Severe COVID-19 and inactivated vaccine in diabetic patients with SARS-CoV-2 infection

To the Editor: Individuals with diabetes have been reported to have an increased susceptibility to severe illness or mortality when infected with coronavirus disease-2019 (COVID-19).[1] Limited evidence exists regarding the efficacy of inactivated COVID-19 vaccines in real-world settings for protecting diabetic patients from developing severe COVID-19. The present study aimed to evaluate the effectiveness of Chinese-made inactivated COVID-19 vaccines in preventing severe COVID-19 among individuals with diabetes who have been infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This single-center, retrospective cohort study was approved by the Ethics Committee of Shanghai Public Health Clinical Center (No. 2023-S069-01), and the need for informed consent was waived. Patients infected with SARS-CoV-2 and admitted to Shanghai Public Health Clinical Center between February 18 and May 18, 2022, were enrolled in the present study. Clinical data were extracted from the electronic medical record system at Shanghai Public Health Clinical Center. The present study utilized vaccination status as the primary exposure variable, with SARS-CoV-2 antibodies as additional supporting exposure measurements. Covariates included patients’ age, gender, and clinical tests examined within 24 h of admission, including complete blood count, renal function, liver function, thyroid function, coagulation function, and SARS-CoV-2 antibodies. The primary outcome was the occurrence of severe COVID-19. Detailed descriptions of vaccination status, measurement of SARS-CoV-2 antibodies, and severe COVID-19 are provided in Supplementary Data, https://links.lww.com/CM9/C398. Modified Poisson regression was used to evaluate the association between vaccination status and the likelihood of developing severe COVID-19. Propensity score matching was used to minimize the potential influence of confounding factors in the association analysis. The statistical analyses were conducted using SPSS 26 (SPSS/IBM, Armonk, NY, USA). Detailed descriptions of statistical analysis are provided in Supplementary Data, https://links.lww.com/CM9/C398. A total of 3636 local patients were hospitalized at our clinical center due to SARS-CoV-2 infection. Among this group, 976 (26.6%) patients had diabetes. In the present study, 15 patients were excluded due to reinfection with SARS-CoV-2, and 3 patients were excluded due to the use of adenoviral or mRNA vaccines. Consequently, 958 diabetic patients were included in the present study [Supplementary Figure 1, https://links.lww.com/CM9/C398]. Among the included patients, 547 (57.1%) patients were diagnosed before admission, and 411 (42.9%) patients had a glycated hemoglobin (HbA1c) level of ≥6.5% upon admission. According to the baseline characteristics of the 958 diabetic patients on admission, the median age of the patients was 71 years (1st quartile–3rd quartile [Q1–Q3]: 59–82 years), and there were 54.4% (521/958) of males [Supplementary Table 1, https://links.lww.com/CM9/C398]. On admission, the HbA1c was 6.9% (Q1–Q3: 6.6%–8.2%). Moreover, 38.2% (366/958) of the patients had received at least one dose of the inactivated vaccine. Among these patients, 5.2% (19/366) patients received only one dose of the inactivated vaccine, while 43.4% (159/366) patients and 51.4% (188/366) patients received two and three doses of the inactivated vaccine, respectively. Compared with non-vaccinated patients, vaccinated patients were much younger (61 [49, 70] vs. 76 [68, 86] years, P <0.001), and there were more vaccinated male patients (59.8% vs. 51.0%, P = 0.008). In general, vaccinated patients had better liver and kidney function test results, such as lower lactate dehydrogenase (LDH) levels, higher albumin (ALB) levels, higher estimated glomerular filtration rate (eGFR) (median 100 mL·min−1·1.73 m−2vs. 86 mL·min−1·1.73 m−2), higher serum calcium (Ca) levels (median 2.08 mmol/L vs. 1.95 mmol/L), higher total triiodothyronine (TT3) levels (median 1.06 pmol/L vs. 0.96 pmol/L), and higher free triiodothyronine (FT3) levels (median 4.71 pmol/L vs. 4.15 pmol/L). Vaccinated patients had higher hemoglobin levels (median 133 g/L vs. 125 g/L; P <0.001) and higher lymphocyte counts (median 1.53 × 109/L vs. 1.25 × 109/L) but lower d-dimer levels (median 0.29 μg/mL vs. 0.67 μg/mL) compared to non-vaccinated patients. Fewer vaccinated patients experienced severe COVID-19 compared to non-vaccinated patients (2.7% vs. 20%, P <0.001), and most vaccinated patients (87%, 318/366) had not been prescribed oxygen therapy during their hospital stay. Fewer vaccinated patients used oxygen inhalation, non-invasive mechanical ventilation, and invasive mechanical ventilation (11.5%, 0.8%, and 0.5%, respectively) than non-vaccinated patients (27%, 9.8%, and 6.4%, respectively), P <0.001 respectively. Only one patient (0.3%, 1/366) in the vaccinated group was treated with hemodialysis during her hospital stay, while 28 patients (4.7%) in the non-vaccinated group were treated with hemodialysis during their hospital stay. Vaccinated patients had a shorter time to convert to a negative COVID-19 test result (median 11 days vs. 12 days, P = 0.031) and length of hospital stay (median 9 days vs. 10 days, P = 0.006) compared to non-vaccinated patients. The risk of severe COVID-19 was significantly lower in vaccinated individuals than in non-vaccinated individuals, as indicated by the unadjusted relative risk (RR) of 0.14 (95% confidence interval [CI], 0.07–0.26; P <0.001, Figure 1). After adjusting for age and sex, the RR remained low at 0.24 (95% CI: 0.12–0.46; P <0.001), and further adjustment for clinical characteristics at admission resulted in an RR of 0.35 (95% CI: 0.18–0.67; P = 0.002). To ensure comparability between the groups, 236 pairs of vaccinated and non-vaccinated patients were included in a propensity score matching analysis, in which all measured characteristics at baseline were balanced [Supplementary Figure 2 and Supplementary Table 2, https://links.lww.com/CM9/C398]. In the propensity score matching analysis, the vaccinated patients demonstrated a lower risk of severe COVID-19 with an RR of 0.38 (95% CI: 0.17–0.84; P = 0.010, Figure 1).Figure 1: Association between baseline characteristics and severe COVID-19. Model 1 represents the modified Poisson regression adjusted for age and sex; Model 2 was adjusted for age, sex, HbA1c, AST, ALB, eGFR, Ca, WBC, N/ly, TT3, and d-dimer. Alb: Albumin; AST: Aspartate transaminase; Ca: Calcium; COVID-19: Coronavirus disease-2019; eGFR: Estimated glomerular filtration rate; HbA1c: Glycated hemoglobin; N/ly: Neutrophil-lymphocyte ratio; RR: Relative risk; CI: Confidence interval. TT3: Total triiodothyronine; ULN: Upper normal limit; WBC: White blood cell count. The prevalence of severe COVID-19 decreased linearly with the number of vaccine shots received, with percentages of 20.1%(118/592), 10.5% (2/19), 5.0% (8/159), and 0 for the non-vaccinated, one-shot, two-shot, and three-shot groups, respectively (P <0.001). Similarly, the proportion of patients receiving mechanical ventilation decreased linearly with the increase in vaccine shots, with percentages of 16.2%(96/592), 10.5% (2/19), 1.9% (3/159), and 0 for the non-vaccinated, one-shot, two-shot, and three-shot groups, respectively (P <0.001) [Supplementary Figure 3, https://links.lww.com/CM9/C398]. The prevalence of Immunoglobulin G (IgG) positivity demonstrated a linear increase with the number of vaccine shots administered. Among the non-vaccinated, one-shot, two-shot, and three-shot groups, the IgG-positive rates were 26.7%, 44.4%, 45.8%, and 53.4%, respectively (P <0.001). Additionally, a significantly lower occurrence of severe COVID-19 was observed in IgG-positive patients compared to IgG-negative patients, with respective percentages of 9.7% and 14.7% (P = 0.032) [Supplementary Figure 4, https://links.lww.com/CM9/C398]. The present study provides compelling evidence that inactivated COVID-19 vaccines effectively protect diabetic patients from severe COVID-19. Vaccinated patients experienced shorter hospital stays and faster viral clearance compared to non-vaccinated patients. Furthermore, the present analysis revealed an enhanced protective effect against severe COVID-19 with increasing vaccine doses. A previous review of three clinical studies has reported that vaccination is associated with reduced COVID-19 severity among diabetic patients (RR = 0.32, 95% CI = 0.26–0.38);[2] however, the vaccines used in these studies were primarily mRNA and adenoviral vaccines, with inactivated vaccines making up a small portion. Only one study conducted in Chile has reported the effectiveness of inactivated vaccine (CoronaVac) in preventing intensive care unit (ICU) admission in the general population, with an unadjusted hazard ratio of 0.38 for vaccinated individuals compared to non-vaccinated individuals.[3] The present study, observed the protective effect of inactivated COVID-19 vaccines specifically among diabetic patients. The present study identified a linear association of the number of vaccination shots with a decreased risk of severe COVID-19 and related clinical outcomes among diabetic patients. A similar dosage effect has been reported in a meta-analysis comprised of 32 observational studies in the general population, demonstrating a two-fold increase in the protective effect in reducing death and severe cases when increasing the dosage from one to two shots.[4] A third dose of the COVID-19 vaccine has been shown to provide additional protection against severe or fatal outcomes compared to two doses.[5] The present study demonstrated the dosage-dependent protective effect of inactivated vaccines in preventing severe COVID-19 in diabetic patients. Vaccinated patients in the present study exhibited higher rates of positive IgG and Immunoglobulin M (IgM) antibodies, as well as faster viral clearance, compared to non-vaccinated patients. Thus, these findings suggested that vaccination induces an elevated humoral response, as indicated by the presence of IgG and IgM antibodies, which may in turn aid in the clearance of SARS-CoV-2. The present study had several limitations. First, the present study relied solely on medical history, medication use, or HbA1c levels to confirm the presence of diabetes, which may have resulted in the exclusion of certain individuals. Second, some of the baseline characteristics exhibited incompleteness or imbalances between vaccinated and non-vaccinated patients, such as body mass index, smoking habits, chronic lung disease, interstitial lung disease, stroke, and immune deficiency diseases, which may potentially impact the levels of SARS-CoV-2 IgG levels after SARS-CoV-2 vaccination and further impact the COVID-19 clinical outcomes. To minimize the potential impact of confounding factors, various analytical methods were employed, including propensity score matching analysis. Third, the present study was conducted at a single center, indicating that caution should be exercised when extrapolating these findings to other subject groups. Finally, the COVID-19 strains were not consistently monitored among the patients; however, the dominant SARS-CoV-2 variant in Shanghai was the BA.2.2 strain at the time of patient enrollment. The present findings demonstrated the effectiveness of inactivated COVID-19 vaccines in mitigating severe COVID-19 outcomes among diabetic patients in our clinical center. This real-world evidence underscores the importance of COVID-19 vaccination, particularly among elderly and female individuals with diabetes, and it advocates for broad vaccine coverage given the ongoing threat posed by the COVID-19 virus to human health. Funding This work was funded by grants from the Programs of Science and Technology Commission of Shanghai Municipality (No. 21Y11904700) and Shanghai Municipality Health Commission (No. 202140085). Conflicts of interest None.