In our study population of PHCPs, we found that the most frequently reported side-effects are similar across COVID-19 mRNA doses with fatigue, local pain at the injection site, general pains, and headache most frequently reported. The median duration of those side-effects is similar across booster doses with most symptoms lasting for a median of 2 days.
The prediction model includes five predictors: sex, alcohol consumption, recent COVID-19 infection, history of moderate-to-severe side-effects after any of the previous COVID-19 vaccines, and the booster dose (first or second). Participants reported moderate-to-severe side-effects for 281 of the 2309 first boosters (12%), and 121 of the 1304 second boosters (9%). The strongest determinant in experiencing moderate-to-severe side effects following a booster COVID-19 vaccine is having previously reported moderate-to-severe side effects after one of the earlier COVID-19 vaccine doses with an adjusted odds that is 3.6 times higher. Women are 1.49 times more likely to experience moderate-to-severe side effects after booster COVID-19 vaccines. The other determinants in the final predictive model (e.g., booster dose, a recent COVID-19 infection and alcohol consumption) showed no statistically significant effect on the probability of moderate-to-severe side effects when included in the multivariable model.
In a research study conducted among Saudi Arabian healthcare workers, 81% of participants experienced side-effects after the first booster dose, with body pains (89%) and injection site pain (88%) being the most common symptoms.(30) Fatigue was reported by only 7% of healthcare providers. We focused on the frequencies of moderate-to-severe side-effects, making it challenging to compare directly. Among the 2309 individuals who received their first booster dose, 218 (9%) reported muscle pains, 213 (9%) reported pain at the injection site, and 251 (11%) reported fatigue. Our study’s frequencies of side-effects after the first booster were lower than a convenience sample in Greece, which found the most prominent symptoms to be injection site pain (84%), fatigue (70%), muscle pains (61%), and headache (50%).(31) Pfizer’s placebo-controlled randomized trial reported even lower frequencies after the first booster dose: 12.9% for injection site pain, 7.2% for fatigue, and 4.7% for muscle pains.(5) This suggests that while the overall frequency of these symptoms may be lower, when considering moderate-to-severe cases, they may be more pronounced in our study population.
Several studies have investigated risk factors that increase the likelihood of experiencing side-effects after the first two doses of COVID-19 vaccines. These factors include younger age, female sex, vaccine dose, brand of vaccine, a past COVID-19 infection, and severity of those symptoms, all of which have been found to be associated with the occurrence of side-effects. (17, 32–34) To our knowledge, only one study reported risk factors associated with experiencing side-effects after the booster dose. This study found a positive association of side-effects with female sex, younger age, and brand of the vaccine.(35) In our study, we did not find an association between age and side-effects. Consistent with existing literature, we found a strong association of our outcome with female sex, and a weak association with vaccine dose, and a recent COVID-19 infection. None of the aforementioned papers looked at a possible association with alcohol consumption and history of side-effects after any of the previous doses. In our longitudinal study, experiencing moderate-to-severe side-effects after one of the previous doses is a strong determinant.
Our study provides a comprehensive examination of the probability of experiencing moderate-to-severe side-effects following COVID-19 booster doses, considering patient -and vaccine characteristics. The model incorporates a wide range of potential predictors, offering valuable insights into key determinants of side-effects.
A significant strength lies in the substantial dataset, comprising side-effects data reported by 3096 PHCPs. From this study population a more objective evaluation is to be expected compared to the general public. Additionally, having longitudinal data on the same individuals across multiple doses enables us to assess the impact of the booster dose and the influence of a history of side-effects after any of the previous doses. Notably, we are the first to report the substantial influence of a history of side-effects on future risk of side-effects after COVID-19 booster doses.
Our study provides a precise assessment of the risk of side-effects following booster doses of COVID-19 mRNA vaccines. Our prognostic model relies on only four predictors: sex, history of side-effects after any of the previous doses, booster dose, and alcohol consumption. Furthermore, with this externally validated predictive model, we offer detailed insights into the specific impact of each predictor on the likelihood of having moderate-to-severe side-effects after COVID-19 booster doses.
Several limitations must be acknowledged. First, a part of the study involves a retrospective analysis of a prospectively collected cohort, where data were not exclusively gathered for this specific investigation. Consequently, detailed information regarding mild side-effects is lacking. This influenced our decision to focus on moderate-to-severe side-effects. This limitation hinders our ability to assess the overall incidence rates of side-effects within our study population. Moreover, participants were limited to the predefined side-effects presented in the questionnaire. However, we did include an “other” option for responses, yet consistent answers were not identified alongside the provided symptoms.
Second, a substantial time gap exists between the eight measurement of the original study and the ninth, conducted for this research. Consequently, a significant number of participants provided information about their fifth dose while omitting details about their fourth dose. This has led to a lack of interval-length information for the third booster dose and necessitated the use of multiple imputation techniques. Furthermore, the extended time interval between the fourth and fifth dose surveys introduced the potential for recall bias in reporting side-effects.
Third, maximum likelihood-based model selection methods cannot be used to select variables in GEE models. We used QIC to select a correlation structure for the model and for backwards selection for the final model. This is less optimal than using the Correlation Information Criterion (CIC) which could be addressed in the future.(27, 36)
Fourth, it is important to note that we cannot establish a definitive causal relationship between the reported side-effects and the vaccines. This limitation arises from several factors. Firstly, the surveys were conducted days to months after their last vaccine, making it challenging to attribute the reported side-effects exclusively to the vaccines. Additionally, we lack information regarding participants' mental health status and other potential past infections, which could have influenced the occurrence of those symptoms. However, it is worth mentioning that the side-effects reported in the questionnaire align with those documented in the existing literature.
The last important possible limitation is the subjective nature of assessing side-effect severity. Experts caution that risk factors for side effects may be difficult to generalize between different vaccines and even between doses of the same vaccine (P Van Damme, personal communication, 2023). Our finding, that a history of moderate-to-severe side-effects has a major influence on future side-effects, may be influenced by participants' perceptions.
4.1 Interpretation and implication of the results
COVID-19 booster vaccines may potentially be administered seasonally. Vaccine hesitancy often arises due to concerns regarding side-effects.(37) The significance of this study lies in its contribution to understanding the factors that influence the occurrence of moderate-to-severe side-effects following COVID-19 booster vaccination. The low prevalence of moderate-to-severe side-effects and short duration of those symptoms can be used to communicate to hesitant people and health care providers. In our population of PHCPs we found during the nineth measurement that even 14% of them would not take a next booster dose (results not yet reported).
Given our emphasis on primary healthcare providers, who generally have a younger age profile compared to the more vulnerable population, age was not found as a determinant in our findings. Therefore, prudence is warranted when applying this prognostic model to an elderly and frail population. It remains uncertain whether the determinants identified in our study remain consistent within this group, and additionally, whether their risk profile significantly differs.
The misclassification rate in our test set is 14% with a sensitivity of 65% and a specificity of 87%. This suggests that our model is only moderately able to identify those participants with an elevated risk on developing moderate-to-severe side-effects. However, it has a high ability to correctly identify the true negative cases. These insights can aid in risk assessment, informed counseling, and decision-making regarding booster vaccinations in PHCPs.
It is important to acknowledge that a substantial number of concerns and theories concerning COVID-19 vaccinations relate to the potential long-term effects of these vaccines. However, our study does not provide any specific insight into this aspect. To address these concerns, active surveillance systems such as the Vaccine Safety Datalink are implemented to closely monitor vaccine long-term safety.(38)