment of this outcome, 
we will:  
1) Review the EHR the day after participants’ index visit (as described for the secondary 
outcome ascertainment below). 
2) Review the EHR at 30 days for receipt of a booster vaccine. 

 
13 
3) Conduct follow-up phone calls (Have you received a booster vaccine since your 
emergency department visit?) 30 days after index ED visits for those who did not get the 
vaccine in the ED and who consented to follow up.  
Secondary outcome (vaccination in the ED) ascertainment will occur by review of each 
participant’s ED EHR by research staff on the next workday after their index ED visit. Staff will 
check the EHR to confirm receipt (or non-receipt) of a booster vaccine in the ED. This review 
will be conducted in a blinded fashion – the research staff person reviewing the EHR will be 
unaware of participant’s study group assignment.  
Participants who have confirmed receipt by EHR review will be deemed “vaccinated in the ED”. 
Conversely, participants who do not have confirmed receipt by review will be deemed to be “not 
vaccinated in the ED”. 
Outcome and Ascertainment of Specific Aim II  
Our outcome for Specific Aim II is booster vaccine acceptance (defined as a response of “yes” 
to the question, “Would you accept the booster vaccine in the emergency department today if 
your doctor asked you?”), comparing the Intervention M arm versus Intervention Q arm. This 
outcome will be ascertained during the Vaccine Acceptance Survey in both arms.  
Outcomes and Ascertainment of Specific Aim III  
Our outcome for Specific Aim III is 30-day booster vaccine uptake (at any vaccination location), 
comparing the Intervention Q arm (Vaccine Acceptance Question, No Messaging) versus the 
Control arm (No Messaging, No Vaccine Acceptance Question). This outcome will be 
ascertained in the same manner as the primary outcome of Specific Aim I. 
A secondary outcome for Specific Aim III is booster vaccination in the ED, comparing the 
Intervention Q arm versus the Control arm. This outcome will be ascertained in the same 
manner as the secondary outcome of Specific Aim I. 
30-Day Phone and EHR Follow Up  
CRCs will only review EHR and conduct phone follow-up with study subjects who have given 
written consent for these follow-up techniques. CRCs will check the EHR at two time periods – 
the day after their index visit and, if not vaccinated during their ED visit, again 30 days after their 
visit. CRCs will review Master Data Flow daily (workdays) to determine which subjects have 
reached the 1-month follow-up period. By convention, we will use the next month’s day that has 
the same number as the index study visit date, i.e., if the study index visit was on November 5, 
then the 1-month follow-up should occur on December 5. If December 5 falls on a weekend, 
then the CRC will use the next study workday (typically the next Monday) as the follow-up date. 
Study subject’s medical record #s and telephone #s will be accessed from the Booster Vaccine 
Follow Up sheet. The CRC who conducts EHR and phone follow-up will be blinded to the 
subject’s study group assignment (intervention vs control arms), i.e., a separate CRC who did 
not recruit at that site during that day will conduct this phone follow up.  
1) The CRC will first review the EHR to determine whether there is any record of a booster 
vaccine received in the preceding time period from the study index visit. If there is a record 

 
14 
of vaccination, the CRC will record what date and where the participant received it (if 
available). See Follow-Up Data Collection form. 
2) If there is no record of vaccination in the EHR, the CRC will proceed with a phone call to the 
study subject. See Follow-Up Phone Call Collection form. CRCs will enter follow up data on 
both the Master Data Flow and Follow up spreadsheets via REDCap links.  
a. If the patient does not answer the phone that morning, the CRC will place two more 
calls to the study subject over the next 2 workdays. They will vary the time of these 
calls to improve response.  
b. If the patient does not answer the phone by the third call, the CRC will leave a 
message with the phone # of the study team. No more calls will be initiated by the 
study team after this third call.  
XIV. 
Data Recording and Entry  
CRCs will record survey responses and other data via two mechanisms: 
1) Direct entry into the Booster Vaccine Study REDCap database in real time during surveys 
via secure links  
2) Recording onto paper forms first. Then entry of survey information and data after each 
participant enrollment. 
CRCs will keep a running log of all study flow and enrollment, recording the following data for all 
patients approached: study date, study arm, “Yes” and “No” agreeing to surveys, delivery or 
non-receipt of messaging platforms, agreeing to receipt of study vaccines, ED vaccine 
availability, receipt of vaccines in the ED, “Yes” and “No” agreeing to follow-up calls and EHR 
review.  See Master Data Flow.  
XV. 
Data Analysis 
Analysis for Specific Aim I 
The primary study comparison is uptake (receipt) of a booster vaccine at any vaccination 
location within 30 days of the index ED visit, comparing participants seen on Intervention M 
dates with those seen on Control (No Messaging, No Vaccine Acceptance Question) dates to 
test our study hypothesis: Implementation of PROBOOSTVAXED trusted messaging platforms 
in EDs will be associated with increased booster vaccine uptake in vaccinated ED patients. This 
outcome will be ascertained by either review of a participant’s EHR 30 days after their index ED 
visit or a follow-up phone call. 
There are three secondary comparisons for Specific Aim I: 
1) Comparison of 30-day booster vaccine uptake between the Intervention M and Intervention 
Q arms  
2) Receipt of a booster vaccine during the index ED visit, comparing participants seen on 
Intervention M dates with those seen on Control dates - ascertained by check of the 
participant’s EHR on the day after their ED visit 
Outcomes will be compared using mixed logistic regression with a fixed effect for randomization 
assignment, a normally distributed random effect to allow for clustering by enrolling center, and 
restricted cubic splines to allow for secular trends during the study period. The treatment effects 

 
15 
will be tested by the coefficient for the fixed effect of study arm along with 95% confidence 
intervals. 
 
Analysis for Specific Aim II 
For Specific Aim II, we will compare outcomes in participants seen on Intervention M arm dates 
with those seen on Intervention Q arm dates to test our study hypothesis: Implementation of 
PROBOOSTVAXED trusted messaging platforms in EDs will be associated with increased 
booster vaccine acceptance in vaccinated ED patients. 
The outcome is booster vaccine acceptance (defined as a response of “yes” to the question 
“Would you accept the booster vaccine in the emergency department today if your doctor asked 
you?”). This outcome will be compared using mixed logistic regression with a fixed effect for 
randomization assignment, a normally distributed random effect to allow for clustering by 
enrolling center, and restricted cubic splines to allow for secular trends during the study period. 
The treatment effects will be tested by the coefficient for the fixed effect of study arm along with 
95% confidence intervals. 
 
Analysis for Specific Aim III 
For Specific Aim III, the outcome is uptake (receipt) of a booster vaccine at any vaccination 
location within 30 days of the index ED visit. We will compare outcomes in participants seen on 
Intervention Q arm dates with those seen on Control dates to test our study hypothesis: 
Implementation of an ED protocol in which patients are asked whether they will accept a booster 
vaccine (and notifying ED providers when they say they will accept it) will be associated with 
increased booster vaccine uptake in vaccinated ED patients. 
A secondary outcome for Specific Aim III is receipt of a booster vaccine during the index ED 
visit, comparing participants seen on Intervention Q dates with those seen on Control dates - 
ascertained by check of the participant’s EHR on the day after their ED visit. 
 
Subgroup Analyses 
Another focus of this research is on ED patients who lack primary care group, defined on the 
Intake survey question: “Do you have a regular clinic or doctor for medical care?” We will 
analyze outcomes according to the binary indicator of having primary care – yes versus no (and 
unsure). 
We will additionally stratify outcomes by study site (representing different regions of the country 
and different communities), vaccine administration capability, age, gender, primary language, 
and race/ethnicity. 
Subgroups will be tested by adding a subgroup by intervention interaction to the mixed logistic 
regression. A subgroup will be considered significant if the pairwise intervention by subgroup 
omnibus test is significant at the 0.05 level. 
Rationale for time (1-day unit) cluster and consideration of Alternative Study Designs:  

 
16 
In the study Overview, we described our rationale for switching from a one-week unit to a one-
day unit cluster. Our primary goal with this research is to determine whether real-world 
implementation of booster vaccine messaging as an ED-site level intervention results in greater 
acceptance and uptake of booster vaccines in vulnerable ED populations. Each site sees 
approximately 150-250 patients per day and applying or not applying the intervention (delivery 
of booster vaccine messaging) for individual patients in this high workflow, rapid patient turnover 
ED environment is simply impractical. Given that booster vaccine messaging may be seen and 
received by all patients non-selectively in the EDs, patient level randomization would result in 
high risk of cross-contamination between intervention and control arms. Therefore, removal of 
the messaging intervention from the site completely during specified time periods (1-day units) 
of Intervention Q, and removal of both interventions (messaging and the vaccine acceptance 
question) during Control days is the optimal approach. Although single switches of turning on 
the interventions at each site (i.e., stepped-wedge trial design) is easier to enact, changes in 
general population attitudes over time introduce bias that limit the validity of this trial method. 
We expect gradually increasing acceptance and uptake of the booster vaccine over time, which 
would introduce substantial bias toward the intervention. Finally, cost considerations and 
feasibility limit the number of sites in this trial, negating the potential advantages of a cross-over 
trial with randomization by sites. These practical and methodological benefits of the 1-day unit 
cluster RCT far outweigh the smaller sample size and easier analysis with an individual patient 
unit RCT or a stepped-wedge design. 
Statistical approach: In terms of statistical approach, this is a superiority trial in which we seek 
to verify our central study hypothesis that provision of booster vaccine messaging will result in 
greater acceptance and uptake of the booster vaccine. Following the recommendations 
of Hussey and Hughes, our statistical analyses will focus on comparing the vaccine uptake rates 
during the time periods when booster vaccine messaging is in place (Intervention M) and when 
the system is not in place (Control - usual care) using mixed effects logistic models. The 
outcome of interest is the binary indicators of whether they have received a booster vaccine in 
the ED (uptake - yes/no). Models will include a normally distributed random center effect (on the 
logit scale) to accommodate potential within-center characteristics (e.g., case mix, 
demographics), as well as terms for time and intervention. Hypotheses testing will focus on the 
statistical significance of the intervention indicator. We will fit the mixed effects models using 
maximum likelihood and routines in Stata.  
We will test our primary hypotheses and analyze outcomes according to the study arm (index 
visit in Intervention M day versus control day) to which patients were allocated, regardless of 
whether they received booster vaccine messaging or not - intention to treat analysis.  
In addition to the effects on total vaccine acceptance, we will also examine the effect of booster 
vaccine messaging on acceptance in patient sub-groups, especially African American and 
Latinx persons. Booster vaccine messaging may work for one patient sub-group and not others 
-- these additional analyses will guide future directions and modifications of booster vaccine 
messaging.  
XVI. 
Data Management Plan  
We will manage data using REDCap, hosted by the core site (UCSF) for secure data entry and 
management. Patient identifiers (medical record numbers and phone numbers) only link will be 

 
17 
to unique study ID numbers, which will be housed in files that are kept separate from other 
study data. We will develop a detailed data dictionary to ensure consistent standards across 
sites. We will reduce missing or erroneous data using the REDcap data quality tool.  
XVII. 
Sample Size Considerations  
The sample size calculations for this research are governed by hypothesis testing of Specific 
Aim I -- Implementation of booster messaging platforms will be associated with increased 
booster vaccine uptake (primary outcome) in unvaccinated ED patients. Considering the high 
benefit of increasing vaccine uptake and the negligible risk of the intervention (a trusted 
messaging program), even a small effect size of increased uptake would be a clinically 
important difference. By investigator consensus, we have determined that the intervention would 
be clinically useful if it increased booster vaccine uptake by 7%.  
We base the sample size calculation on the comparison of the proportion of patients who accept 
the vaccine between the Intervention M and Control time periods using standard formulae for 
individual randomization. We have verified that these sample sizes are conservative by 
simulation of data using a mixed random effects model. Our baseline level of vaccine uptake in 
the control arm is estimated to be approximately 5%. With this uptake level we find that at an 
alpha=0.05 level and a power of at least 0.80, we will need to enroll 744 participants (248 in 
each arm) in the study to detect the difference of interest (a setting in which the vaccine uptake 
rate will increase by 7% during Intervention periods vs Control periods).