Association between Overweight/Obesity and the Safety and Efficacy of COVID-19 Vaccination: A Systematic Review

Objective: The objective of this study was to appraise the interrelation between overweight/obesity and the safety and efficacy of COVID-19 vaccination by synthesizing the currently available evidence. Methods: A systematic review of published studies on the safety and efficacy of the COVID-19 vaccine in people who were overweight or obese was conducted. Databases including Embase, Medline Epub (Ovid), PsychInfo (Ovid), Web of Science, PubMed, CINAHL, and Google Scholar were searched to identify relevant studies. The databases of the Centers for Disease Control (CDC) and World Health Organization (WHO) were also searched for relevant unpublished and gray literature. Results: Fifteen studies were included in the review. All the included studies used observational study designs; there were ten cohort studies and five cross-sectional studies. The sample size of these studies ranged from 21 to 9,171,524. Thirteen studies reported using BNT162b2 (Pfizer-BioNTech, USA), four reported using ChAdOx-nCov19 (AstraZeneca, U.K), two were reported using CoronaVac (Sinovac, China), and two were reported using mRNA1273 (Moderna, USA). The efficacy and safety of COVID-19 vaccines have been extensively studied in individuals with overweight/obesity. Most studies have shown that the humoral response decreases with increasing BMI. The available evidence does not conclusively indicate that these vaccines are generally safe in this population. Conclusion: While the efficacy of the COVID-19 vaccine may be less than ideal in people who are overweight or obese, it does not mean that obese people should not be vaccinated, as the vaccine can still provide some protection. There is a lack of evidence for conclusions to be drawn about the safety of the vaccine in the population. This study calls on health professionals, policymakers, caregivers, and all other stakeholders to focus on monitoring the possible adverse effects of injections in overweight/obese people.


Introduction
Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, SARS-CoV-2 has rapidly spread and caused over 656 million confirmed cases and over 6.6 million deaths globally, as reported by the WHO on 1 January 2023 [1]. COVID-19 has caused widespread damage and trauma to people, but the epidemic is still not under control. COVID-19 vaccines, including inactivated vaccines, live-attenuated vaccines, viral vector vaccines, and mRNA vaccines, are effective in preventing and controlling COVID-19 infections by stimulating the human immune system to produce specific antibodies to generate protection for the immunized individual [2]. Although the emergence of SARS-CoV-2 variants, which appear to be more transmissible and may escape from convalescent immune responses, has slowed the progress of controlling the pandemic [3], vaccinations and booster doses can still curb the spread of the disease and potentially help to achieve herd immunity [4].
Promoting vaccination is crucial for ending the spread of COVID-19. There were twenty-four COVID-19 vaccines approved by the WHO Emergency Use Listing Procedure 1.
To explore the effectiveness of the COVID-19 vaccine in obese people.

2.
To explore the safety of the COVID-19 vaccine in obese people.

Registration
This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines (available in the Supplementary Materials) [15]. The systematic review protocol was registered at PROSPERO (registration number: CRD42023426734).

Literature Search
A systematic literature search was conducted in Embase, Medline Epub (Ovid), Psych-Info (Ovid), Web of Science, PubMed, CINAHL, and Google Scholar to identify relevant studies.
Databases were searched from inception to January 2023. The following keywords and their synonyms were included in the search: "COVID-19 vaccine", "SARS-CoV-2 vaccine", "efficacy", "safety," "overweight", "obese", and "body mass index". The search strategy was adapted for each database. Relevant reviews and the included articles were hand-searched for additional eligible studies. In addition, the databases of the Centers for Disease Control (CDC) and World Health Organization (WHO) were also searched for relevant unpublished and gray literature. The Supplementary Material (File S1) describes the search strategies in their entirety.

Inclusion and Exclusion Criteria
The included studies met the following eligibility criteria: (1) participants were previously vaccinated for COVID-19; (2) they originated from randomized trials and observational studies (including cohort studies, case-control studies, cross-sectional study designs, and case reports); (3) they provided data regarding the association between overweight/obese and the safety (e.g., the incidence of adverse events) and efficacy (e.g., cases of (post-vaccination) SARS-CoV-2 infection) of the COVID-19 vaccine; (4) they were published in peer-reviewed journals; and (5) they were available in English. Studies were excluded for the following reasons: (1) studies on animals; (2) in vitro/ex vivo; and (3) qualitative studies, reviews, theses, conference papers, book chapters, news reports, and letters.

Selection Process
All references were exported and managed with Endnote X9. Title/abstract screening was independently performed by two reviewers (N.L. and C.F.) based on the inclusion criteria. Relevant articles were retrieved for full-text reading and further review by two reviewers (N.L. and C.F.). The two authors discussed disagreements until they agreed. The remaining disagreements were discussed with a third author (J.Z.) until a consensus was reached.

Data Extraction
Data from individual studies were extracted and organized with an extraction form by one reviewer (N.L.) and then verified by another (C.F.). The extracted information included (1) the basic characteristics of the included studies (first authors, year of publication, study design, location, and period), (2) the characteristics of participants (age, sex, sample size, indicators of overweight/obesity), (3) vaccines (vaccine name, platform, number of doses), (4) covariate adjustment, and (5) outcomes regarding the association between overweight/obesity and the safety (e.g., the incidence of overall, local, and systemic adverse events) and efficacy (e.g., number of (postvaccination) SARS-CoV-2 infections, hospitalization for COVID-19, and admission to the ICU for COVID-19) of the COVID-19 vaccine. Effect estimates were extracted from the fully adjusted models (if available).

Assessment of Risk of Bias
Two reviewers independently assessed the risk of bias in the included studies by using the Joanna Briggs Institute (JBI) critical appraisal checklist [16]. The checklist allows for methodological and bias assessment in quantitative and qualitative analyses with varying study designs, including cohort studies and cross-sectional studies [17]. The response options of the checklist included "Yes" (the criteria are identifiable through the report description), "Unclear" (the criteria are not identified in the report), and "No" (the criteria are not identifiable). Based on the number (%) of "Yes" responses, the risk of bias was further rated as "high" (≤49%), "moderate" (50%−69%), and "low" (≥70%) [16]. All of the disagreements during the evaluation were later discussed, and a consensus was reached. There were no exclusions made based on a minimum threshold. The interrater reliability (IRR) test was performed with the Kappa calculator in the bias risk test. The percentage of user consent was calculated by dividing the number of studies in which both authors gave the same risk score for bias by the total number of studies. Cohen's Kappa test was used to consider the same risk-of-bias scores, with Kappa values ranging from 0.457 to 1.
Vaccine Efficacy: Patients with obesity were less likely to have positive antibodies after the first and second doses compared to the controls The humoral re the COVID-19 was lower in p with obesity on after the secon  Table 1, and the characteristics of the included studies (n = 15).

Study Characteristics
The characteristics of the included studies are described in Table 1. All included studies used observational study designs; there were ten cohort studies and five cross-sectional studies. The sample size of these studies ranged from 21 to 9,171,524. Thirteen studies reported using BNT162b2, four reported using ChAdOx-nCov19, two reported using CoronaVac, two reported using mRNA1273, and one study compared the safety between the Sinovac vaccine and the Pfizer vaccine.

Quality Appraisal
The risk-of-bias assessments for cohort studies, cross-sectional studies, and case series are summarized in Table S1 and Table S2 in the Supplementary Materials. Of the 15 included studies, ten had a 'low' risk of bias, four had a 'moderate' risk of bias, and one had a 'high' risk of bias.

Synthesis of Results
Six studies [13,19,[26][27][28][29] investigated the association between overweight/obesity and the safety of COVID-19 vaccination. Study 3 [19] was a cohort study aimed at evaluating the safety of COVID-19 vaccine-induced humoral and cellular immune responses in Chinese individuals with obesity/overweight. The findings showed that inactivated COVID-19 vaccines were safe, and no serious vaccine-related adverse events occurred. Study 11 [26] was a national cohort study among 9,171,524 participants in England. Their results suggested that there were significant linear associations between BMI and COVID-19 hospitalization and death after the first dose and J-shaped associations after the second dose. However, Study 12 [13] was a cohort study that explored variables associated with the serological response following an mRNA COVID-19 vaccine in 86 healthcare workers and found that central obesity, such as that in people with a higher waist circumference, waist-to-hip ratio, BMI, or body fat, was not associated with more adverse events. Study 13 [27] was a cross-sectional study that investigated 2136 adults and found that nonoverweight status was associated with a higher risk of side effects, such as fever, vomiting, diarrhea, and chills, than overweight status. Study 14 [28] was a cohort study on the type and frequency of adverse reactions in healthy individuals and those with allergic disease aged 5-11 years over the first seven days following the first and second BNT162b2 vaccinations. The participants were recruited from a hospital and four municipalities in the Ishikawa district of Japan. The results of the logistic regression showed no statistically significant associations between BMI and experiencing adverse systemic reactions after seven days of vaccination, with odds ratios and 95% confidence intervals of 0.80 (0.46-1.40) (thin vs. normal) and 0.69 (0.42-1.13) (overweight vs. normal), respectively. Study 15 [29] was a cross-sectional study aimed at evaluating a comparison between the Sinovac vaccine and the Pfizer vaccine for children and teenagers under 18 years old and other factors that influenced it. The participants were a convenience sample of 400 children and teenagers who received the total doses of the Sinovac and Pfizer vaccines in Indonesia. Their findings suggested that vaccine recipients with a BMI of less than 25 had a higher risk of having side effects, including fever, pain in the injection area, lost smell and taste after the first vaccination, sleepiness and fever after the second vaccination, and menstrual problems after 1-3 months and 4-6 months postvaccination (p < 0.05).

Discussion
The results of this study partially support the hypothesis of the study. The relationship between obesity and COVID-19 vaccination has been a subject of considerable attention and debate due to the potential influence of obesity on both severe COVID-19 disease and vaccine efficacy against infectious diseases [27]. Therefore, it is crucial to assess the potential impact of obesity on COVID-19 vaccinations. A longitudinal study was conducted to assess the impact of central obesity on the efficacy of Pfizer/BioNTech vaccination in a cohort of 86 healthcare workers in Italy [13]. The study revealed that lower antibody titers were associated with central obesity, independently from BMI. In another investigation, Pellini and colleagues [25] examined the antibody titers of individuals with a healthy weight, overweight, or obesity between the first and second doses of the Pfizer/BioNTech vaccine. They observed that a humoral immune response was activated by a single vaccination in individuals with healthy weight, while some overweight or obese subjects (age > 47 and BMI > 25 kg/m 2 ) did not experience a change in their IgG antibody levels. Nine of the twelve studies that investigated the humoral response reported a reduced response with increasing BMI. Overall, BMI was associated with a higher initial increase in IgG antibodies after immunization, and a higher BMI was associated with a greater decline in antibody titers. This may be because obesity can lead to inflammation and immune dysfunction, which can affect the body's immune response after vaccination, thus reducing its protective effect. However, most of the studies did not follow up for more than 12 months, so more studies are needed to better understand the long-term efficacy of COVID-19 immunization in obese populations.
Despite the possible effects of obesity on vaccine efficacy, it is noteworthy that vaccination is still recommended for overweight or obese individuals. The benefits of vaccination, such as reductions in severe COVID-19 disease and hospitalization, outweigh the potential risks associated with a weaker immune response in this population [26,30]. Furthermore, addressing the root causes of obesity may enhance individuals' overall health and potentially improve their immune responses to the vaccine [31]. Implementing strategies for encouraging healthy eating habits, physical activity, and weight reduction could increase vaccine efficacy and lower the risk of severe COVID-19 infections in this population [22].
Vaccination is considered the most effective tool for controlling the spread of COVID-19 and reducing severe outcomes. However, it remains unclear how overweight/obesity, a common comorbidity, affects the safety of COVID-19 vaccination [32]. Several studies have investigated the safety of COVID-19 vaccination in individuals with overweight/ obesity [13,19,[26][27][28][29]. Three studies suggested that COVID-19 vaccines have been shown to be safe in people with overweight/obesity, and there was no direct link between BMI and vaccine side effects [13,19,28]. However, a study focused on adolescents suggested that the association between BMI and COVID-19 vaccine side effects may vary with dose and time [29]. Interestingly, two studies showed that nonobese individuals were more likely to experience side effects than obese individuals [27,29]. A national study reported more adverse effects at the high and low extremes of BMI [26]. The immune system's response to the vaccine is not significantly affected by obesity in most cases, so there might be no increased risk of side effects for individuals who are overweight or obese. Underweight individuals may have weaker immune systems due to malnutrition or underlying health conditions, making them more susceptible to vaccine side effects [33]. The relationship between body weight and vaccine side effects may be influenced by other factors, such as age, sex, or underlying health conditions. Therefore, the available evidence is not yet conclusive, and further research is needed to investigate the optimal vaccine regimen for this population.
Our study has some limitations. First, there are only a limited number of studies on COVID-19 vaccines and obesity, most of which have small and limited sample sizes and large heterogeneity, making it difficult to reach research conclusions. Consequently, there is usually a different set of comorbidities associated with adults with obesity when compared with children with obesity. Comparing both groups without much consideration for these confounders or stratifying by the age group would in itself contribute to some bias.

Conclusions
In conclusion, the association between obesity and COVID-19 vaccination warrants further investigation, as it could impact vaccine efficacy and the overall health outcomes for this population. This study found that the humoral response decreased with increasing BMI, but this result may slightly vary by gender, vaccine dose, and comorbidity. Moreover, the safety of novel coronavirus vaccines cannot be concluded because the results vary too widely from study to study. Interestingly, this study found that novel coronavirus vaccines may cause more side effects in nonobese people, which also provides some new ideas for the design and focus of follow-up studies. Implementing strategies to address the underlying causes of obesity could also enhance vaccine efficacy and overall health outcomes.
Supplementary Materials: The following supporting information can be downloaded at https: //www.mdpi.com/article/10.3390/vaccines11050996/s1, File S1: Search Strategies; Table S1: Riskof-Bias Assessment using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Cohort Studies; Table S2  Data Availability Statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Conflicts of Interest:
The authors declare that this research was conducted without any commercial or financial relationships that could be construed as potential conflicts of interest.