Expectations and Prior Experiences Associated With Adverse Effects of COVID-19 Vaccination

Key Points Question Are positive and negative expectations prior to COVID-19 vaccination associated with systemic adverse effects in individuals receiving their second dose of COVID-19 vaccines? Findings In this cohort study of 1678 participants, expectations of low benefit and high adverse effects, the tendency to catastrophize instead of normalize benign bodily sensations, and prior negative experiences were associated with vaccination adverse effects. Meaning These finding suggest that risk factors for nocebo effects exist that can be assessed prior to vaccination and in some cases (ie, negative expectations) can potentially be changed via expectation management strategies.


Introduction
COVID-19 vaccines effectively reduce mortality and disease burden. 1 Their impact on the ongoing SARS-CoV-2 pandemic, however, depends on effective dissemination and high acceptance in the population.Despite ample vaccine availability, vaccine uptake remains less than desirable in many industrialized countries. 2[5] Adverse effects following COVID-19 vaccination include systemic reactions such as myalgia and fever. 6,7][10] Nocebo effects are phenomena whereby people taking inert substances experience adverse effects.However, they also influence clinical outcomes in active treatments. 11,12For example, in COVID-19 vaccine trials, adverse effects in placebo groups overlapped by 76% (first dose) and 52% (second dose) with those in vaccine groups, while underlying mechanisms were not investigated. 12gative expectations and contextual factors like prior experiences and observed experiences of significant others can amplify nocebo effects. 13Nevertheless, participants' expectations about benefits and risks of vaccines are typically not reported in COVID-19 vaccination trials.Psychological characteristics including anxiety, depression, and the tendency to amplify benign bodily sensations have been associated with higher reported adverse effects for active drugs and nocebo effects. 14,15reover, positive vaccination attitudes and low concern over COVID-19 vaccine adverse effects were associated with intentions for booster vaccination. 16More knowledge on these factors could aid in strategies to attenuate nocebo-related adverse effects.Therefore, we aimed to investigate whether expectations are associated with systemic adverse effects in individuals receiving their second dose of COVID-19 vaccines.We hypothesized that severity of systemic adverse effects would be increased in participants with lower benefit expectations, with higher expectations of adverse effects, and with more of their personal and observed prior experiences regarding adverse reactions to COVID-19 vaccines, after controlling for prevaccine symptom levels.Furthermore, we hypothesized that higher levels of anxiety and depression as well as a higher tendency to amplify bodily sensations would be associated with increased adverse effect reports.

Study Design, Setting, and Participants
We conducted a longitudinal cohort study at the COVID-19 vaccination center in Hamburg, Germany, which operated from Mondays through Saturdays from 8 AM to 8 PM.Study participants were recruited locally between August 16 and 28, 2021.All individuals receiving a second dose of BNT162b2 (Pfizer-BioNTech) or messenger RNA (mRNA)-1273 (Moderna) were eligible for the study if they were 18 years or older, had sufficient German language skills, and had capacity to consent.
After vaccination, individuals had to rest for 15 minutes before receiving their vaccination certificate and leaving the center.The project staff handed out a short information leaflet inviting individuals to participate in the study and answered questions.Due to time constraints for recruiting, individuals not fulfilling criteria for eligibility were excluded retrospectively.The study was approved by the local in Epidemiology (STROBE) reporting guideline.The study leaflet included a QR code facilitating installation of the application m-Path (KU Leuven) developed for clinical assessments and blended care interventions.After informed consent was obtained within the application, participants were asked to complete the baseline questionnaire in the waiting session directly following vaccination.
The first follow-up was activated at 9 PM on the same day.The remaining follow-ups were activated at 6 PM on days 2 to 7. A notification was sent when a questionnaire was activated and another reminder followed after 60 minutes.All questionnaires remained available until midnight and expired afterward.Expiration of a questionnaire did not exclude participants from participation, and notifications for future follow-up questionnaires continued as scheduled.

Outcome Variables
The primary outcome was a composite severity index of systemic adverse effects measured with an electronic symptom diary over 7 consecutive days.Systemic adverse effects of vaccines are defined as whole-body reactions (eg, body aches, fever) occurring in the days following vaccination as opposed to allergic reactions that followed minutes after the injections or local adverse effects that followed within a few hours after the vaccination. 17,18The items of the symptom diary were derived from phase 3 trials of BNT162b2 7 and mRNA-1273 6 and included aching limbs, chills, deep leg pain, diarrhea, fever, hematomas and/or punctiform hemorrhages, headache, heart pain, joint pain, shortness of breath, tiredness or fatigue, and vomiting (eBoxes 1 and 2 and eMethods in Supplement 1).
At baseline, study participants were instructed to rate the highest severity of these symptom areas during the last 2 weeks before vaccination.At each follow-up, participants were asked to report the current severity in each symptom area.For our multivariable analyses, a composite index of symptom severity was calculated.It was defined by the highest severity in the 12 symptom areas.For example, if a study participant had headache with light severity and tiredness with moderate severity, the composite index showed moderate severity.

Independent Variables
Independent variables measured expected benefits and risks as well as personal and observed prior experiences related to COVID-19 vaccination and were reported at baseline using a self-developed scale based on an existing questionnaire. 19The study participants used a numerical rating scale ranging from "no benefit" to "very high benefit" to rate expected benefit of vaccination.Numerical rating scales ranging from "no risk" to "very high risk" were used to report expected risks connected with COVID-19 infection and vaccination.The 4-item version of the Patient Health Questionnaire was used to screen for anxiety and depression. 20,21The Somatosensory Amplification Scale was used to measure the tendency to catastrophize instead of normalize benign bodily sensations such as itching or pain due to insect bites or hunger contraction of stomach. 22,23tential confounders were prespecified based on our experience from other studies and without statistical exploration.They included the vaccine used on the day of recruitment, health status, and sociodemographic data assessed at baseline.Sociodemographic data included age, sex, living arrangements, educational level, and migration status.Educational level was operationalized by highest general and vocational qualification and coded pursuant to the Comparative Analysis of Social Mobility in Industrial Nations classification. 24Migration status was assessed by country of birth of study participants and their parents.Health status was assessed by self-report based on a list of 13 medically treated health problems. 25More details about the used scales can be found in eMethods in Supplement 1.

Statistical Analysis
We conducted mixed-effects multivariable ordered logistic regression analyses adjusted for random effects on study participant level to analyze the association between independent variables and the composite index of self-reported systemic adverse effects (outcome).Sensitivity analyses identified associations between independent variables and specific outcomes that were reported at any time of observation by at least 10% of the population.These analyses used the same statistical model as the main analysis.Additionally, we provided ORs for unadjusted associations between independent variables and the composite outcome index, which were controlled for baseline values, time of observation, and random effects on the study participant level.The interrelation between the independent variables in the main analysis was analyzed by Pearson correlation.An α level of 5% (2-sided P < .05)was defined as statistically significant.The statistical analyses were performed using Stata, version 15.1 (StataCorp LLC).

Results
The

Discussion
In agreement with a priori specified hypotheses, participants who expected a lower benefit from vaccination, those who expected more adverse effects of vaccine, and those who had experienced more adverse effects after first vaccination reported higher severity of most systemic adverse effects after adjusting for prevaccine symptom levels.Likewise, individuals reporting higher scores in anxiety and depression and those scoring higher on the Somatosensory Amplification Scale reported more symptoms in some observed categories.Generally, more severe symptoms were reported by women.Contrary to our hypothesis, observing adverse effects of vaccine in others was not associated with personal systemic adverse effects.
Nocebo effects after vaccination can be caused by 3 main mechanisms: learning, expectations, and misattribution. 26Our results suggest the presence of all these mechanisms in our sample.
Symptoms after the first vaccination had the strongest association with adverse effects in our model, indicating the presence of learning mechanisms from prior experiences as a conditioning phenomenon.Such learning mechanisms were already proposed in a comparison of vaccine and placebo groups of the phase 3 trials of mRNA vaccines, where following the second dose, an increase of all adverse effects except local pain could be observed. 27However, it is also possible that a certain immunological predisposition regarding adverse effects exists in some patients, which could be responsible for experiencing similar adverse effects in both vaccinations.
Additionally, perceived individual risk for adverse effects indicated negative expectations as another trigger for nocebo effects.Another study that investigated nocebo effects in vaccinationnaive participants 28 also identified that negative expectations, as well as worries about COVID-19 and depressive symptoms, as associated with adverse effects.In our sample, worries about COVID-19 were not a significant factor.
We also observed that the risk for adverse effects increased with the severity of baseline symptoms, indicating misattribution of preexisting symptoms.Our results are in accordance with other studies reporting higher levels of anxiety, depression, and somatosensory amplification as predisposing factors of higher somatic symptom load. 20The involved mechanisms include cognitive, emotional, and behavioral factors such as selective attention toward interoceptive cues, amplified perception of benign bodily sensations, and maintenance of these processes through catastrophizing cognitive interpretations and unhelpful illness behaviors.In addition, we observed that a belief in the personal benefit of vaccination was inversely associated with systemic vaccine adverse effects, whereas neither the perceived risk to contract COVID-19 nor the perceived risk for hospitalization due to COVID-19 were associated with vaccine adverse effects.

Implications for Clinical Practice
In contrast to other predisposing factors for adverse effects like preexisting symptoms, prior experiences, or sex that are documented in our data as well as in other studies, 28 expectations might be changed via short and economic psychological interventions. 29,30Probable effective strategies include framing of adverse effects information by emphasizing the probability of being free from adverse effects, 31 by elaborating on anticipated positive effects and their working mechanisms, 32 or by accompanying adverse effect information with specific coping strategies. 29rthermore, counteracting symptom misattribution by explicitly informing about nocebo effects (ie, "Worrying about potential adverse effects can intensify concerns like a self-fulfilling prophecy.People taking placebos in clinical trials often report adverse effects, thereby, misattributing benign bodily sensations such as common headaches or fatigue to the vaccine") has been shown to be effective in other contexts in reducing experimentally induced nocebo effects 33 and in functionally adapting patients' informational needs regarding medication. 34Furthermore, patients' prior experiences and psychosocial characteristics such as the tendency to amplify bodily sensations might be included in contextualized informed consent procedures. 35

Limitations and Strengths
This study has some limitations.Our results identify approaches for improving patient information by avoiding triggering potential nocebo effects.However, to evaluate their effectiveness, these approaches must be tested in randomized clinical studies.Furthermore, we did not conduct a sample size calculation; therefore associations with systemic adverse effects could have been missed.
Many COVID-19 studies and mobile application-based studies have large sample sizes (n > 1000), but seemingly low response rates (eg, 12% in Ayoubkhani et al 36 and 2.4% in Ryan et al 37 ).In our case, the response rate of 24.0% is related to high throughput of the vaccination center, in which communication with individuals cannot be as detailed as in other studies.Therefore, response rates are lowered by individuals who were invited to participate but were not eligible (eg, no smartphone, vector vaccines, or first vaccination).Nevertheless, as in other studies, this can limit representativeness if the sample systematically deviates from the population in variables that are associated with the dependent variable, but not included as covariate in the statistical models.For example, one might overestimate nocebo effects if individuals with lower tendency to somatize risk expectations had been less likely to participate.
The low number of participants without secondary education and the high number of participants with tertiary education indicate that our sample is not fully representative of the general population.9][40] The distribution in this variable might also correspond with education-based differences in general willingness to participate in scientific studies. 41,42Furthermore, 82.6% were younger than 50 years and expectations of symptom load after COVID-19 vaccination might differ in older groups.Also, we did not adjust for possible clusters of vaccinated individuals (eg, family or social ties).
Moreover, we used a composite index as end point that ignores differences between symptoms and neglects multiplicative burden of multiple symptoms.

Table 2 .
Associations With Systemic Adverse Effects: Results of Mixed-Effects Ordered Logistic Regression Analysis Adjusted for Random Effects on the Patient Level a (continued) Expectations and Prior Experiences Associated With Adverse Effects of COVID-19 Vaccination JAMA Network Open.2023;6(3):e234732.doi:10.1001/jamanetworkopen.2023.4732(Reprinted) March 27, 2023 10/16 Downloaded From: https://jamanetwork.com/ on 09/18/2023 Expectations and Prior Experiences Associated With Adverse Effects of COVID-19 Vaccination 38.Finney Rutten LJ, Zhu X, Leppin AL, et al.Evidence-based strategies for clinical organizations to address COVID-19 vaccine hesitancy.Mayo Clin Proc.2021;96(3):699-707.doi:10.1016/j.mayocp.2020.12.024 39.Hudson A, Montelpare WJ.Predictors of vaccine hesitancy: implications for COVID-19 public health messaging.Int J Environ Res Public Health.2021;18(15):8054.doi:10.3390/ijerph1815805440.Umakanthan S, Lawrence S. Predictors of COVID-19 vaccine hesitancy in Germany: a cross-sectional, population-based study.Postgrad Med J. 2022;98(1164):756-764.doi:10.1136/postgradmedj-2021-14136541.Korkeila K, Suominen S, Ahvenainen J, et al.Non-response and related factors in a nation-wide health survey.Histogram and Kernel Density Estimation of Somatosensory Amplification Scale Score (N = 1678) eFigure 5. Composite Severity Score of Baseline Symptom Load and Systemic Adverse Effects in Any of the 12 Categories (N = 1678) eFigure 6. Correlation Matrix of Independent Variables in Main Analysis (N = 10 447) eTable 1. Unadjusted Association Between Expected Benefit of Vaccination and Systemic Adverse Effects: Results of Mixed-Effects Ordered Logistic Regression Analysis Adjusted for Random Effects on the Patient Level eTable 2. Unadjusted Association Between Expected Risk for COVID-19 Infection and Systemic Adverse Effects: Results of Mixed-Effects Ordered Logistic Regression Analysis Adjusted for Random Effects on the Patient Level eTable 3. Unadjusted Association Between Expected Risk for Hospitalization due to COVID-19 Infection and Systemic Adverse Effects: Results of Mixed-Effects Ordered Logistic Regression Analysis Adjusted for Random Effects on the Patient Level eTable 4. Unadjusted Association Between Expected Risk for Adverse Effects of Vaccination and Systemic Adverse Effects: Results of Mixed-Effects Ordered Logistic Regression Analysis Adjusted for Random Effects on the Patient Level eTable 5. Unadjusted Association Between Expected Risk for Hospitalization Due to Adverse Effects of Vaccination and Systemic Adverse Effects: Results of Mixed-Effects Ordered Logistic Regression Analysis Adjusted for Random Effects on the Patient Level eTable 6. Unadjusted Association Between Expected Risk for Long-term Adverse Effects of Vaccination and Systemic Adverse Effects: Results of Mixed-Effects Ordered Logistic Regression Analysis Adjusted for Random Effects on the Patient Level eTable 7. Unadjusted Association Between Adverse Effects Experienced at First Vaccination and Systemic Adverse Effects: Results of Mixed-Effects Ordered Logistic Regression Analysis Adjusted for Random Effects on the Patient Level eTable 8. Unadjusted Association Between Adverse Effects Observed in Close Contacts and Systemic Adverse Effects: Results of Mixed-Effects Ordered Logistic Regression Analysis Adjusted for Random Effects on the Patient Level eTable 9. Unadjusted Association Between Anxiety and Depression and Systemic Adverse Effects: Results of Mixed-Effects Ordered Logistic Regression Analysis Adjusted for Random Effects on the Patient Level eTable 10.Unadjusted Association Between Somatosensory Amplification and Systemic Adverse Effects: Results of Mixed-Effects Ordered Logistic Regression Analysis Adjusted for Random Effects on the Patient Level eTable 11.Associations With Tiredness/Fatigue: Results of Mixed-Effects Ordered Logistic Regression Analysis Adjusted for Random Effects on the Patient Level eTable 12. Associations With Headache: Results of Mixed-Effects Ordered Logistic Regression Analysis Adjusted for Random Effects on the Patient Level eTable 13.Associations With Aching Limbs: Results of Mixed-Effects Ordered Logistic Regression Analysis Adjusted for Random Effects on the Patient Level JAMA Network Open | Infectious Diseases Expectations and Prior Experiences Associated With Adverse Effects of COVID-19 Vaccination Associations With Joint Pain: Results of Mixed-Effects Ordered Logistic Regression Analysis Adjusted for Random Effects on the Patient Level eTable 15.Associations With Chills: Results of Mixed-Effects Ordered Logistic Regression Analysis Adjusted for Random Effects on the Patient Level eTable 16.Associations With Fever: Results of Mixed-Effects Ordered Logistic Regression Analysis Adjusted for Random Effects on the Patient Level eTable 17.Associations With Deep Leg Pain: Results of Mixed-Effects Ordered Logistic Regression Analysis Adjusted for Random Effects on the Patient Level eBox 1. Symptom Diary-English Version, Translated From German eBox 2. Symptom Diary-German Version Possible bias resulting from this decision JAMA Network Open | Infectious Diseases JAMA Network Open.2023;6(3):e234732.doi:10.1001/jamanetworkopen.2023.4732(Reprinted) March 27, 2023 15/16 Downloaded From: https://jamanetwork.com/ on 09/18/2023 eTable 14.