Robust Neutralizing Antibodies to SARS-CoV-2 Develop and Persist in Subjects with Diabetes and COVID-19 Pneumonia

Abstract

Context: Demonstrating the ability to mount a neutralizing antibody response to SARS-CoV-2 in the presence of diabetes is crucial to understand COVID-19 pathogenesis, reinfection potential, and vaccine development.

Objective: The aim of this study was to characterize the kinetics and durability of neutralizing antibody (Nab) response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the presence of hyperglycemia.

Methods: Using a lentiviral vector-based SARS-CoV-2 neutralization assay to measure Nabs, we characterized 150 patients randomly selected from a cohort of 509 patients with confirmed COVID-19 pneumonia. We analyzed Nab response according to the presence of diabetes or hyperglycemia, at the time of hospitalization and during the postdischarge follow-up: 1-, 3-, and 6-month outpatient visits.

Results: Among 150 randomly selected patients 40 (26.6%) had diabetes. Diabetes (hazard ratio [HR] 8.9, P < .001), glucose levels (HR 1.25 × 1.1 mmol/L, P < .001), and glucose variability (HR 1.17 × 0.6 mmol/L, P < .001) were independently associated with an increased risk of mortality. The neutralizing activity of SARS-CoV-2 antibodies in patients with diabetes was superimposable, as for kinetics and extent, to that of patients without diabetes. It was similar across glucose levels and correlated with the humoral response against the SARS-CoV-2 spike protein. Positivity for Nabs at the time of hospital admission conferred protection on mortality, both in the presence (HR 0.28, P = .046) or absence of diabetes (HR 0.26, P = .030). The longevity of the Nab response was not affected by diabetes.

Conclusion: Diabetes and hyperglycemia do not affect the kinetics and durability of the neutralizing antibody response to SARS-CoV-2. These findings provide the rational to include patients with diabetes in the early phase of the vaccination campaign against SARS-CoV-2.

Keywords: COVID-19; SARS-CoV-2; diabetes; humoral response; neutralizing antibodies; survival rate.

Figure 1.

Neutralizing antibodies prevalence and titers based on diabetes status. Correlation between neutralizing antibody titers and days since symptoms onset (A) and neutralizing titers of Nab positive sample (B) in patients with COVID-19 pneumonia. Nabs were measured in 150 subjects at the first sampling available after hospital admission (median days from symptoms onset: 10.5 [7-16] and 11 [6-17.7] in patients without [n = 110] or with diabetes [n = 40], respectively). Results are shown as the reverse serum dilution giving an ID50 measured in each sample (circles), and below that we report a probability density estimate and a boxplot showing median, IQR with whiskers extending to 1.96 times the median, and outlier omission. Solid circles are positive (green) or negative (magenta) cases for SARS-CoV2 RBD IgG and/or IgM. Nabs, anti-SARS-CoV-2 RBD IgG and IgM, and S1 + S2 IgG were also stratified by duration of symptoms (weeks 1, 2, 3, ≥4) at the time of sampling and diabetes status (C). For each time point, results are percentage of positivity (left) and median of titers (right) (sample size: week 1: no diabetes n = 29, diabetes n = 14; week 2: no diabetes n = 45, diabetes n = 13; week 3: no diabetes n = 23, diabetes n = 7; week ≥4: no diabetes n = 13, diabetes n = 6). *P < .05 and **P < .01, χ ² test or Mann–Whitney U test, diabetes vs no diabetes.

Figure 2.

Correlation matrix of different antibody responses in subject with or without diabetes. Correlograms show coefficients for various antibody responses with corresponding values matched to colors in the legend. Correlations are presented as Pearson coefficients after Log1p normalization. Crosses indicate correlation with P > .05.

Figure 3.

Neutralizing antibodies to SARS-CoV-2 and survival in patients with COVID-19, with or without diabetes. Kaplan–Meier patient survival estimates for 150 patients with COVID-19 pneumonia (A). Survival rate was estimated for the presence of neutralizing antibodies after stratification for diabetes or fasting plasma glucose. The log rank test was used to test differences in the estimated survival rate between Nab+ and Nab- individuals. Crosses indicate censored patients (censoring for lack of follow-up data). The forest plots (B) show the hazard ratios for death for each antibody tested. Cox regression analysis was adjusted for sex and age and stratified for the duration of symptoms at the time of blood sampling. Dots represent the HR; solid dots indicate P < .05.

Figure 4.

Durability of neutralizing antibodies to SARS-CoV-2 in subject with or without diabetes. Kinetics of neutralizing antibodies titers and SARS-CoV-2 IgG expansion in COVID-19 sera stratified by the duration of symptoms at serum sampling (admission n = 150, 1st visit, n = 75, 2nd visit, n = 72, 3rd visit n = 40; see also Table 1). For each sample are shown the measured ID50 or arbitrary units (circles), the probability density estimate (with the half violin plot upscaled to maximum width for better visualization), box plot displaying median, IQR, and whiskers extending to 1.96 times the IQR.