ABSTRACT
Patients with type 2 diabetes (T2D) are at an increased risk of morbidity and mortality of coronavirus disease 2019 (COVID-19). Data on the antibody response to COVID-19 vaccines in T2D patients are less studied. This study aimed to evaluate IgG antibody response to inactivated COVID-19 vaccines in hospitalized T2D patients. Hospitalized patients with no history of COVID-19 and received two doses of inactivated COVID-19 vaccines (Sinopharm or CoronaVac) were included in this study from March to October 2021. SARS-CoV-2 specific IgG antibodies were measured 14–60 days after the second vaccine dose. A total of 209 participants, 96 with T2D and 113 non-diabetes patients, were included. The positive rate and median titer of IgG antibody against receptor-binding domain (anti-RBD) of spike (S) protein of SARS-CoV-2 in T2D group were lower than in control group (67.7% vs 83.2%, p = .009; 12.93 vs 17.42 AU/ml, p = .014) respectively. Similarly, seropositivity and median titers of IgG antibody against the nucleocapsid (N) and S proteins of SARS-CoV-2 (anti-N/S) in T2D group were lower than in control group (68.8% vs 83.2%, p = .032; 18.81 vs 29.57 AU/mL, p = .012) respectively. After adjustment for age, sex, BMI, vaccine type, days after the second vaccine dose, hypertension, kidney disease, and heart disease, T2D was identified as an independent risk factor for negative anti-RBD and anti-N/S seropositivity, odd ratio 0.42 (95% confidence interval 0.19, 0.89) and 0.42 (95% CI 0.20, 0.91), respectively. T2D is associated with impaired antibody response to inactivated COVID-19 vaccine.
Introduction
Coronavirus disease 2019 (COVID-19) has emerged as a global health crisis because of the high infectivity and high fatality rate. Fortunately, COVID-19 vaccines have been demonstrated to be effective in the prevention of COVID-19 and in the alleviation of disease severity if breakthrough infection occurred.Citation1–4 Since December 2020, several types of COVID-19 vaccines prepared with different techniques, such as inactivated virus, mRNA-based vaccine, non-replicating viral vector vaccine, and protein subunit, have been approved and recommended for use in human throughout the world.Citation5–8
Patients with type 2 diabetes (T2D) are associated with an increased risk of severe COVID-19 and death from COVID-19;Citation9,Citation10 thus, they should be prioritized in the prevention of COVID-19. After COVID-19 vaccination in general population, the antibody seroconversion rates are as high as 96–100%,Citation11–17 however, the antibody response to COVID-19 vaccine appears to be lower in organ transplant recipients,Citation18 patients on dialysis,Citation19 and other immunocompromised groups.Citation20,Citation21 T2D patients tend to have a reduced immune response to infection or vaccination, as demonstrated in the vaccination against hepatitis B.Citation22 Recently, the immunogenicity of COVID-19 vaccines in patients with diabetes has been reported to be lower than that in healthy subjects.Citation23 However, these reports mainly focused on the mRNA or adenovirus-vector vaccines,Citation23–25 and the antibody response to inactivated SARS-CoV-2 vaccines was just evaluated in a limited number of diabetes patients.Citation15–Citation16-26–Citation29 Moreover, some reports showed that diabetes patients had reduced immunogenicity to inactivated COVID-19 vaccines, whereas others reported that diabetes patients had high immunogenicity (99% seroconversion after vaccination), same as non-diabetes subjects had.Citation16,Citation17 The present study aimed to investigate the antibody response to inactivated COVID-19 vaccines in T2D patients as compared to subjects without diabetes.
Materials and methods
Study design and participants
This cross-sectional study recruited hospitalized patients by convenient sampling method from Zhongda Hospital, Nanjing, China, from March 11 to October 31, 2021. The patients were admitted to Zhongda Hospital for various reasons (). Diabetes group was composed of T2D patients. The diagnosis of T2D was based on the criteria; those who had fasting plasma glucose (FPG) ≥7.0 mmol/L, glycated hemoglobin (HbA1c) ≥6.5%, or documented history of diabetes were diagnosed with T2D.Citation30 The inclusion criteria included (1) ≥18 years old, (2) immunized with two doses of COVID-19 vaccine (Sinopharm or CoronaVac) composed of inactivated SARS-CoV-2, within 14–60 days before recruitment. Patients with any of the following conditions were excluded (1) malignant cancer, (2) autoimmune diseases, (3) uremia and/or dialysis patients, (4) current use of steroid hormone(s) or immunosuppressive agent(s), (5) history of using steroid hormone(s) or other immunosuppressive agent(s) within recent one month, (6) type 1 diabetes, and (7) pregnancy. Non-diabetes group, served as controls, consisted of hospitalized patients who had no history of diabetes and had normal FPG and HbA1c. The inclusion and exclusion criteria were same as those mentioned above. Since diabetes patients enrolled in the present study were conveniently selected from the hospitalized patients, we also chose hospitalized patients without diabetes as the control group to balance confounding factors. Fasting blood samples were obtained and used for the measurement of FPG, HbA1c, and IgG antibodies to SARS-CoV-2.
Table 1. Principal reasons for hospitalization of study participants.
This study was approved by the Human Research Ethics Committee of Zhongda Hospital, Southeast University (2021ZDSYLL096-P01). Written informed consent was obtained from each participant.
Determination of sample size
Based on previous studies of seropositive rates in the general populationCitation13,Citation14 and considering that the participants in this study were hospitalized patients, we assumed that the seropositive rate after two doses of inactivated COVID-19 vaccines was 90% in the non-diabetes group and 70% in those with diabetes. To ensure a power of 80% and a type I error rate of 0.05, at least 62 patients would be needed in each group.
Measurement of IgG antibody to SARS-CoV-2
Serum IgG antibodies against the nucleocapsid (N) and spike (S) proteins of SARS-CoV-2 (anti-N/S) and IgG antibodies directed to the receptor-binding domain (RBD) of the S protein (anti-RBD) were detected, respectively, with two chemiluminescence immunoassay kits (YHLO Biotech Co., Ltd., Shenzhen, China). Based on the manufacturer’s instructions, a measurement result with ≥10 arbitrary units (AU)/ml was defined as positive and a result with <10 AU/ml was defined as negative. Anti-RBD IgG is considered to be neutralizing antibody against SARS-CoV-2,Citation31 and thus measurement of anti-RBD IgG is a surrogate assay of detecting neutralizing antibody against SARS-CoV-2.
Statistical analysis
Categorical data were presented as percentages, and continuous data as mean ± standard deviation (SD) or median (25th–75th percentile). Characteristics of participants with and without diabetes were compared using the unpaired Student’s t test or Mann-Whitney U test for continuous variables and χ2 test for categorical variables. Logistic regression analyses were used to assess the association between diabetes and SARS-CoV-2 antibody seropositivity. A two-sided P value of less than .05 was considered significant. All statistical analyses were conducted using SPSS 25.0 (version 25.0, SPSS, Chicago, IL, USA).
Results
Study population and characteristics
A total of 209 participants were included in this study; 96 patients who had been defined with T2D were included in the diabetes group and 113 subjects who had no history of diabetes and had normal FPG and HbA1c acted as controls. The general characteristics and comorbidities are shown in . The mean age (56.3 years) and gender proportions (male 61.5%) in the diabetes group were similar to those (53.8 years, male 56%) in the control group, respectively, whereas the body mass index (BMI) (24.85 kg/m2) in the diabetes group was higher than that (23.48 kg/m2) in the control group (p = .024). The prevalence of hypertension and nonalcoholic fatty liver disease (NAFLD) in the diabetes group were higher than those in the control group (68.8% vs 40.7%, p < .001; 37.5% vs 15.0%, p < .001; respectively), while the prevalence of other comorbidities, including heart disease, pulmonary disease, and kidney disease, did not differ between the two groups.
Table 2. General characteristics of participants by diabetes status.
Antibody responses to COVID-19 vaccination
As the participants enrolled in this study were vaccinated with the inactivated COVID-19 vaccines, which contain all viral proteins of SARS-CoV-2, we measured IgG antibodies directed to RBD and to the combination of the N and S proteins, respectively. shows the antibody responses in the diabetes and non-diabetes groups. The proportions of vaccinated vaccine types (CoronaVac or Sinopharm) in these two groups were similar. The interval time of antibody measurement after the second vaccine dose was relatively longer in the non-diabetes group than in the diabetes group (37 vs 33 days, p = .012). Forty and 39 participants were measured for antibodies shorter than 30 days after the second dose in the diabetes and non-diabetes group, respectively (p = .288). The seropositivity and median titers of anti-RBD in the diabetes group were lower than those in the control group (67.7% vs 83.2%, p = .009; 12.93 vs 17.42 AU/ml, p = .032), respectively. Similarly, anti-N/S seropositivity in the diabetes group was significantly lower than that in the control group (68.8 vs 83.2%, p = .014), and the median antibody titers of anti-N/S IgG were also lower in the diabetes group (18.81 vs 29.57 AU/ml, p = .012).
Table 3. Antibody response to inactivated COVID-19 vaccines in diabetes and non-diabetes patients.
Logistic regression models were used to further analyze the association between diabetes and COVID-19 vaccination responses (). In the univariable regression model, diabetes was significantly associated with negative anti-RBD and anti-N/S responses, with odd ratio (OR) 0.42 (95% confidence interval [CI] 0.22, 0.81) and 0.45 (0.23, 0.86), respectively. After adjustment for age, gender, BMI, days after the second vaccine dose, vaccine type, hypertension, kidney disease, and heart disease, diabetes was still an independent risk factor for negative anti-RBD and anti-N/S seropositivity, OR 0.42 (0.19, 0.89) and 0.42 (0.20, 0.91), respectively.
Table 4. Association of diabetes with antibody seropositivity.
Factors associated with antibody responses in diabetes patients
To further identify factors associated with negative serology in diabetes patients after COVID-19 vaccination, we compared variables between antibody positive and negative patients. The proportion of diabetes patients with BMI≥24 kg/m2 in anti-RBD negative subgroup was borderline statistically significantly higher than that in anti-RBD positive subgroup (66.7 vs 45.9%, P = .062), and other parameters, including gender, age, duration of diabetes, number of glucose-lowering medications, FPG, other comorbidities, and vaccine type, had no significant influence on the production of anti-RBD or anti-N/S after the vaccination (). Similarly, the median anti-RBD titers in diabetes patients with BMI≥24 kg/m2 were statistically significantly lower than that in patients with BMI<24 kg/m2 (11.84 vs 15.62 AU/ml, p = .048), whereas other parameters, including gender, age, duration of diabetes, and number of glucose-lowering medications, had no significant influence on the antibody titers (Table S1). However, BMI was not a risk factor for negative serology in logistic regression models, nor was it correlated with antibody titers.
Table 5. Comparison of characteristics between antibody positive and negative diabetes patients.
Discussion
This study showed that, compared to those without diabetes, patients with diabetes had lower anti-RBD and anti-N/S antibody seropositivity as well as lower antibody levels after vaccinated with inactivated COVID-19 vaccines. The results demonstrated that diabetes is an independent risk factor for the reduced antibody response to the inactivated COVID-19 vaccine.
In this study, while the overall general characteristics of participants were comparable between the diabetes and non-diabetes groups, the mean time interval between the second vaccine dose and blood sampling in the diabetes group was statistically significantly shorter than that in the non-diabetes group (33 vs 37 days, p = .012, ). However, we considered that this four-day difference was less likely to cause the statistical difference in the seroconversion and levels of the vaccine-induced IgG antibodies between these two groups, since the antibody response to a full course of vaccination usually peaks around 30 days post-vaccination and the half-life of IgG antibody is 21–24 days. In addition, the subjects in both diabetes and non-diabetes group were all hospitalized patients, and just the proportion of subjects with digestive diseases in the diabetes group was statistically significantly lower than that in the non-diabetes group (). We considered that such a difference was less likely to cause a different antibody response to the inactivated COVID-19 vaccines. Thus, the findings in the present study should reflect the real scenario that the diabetes patients have reduced antibody response to inactivated COVID-19 vaccines.
Notably, in the present study, the overall positive rates of anti-RBD and anti-N/S were 76.1% (159/209) and 76.6% (160/209), respectively, and even in the non-diabetes subjects, the positive rates of anti-RBD and anti-N/S were each 83.2% (94/113). The antibody seroconversion rates in the present study were considerably lower than the reported rates (95.7%–99.0%) in the clinical trialsCitation32 or the reported rates (94.4%–99.5%) in real-world applications in healthcare workers in China and Turkey.Citation15,Citation33,Citation34 This might be related to the fact that study subjects enrolled in this study were hospitalized patients and were in “suboptimal” health conditions with different comorbidities, such as heart disease, and studies have shown that these patients have weaker antibody responses after COVID-19 vaccination.Citation35
It has long been considered that the innate and adaptive immune responses to infections in diabetes patients are compromised. COVID-19 patients who had diabetes are at an increased risk for more serious illness.Citation36,Citation37 One of the reasons for the poor prognosis may be associated with the relatively weaker immune responses to SARS-CoV-2.Citation38 In the present investigation, we found that antibody response to inactivated COVID-19 vaccine was significantly reduced. Previous studies also showed that the antibody responses to various types of COVID-19 vaccines, such as mRNA vaccine, adenovirus-based vaccine, or inactivated vaccine, in diabetes patients were lower than subjects without diabetes,Citation15,Citation25,Citation28,Citation29,Citation39 although other studies showed that the antibody response to inactivated COVID-19 vaccines in diabetes subjects was comparable to that in non-diabetes subjects.Citation16,Citation17 Together, the antibody response to COVID-19 vaccine in diabetes patients is relatively weaker than that in non-diabetes people. However, whether the relatively lower antibody response to COVID-19 vaccines means that diabetes patients are prone to have breakthrough SARS-CoV-2 infection remains further observation.
The reasons for impaired antibody response to COVID-19 vaccines in diabetes patients are currently not clear. Generally, to produce specific antibodies, B cells need helper signals from T helper cells to activate plasma cells. Studies showed that T2D patients have a reduced pathogen-specific memory CD4+ and Th17 response.Citation40 This is combined with the fact that COVID-19 is associated with T cell depletion, and a significant reduction in T cell activation as determined by CD25/CD28/CD69 expression in CD4+ and CD8+ T cell subsets.Citation41,Citation42 Since T helper cells appear to be required for optimal production of serum antibody after vaccination of SARS-CoV-2 mRNA vaccine, ChAdOx1 nCoV-19 vaccine, and protein subunit vaccine,Citation43,Citation44 the impaired antibody response to COVID-19 vaccines suggests that T helper cells may differentiate abnormally in diabetes individuals.
There are several limitations in this study. First, the study participants in this study were enrolled based on a convenient sampling method from a single hospital; thus, there could be possible selection bias. Combined with the fact that the participants in this study were all hospitalized patients, the study population was not representative of the general population, which limits the generalizability of the results. Second, since T2D is usually related to metabolic syndrome, the proportions of hypertension and NAFLD in the diabetes group were each higher than those in the non-diabetes group. Studies showed that NAFLD or hypertension appears not to cause a reduced antibody response to COVID-19 vaccines.Citation45,Citation46 However, diabetes patients hospitalized for COVID-19 are at high risk of adverse events possibly due to clustering with other cardiometabolic conditions.Citation47 In this study, after adjustment for hypertension, heart disease, and other factors, diabetes was still an independent risk factor for negative antibody seropositivity. Third, the antibody levels were measured only once between 14 and 60 days after the second vaccine dose, and blood sampling time was shorter than 30 days in about a third of the participants, possibly meaning that these patients did not yet reach peak antibody levels. However, the proportion of participants measured for antibodies in less than 30 days after the second vaccine dose in the diabetes and non-diabetes group was not of statistical significance (41.7% vs 34.5%, p = .288). In addition, other studies with a sampling time of 21–28 days after the second vaccine dose have also shown lower responses in diabetes patients.Citation27,Citation28 Fourth, currently, the COVID-19 vaccination guidelines recommend three vaccine doses, and the third dose serves as a booster dose. The present study just evaluated the immune response to two doses of the vaccines. However, it is usually believed that, if the antibody response after the primary vaccination (two vaccine doses) is lower, the antibody response after the third dose may also be relatively low. Whether the third dose can improve antibody responses in diabetes patients merits further investigation.
Conclusions
Our results demonstrate that the antibody response to inactivated COVID-19 vaccines in diabetes patients is significantly lower than that in non-diabetes people. The practical implication of the reduced antibody response remains further investigation.
Author contributions
XZ, LH, JC, and ZS conceived and designed the study. XZ, LH, YT, and MS collected the clinical data. XZ, LH, MS, JC, and ZS analyzed the data. XZ and JC wrote the manuscript. LH and ZS critically revised the manuscript. All authors have read and approved the manuscript. Prof. Zilin Sun is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
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Supplementary material
Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2023.2184754
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References
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