Association between COVID-19 Vaccine Side Effects and Body Mass Index in Spain

COVID-19 vaccines have shown high efficacy, with most side effects being mild–moderate and more frequently reported by females and people at younger ages. Since no studies have assessed the impact that weight status could have on the reported adverse reactions, we aim to study the association between weight status and reported side effects. We included data on 2136 adults from an online survey conducted from 6 May to 9 June 2021. The questionnaire was filled in by participants over Google forms. Generalized Linear Mixed Models were used. A higher risk of presenting fever ≥38°, vomiting, diarrhea and chills was found in those with a non-overweight status compared to those overweight after adjusting for age, sex, education, medication to prevent/relieve post-vaccination effects and vaccine administered. When adjusting, most of the significant effects, in the association between side effects of the COVID-19 vaccine and weight status, did not remain significant. In conclusion, a non-overweight status was associated with a higher risk of presenting fever ≥38°, vomiting, diarrhea and chills compared to those overweight. Nevertheless, most of the reported side effects to COVID-19 vaccine were not associated with a higher risk of presenting more adverse effects, and individual differences were determined by sex and age.


Introduction
Coronavirus disease 2019 (COVID-19) has caused over four million deaths worldwide [1]. In this pandemic context, immunization of the population through vaccination is a public health priority [2]. Different studies have shown the efficacy of the vaccines currently on the market, reporting levels above 90% for Pfizer, Moderna and Sputnik V or above 60% in the case of AstraZeneca/Vaxzevria or Janssen [3,4].
Male patients, elderly, obese and those with an excess visceral fat have shown to have a higher risk for the development of complications following COVID-19 infection [5]. Sex, age and co-morbidities may also determine differences in vaccine response [6]. In a recent study, it was suggested that side effects of COVID-19 vaccines are a product of a short burst of Type I interferon (IFN-I) generation together with the induction of an effective immune response [7]. Thus, side effects can vary considerably according to the recipient's age and sex, with more severe effects in females than males and in younger people than in the elderly [8].
What researchers have not yet identified is whether there is any relationship between the initial inflammatory reaction and the long-term response that leads to protection. In fact, there is no study proving that those that have experienced more side effects from the COVID-19 vaccine are having higher levels of antibody titers and therefore a higher protection. However, younger people and female patients have reported stronger side effects with higher antibody titers than older age groups and males, respectively [8,9].
A latest work found that central obesity, smoking habit and hypertension were associated with lower antibody titers in response to COVID-19 mRNA vaccine [6]. Since obesity is a strong predictor of mortality among patients with COVID-19, it is important to take these data into account to develop future vaccine strategies for COVID-19 [10].
To the best of our knowledge, no studies have investigated the relationship between weight status (underweight, normal weight, overweight and obesity) with severity of side effects. Therefore, the present study aims to analyze the association between weight status and side effects after adjusting for important covariates such as age, sex, education, medication to prevent or relieve post-vaccination side effects and vaccine administered.

Study Design and Participants
Data were collected from an online anonymous survey conducted from 6 May to 9 June 2021. This cross-sectional study included a convenience sample of adult population Spain.
We used Google Forms, an online survey platform, to publish the questionnaire, and the link generated was then shared via social networks such as Facebook, Twitter and WhatsApp. The interviewees visited the URL on their electronic devices to answer the questionnaire. The inclusion criteria were individuals who (1) were 18 years old or older, (2) voluntarily agreed to participate in the online survey and (3) were able to read and complete the self-administered questionnaire independently.
After excluding those participants who did not complete more than 50% of the required questions (n = 45), a total of 2136 participants were finally included in the present study. During data collection in Spain, around 40% of the participants had not received any vaccination; only 1189 had received at least the first dose, and 690 had received the necessary vaccines (two doses in case of Pfizer, Moderna or AstraZeneca/Vaxzevria or just one dose in case of Janssen or those who have had COVID-19 infection). The sampling technique in this dataset is convenience sampling.
This survey data was approved by the Ethics Committee of Aragon (CEICA), Spain (No. C.I. 422 PI21/195 and the Ethics Committee of the University of Murcia (ID: 3449/2021). The survey data was conducted according to the Declaration of Helsinki.

Measures Sociodemographic and Vaccine-Related Information
Potential post-vaccination side effects were identified and covered in this survey after conducting a literature search on different databases including Pubmed, Science Direct and Google Scholar.
The study questionnaire was divided into three main sections. The first section was designed to collect general information about the participants such as gender, age group, migrant status, socioeconomic status (SES) information that included study level and profession, self-reported weight and height and possible infection status with SARSCoV-2 with experienced symptoms. The second section focused on measuring the attitudes and intention to vaccinate against COVID-19. The third section focused on the COVID-19 vaccine-related data such as type and date of COVID-19 vaccine, possible side effects experienced after the first and the second jab, timing and duration of the side effects, medication to prevent or relieve post-vaccination side effects and information received before getting the vaccine about possible side effects and co-morbidities.
Moreover, we included some questions about receiving flu vaccine in the previous year; possibility of vaccination against COVID-19 ("no, for medical reasons" (i.e., the hematologist recommended not to have it); "no, because I was pregnant"; "no, because they did not offer me the vaccine yet"; "no, because I just had COVID-19"; "no, because I refused to"; "yes, but I only got one dose (and I need two doses)"; "yes, and I got all doses" (i.e., one for Janssen or two for Pfizer, Moderna or AstraZenca/Vaxzevria)); and possibility of being vaccinated after knowing previously possible side effects ("yes, of course"; "yes, but I would think about it more"; "I will have doubts"; "no, side effects that I had do not make up for it").

Statistical Analysis
For descriptive analyses, numbers and percentage were used to detail sample characteristics. Percentages and chi-square tests were used to evaluate the associations between weight status and possible side effects during the first and the second dose.
Subsequently, we conducted Generalized Linear Mixed Models to study the associations between weight status (independent variable) and possible side effects (dependent variables) during the first and the second doses. When dividing into four categories (underweight, normal weight, overweight and obesity used as reference), models did not run properly, since a low number of cases were included in some categories. Therefore, analyses were also conducted combining non-overweight group (BMI < 25) vs. overweight group (BMI ≥ 25 used as reference). For the above regression, odds ratio (OR) and the respective 95% confidence intervals (CI) were estimated. All analyses were performed using SPSS version 26.0 (IBM Corporation, New York, NY, USA). The alpha level was set at 0.05, and p < 0.05 was considered statistically significant.

Results
Supplementary Tables S2 and S3 show the side effects in the first and the second doses per COVID-19 vaccine (in percentage), respectively. In the first dose, AstraZeneca/Vaxzevria had the highest percentage of side effects compared to the rest of vaccines (Janssen, Moderna or Pfizer). In contrast, people vaccinated with Pfizer presented the lowest percentage of side effects. In the second dose, Moderna presented a higher percentage of side effects compared to Pfizer and AstraZeneca/Vaxzevria.
Supplementary Tables S4 and S5 present the associations between side effects experienced in the first and second doses of COVID-19 vaccine and weight status (underweight, normal weight, overweight and reference: obese). The results from the Multinomial Logistic Regression Models showed that side effects (myalgia; arm soreness, redness or swelling; headache and chills) were in a higher percentage when decreasing weight status in raw models. That is, side effects were more prevalent in those who were underweight and normal weight compared to those who were obese. However, no results remained significant when using adjusted models. Similar results were found when conducting sensitivity analyses (Supplementary Table S6) to explore the association between weight status and side effects for the first dose of the COVID-19 vaccine in the population receiving Pfizer (n = 568) and, in the population, receiving AstraZeneca/Vaxzevria (n = 459).

Discussion
The present study aimed to study the association between possible side effects after receiving a COVID-19 vaccine and weight status. We found a higher risk of presenting some side effects against COVID-19 vaccine (fever ≥ 38 • , vomiting, diarrhea and chills) in those with a non-overweight status (underweight and normal weight) compared to those overweight (including obesity) after adjusting for important covariates such as age, sex, education, medication to prevent or relieve post-vaccination and vaccine administered. Most of the side effects experienced were significantly higher in those who were nonoverweight compared to those overweight. Nonetheless, sex and age were the most important variables to predict possible side effects experienced against COVID-19 vaccine. In fact, when adjusting for sex and age, most of the significant effects, in the association between side effects of the COVID-19 vaccine and weight status, did not remain significant. These results are in agreement with previous works that reported lower adverse effects in males and those aged over 55 years [14][15][16].
In our sample, most of the people who were overweight or obese were also those who were older (over 55 years), which could partly explain why a BMI over 25 was related to lower side effect experienced in our study.
Other factors such as type of COVID-19 vaccine and dose received might also play an important role [14][15][16]. Those who received a chimpanzee adenovirus-vectored vaccine such as AstraZeneca/Vaxzevria reported more commonly adverse reactions than those who received a mRNA-based vaccine such as Pfizer or Moderna (and among these two vaccines, those who received Moderna experienced more adverse reactions than those who received Pfizer). We have to bear in mind that, in the case of AstraZeneca/Vaxzevria, during the first months of use (February and March and mid-April 2021), health authorities in Spain recommended inoculation in the population under 55 years of age. However, after some studies suggested a possible link of blood clots with low blood platelets due to the AstraZeneca/Vaxzevria vaccine [17], health authorities in Spain prohibited it in people under 60 years old [18]. Those who had received AstraZeneca/Vaxzevria in the first dose could choose between being vaccinated with AstraZeneca/Vaxzevria or Pfizer in the second dose after the recommended period between doses (at least three months). This fact made side effects stronger after the first dose compared to those after the second dose, partly because only younger adults were eligible for receiving the former. Currently, only people who are 60 or older can be vaccinated with AstraZeneca/Vaxzevria. Hence, a lower number of people received vaccinated with AstraZeneca/Vaxzevria vaccine in both doses. Furthermore, regarding the age-based COVID-19 vaccine strategy, Spain started the vaccination with those at a higher risk of complications (>80 years old). Therefore, in the present study, mean age of people with both doses was higher compared to those who had only one dose. As younger people generally have a more a robust immune system, the immune response to the vaccine and the reported side effects are higher.
To the best of our knowledge, no previous investigations have studied a relationship between side effects experienced against COVID-19 vaccine and weight status. Although a recent study that aimed to investigate the safety and effectiveness of these vaccines in a UK community setting and used obesity to adjust all models found some differences between strata of BMI, there was no clear trend across vaccines and doses [14]. However, previous studies investigating side effects with other vaccines (particularly with the Anthrax vaccine) suggested that obese women may experience elevated arm soreness, and a depressed pre-vaccination serum progesterone level may increase a woman's odds of experiencing injection site arm swelling [19]. Similarly, in another study, redness and swelling were more common for obese participants compared to participants who were not overweight [20]. A higher reaction in the infection-site could be caused by inadvertent sub-cutaneous administration rather than intra-muscularly [21]. Contrary to these studies, Petousis-Harris et al. showed that those with a lower BMI reported more pain when meningococcal B vaccine was administrated [22].
Although obesity is associated with a low-level chronic inflammation [23], a higher reactogenicity in the overweight population seemed to be linked to the vaccine administration technique and not to BMI, itself [24]. In a study of overweight/obese participants and in normal weight controls, the frequency of injection-site and systemic reactions after trivalent influenza vaccine was statistically similar between groups, which is in agreement with our results. Thus, for the adverse reaction of arm soreness, redness or swelling, individual injection technique (that depends on the vaccinator) could be the reason behind observed differences in some studies [25].
No other side effects such as fever; myalgia; diarrhea; tiredness, sleepiness or dizziness; nausea or vomiting have been studied in other vaccines regarding BMI status. Investigations have not identified any relationship between the initial inflammatory reaction and the long-term response that leads to protection. Hence, individuals with stronger side effects from the vaccine are not better protected from COVID-19 [26]. Nevertheless, younger people and females experience higher side effects due to a more a robust immune system and produce higher antibody titers after being vaccinated [27]. In contrast, central obesity as well as smoking habit and hypertension were associated with lower antibody titers in response to COVID-19 mRNA vaccine [6]. Lower adverse effects experienced after receiving COVID-19 vaccine may explain why those obese had lower antibodies titers and lower percentage of some side effects against COVID-19 vaccine (fever ≥ 38 • , vomiting, diarrhea and chills) compared with non-overweight individuals after adjusting for important covariates such as age, sex, education, medication and vaccine administered to prevent or relieve post-vaccination.
To our knowledge, this is the first study conducted in Spain to investigate the association between possible side effects after receiving a COVID-19 vaccine and weight status with a sample size of 2136 individuals (of which 31.1% were healthcare professionals) after the approval of the vaccine. In addition, although we used a convenience sampling, we have a good representation of different age groups, and women represented 67.7% of the respondents which is in agreement with the percentages of healthcare professionals in Spain and worldwide [28].
Nevertheless, our investigation has several limitations. This study is not random and therefore is not representative of the Spanish population. Moreover, there are some groups that could be underestimated, in part due to the collection method used (i.e., males represented 32.3% of the sample, and migrants were 6.4%). Hence, the extrapolation of these results can be difficult. In fact, although online questionnaires are simple tools that can offer advantages such as the access to different population and prompt answers, some questions that can arise when auto-filling the questionnaire and could be responded to in a face-to-face interview are difficult to address in online surveys. Besides, we used self-reported data for weight and height, the reliability and validity of which have been found conflicting by some studies [28]. However, a recent study revealed good agreement between self-reported and direct anthropometric measurements [29]. Additionally, it should be borne in mind that side effects experienced depend mainly on age and sex. Most of the fully vaccinated people included in the present sample were above 56 years old (46.1%), and thus, side effects could be underestimated. Finally, it should be noted that, although the total sample amounted to 2136 subjects, the effective sample of participants who received both doses was 590, which resulted in the impossibility of performing certain sub-group analyses. Consequently, results should be interpreted and considered on the bases of all the above.

Practical Implications
Previous investigations have demonstrated that people who are obese are more likely to have severe COVID-19 outcomes [5]. Nonetheless, the present paper has shown that overweight or obese individuals are not at a higher risk of presenting adverse events compared to those underweight or normal weight. A recent study indicated the antibody levels are lower in a person who is overweight or obese as compared to a person of normal weight [6]. This speculation about variable effectiveness of COVID-19 vaccines in obesity likely increases vaccine hesitancy among individuals with obesity. Considering that adverse effects were found to be mild or moderate and that there is likelihood that the levels of antibody (and subsequent immunity) are still high enough to protect against COVID-19, our results suggest the need for being vaccinated among people with overweight or obesity.

Conclusions
The success of COVID-19 vaccination depends, to a large extent, on the confidence that the population has in vaccines. To date, the current vaccines against COVID-19 have shown high efficacy and are expected to perform well in terms of side effects. However, the scarcity of post-vaccination studies makes it advisable to promote research that contributes to a deeper understanding of the results of vaccination in practice and counteracts the risks of a priori loss of confidence in certain vaccines on the part of the population. Mostly all reported side effects from the COVID-19 were mild or moderate. Sex and age were the most important variables to predict possible side effects experienced against COVID-19 vaccine. We also found a higher risk of presenting some side effects against COVID-19 vaccine (fever ≥ 38 • , vomiting, diarrhea and chills) in those with a non-overweight status (underweight and normal weight) compared to those overweight (including obesity) after adjusting for important covariates such as age, sex, education, medication to prevent or relieve post-vaccination and vaccine administered. Nonetheless, when adjusting for sex and age, most of the significant effects, in the association between side effects of the COVID-19 vaccine and weight status, did not remain significant.
Supplementary Materials: The following are available online at https://www.mdpi.com/article/ 10.3390/vaccines9111321/s1, Table S1: COVID-19 vaccine information and side effects., Table S2: Side effects in the first dose per COVID-19 vaccine (in percentage). Table S3: Side effects in the second dose per COVID-19 vaccine (in percentage)., Table S4: side effects experienced in the first dose of COVID-19 vaccine and weight status (underweight, normal weight, overweight and reference: obese)., Table S5: Side effects experienced in the second dose of COVID-19 vaccine and weight status (underweight, normal weight, overweight and reference: obese)., Table S6: Weight status and side effects for the first dose of the COVID-19 vaccine in the population receiving Pfizer and in the population, receiving AstraZeneca/Vaxzevria.

Informed Consent Statement:
Informed consent was obtained from all subjects involved in the study.

Data Availability Statement:
The raw data supporting the conclusions of this article will be made available by the authors upon request, without undue reservation.