Altered transcriptomic immune responses of maintenance hemodialysis patients to the COVID-19 mRNA vaccine
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eLife assessment
This study presents a valuable inventory of immune responses to the BTN162b2 mRNA COVID-19 vaccination in 20 hemodialyses (HD) patients and controls at different time courses. The transcriptomic sequencing data were collected and analyzed using a solid and validated methodology. The data analysis and clinical predictors to predict anti-Spike IgG titers in HD can be a starting point for further studies characterizing the immune dysregulation seen in ESRD.
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Abstract
End-stage renal disease (ESRD) patients experience immune compromise characterized by complex alterations of both innate and adaptive immunity, and results in higher susceptibility to infection and lower response to vaccination. This immune compromise, coupled with greater risk of exposure to infectious disease at hemodialysis (HD) centers, underscores the need for examination of the immune response to the COVID-19 mRNA-based vaccines.
Methods:
The immune response to the COVID-19 BNT162b2 mRNA vaccine was assessed in 20 HD patients and cohort-matched controls. RNA sequencing of peripheral blood mononuclear cells was performed longitudinally before and after each vaccination dose for a total of six time points per subject. Anti-spike antibody levels were quantified prior to the first vaccination dose (V1D0) and 7 d after the second dose (V2D7) using anti-spike IgG titers and antibody neutralization assays. Anti-spike IgG titers were additionally quantified 6 mo after initial vaccination. Clinical history and lab values in HD patients were obtained to identify predictors of vaccination response.
Results:
Transcriptomic analyses demonstrated differing time courses of immune responses, with prolonged myeloid cell activity in HD at 1 wk after the first vaccination dose. HD also demonstrated decreased metabolic activity and decreased antigen presentation compared to controls after the second vaccination dose. Anti-spike IgG titers and neutralizing function were substantially elevated in both controls and HD at V2D7, with a small but significant reduction in titers in HD groups (p<0.05). Anti-spike IgG remained elevated above baseline at 6 mo in both subject groups. Anti-spike IgG titers at V2D7 were highly predictive of 6-month titer levels. Transcriptomic biomarkers after the second vaccination dose and clinical biomarkers including ferritin levels were found to be predictive of antibody development.
Conclusions:
Overall, we demonstrate differing time courses of immune responses to the BTN162b2 mRNA COVID-19 vaccination in maintenance HD subjects comparable to healthy controls and identify transcriptomic and clinical predictors of anti-spike IgG titers in HD. Analyzing vaccination as an in vivo perturbation, our results warrant further characterization of the immune dysregulation of ESRD.
Funding:
F30HD102093, F30HL151182, T32HL144909, R01HL138628. This research has been funded by the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS) award UL1TR002003.
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eLife assessment
This study presents a valuable inventory of immune responses to the BTN162b2 mRNA COVID-19 vaccination in 20 hemodialyses (HD) patients and controls at different time courses. The transcriptomic sequencing data were collected and analyzed using a solid and validated methodology. The data analysis and clinical predictors to predict anti-Spike IgG titers in HD can be a starting point for further studies characterizing the immune dysregulation seen in ESRD.
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Reviewer #1 (Public Review):
Chang et al. demonstrate through their findings that COVID-19 mRNA vaccination of hemodialysis patients produces no significant difference in antibody levels achieved across the vaccination series. They correlate the antibody responses through RNA sequencing data of dialysis patients versus healthy controls throughout the vaccination series. They also compare those with prior infection versus those who are infection naive. The antibody findings are interesting because they disagree with previous publications showing that dialysis patients have a significantly lower antibody titer level achieved from vaccination than controls. The authors posit that this may be age-related, but subject numbers in the current study are not adequately powered to make that definitive determination.
However, they find that T-cell …
Reviewer #1 (Public Review):
Chang et al. demonstrate through their findings that COVID-19 mRNA vaccination of hemodialysis patients produces no significant difference in antibody levels achieved across the vaccination series. They correlate the antibody responses through RNA sequencing data of dialysis patients versus healthy controls throughout the vaccination series. They also compare those with prior infection versus those who are infection naive. The antibody findings are interesting because they disagree with previous publications showing that dialysis patients have a significantly lower antibody titer level achieved from vaccination than controls. The authors posit that this may be age-related, but subject numbers in the current study are not adequately powered to make that definitive determination.
However, they find that T-cell responses may be muted in hemodialysis patients as they have lower activation of T-cell genes than healthy controls. The RNA sequencing evidence is solid. However, they lack data on a clinical correlation to T-cell responses.
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Reviewer #2 (Public Review):
In HD patients, immune pathways alteration leads to higher susceptibility to infection and lower response to the COVID-19 mRNA vaccine. Therefore, it is important to understand the immune response to vaccines in ESRD patients against the COVID-19 pandemic. In this MS, the authors recruited 20 HD patients and cohort-matched controls to perform multiple experimental studies (including transcriptomic analysis, RNAseq, and Anti-Spike (trimer) IgG Titer Quantification) to investigate how immune pathways alteration in HD patients after COVID-19 mRNA vaccine injection. They demonstrate differing expression of BTMs and differing time courses of immune responses to the BTN162b2 mRNA COVID-19 vaccination in maintenance hemodialysis subjects (HD) compared to controls, which warrants further characterization of the …
Reviewer #2 (Public Review):
In HD patients, immune pathways alteration leads to higher susceptibility to infection and lower response to the COVID-19 mRNA vaccine. Therefore, it is important to understand the immune response to vaccines in ESRD patients against the COVID-19 pandemic. In this MS, the authors recruited 20 HD patients and cohort-matched controls to perform multiple experimental studies (including transcriptomic analysis, RNAseq, and Anti-Spike (trimer) IgG Titer Quantification) to investigate how immune pathways alteration in HD patients after COVID-19 mRNA vaccine injection. They demonstrate differing expression of BTMs and differing time courses of immune responses to the BTN162b2 mRNA COVID-19 vaccination in maintenance hemodialysis subjects (HD) compared to controls, which warrants further characterization of the immune dysregulation of ESRD and immune biomarkers. Overall, the study is well designed, and the result has potential clinical value and will interest nephrologists. The major concern of this study is the cohort set up. The sample sizes of recruited candidates are relatively small, and no validation cohort was designed. More importantly, between the two groups, the race distribution is uneven. For example, 10 black and 2 white HD patients were included, but accordingly, 3 black and 8 white people were recruited as controls. In such a small size of the clinical study, this kind of unevenness might cause potential issues in concluding. In addition, the control cohort also included 1 diabetes and 4 hypertension, patients. Will these existing primary diseases in controls cause noise in the data analysis because these metabolic diseases also can directly cause immune system dysfunction? In addition, there were 8 HD patients and 5 HC with a positive test of SARS-CoV-2 from 8 months to four weeks preceding vaccination. How long does the immune response last after being infected with COVID-19? Several studies have found that people infected with COVID-19 continue to produce antibodies to the virus for seven or eight months after recovery. Therefore, people with a COVID-19 history might not be suitable for this trial.
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