COVID-19 vaccination, from first dose to booster: New insights into the frequency of most common systemic adverse events and possible booster nocebo effects based on a systematic review
Authors: Behrens Claudia , Samii-Moghadam Maria , Gasperazzo Tatiana , Gross Anna M. , Mitchell Jack , Lampe Johannes B. 
Published: December 2021

AbstractBackgroundBased on placebo data, it has been recently demonstrated that the frequencies of most common adverse events (AEs) of COVID-19 vaccination are overestimated due to negative expectation bias of vaccine recipients (nocebo effect). Since booster studies lack comparators, estimating the extent of the nocebo effect is difficult. We aimed to overcome this obstacle through a systematic comparison of most common AE frequencies across vaccine doses (first, second, booster), age groups, and vaccine vs. placebo arms.MethodsWe systematically assessed systemic AEs in approved COVID-19 vaccines according to the PRISMA guidelines. All documents regarding COVID-19 vaccines with a booster dose authorized by the FDA (cutoff date 19 November 2021) were systematically searched on PubMed and the FDA website. Solicited systemic AEs from all documents supporting approval/authorization were collected. After standardization of doses and age groups, AE frequencies were compared between vaccine and placebo.FindingsTwo trials were identified for BNT162b2 (n=21,785 participants), two for mRNA-1273 (n=22,324), and one for Ad26.COV2.S (n=4,085). Fever cases dropped to about half with the booster dose in all vaccines, whereas all other systemic AE frequencies were similar to the preceding dose. Almost no fever cases occurred with placebo (first/second dose); all other systemic AEs occurred at high frequencies. After subtracting placebo arm values from vaccine values, the frequencies for the various AEs were roughly comparable within each dose for each vaccine.InterpretationFever is the only solicited systemic AE that can be assessed objectively. It occurs about 50% less often with the booster than with the preceding dose. This may indirectly indicate a considerable overestimation of systemic AEs in the case of booster vaccinations and a pronounced nocebo effect. The nocebo effect appears to substantially contribute to the differences in the frequencies of the various systemic AEs.FundingNo funding received.Research in contextEvidence before this studyA high nocebo effect has recently been shown for the most common solicited adverse events (AEs) based on the randomized controlled trials of several vaccines approved for COVID-19. To date, there has been no systematic review of systemic AEs in COVID-19 vaccines with a booster dose approved by the FDA. Normally, assessing the extent of the nocebo effect requires the implementation of randomized, placebo-controlled studies. However, for ethical reasons, studies underlying the authorization of COVID-19 booster vaccines are not controlled. Therefore, reported AEs lack any reference parameter.We searched PubMed and medRxiv for nocebo effects regarding the objectively measurable AE fever using the terms “(COVID) AND (nocebo) AND (fever)” with no language restrictions; no hits were found on PubMed and six were found on medRxiv. The search without any indication, using only the search terms “(nocebo) AND (fever)”, resulted in two hits on PubMed and six hits on medRxiv. An additional search was performed for “(vaccine or COVID) AND nocebo”; 21 hits were found on PubMed and 12 on medRxiv. None of the hits obtained with the three searches showed evidence of relevance for the present topic of a direct association of fever with the nocebo effect.Added value of this studyInstead of placebo AE data as reference parameter, we suggest fever as an objectively measurable value to estimate the extent of the nocebo effect in uncontrolled vaccination studies. To our knowledge, this is a new concept with which evidence for the extent of a possible nocebo effect in COVID-19 booster vaccination can be provided. With this approach we directly supplement information on the most recently reported nocebo effects in first, second and booster vaccine doses.To the best of our knowledge, this is the first study to indirectly compare the solicited systemic AE frequencies of approved COVID-19 vaccines across all doses, with easy-to-understand graphs and based on all approval-relevant trials. This is astonishing, as in the context of a pandemic it is essential to communicate scientific data in a generally understandable manner and according to the highest scientific standards. The graphs provided in this work could serve as an example for such clear communication.Implications of all the available evidenceUsing the example of systemic AEs, we were able to show that the frequency of AEs in COVID-19 booster vaccination may be overestimated. Fever as an objective measure to estimate the nocebo effect could help to optimize public awareness campaigns in the future. The graphic presentation of results facilitates a deeper understanding of complex scientific data and provides new insights. It is therefore ideal for a highly dynamic scientific field and may also be applied to other challenges in the COVID-19 pandemic and beyond.