Similar Time Course of Humoral Response to SARS-CoV-2 mRNA Vaccines in People With and Without Type 1 Diabetes

Abstract

Objective:

To assess whether the immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines or breakthrough infection rates differ between patients with type 1 diabetes (T1D) and control subjects.

Research Design and Methods:

A prospective 12-month follow-up of 27 adults with T1D and 89 control subjects who received at least two doses of either the mRNA-1273 or BNT162b2 vaccine. Primary outcomes: total antibodies against the receptor-binding domain and neutralizing antibodies. A multivariate repeated measures model evaluated potential determinants of antibody response.

Results:

Neither antibody levels nor breakthrough infection rates after vaccination differed in T1D and non-T1D groups. Older age predicted lower antibody levels, whereas SARS-CoV-2 infection or booster vaccine resulted in higher antibody levels in both groups. mRNA-1273 was associated with higher antibody levels than BNT162b2 until 6 months after the first dose.

Conclusions:

Persons with and without T1D have similar humoral antibody responses to SARS-CoV-2 mRNA vaccines during 12-months of follow-up.

Introduction

SARS-CoV-2 (severe acute respiratory disease coronavirus 2) causes coronavirus disease 2019 (COVID-19) and has resulted in a global pandemic. People with type 1 or type 2 diabetes are at a higher risk for more severe outcomes with COVID-19 compared with the general population.¹ To fight the COVID-19 pandemic, a variety of vaccines were applied worldwide since December 2020. The mRNA vaccines provided by Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273) have shown high efficacy with reduced rates of SARS-CoV-2 infection and decreased burden of COVID-19 on the health care system.^2,3 However, patients with type 1 diabetes (T1D) and their caregivers report a wide range of attitudes, intentions, and behaviors regarding the vaccination.⁴

Impaired immune response and lower protective immune responses after immunization have been reported in patients with T1D,^5,6 which raise the possibility of lower efficacy of the SARS-CoV-2 vaccines in this population. Longitudinal studies measuring the humoral immune response post-vaccination in patients with T1D are limited. We launched this study just after the Food and Drug Administration issued an Emergency Use Authorization for the Pfizer-BioNTech COVID-19 (BNT162b2) and Moderna (mRNA-1273) vaccines. This prospective study longitudinally measured the antibody response, including the neutralizing ability of these antibodies, to the SARS-CoV-2 mRNA vaccines for 12 months in patients with T1D compared with control subjects to provide evidence for the immunogenicity of SARS-CoV-2 mRNA vaccines in patients with T1D.

Research Design and Methods

Subjects

From December 18, 2020 to April 12, 2022, 27 adults with T1D attending the Barbara Davis Center for Diabetes (Denver, Colorado) and 89 normoglycemic control subjects were enrolled and followed for 12 months. All participants received two doses of either mRNA-1273 (Moderna) or BNT162b2 (BioNTech/Pfizer) vaccine. Serum samples were obtained after the first and second dose of vaccine, and at 3, 6, 9, and 12 months after the first dose. Specifically, the timepoints of serum samples obtained were defined as follows: after first dose—more than 17 days after the first dose of vaccine and up to 3 days before the second dose of vaccine; after second dose—more than 17 days after the second dose of vaccine; 3 months—71 to 109 days after the first dose of vaccine; 6 months—161 to 199 days after the first dose of vaccine; 9 months—240 to 300 days after the first dose of vaccine; and 12 months—335 to 395 days after the first dose of vaccine.

Serum samples obtained outside the definition of these timepoints were excluded from the analysis. Durations of T1D and glycated hemoglobin (HbA1c) tested within 120 days of the first vaccine dose were collected among T1D participants. All participants provided written informed consent. The Colorado Multiple Institutional Review Board approved the study.

SARS-CoV-2 antibody assays

Serum SARS-CoV-2 antibodies to receptor-binding domain (RBD) of the spike protein (total RBD antibodies) and SARS-CoV-2 nucleocapsid protein (NP) antibodies were measured by electrochemiluminescent assay.⁷ Both antibodies levels were reported as an index (index = [(Signal_sample – Signal_{negative control})/(Signal_{positive control} − Signal_{negative control})] × 100). The cutoff values for total RBD antibody index and NP antibody index were both set at 5.0 upon the 99.9th percentile of 922 control serum samples obtained before September 2019 (pre-COVID-19 period).⁷ The NP antibody was used to confirm self-reported SARS-CoV-2 infection.

Serum SARS-CoV-2 neutralizing antibody against SARS-CoV-2 RBD were assessed using a surrogate virus neutralization test kit (cPass™, GenScript). Neutralizing antibody levels were reported as index (index = [(Signal_sample – Signal_{negative control})/(Signal_{positive control} − Signal_{negative control})] × serum dilution rate), and the cutoff value was set at 0.31 according to the manufacturer instructions. SARS-CoV-2 infection was defined by positive nucleic acid amplification test, or total RBD antibody positivity before vaccination, or NP antibody positivity at any point during the study as the NP is not contained in the mRNA-based vaccines.

Statistical analyses

Statistical analyses were performed using GraphPad Prism 9.2.0 (GraphPad Software, LLC) and SAS v9.4 (SAS Institute, Inc., Cary, NC). To normalize SARS-CoV-2 antibody levels, Box-Cox transformation was performed and the optimal power parameter (λ = 0.25) was obtained using PROC TRANSREG by using a maximum likelihood criterion.⁸ A multivariate repeated measures model with an autoregressive covariance structure was used to estimate mean antibody levels at each timepoint after vaccination by their vaccine type and T1D status. Covariates included age, sex, T1D status, vaccine types, and receipt of a booster. Confirmed SARS-CoV-2 infection was included as a time-varying variable. Two-tailed P-values <0.05 were considered significant.

Results

Characteristics of the T1D and non-T1D groups

For participants in the T1D group, the average duration of diabetes was 25.7 ± 14.5 years, and the average HbA1c was 6.7% ± 0.8% (50.4 ± 8.4 mmol/mol). The age and sex distributions were similar between the two groups (Supplementary Table S1). In the T1D group, 85% of participants received the BNT162b2 vaccine and 15% received mRNA-1273 vaccine with 89% receiving a booster dose. In non-T1D group, 70% of participants received the BNT162b2 vaccine and 30% received mRNA-1273 vaccine with 79% receiving a booster.

There were no significant differences in the vaccine types or rates of booster vaccination between the T1D and non-T1D groups. All the booster doses were consistent with the vaccine types administered at the first and second doses. The rates of SARS-CoV-2 infections during the 12-month follow-up did not differ by groups with similar infection rates before the second dose and among breakthrough infections after being fully vaccinated, which were 15% in T1D participants and 18% in controls (Supplementary Table S1).

Multivariate analysis of the determinants of antibody response

Using multivariate repeated measures model, we analyzed the determinants of humoral response to mRNA vaccination (Table 1). In both groups, older age was associated with lower antibody levels after vaccination, whereas sex was not. SARS-CoV-2 infection or booster vaccination predicted a stronger humoral response in both groups. Both the total RBD antibody levels and the neutralizing ability of these antibodies remained higher in participants who received mRNA-1273 than in those who received BNT162b2 until the 6-month visit, and then became similar for the two types of vaccines at 9 and 12 months. Overall, the humoral immune response to vaccines did not differ in people with or without T1D.

Table 1.

Multivariate Repeated Measures Analysis of Total Receptor-Binding Domain Antibody and Neutralizing Antibody Levels

Variates	Total RBD antibody		Neutralizing antibody
Variates	Estimate (95% CI)	P	Estimate (95% CI)	P
Age	−0.11 (−0.16 to −0.06)	<0.0001	−0.03 (−0.04 to −0.01)	<0.0001
Female vs. male	0.12 (−1.44 to 1.68)	0.88	−0.17 (−0.54 to 0.20)	0.36
SARS-CoV-2 infection	8.48 (6.71 to 10.25)	<0.0001	2.50 (2.07 to 2.93)	<0.0001
Yes for booster vaccine	9.82 (7.54 to 12.10)	<0.0001	3.20 (2.63 to 3.76)	<0.0001
mRNA-1273 vs. BNT162b2	Overall P < 0.0001		Overall P < 0.0001
After first dose	12.47 (5.36 to 19.59)	0.001	2.82 (1.09 to 4.56)	0.002
After second dose	7.61 (0.57 to 14.65)	0.034	2.27 (0.55 to 3.98)	0.010
3 months	16.51 (8.75 to 24.26)	<0.0001	4.28 (2.38 to 6.17)	<0.0001
6 months	13.58 (4.53 to 22.62)	0.003	3.54 (1.32 to 5.76)	0.002
9 months	4.52 (−4.59 to 13.63)	0.33	1.40 (−0.83 to 3.63)	0.22
12 months	−4.80 (−12.65 to 3.05)	0.23	1.12 (−0.80 to 3.04)	0.25
T1D vs. non-T1D	Overall P = 0.34		Overall P = 0.74
After first dose	−5.21 (−12.39 to 1.97)	0.15	−0.34 (−2.08 to 1.41)	0.71
After second dose	−3.78 (−10.87 to 3.31)	0.30	−0.17 (−1.90 to 1.56)	0.85
3 months	−4.75 (−12.37 to 3.22)	0.25	0.19 (−1.72 to 2.09)	0.85
6 months	−1.81 (−10.90 to 7.28)	0.70	−1.46 (−3.69 to 0.77)	0.20
9 months	5.00 (−4.07 to 14.08)	0.28	−0.69 (−2.91 to 1.54)	0.54
12 months	−3.87 (−11.70 to 3.97)	0.33	−1.23 (−3.15 to 0.68)	0.21

RBD, receptor-binding domain; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; T1D, type 1 diabetes.

Comparison of humoral response after vaccinations between T1D and non-T1D groups

In participants with or without T1D, the levels of total RBD antibody and neutralizing antibody increased after the first and second doses and decreased after 3 months until 9 months (Fig. 1). In Supplementary Table S4A–D, the least squares (LS) means of total RBD antibody and neutralizing antibody levels, and the back-transformed LS-means by vaccine types and T1D status at different timepoints were provided to more specifically show the changes in antibody levels. In the repeated measures model, controlling for age, sex, T1D status, vaccine types, booster, and SARS-CoV-2 infection, there were no significant differences in total RBD antibody levels or neutralizing antibody levels between non-T1D and T1D groups at each timepoint (Table 1). The neutralizing antibodies levels did not have significant differences in stratified analysis by vaccine types and T1D status at each timepoint (Supplementary Table S2, S3A, B and Supplementary Fig. S1).

FIG. 1.

(A) Comparison of levels of total RBD antibody between non-T1D (no stripes) and T1D (with stripes) groups. (B) Comparison of levels of neutralizing antibody between non-T1D (no stripes) and T1D (with stripes) groups. The timepoints were defined as follows: first dose—more than 17 days after the first dose of vaccine and up to 3 days before the second dose of vaccine; second dose—more than 17 days after the second dose of vaccine; 3 months—71 to 109 days after the first dose of vaccine; 6 months—161 to 199 days after the first dose of vaccine; 9 months—240 to 300 days after the first dose of vaccine; and 12 months—335 to 395 days after the first dose of vaccine. RBD, receptor-binding domain; T1D, type 1 diabetes. Color graphics can be found online.

Conclusions

This study provides real-world data for the humoral immune response to mRNA-based vaccines directed against SARS-CoV-2 for 12 months after the initial vaccine dose in people with T1D compared with controls. A prior short-term observational study reported lower antibody levels in people with T1D versus controls after the first dose of COVID-19 vaccines, but similar levels after the second dose.⁹ Another cohort study observed no difference between patients with T1D and controls in response to SARS-CoV-2 mRNA vaccines 3–4 weeks after the first dose or 4 weeks after the second dose.¹⁰ Humoral immune response to vaccination is variable due to host factors as well as vaccine types and concurrent infections.

We found no difference in antibody levels to the mRNA vaccines in people with or without T1D at every timepoint until 12 months, controlling for age, sex, previous SARS-CoV-2 infection, mRNA vaccine types, and booster dose. Furthermore, the breakthrough infection rates were equally infrequent in non-T1D and T1D group, suggesting comparable protective effect of mRNA vaccines. In a previous study in type 2 diabetes patients with suboptimal glycemic control, lower antibody responses to COVID-19 vaccination were observed compared with the patients with good glycemic control.¹¹ In our study, the T1D participants had optimal glycemic control, which may contribute to the comparable antibody levels to the control participants.

This study contributes to our understanding of the kinetics and determinants of humoral response to SARS-CoV-2. The mRNA vaccines induced robust total RBD antibodies and neutralizing antibodies regardless of diabetes status. Neutralizing antibodies predict protection from severe SARS-CoV-2 infections.^12,13 The levels of total RBD antibodies correlated well with the levels of neutralizing antibodies in our study (Supplementary Fig. S2) and can be used as a surrogate biomarker. Our study confirmed that an older age is associated with lower antibody response supporting the booster recommendations for older individuals.¹⁴ Individuals vaccinated with mRNA-1273 exhibited stronger humoral responses than those vaccinated with BNT162b2 up to 6 months after vaccination.

The rates of breakthrough infection did not differ between mRNA-1273 and BNT162b2 (Supplementary Table S2). The decline of antibody levels at 6 and 9 months, before the booster, was similar among non-T1D and T1D participants, similar to a previous report in non-T1D population.¹⁵ Our data support the importance of booster vaccines not only for higher-risk individuals but also for the general population.^16,17 In contrast, 20 (17%) of the fully vaccinated study participants, including 4 T1D patients, had a breakthrough COVID-19 infection, with the majority (18/20) happening after 6 months from the first dose and after September of 2021, which may be partly attributed to decreased efficacy of vaccines against the delta and omicron variants.¹⁸

In conclusion, our study demonstrates that individuals with and without T1D have similar humoral immune response to SARS-CoV-2 mRNA vaccines. The study has some limitations. Although we found that age is an important factor on antibody levels, stratified analysis for different age groups was not performed because of the limitation of sample size. The ability of RBD antibodies to neutralize the SARS-CoV-2 virus was not directly measured in our study. These observations need to be confirmed in a larger diverse population controlling for potential confounders such as occupation and ethnicity.

Footnotes

Authors' Contributions

M.R., A.W.M., and L.Y. designed the study. M.R. and X.J. wrote the article. X.J. and L.Y. collected the data and performed the laboratory tests. F.D. and L.P. completed statistical analyses. All authors reviewed and approved the final version of the article. M.R. and L.Y. are the guarantors of this study, have full access to all the data in the study, and take responsibility for the data integrity and accuracy of analysis.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This study was supported by NIH grants (DK032083 and DK116073) and the Patten-Davis Foundation. We thank Daniel Felipe-Morales and Rachel Karban, MSPH for technical support.

Supplementary Material

Supplementary Figure S1

Supplementary Figure S2

Supplementary Table S1

Supplementary Table S2

Supplementary Table S3

Supplementary Table S4

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Supplementary Material

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