Use of Construal Level Theory to Inform Messaging to Increase Vaccination Against COVID-19
Phase: NA
Conditions: Covid19, Vaccine Refusal
Sponsor: Brigham and Women's Hospital

 
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CLINICAL TRIAL PROTOCOL 
 
“Use of Construal Level Theory to inform messaging to increase vaccination against COVID-19” 
 
National Clinical Trial (NCT) Identified Number: NCT04871776 
 
 
Principal Investigators: 
Nancy Haff, MD, MPH, 
Primary Care Physician, Bulfinch Medical Group, MGH 
Associate Epidemiologist, Division of Pharmacoepidemiology and Pharmacoeconomics, BWH 
Instructor in Medicine, HMS 
 
Julie Lauffenburger, PharmD, PhD 
Assistant Professor, HMS 
Associate Epidemiologist, Division of Pharmacoepidemiology and Pharmacoeconomics, BWH 
 
Co-investigator: 
Niteesh Choudhry, MD, PhD 
Associate Physician, the Hospitalist Service and Division of Pharmacoepidemiology and 
Pharmacoeconomics, BWH 
Professor of Medicine, HMS 
 
 
Center for Healthcare Delivery Sciences and Division of Pharmacoepidemiology and 
Pharmacoeconomics, Brigham and Women’s Hospital and Harvard Medical School 
 
 
Funded by the National Institute on Aging 
Grant Number: P30AG064199 
Version Number: 5 
January 10, 2022 
 
 

 
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1. 
BACKGROUND AND SIGNIFICANCE  
 
COVID-19 causes severe respiratory disease, disability, and death among older adults.1 Vaccination is an 
essential step in the prevention of disease spread and mitigation of disease severity to promote healthy 
aging. Despite this, about 1 in 4 Americans report hesitation about receiving the COVID vaccine, even 
when free and reported as safe by scientists.2 Moreover, hesitancy is higher among Black and Hispanic 
populations, which, if not directly addressed, could result in ongoing disparities in COVID infections and 
deaths.3,4 Early efforts to vaccinate Americans has shown a lot of early demand, but racial disparities in 
vaccination rates are already emerging,5 and once the initial interest from vaccine eager individuals has 
passed, interventions to engage more hesitant or resistant individuals will be needed to maximally protect 
the population from COVID-19.6 
 
Patient outreach strategies for other vaccines have had modest success.7–9 Most of these approaches have 
focused on abstract concepts of why patients should receive a vaccine. However, messages that describe 
how to do something may be more effective at inducing behaviors that are psychologically near (e.g., 
imminent, personal), like scheduling a vaccination appointment for yourself within a week.  
 
According to Construal Level Theory, emphasizing “why” elicits more abstract thinking, or high-level 
construals, and can induce an emotional mindset, which could challenge an individual’s sense of identity, 
autonomy, or political preferences. Conversely, emphasizing “how” is more cognitive and evokes 
concrete thinking, or low-level construals, and encourages a planning or implementation mindset.10,11 
Low-level construals (“how” messages) have been shown to increase intention to or uptake of several 
heath behaviors including dietary changes,12 use of relaxation techniques,13 blood donation,14 and 
completion of biometric screening and health surveys.15 Though prior studies of vaccine acceptance have 
not explicitly applied Construal Level Theory, aspects of interventions that elicit low-level construals 
have been successful compared to other techniques. For example, straightforward messages stating that a 
dose of the flu vaccine was “reserved” for the patient at their upcoming appointment (low-level construal) 
were more effective than messages about protecting loved ones (high-level construals).16 Similarly, 
information on where and when to receive the flu shot outperformed gain- or loss-framed reminder 
messages,8 and a map of flu vaccine locations was more effective than a loss-framed message or an entry 
to win a $100 gift card.17 
 
Because of the political and emotional valence of the COVID-19 vaccine, “how” messaging to elicit 
concrete thinking may be particularly important. Direct comparison of “how” vs “why” messages has not 
been tested for vaccines, and it has never been tested for COVID-19. Moreover, COVID vaccine 
hesitancy differs by age, gender, and race,4,6 and demographic groups may respond differently to 
messages. Tailoring a message to a specific group with higher rates of vaccine hesitancy could help 
reduce health disparities. 
 
Thus, in this study we propose a pilot randomized trial to test the effects of “how” vs “why” framing on 
COVID-19 booster vaccination rates using electronically delivered communication (e.g., patient portal 
messages delivered through the electronic health record [EHR]), followed by analyses to identify patient 
characteristics that might predict intervention responsiveness to allow for further tailored communication 
after the completion of the trial. 
 
 
 
 

 
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2. 
SPECIFIC AIMS  
 
The main aims are to 1) test the effect of “how” vs “why” framed messages on the rates of COVID-19 
booster vaccination and 2) assess association of clinical and demographic characteristics with intervention 
responsiveness.  
 
The objectives and endpoints for this project are summarized below. 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
Aim 1 
To test the effect of “how” vs 
“why” framed messages on the 
rates of COVID-19 vaccination 
Primary: the rate of booster 
vaccination at the targeted visit 
 
Secondary: the rate of receipt of a 
COVID booster vaccine within 6 
weeks of the targeted visit 
These outcomes are directly related to 
the interventions, are clinically 
meaningful, and are measurable using 
routinely collected data in the Mass 
General Brigham COVID-19 Vaccine 
Registry and the Research Patient Data 
Registry (RPDR) and/or Epic 
Enterprise Data Warehouse (EDW). 
We plan to use RPDR for variable 
collection as long as all the variables 
needed are available in the RPDR. If a 
variable is not available in the RPDR 
then we will supplement with use of 
the EDW for those variables. 
Aim 2 
To assess association of 
clinical and demographic 
characteristics with 
intervention responsiveness 
A model to predict likelihood of 
response to each intervention based 
on patient characteristics 
A model predicting intervention 
responsiveness could be used to tailor 
future interventions to specific patients 
 
 
3. 
SUBJECT SELECTION 
 
This study will include patient subjects for intervention and analysis. We will use the Mass General 
Brigham Research Patient Data Registry (RPDR) and/or Epic Enterprise Data Warehouse (EDW) to 
identify Mass General Brigham (MGB) patients age 18 who are eligible for the COVID booster vaccine, 
who have not received a dose as of the time of upcoming primary care clinic visit. We will then cross 
check that with the COVID-19 vaccine registry so that we can additionally exclude patients who may 
have received a vaccination that has not yet been entered into RPDR. 
 
Patients will be excluded if they did not receive the full set of their primary COVID-19 series or had a 
severe allergic reaction to either dose of their primary series. All MGB patients who meet the criteria 
above will be eligible for the study. We plan to begin the study after the booster vaccine is widely 
available to individuals 18 years of age or older.  Based on a recent survey data from the Kaiser Family 
Foundation, at least 45% of the fully-vaccinated population are at least somewhat skeptical about 
obtaining a booster vaccination.   
 

 
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4. 
SUBJECT ENROLLMENT 
 
4.1 Methods of enrollment 
We will use the Mass General Brigham COVID-19 Vaccine Registry and Research Patient Data Registry 
(RPDR) and/or Epic Enterprise Data Warehouse (EDW) to identify eligible patients. The COVID-19 
Vaccine Registry contains identified patient data, including the type of vaccine administered, first or 
second dose, as well as when and where the patient received their vaccine. The registry integrates 
information from vaccines administered by MGB, administrations entered into Epic based on patient 
report, and the state’s Massachusetts Immunization Information System (MIIS) that includes vaccination 
sites across the state. General patient demographic information, adverse reactions and patient identifiers 
are included in the COVID-19 Vaccine Registry.  
 
We will thus use the Mass General Brigham COVID-19 Vaccine Registry and EHR information in the 
Research Patient Data Registry (RPDR) and/or Epic Enterprise Data Warehouse (EDW) to identify MGB 
patients age 18 with an upcoming primary care outpatient appointment who are also eligible for the 
COVID booster vaccine based on routinely-collected data from these sources. We plan to launch the 
study after the booster vaccine has become widely available to adults and supply of vaccines at MGB is 
anticipated to be sufficient. Because the intervention cost is extremely low per patient, we plan to include 
all eligible patients. 
 
4.2 Informed consent 
As with other minimal-risk studies we have performed where informed consent is impracticable, we are 
requesting a waiver of informed consent and HIPAA authorization. There are several reasons for this. 
One, the nature of this communication-oriented intervention involves testing different messaging types 
utilizing secure communication channels that are already in use in routine clinical care. Second, the 
ability to understand the true effect of the intervention as it is delivered in the real world would be 
impossible to ascertain if formal informed consent from patients were sought. Third, obtaining formal 
informed consent would likely reduce the number of patients participating in the study, especially those 
from under-represented populations, and therefore undermine the generalizability of the study results, a 
foundational aspect of pragmatic clinical trial principles. Fourth, it would be extremely impractical as we 
expect more than 5,000 patients to still be eligible at the time of study launch. Fifth, contacting them in 
advance would actually introduce a co-intervention and reduce the ability to interpret the study findings. 
Finally, we will launch this project with approval by appropriate clinical leadership.  
 
4.3 Treatment assignment and randomization 
All eligible patients will be randomized to one of three arms: 1) “why” messaging, 2) “how” messaging, 
or 3) “standard of care (“usual care”). We plan to conduct stratified randomization based on the primary 
care clinic the patient attends to account for differences in patient populations between clinics. We will 
also use block-stratified randomization, in which the unit of randomization is the day of the week the 
study visit is on. This choice was made in response to the logistical difficulties randomizing at the patient 
level presented. Each weekday, eligible patients will be identified that have an upcoming visit 2-3 days 
from then. The day of the week of that visit will be randomized in a 1:1:1 ratio with a random number 
generator to one of three arms: 1) “why” messaging, 2) “how” messaging or 3) “standard of care” (“usual 
care”).    
 
 
5. 
STUDY PROCEDURES 
 

 
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5.1 Study Site 
Study participants will be selected from Mass General Brigham (MGB), a large integrated delivery 
network in Boston, MA, specifically from Mass General Hospital primary care clinics, where Dr. Haff 
practices. 
 
5.2 Overall Design 
We will use the Mass General Brigham COVID-19 Vaccine Registry and EHR information in the 
Research Patient Data Registry (RPDR) and/or Epic Enterprise Data Warehouse (EDW) to identify all 
patients age 18 with an upcoming primary care outpatient appointment who are eligible for the COVID 
booster vaccine. We plan to launch the study after the booster vaccine has become widely available to 
adults over age 18 and supply of vaccines at MGB is anticipated to be sufficient. All eligible patients will 
be randomized to one of three arms: 1) “why” messaging, 2) “how” messaging, or 3) standard of care 
(“usual care”). We will conduct stratified randomization based on the primary care clinic the patient 
attends and day of the week the upcoming visit is on. 
 
The primary outcome will be the rate of booster vaccination at the targeted visit. Secondary outcome will 
be receipt of a booster vaccine within 6 weeks of the target visit at any location. After completion of the 
trial, we will utilize data from the RPDR and/or EDW to develop models that predict which patients are 
most likely to respond to each intervention using patient baseline characteristics, which in the future could 
allow for targeting of interventions to specific patients. We will use the Mass General Brigham COVID-
19 Vaccine Registry and the RPDR/EDW for outcome measurement.   
 
5.2.1 Aim 1 Design 
In Aim 1 of the study, we will conduct a 3-arm randomized controlled trial to compare the effectiveness 
of two interventions compared to usual care on COVID-19 vaccination uptake. We will include Mass 
General Brigham (MGB) patients age 18 with an upcoming primary care outpatient visit with a Mass 
General Hospital primary care provider who are eligible for the COVID booster vaccine and who have 
not received a dose. This approach has been approved by MGH primary care leadership. Patients will be 
excluded if they did not receive the full set of their primary COVID-19 series.  
 
Patients will be randomized equally to one of three arms: 1) “why” messaging, 2) “how” messaging, 
or 3) standard of care (“usual care”). We plan to conduct stratified randomization based on the primary 
care clinic the patient attends to account for differences in patient populations between clinics and based 
on the day of the week the upcoming visit is on to minimize logistic difficulties in the intervention 
delivery. “Why” messages will focus on reasons to get the vaccine, including protecting self and loved 
ones or the idea of herd immunity. “How” messages will focus on the details of obtaining a vaccination at 
MGB, what to expect, and how to prepare for the visit. The messages will be sent through the EHR 
electronic patient portal for portal users. For patients whose primary language listed in the EHR is not 
English, they will be offered translated messages following standard MGB Gateway messaging practices. 
Gateway messages will first include a message translated in their primary language (Spanish, Portuguese, 
Arabic, Chinese, Russian, Haitian Creole or Bosnian) followed by an English version of the message. 
Consistent with recent studies for influenza vaccination and the approach approved by MGH primary care 
leadership, we will send a message to patients a few days in advance of their office visit.16 Based on 
current MGH practice (i.e., standard of care), patients in Arm 3 will not receive any additional message 
about their upcoming visit, beyond what they already receive by MGH. Initial examples of these 
messages are attached. 
 
 
 

 
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5.2.2 Aim 2 Design 
In Aim 2, we will assess association of clinical and demographic characteristics with intervention 
responsiveness. To do this, we will measure baseline patient clinical, historical, and demographic 
characteristics. Characteristics measured from the RPDR/EDW will include age, gender, race, prior 
influenza vaccine history, and comorbidities that increase risk of severe COVID disease, among others. 
We will also measure zip-code linked variables including mean household income, education level, 
rurality, and prevalence of COVID in the patient’s surrounding community. We will develop models that 
predict which patients are most likely to respond to each intervention using patient baseline 
characteristics, which in the future could allow for targeting of interventions to specific patients.  
 
 

 
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5.3 Study Schema 
 
Aim 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aim 2 
 
 
 
 
 
 
5.4 Scientific rationale for study design 
The use of a randomized trial design will be able to both provide stronger evidence of causality in the 
effectiveness of the interventions and allow for empiric derivation of patient characteristics that may 
influence intervention responsiveness. An observational study design or patient self-report of factors that 
influence intervention responsiveness are more subject to bias.  
 
5.5 Justification for intervention 
According to Construal Level Theory, emphasizing “why” elicits more abstract thinking, or high-level 
construals, and can induce an emotional mindset, which could challenge an individual’s sense of identity, 
autonomy, or political preferences. Conversely, emphasizing “how” is more cognitive and evokes 
concrete thinking, or low-level construals, and encourages a planning or implementation mindset.10,11 
Low-level construals (“how” messages) have been shown to increase intention to or uptake of several 
heath behaviors including dietary changes,12 use of relaxation techniques,13 blood donation,14 and 
completion of biometric screening and health surveys.15 Though prior studies of vaccine acceptance have 
not explicitly applied Construal Level Theory, aspects of interventions that elicit low-level construals 
have been successful compared to other techniques. 
 
3,300 patients who have not received COVID booster vaccination 
Randomization of patients 1:1:1 
Arm 1 
“WHY” 
N = 1100 
Arm 2 
“HOW” 
N = 1100 
Arm 3 
Usual Care 
N = 1100 
Regression or predictive modeling to: 
a) Identify patient clusters 
b) Develop responsiveness profiles 

 
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Because of the political and emotional valence of the COVID-19 vaccine, “how” messaging to elicit 
concrete thinking may be particularly important  Direct comparison of “how” vs “why” messages has not 
been tested for vaccines, and it has never been tested for COVID-19. Moreover, COVID vaccine 
hesitancy differs by age, gender, and race,4,6 and demographic groups may respond differently to 
messages. Tailoring a message to a specific group with higher rates of vaccine hesitancy could help 
reduce health disparities. 
 
5.6 End-of-study definition 
The active interventions in Aim 1 are expected to last no more than 1 week.  The study data collection of 
vaccination receipt will begin after the target primary care outpatient visit will conclude 1 month after the 
target visit is complete, as we anticipate some lag for complete vaccination information to be included in 
the MGB COVID-19 Vaccine Registry data source. Development of the prediction models will be done 
following Aim 1 data collection.  
 
5.7 Data sources 
Sources of research material, data that will be recorded, when data will be collected 
Data regarding patients' medical history, disease control, medication use and health care utilization will 
be obtained from The Mass General Brigham COVID-19 Vaccine Registry and EHR data from the 
Research Patient Data Registry (RPDR) and/or Enterprise Data Warehouse (EDW), supported by Epic 
Systems, Inc.  
 
The Mass General Brigham COVID-19 Vaccine Registry is a secure repository of data containing 
COVID-19 vaccine administration, utilization and adverse event information for analysis by the research 
community. This registry contains identified patient vaccination data for patients with a record of any 
type or dose of the COVID-19 vaccine.  The data lives on a secure server within the Mass General 
Brigham firewall. It is only accessible to IRB-approved researchers. The data in the registry is updated 
every week. Its usage is logged and audited. 
 
The Enterprise Data Warehouse for Epic EHR data resides in an Oracle 9i environment and consists of 
the Clarity and Payer databases. The Clarity database is a relational database that contains clinical and 
financial information from the Epic Suite of products; including the electronic medical record system 
(EpicCare), the appointment scheduling system (Cadence), the patient accounting system (Resolute), the 
patient web portal and the master patient index (Identity). The various tables within the Clarity database 
are refreshed on a daily, weekly or monthly basis. The data extracts obtained from the RPDR/EDW are 
maintained on secure MGB servers housed at the Division of Pharmacoepidemiology in the Department 
of Medicine at BWH. 
 
Linkages to subjects, access to subject identities 
Individually identifiable data are required to link patients between the Mass General Brigham COVID-19 
registry and the RPDR/EDW, and to send messages to patients as part of this trial. Without this linkage, 
we could not fulfill the study’s objectives. To protect the confidentiality of these data, only the minimal 
necessary research staff will have access to personal identifiers. After the intervention is completed and 
study variables are created, all identifiable information will be deleted from the study database. All 
research staff are properly trained in research management and will be approved by the IRB. All 
personally identifiable health information will be kept under lock and key.  
 
 
 

 
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Schedule of activities 
 
Screening Enrollment Intervention Analysis 
Identification of eligible patients 
X 
 
 
 
Randomization 
 
X 
 
 
Control and experimental interventions 
 
 
X 
 
Primary outcome analysis 
 
 
 
X 
Predictive modeling analysis 
 
 
 
X 
 
 
6 BIOSTATISTICAL ANALYSIS 
 
6.3 Statistical Hypothesis 
The null hypothesis is that rates of COVID booster vaccination will be equal in both of the intervention 
groups when compared to control.  
 
6.4 Samples size determination 
Sample size estimates suggest that ~1,100 individuals in each arm will allow us to observe a 5% 
difference in vaccination rates compared to the usual care arm, assuming a usual care arm vaccination rate 
of 20% as well as assumptions of alpha=0.05 and power=0.80. Given that more than 1 million patients 
receive care at MGB, we expect to identify at least 5,000 patients who have not yet received the booster 
vaccination at the outset of the trial and who will be eligible to receive one of the messages. This will also 
provide sufficient power for secondary outcomes. Under the same assumptions, we should be able to 
observe a <6% difference in 6-week vaccination rates compared to usual care, assuming a usual care arm 
vaccination rate of 25%.  
 
6.5 Statistical analyses 
6.5.1 
Analysis of the primary endpoint 
The primary outcome will be the rate of receipt of COVID booster vaccine dose in each arm at the target 
primary care outpatient appointment, treated as a binary outcome. We will use logistic regression to 
compare outcomes between each intervention arm versus usual care and against each other. Of note, we 
chose not to formally adjust for multiple testing in the primary analysis for several reasons. First, 
although the chance of finding at least one false positive among several tests is >5%, a Bonferroni 
correction would be much too conservative in this case, because the multiple comparisons among the 
treatment arms share the same four exposure groups. Second, a recent systematic review of multiple arm 
trials showed that more than half of all randomized trials with multiple exposure groups do not adjust for 
multiple comparisons,18 reasoning that if each exposure was compared with control in a separate trial, no 
adjustment would be necessary. 
 
6.5.2 
Analysis of the secondary endpoints 
Secondary outcomes will include in each arm the rate of receipt of COVID booster vaccine 6 weeks after 
the target primary care outpatient appointment. . As in the primary analysis, we will use the MGB 
Research Patient Data Registry (RPDR) and/or Electronic Data Warehouse (EDW) for outcome 
measurement. We will use logistic regression to compare outcomes between each intervention arm versus 
usual care and against each other; in secondary analyses, we will additionally adjust for any imbalanced 
baseline characteristics. 
 
6.5.3 
Baseline descriptive analyses 
We will report the means and frequencies of baseline variables for eligible patients.  

 
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6.5.4 
Exploratory analyses 
In subsequent analyses, we will develop a model to predict intervention responsiveness based on 
observable patient characteristics. We will fit separate logistic and boosted regression models using sets 
of these predictors to evaluate the ability to predict responsiveness to each messaging type. Boosted 
regression is a machine learning method robust to multi-collinearity and overfitting.19,20 For each, we will 
use 10-fold cross-validation to compare C-statistics for the ability to predict intervention response and 
calculate a continuous net reclassification index to assess changes in predicted response with additional 
predictors.21,22 We will also measure the relative influence of predictors to determine those that are most 
influential at predicting intervention responsiveness for a given arm.  
 
7 RISKS AND DISCOMFORTS  
 
We believe there is no more than minimal risk involved to patient subjects, as subjects will be receiving 
COVID-19 booster vaccination information through routine communication methods that will encourage 
the uptake of a vaccine recommended by the CDC and MGB in order to prevent COVID-19 disease. The 
study team will not be providing any direct care to patients and all vaccination decisions will ultimately 
be made by the patient, with the potential consultation of their medical team at Mass General Brigham. 
Thus, the main potential risk to subjects in this study is related to privacy of data, and we will take several 
measures to ensure that this risk is minimal, and that patient information is safeguarded.  
 
Patient data for study outcome evaluation will be drawn from the Mass General Brigham COVID-19 
Vaccine Registry and EHR information in the Research Patient Data Registry (RPDR) and/or Epic 
Enterprise Data Warehouse (EDW). The Mass General Brigham COVID-19 Vaccine Registry is a secure 
repository of data containing COVID-19 vaccine administration, utilization and adverse event information 
for analysis by the research community. The investigators are aware of the sensitive nature of the data and 
are committed to protecting patient privacy. Only the minimum necessary identifiable health care data 
needed to achieve the intended purpose will be used. All the data in the registry is contained within the 
Mass General Brigham firewall, and its usage is logged and audited. It is only accessible to IRB-approved 
researchers.  
 
For all study data, we will safeguard any identifiable information in accordance with IRB practices, limit 
access to the information to study investigators actively involved in the research who have all undergone 
human subjects research training, and store any data in accordance with IRB practices. Finally, as is our 
routine practice, great care will be taken to ensure the confidentiality of all data and to protect the privacy 
of participants through translation of all potentially traceable identifiers into untraceable coded subject 
numbers whenever possible. 
 
Of note, MGB has already set up an internal safety reporting system, which records any adverse events 
occurring after receipt of the vaccine and escalates serious medical issues resulting from vaccination to 
the patient’s provider as appropriate. Additionally, the CDC has also set up mechanisms to track vaccine 
safety. As such, any effort to collect information on vaccine side effects for our subjects would be 
duplicative and we will therefore not capture safety events through our own independent tracking system. 
However, we will be in regular contact with MGB clinical leadership and will be notified if patients or 
staff reach out to MGB with feedback about the intervention messages.    
 
8 POTENTIAL BENEFITS 
 

 
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The potential benefits to study participants include protection against COVID-19 disease if they choose to 
get vaccinated. Additionally, society may benefit in the future from potentially higher vaccination rates 
and the accumulated knowledge that originates from this research. 
 
 
9 MONITORING AND QUALITY ASSURANCE 
 
9.3 Ethical conduct 
General oversight of the project by the principal investigators (Drs. Haff and Lauffenburger) will occur 
throughout the study period, including regular contact with clinical leadership to obtain ongoing 
feedback. In addition, this protocol will undergo Institutional Review Board (IRB) evaluation by an 
institutional IRB. Study data will be accessible at all times for the principal investigators and co-
investigators to review, if applicable. The principal investigator will review study conduct (e.g., protocol 
deviations) on a monthly basis. The principal investigators will also ensure that all protocol deviations for 
the trials are reported to the NIH and the IRB according to the applicable regulatory requirements. We are 
also using an NIA-appointed Safety Officer (SO) for this study.  
 
The study team will not be providing any direct care to patients, and all vaccination decisions will 
ultimately be made by the patient, with the potential consultation of their medical team at Mass General 
Brigham. Any adverse events will be handled in the course of regular clinical care. Given the minimal 
risks involved in participation in this study, we do not anticipate any unacceptable adverse events. 
However, our plan for data and safety monitoring does include multiple mechanisms to ensure minimal 
risk of participation in the research. 
 
Of note, MGB has already set up an internal safety reporting system, which records any adverse 
events occurring after receipt of the vaccine and escalates serious medical issues resulting from 
vaccination to the patient’s provider as appropriate. Additionally, the CDC has also set up 
mechanisms to track vaccine safety. As such, any effort to collect information on vaccine side effects for 
our subjects would be duplicative and we will therefore not capture safety events through our own 
independent tracking system. However, we will be in regular contact with MGB clinical leadership and 
will be notified if patients or staff reach out to MGB with feedback about the intervention messages.  
 
However, if we receive communication from MGB leadership or participants themselves and thus we 
become aware of any AEs or SAEs throughout the course of the study, we will collect this information. 
Any reports of deaths will be submitted to the NIA Program Officer and to the SO within 24 hours. Any 
unexpected SAEs will be reported to the NIA PO, SO and the IRB within 48 hours of the study’s 
knowledge of the SAE. All other reported SAEs and AEs received by the study team will be reported to 
the NIA Program Officer and to the SO quarterly. 
 
9.4 Informed Consent 
As with other minimal-risk studies that utilize routinely collected patient data, we request a waiver of 
informed consent and HIPPA authorization. There are several reasons for this. One, the nature of this 
communication-oriented intervention involves testing different messaging types utilizing secure 
communication channels that are already in use in routine clinical care and will be done in collaboration 
with MGB leadership. Second, the ability to understand the true effect of the intervention as it is delivered 
in the real world would be impossible to ascertain if formal informed consent from patients were sought. 
Third, obtaining formal informed consent would likely reduce the number of patients participating in the 
study, especially those from under-represented populations, and therefore undermine the generalizability 
of the study results, a foundational aspect of pragmatic clinical trial principles. Finally, we expect 

 
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approximately 5,000 individuals to be eligible at the time of the messaging, and contacting them in 
advance would introduce a co-intervention as well as be impracticable. 
 
9.5 Confidentiality and privacy 
Data will be extracted from the Mass General Brigham COVID-19 Vaccine Registry and EHR 
information in the Research Patient Data Registry (RPDR) and/or Epic Enterprise Data Warehouse 
(EDW) at MGB. The COVID-19 Vaccine Registry contains identified patient data, including the type of 
vaccine administered, first or second dose, as well as when and where the patient received their vaccine. 
General patient demographic information, adverse reactions and patient identifiers are included in the 
COVID-19 Vaccine Registry. The investigators are aware of the sensitive nature of the data and are 
committed to protecting patient privacy. Only the minimum necessary identifiable health care data needed 
to achieve the intended purpose will be used. All the data in the registry is contained within the Mass 
General Brigham firewall, and its usage is logged and audited. The data extracts obtained from the 
RPDR/EDW are similarly maintained on secure MGB servers. RPDR/EDW extracts are continuously 
used by clinical operations staff for quality assessment and improvement, and undergo routine, rigorous 
peer-review by experienced data analysts to ensure accuracy and completeness.  Patient identifiers will be 
needed to link RPDR/EDW data to COVID vaccine registry data and to send messages to patients.  Once 
all data linkages and study interventions have been completed, patient identifiers will be removed and 
replaced with study IDs for data analysis.  
 
Data for the study will be safeguarded by state-of-the-art security protocols. The facilities have 24-hour 
security and are protected by locked entrances. MGB has computer networks in place that employ up to 
date virus protection software and enable password protected access only to study investigators. The setup 
for analysis of these data will be the same as all the other IRB applications that our MGB research 
division submits for secondary use of data. All the datasets, including limited protected health 
information (PHI), will be stored only on secure servers at MGB’s data center and will only be accessed 
by a limited number of individuals in the study team from this division who are all trained in data security 
and patient privacy.  
 
To ensure the confidentiality and security of all data, the research team operates a secure, state-of-the-art 
computing facility housed at MGB’s data center. The MGB data center is a secure facility that houses 
both computing environments as well as clinical systems and electronic medical records for several large 
hospitals in Eastern Massachusetts. Entry into the computer room requires staffed computer room 
security. The Division of Pharmacoepidemiology’s computers are connected to the MGB networking 
backbone with 10 gigabit-per-second fiber links. Network security is overseen by electronic medical 
records systems to the research team’s data. All data are transmitted to programmers’ workstations in an 
encrypted state. Backups are created using 256-bit AES encryption, the current Department of Defense 
standard for data security, and are stored in a locked facility. The redundancy, extensive data power, and 
security of our computer facility confirm our capacity to collect and manage data and ensure 
confidentiality for all project participants. 
 
We will also safeguard any identifiable information from the physicians in accordance with IRB 
practices, limit access to any information in accordance with IRB practices, limit access to the 
information to study investigators actively involved in the research who have all undergone human 
subjects research training.  
 
All members of the research team have completed or will complete appropriate human subjects research 
training and patient privacy training related to the Health Insurance Portability and Accountability Act 
(HIPAA). 

 
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9.6 Safety oversight 
We believe this study involves no more than minimal risks to subjects, and we do not anticipate any 
additional adverse events above what is experienced in routine COVID-19 vaccination practice. General 
oversight of this project by the Brigham and Women’s Hospital (BWH) co-leads (Drs. Haff and 
Lauffenburger) will occur throughout the study period, including regular contact with MGB clinical 
leadership involved in the project to obtain ongoing feedback.  
 
As described above, this study will include safety monitoring from an NIA-appointed independent safety 
officer (SO) to perform data and safety monitoring activities. This SO will advise NIA Program staff and 
the PIs regarding participant safety, study risks and benefits, scientific integrity, participant recruitment, 
and ethical conduct of the study. The SO will act in an advisory capacity to the NIA PO and to evaluate 
the progress of the study, including periodic assessments of data quality and timeliness, participant 
recruitment, accrual and retention, participant risk versus benefit, performance of trial sites, and other 
factors that can affect study outcome. The SO will make recommendations to the NIA PO concerning the 
continuation, modification, or conclusion of the trial.  
 
The study team will prepare safety reports at least biannually to be reviewed by the SO and NIA for 
recommendations for or against the trial’s continuation, as well as any modification to the study. In 
addition to safety data, the SO will consider recruitment and retention rates and whether delayed 
recruitment raises concerns of futility or ethical considerations. 
 
9.7 Benefit risk assessment 
9.7.1 
Known potential risks 
We believe there is no more than minimal risk involved to the patient subjects, as subjects will be 
receiving COVID-19 vaccination information through routine communication methods that will 
encourage the uptake of a vaccine recommended by the CDC and MGB in order to prevent COVID-19 
disease. The study team will not be providing any direct care to patients and all vaccination decisions will 
ultimately be made by the patient, with the potential consultation of their medical team at Mass General 
Brigham. Thus, the main potential risk to subjects in this study is related to privacy of data, and we will 
take several measures to ensure that this risk is minimal and that patient information is safeguarded.  
 
9.7.2 
Known potential benefits 
Use of Construal Level Theory for optimizing vaccination information could help increase COVID-19 
booster vaccine uptake by MGB patients. Thus, the potential benefits to study participants include 
protection against COVID-19 disease if they choose to get vaccinated. Additionally, society may benefit 
in the future from potentially higher vaccination rates and the accumulated knowledge that originates 
from this research. 
 
9.7.3 
Assessment of potential risks and benefits 
We will enroll patient-subjects based on their being eligible for the COVID-19 vaccine identified through 
the Mass General Brigham COVID-19 Vaccine Registry and Research Patient Data Registry (RPDR) 
and/or Epic Enterprise Data Warehouse (EDW). We also request a HIPAA waiver of patient authorization 
to access the HER data necessary for outcome evaluation. The main potential risk to subjects in this study 
is related to privacy of data, and we will take measures to ensure minimum necessary use of identifiers 
and that all data are safeguarded.  Individually-identifiable data are required to link patients between the 
Mass General Brigham COVID-19 registry and the RPDR/EDW, and to send messages to patients as part 
of this trial, and without this linkage, we could not fulfill the study’s objectives. To protect the 
confidentiality of these data, only the minimal necessary research staff will have access to personal 

 
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identifiers. All personally identifiable health information will be kept under lock and key. After the 
intervention is completed and study variables are created, all identifiable information will be deleted from 
the study database. Data for the study will be safeguarded by state-of-the-art security protocols and 
handled in accordance with IRB policies. All research staff are properly trained in research management 
and will be approved by the IRB.  
 
 
 
 

 
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