Brief Digital Intervention to Increase COVID-19 Vaccination Among Individuals With Anxiety or Depression
Phase: NA
Conditions: Misinformation, Vaccine Hesitancy, Anxiety, Depression, COVID-19
Sponsor: City University of New York, School of Public Health

Attitudinal inoculation to increase vaccination among adults with anxiety or depression 
RF1MH132360 
Study Protocol and Statistical Analysis Plan 
May 2, 2025
Study Protocol 
Trial Design 
In a 3-arm, parallel-group, assessor-blinded, stratified-randomized trial, participants were 
enrolled based on the following eligibility criteria: aged 18 years or older, having received at 
least one dose of the COVID-19 vaccine but no doses since September 11, 2023, and no SARS-
CoV-2 infection in the three months prior to the study start. We focused on individuals with at 
least one prior dose—the "moveable middle"—who show some willingness to vaccinate but 
remain hesitant about additional doses and may be more responsive to a brief video intervention 
than the unvaccinated. Our team’s prior research informed the trial design, and identified safety 
and efficacy as their main concerns17. 
Eligible individuals were randomly allocated to one of three interventions: 1) attitudinal 
inoculation, 2) CBT-kernels or 3) standard public health messaging. Recruitment and 
randomization started on April 15, 2024 and continued on a rolling basis until May 02, 2024. 
Outcome assessment at 4-week follow-up started on May 13, 2024 and was completed by June 
13, 2024. After consenting, enrolled participants were randomly assigned to one of three arms at 
a ratio of 1:1:1. Each arm was also stratified by presence or absence of moderate to severe 
anxiety or depression symptoms, defined by scoring ≥10 in the Patient Health Questionnaire-818 
or GAD-719 at any point between December 2022 and December 2023. 
Recruitment 
Individuals were recruited from the CHASING COVID cohort, a well-characterized, community-
based sample of geographically and socio-demographically diverse adults aged 18 years and 
older who reside in the US or US territories and enrolled in the cohort between March 28, 2020 
and August 21, 2020. Details of recruitment and follow-up have been described elsewhere20. 
Briefly, participants in the cohort have completed, approximately quarterly, online assessments 
related to health and behaviors, SARS-Cov-2 infection history, COVID-19 symptoms, and 
COVID-19 vaccination status. 
Informed Consent 
The study received approval from the Institutional Review Boards of the City University Of New 
York (CUNY) Graduate School of Public Health and Health Policy (New York, NY, USA) 
(protocol NCT06119854) and followed the Consolidated Standards of Reporting Trials 
(CONSORT) social and psychological interventions (SPI) reporting guidelines21,22.  Informed 
consent forms were completed via web browser on participants’ computers or mobile devices at 
baseline and periodic follow-up assessments. The trial was pre-registered at: 
https://clinicaltrials.gov/study/NCT06119854 
Participants 
Participant eligibility criteria at the time of study enrollment (April-June 2024) were as follows: 
(1) aged 18 and older, (2) able to read in English, (3) current residence in the US, (4) completed 
at least one survey as part of the CHASING COVID Cohort study between December 7, 2022 
and December 22, 2023, and (5) undervaccinated, defined as having received at least one dose of

Attitudinal inoculation to increase vaccination among adults with anxiety or depression 
RF1MH132360 
Study Protocol and Statistical Analysis Plan 
May 2, 2025
the COVID-19 vaccine, but not an updated COVID-19 vaccine dose since September 11, 2023. 
Participants were excluded if they (1) had a SARS-CoV-2 infection in the past three months, (2) 
had never received any dose of a COVID-19 vaccine, or (3) were flagged for fraudulent 
behavior. Fraudulent participants were identified as showing evidence of duplicate or 
inconsistent contact information, suspicious response times, repeated enrolment attempts, or 
fraudulent flags raised from other CHASING COVID-based studies. Further details of 
participant characteristics can be found in Appendix A.  
Intervention delivery and data collection occurred fully online. Participants completed an online 
survey at enrollment and at 4-weeks following enrollment.  
Intervention and Control Conditions 
Participants viewed one of three one-minute videos. The video content of the experimental arms 
was developed using formative mixed-methods research, including a pre-trial survey with 
CHASING COVID participants on vaccine perceptions and qualitative interviews with 
participants reporting anxiety or depression in earlier questionnaires. This process revealed a 
common concern about vaccine effectiveness as a broader “meta-narrative” across participants17. 
Additionally, those with anxiety or depressive symptoms were more likely to cite not “making 
time” as a reason for being behind on vaccination- a theme later incorporated into the CBT-
kernels condition.  
Specifically: 1) The inoculation video addressed concerns about vaccine effectiveness, focused 
on bolstering resistance to mis/disinformation. 2) The CBT-kernels video focused on addressing 
barriers to vaccination, specifically making time to get vaccinated. It focused on cognitive 
reframing—highlighting how individuals might selectively focus on information that reinforces 
vaccine-related anxiety, challenging those beliefs, and encouraging problem-solving around 
making time to get vaccinated. 3) The standard public health messaging arm was a brief video 
adapted from existing public health PSAs, with no inoculation or CBT-kernels elements. 
The videos were professionally created in collaboration with Long Story Short, a production 
company with experience in PSA creation that has worked with local, national, and global public 
health organizations. Our research team worked closely with the production team throughout the 
process, iterating on scripts, refining takes, selecting actors, and providing detailed feedback to 
ensure clarity and consistency. The research team included experts in mental health disorders, 
COVID-19 surveillance, infection and transmission, vaccine hesitancy and uptake, public health 
emergency preparedness and response, and risk communication. A member of the research team 
was present on set during filming to oversee production and ensure fidelity to our intended 
messaging. By creating all videos within the same production process, we maintained control 
over factors such as tone, format, duration, and overall presentation, reducing the risk of 
unintended differences that could influence participants’ responses. This approach allowed us to 
isolate the effects of the different messaging strategies while ensuring that all videos were 
aligned in terms of quality and delivery. A description and scripts of these videos can be found in 
Appendix D. 

Attitudinal inoculation to increase vaccination among adults with anxiety or depression 
RF1MH132360 
Study Protocol and Statistical Analysis Plan 
May 2, 2025
After receiving the brief digital intervention, participants received two reminders to get 
vaccinated by text or email on the first and third days after completing the baseline assessment. 
Messages were tailored to each arm and included a link to a COVID-19 vaccine locator. Their 
content can be found in Appendix A.  
Stratified Randomization Procedure and Masking 
Sequence Generation 
We used a two-stage procedure for randomization. First, participants eligible for recruitment 
were stratified into two groups based on the presence or absence of symptoms of anxiety or 
depression reported at any point between December 2022 and December 2023. Second, 
participants in both strata were randomized to one of the three intervention arms upon being 
enrolled. Thus, participants were randomized separately according to symptoms of anxiety or 
depression. 
Masking 
Participants and two team members involved in study operations and study implementation (AS 
and JN) were not blinded to study assignments. All other study team members, including 
investigators and the data analyst (JS), were blinded to study assignments.    
Measures 
Intervention Implementation (Adherence) Measure 
The survey was programmed to require participants to remain on the video page for at least the 
duration of the video. However, time spent on the webpage doesn’t necessarily reflect 
attentiveness, hence participants were also asked “Did this video hold your attention?” with 
options “Yes, it held my attention” and “No, it did not hold my attention / I did not watch the 
video.”  
Primary Outcome: Receipt of COVID-19 Vaccine Dose at 4 Weeks 
At the 4-week survey, participants were asked, “Have you received a COVID-19 vaccine dose 
since {date of intervention}?” Participants who responded “yes” were considered vaccinated; 
otherwise, they were not. 
Secondary Outcome: Vaccine Willingness at 4 Weeks 
At the 4-week survey, participants who had not received an additional dose of the vaccine were 
asked, “How willing are you to receive another COVID-19 vaccine dose?” with response 
options: “Very willing”, “Somewhat willing”, “Not willing”, or “Don’t know”. Only 
participants who responded ‘Very willing’ were defined as vaccine willing. 
Pre-trial vaccine willingness. After enrollment, but before randomization into an intervention 
arm, participants were asked, “How willing are you to receive another COVID-19 vaccine 
dose?” with response options: “Very willing”, “Somewhat willing”, “Not willing”, or “Don’t 
know”. 

Attitudinal inoculation to increase vaccination among adults with anxiety or depression 
RF1MH132360 
Study Protocol and Statistical Analysis Plan 
May 2, 2025
Post-trial vaccine willingness: Immediately after the intervention, participants were asked: 
“How likely are you to make time to get a vaccine in the next month?” with response options: 
“Very likely,” “Somewhat likely,” “Not likely,” and “Don’t know/not sure.” They were also 
asked: 
“Are you planning to make an appointment to get the COVID-19 vaccine in the next month?” 
with options: “Already made an appointment”, “Planning”, “Not planning”, “Don’t know/not 
sure”. These questions were asked again in the 4-week follow-up survey, but only among 
participants who had not received an additional vaccine dose during that time. For participants 
with missing follow-up data (N=56), responses from the immediate post-intervention survey 
were used as imputed values. 
Post-hoc Stratification Variables  
Post-hoc stratification analyses were performed to assess differences in primary and secondary 
outcomes based on susceptibility to severe COVID-19, worry about COVID-19, and pre-trial 
perceptions of vaccine efficacy. Further details regarding the measurement of these stratification 
variables were provided in Appendix A. 
Statistical Analysis Plan 
All statistical analyses were performed blind to study arm allocation. We present frequencies and 
summaries of characteristics by treatment assignment. Standardized mean differences (SMD) 
were reported. For post-randomization characters, Chi-squared or Fisher’s exact tests were used 
to compare proportions.  
Primary analyses were performed under the intention-to-treat principle, including all participants 
who underwent randomization. Strict intention-to-treat analysis is hard to achieve for two 
reasons: missing outcomes for participants and protocol non-adherence. For the primary 
analysis, we used multiple imputation for those lost to follow-up at some point after 
randomization (as recommended by the CONSORT statement23), which has the benefit of 
including all randomized participants. As a sensitivity analysis, we assessed loss to follow-up 
assumptions under (1) multiple imputation and (2) protocol non-adherence (see Appendix).  
For the primary outcome, we generated risk ratios using a robust Poisson regression model and 
generated risk differences. For the secondary outcome of vaccine willingness, we generated risk 
ratios using a Poisson regression model. The model for the overall effect estimation included the 
randomization arms and a term for the presence or absence of symptoms of anxiety or depression 
reported between December 2022 and December 2023. For an Intention to Treat (ITT) analysis 
of a stratified randomized trial, adjustment is recommended for the stratification variable23,24 on 
the principle that the analysis should follow the design23,25.   
To assess the effect of the intervention according to symptoms of anxiety or depression, we 
restricted them to subsets with or without symptoms. The stratified models included only 
randomization arms as the independent variable. Similarly, post-hoc stratification analyses for 
the primary and secondary outcomes were conducted separately among subsets of participants 
based on the presence or absence of the post-hoc stratification factors (susceptibility to severe 

Attitudinal inoculation to increase vaccination among adults with anxiety or depression 
RF1MH132360 
Study Protocol and Statistical Analysis Plan 
May 2, 2025
COVID-19, worry about COVID-19 and pre-trial perceptions of vaccine efficacy). The model 
included randomization arms and accounted for the presence or absence of symptoms of anxiety 
or depression. 
Lastly, the validity of an ITT effect estimate requires correct adjustment for selection bias due to 
differential loss-to-follow-up and missing outcome data23,26,27 .We used multiple imputation for 
loss-to-follow-up and missing data, hence conducting stratified analyses to assess effect 
modification rather than relying on interaction terms, as standard interaction testing isn’t 
directly applicable to imputed datasets28. Details on imputation methods are included in 
Appendix C. Methods for sensitivity analyses can be found in Appendix B. A series of 
sensitivity analyses were conducted to address assumptions related to loss to follow-up and 
protocol adherence, including complete case analysis, inverse probability weighting, per-
protocol analysis for participants fully adhering to the intervention, and multiple imputation for 
missing outcomes, with consistent results observed across primary and secondary outcomes.