No(cebo) Vax: COVID-19 Vaccine Beliefs Are Important Determinants of Both Occurrence and Perceived Severity of Common Vaccines' Adverse Effects.

This study highlights the role of psychological influences in triggering and amplifying the adverse effects of the COVID-19 vaccine (i.e., nocebo effects). Fear, beliefs, and expectations about the COVID-19 vaccine, trust in health and scientific institutions, and stable personality traits were measured in 315 adult Italian citizens (145 men) during the 15-min waiting time after vaccination. The occurrence and severity of 10 potential adverse effects were assessed 24 hr later. Nonpharmacological variables predicted nearly 30% of the severity of the vaccine's adverse effects. Expectations are important determinants of adverse effects from vaccines, and the results of the path analyses show that these expectations stem primarily from people's vaccine beliefs and attitudes, which can be changed. Implications for increasing vaccine acceptability and limiting the nocebo effect are discussed.

Teenagers' and parental individual needs for side effects information and the influence of nocebo effect education.

OBJECTIVES: When developing a policy on how information about medication and its side effects (SE) should be provided in pediatrics, it is crucial to know individual needs. This paper investigates teenagers' and parental attitudes on information on SE, before and after education on the nocebo effect (NE). METHODS: This multicenter survey study included 226 teenagers (12-18 years) and 525 parents of patients (0-18 years). Questions assessed demographics, clinical characteristics and attitudes towards the amount of SE information before and after the explanation of NE. RESULTS: Before NE education, 679 (93 %) participants preferred to receive SE information: 337 (45 %) about all possible SE and 360 (48 %) desired specific information (i.e., severe, common, visible, or long-term SE). After NE explanation, significantly more participants (58 %) wished to receive information about all possible SE (p < .001). When explaining SE, teenagers preferred positive framing more than parents (64 % vs. 54 %, p = .043). CONCLUSIONS: Most teenagers and parents wish to receive extensive SE information, even after explaining the NE, but variances in individual needs exist. PRACTICE IMPLICATIONS: This study emphasizes the importance of tailor-made communication strategies for providing information on medications to parents and their children.

Vaccine hesitancy prospectively predicts nocebo side-effects following COVID-19 vaccination.

The directionality between vaccine hesitancy and COVID-19 vaccine side-effects has not been hitherto examined. We hypothesized a nocebo effect, whereby vaccine hesitancy towards the second Pfizer vaccination dose predicts subsequent side-effects for a booster dose, beyond other effects. We expected these nocebo effects to be driven by (mis)information in males and prior experience in females. A representative sample of older adults (n = 756, mean age = 68.9 ± 3.43) were questioned in a typical cross-lagged design (wave 1 following a second Pfizer dose, wave 2 after their booster). As hypothesized, earlier vaccine hesitancy predicted subsequent booster side-effects for females (ß = 0.10 p = 0.025, f 2 = 0.02) and males (ß = 0.34, p < 0.001, f 2 = 0.16); effects were stronger in males (χ2Δ (1) = 4.34, p = 0.03). The (W1-to-W2) side-effect autoregression was stronger in females (ß = .34, p < 0.001; males ß = 0.18, p < 0.001), χ2Δ (1) = 26.86, p < 0.001. Results show that a quantifiable and meaningful portion of COVID-19 vaccine side-effects is predicted by vaccine hesitancy, demonstrating that side-effects comprise a psychosomatic nocebo component in vaccinated individuals. The data reveal distinct risk levels for future side-effects, suggesting the need to tailor public health messaging.

The nocebo phenomenon in the COVID-19 pandemic: a nocebodemic effect.

INTRODUCTION: The COVID-19 pandemic had remarkable effects on psychological distress. The main stressors were prolonged quarantine and social isolation, fear of infection and death, stigmatization, infodemic, financial difficulties, and job loss. These negative stressors, which affect mental and physical health, make people more vulnerable to nocebo-related risk behaviors. We aimed to summarize data on nocebo behaviors, such as the negative psychological consequences of the COVID-19 pandemic in terms of how people perceive and interpret medical services and treatments. AREAS COVERED: Limited data were found from randomized controlled trials with SARS-CoV-2 vaccines and from surveys on healthy people, healthcare workers, and patients with chronic pain disorders. EXPERT OPINION: Studies have shown nocebo effects among participants in SARS-CoV-2 vaccines trials, among patients with chronic pain, and among healthcare workers. These effects were widely amplified during the pandemic era, prefiguring a 'nocebodemic effect' to describe the massive negative interpretation of health services and medical treatments. Greater awareness of these findings could reduce the impact of the 'nocebodemic effect' and increase public trust in science.

COVID-19 vaccine safety and nocebo-prone associated hesitancy in patients with systemic rheumatic diseases: a cross-sectional study.

OBJECTIVE: To describe the rate and type of adverse effects (AEs) and the frequency of disease flares after COVID-19 vaccination and to assess the reasons for vaccination hesitancy (non-vaccination) in SRD patients. METHODS: Telephone interviews were conducted of SRD patients consecutively enrolled (15/06/2021-1/7/2021). Participants were asked about the type of AEs and disease flare after vaccination. Reasons for vaccination hesitancy were recorded. Univariate and mutivariable analyses examined associations of demographic, clinical and other features, with occurrence of AEs, disease flare and non-vaccination. For the latter, association with negative vaccination behaviour (not influenza vaccinated for the last 2 years) and nocebo-prone behaviour (denoting AEs attributed to negative expectations [Q-No questionnaire]) was also tested. RESULTS: 561 out of 580 contacted patients were included in the study. 441/561 (78.6%) patients were vaccinated [90% (Pfizer, Moderna), 10% (Astra-Zeneca)]. AEs were reported by 148/441 (33.6%), with rates being comparable between the three vaccines. AEs were more common in females and those with chronic obstructive pulmonary disease [OR, 95% CI; females: 2.23 (1.30-3.83); COPD: 3.31 (1.24-8.83)]. Disease flare was reported in 9/441 (2%) patients. For those unvaccinated, fear that the vaccine would be harmful (53.3%), could cause disease flare (24.2%) and/or could cause thrombosis (21.7%) were the main reasons to do so. Multivariable analysis identified as independent variables for non-vaccination: nocebo-prone behaviour (OR; 95% CI, 3.88; 1.76-8.55), negative vaccination behaviour (6.56; 3.21-13.42) and previous COVID-19 infection (2.83; 1.13-7.05). Higher educational status was protective (0.49; 0.26-0.92). CONCLUSION: No new safety signals for COVID-19 vaccination were observed. Vaccination campaign should target SRD patients with nocebo-prone and negative influenza vaccination behaviour.

Nocebo responses in randomized controlled trials of COVID-19 vaccines.

OBJECTIVE: The aim of this study was to evaluate the frequency and magnitude of nocebo responses in -COVID-19 vaccine trials. MATERIALS AND METHODS: We performed a meta-analysis of adverse effects (AEs), severe adverse effects (SAEs), withdrawal due to AEs, death, and immune-mediated SAEs observed in randomized controlled trials (RCTs) of COVID-19 vaccines. RESULTS: Four RCTs with a total of 119,110 participants (65,254 from the vaccine group and 53,856 from the placebo group) were considered. The pooled estimate of AEs in the placebo and vaccine groups was 16.4% (95% confidence interval (CI), 9.1 - 27.7%) and 25.3% (95% CI, 22.7 - 28.1%), respectively. The pooled SAE rate in the placebo and vaccine groups was 0.7% (95% CI, 0.5 - 1.0%) and 0.6% (95% CI, 0.4 - 0.9%), respectively. The pooled estimate of participants who withdrew from treatment due to AEs in the placebo and vaccine groups was 0.3% (95% CI, 0.1 - 1.0%) and 0.2% (95% CI, 0.1 - 0.5%), respectively. The pooled death rate in the placebo and vaccine groups was 0.02% (95% CI, 0.01 - 0.04%) and 0.01% (95% CI, 0.01 - 0.03%), respectively. The pooled estimate of immune-mediated SAEs in the placebo and vaccine groups was 0.01% (95% CI, 0.01 - 0.04%) and 0.02% (95% CI, 0.01 - 0.05%), respectively. There were no differences observed in the pooled risk of AEs, SAEs, withdrawal due to AEs, death, and immune-mediated SAEs between placebo and vaccine groups. CONCLUSION: The frequency and magnitude of nocebo responses were 16.4% and 0.3%, respectively. Therefore, the incidence of nocebo responses was high, but their magnitude was low in COVID-19 vaccine trials.

Experiencing COVID-19 symptoms without the disease: The role of nocebo in reporting of symptoms.

BACKGROUND: A nocebo effect occurs when inactive factors lead to worsening of symptoms or reduce treatment outcomes. Believing that one is or has been infected with COVID-19 may act as a nocebo. However, not much is known about potential nocebo effects associated with the reporting of COVID-19 symptoms. AIM: An online survey investigated whether certainty of being infected with COVID-19, age, sex, cognitive, emotional and personality factors were associated with perceived severity of COVID-19 symptoms. METHODS: Participants (N=375) filled out an online survey containing 57 questions asking about symptoms resembling COVID-19, certainty of being infected with COVID-19, anxiety, stress and personality dimensions. RESULTS: Certainty of being infected with COVID-19 and anxiety predicted 27% of the variance in reporting of COVID-like symptoms. The mediation analysis showed that both higher certainty of being infected and anxiety independently predicted increased reports of COVID-like symptom. Females had higher anxiety and stress levels, and reported more COVID-like symptoms than males did. Older age was not associated with reporting COVID-like symptoms. CONCLUSIONS: Believing to be infected with COVID-19, along with anxiety, can enhance the severity of COVID-like symptoms. Thus, the nocebo effect was due to both cognitive and emotional factors and was higher in females.

How do nocebo effects in placebo groups of randomized controlled trials provide a possible explicative framework for the COVID-19 pandemic?

Introduction: Randomized clinical trials (RCTs) are useful to study the role of individual and contextual factors in which therapies vs placebos are administered and to provide an important perspective for understanding the phenomenon of nocebo-related risks.Areas covered: The results of nocebo effects in RCT placebo groups, measured in terms of adverse events (AEs) and dropouts, will be presented as an explicative framework for the COVID-19 pandemic. Currently, SARS-CoV-2 vaccines are the only RCTs routinely conducted during the pandemic. Information about efficacy and safety of different vaccines represents a fertile ground for nocebo phenomena. Individual and contextual factors will be emphasized in order to understand the presence of a refusal of immunization associated with a specific vaccine considered less effective and safe. Critical aspects and some guidelines will be presented in order to counteract the nocebo effects and to improve adherence to drug treatments and the vaccination campaign.Expert opinion: The nocebo effect could explain the presence of strong resistance in European countries to immunization with a vaccine perceived as less effective, compared to others. Increased awareness of the nocebo effect would be relevant as it could lead to a greater participation in the vaccination campaign and in protecting individuals against SARS-CoV-2 infection.

Rethinking Clinical Trials and Personalized Medicine with Placebogenomics and Placebo Dose.

Pharmacogenomics, nutrigenomics, vaccinomics, and the nascent field of plant omics are examples of variability science. They are embedded within an overarching framework of personalized medicine. Across these public health specialties, the significance and biology of the placebo response have been historically neglected. A placebo is any substance such as a sugar pill administered in the guise of medication, but one that does not have pharmacological activity. Placebos do have clinical effects, however, that can be substantive in magnitude and vary markedly from person-to-person depending, for example, on the type of disease, symptoms, or clinical trial design. Research over the past several decades attests to a genuine neurobiological basis for placebo effects. All drugs have placebo components that contribute to their overall treatment effect. Placebos are used in clinical trials as control groups to ascertain the net pharmacological effect of a drug candidate. Not only less well known but also relevant to rational therapeutics and personalized medicine is the nocebo. A nocebo effect occurs when an inert substance is administered in a context that induces negative expectations, worsening patients' symptoms. With the COVID-19 pandemic, there are high public expectations for new vaccines and medicines to end the contagion, while at the same time antiscience, post-truth, and antivaccine movements are worrisomely on the rise. These social movements, changes in public health cultures, and conditioned behavioral responses can trigger both placebo and nocebo effects. Hence, in clinical trials, forecasting and explaining placebo and nocebo variability are more important than ever for robust science and personalized health care. Against this overarching context, this article provides (1) a brief history of placebo and (2) a discussion on biology, mechanisms, and variability of placebo effects, and (3) discusses three emerging new concepts: placebogenomics, nocebogenomics, and augmented placebo, that is, the notion of a "placebo dose." We conclude with a roadmap for placebogenomics, its synergies with the nascent field of social pharmacology, and the ways in which a new taxonomy of drug and placebo variability can be anticipated in the next decade.