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[Preprint]. 2023 Jan 19:2023.01.19.23284792.
doi: 10.1101/2023.01.19.23284792.

Immune response to the mRNA COVID-19 vaccine in hemodialysis patients: cohort study

Yi-Shin Chang  1   2 , Kai Huang  1   2 , Jessica M Lee  1   3 , Christen L Vagts  1 , Christian Ascoli  1 , Md-Ruhul Amin  1 , Mahmood Ghassemi  1 , Claudia M Lora  1 , Russell Edafetanure-Ibeh  1 , Yue Huang  1 , Ruth A Cherian  1 , Nandini Sarup  1 , Samantha R Warpecha  1 , Sunghyun Hwang  1 , Rhea Goel  1 , Benjamin A Turturice  1   3   4 , Cody Schott  1   3   5 , Montserrat Hernandez  1 , Yang Chen  1   6 , Julianne Joregensen  1   2 , Wangfei Wang  1   2 , Mladen Rasic  1   2 , Richard M Novak  1 , Patricia W Finn  1   2   3 , David L Perkins  1   2   6
Affiliations

Immune response to the mRNA COVID-19 vaccine in hemodialysis patients: cohort study

Yi-Shin Chang et al. medRxiv. .

Update in

Abstract

Background: 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: A transcriptomic analysis of 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 (PBMCs) 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 seven days after the second dose (V2D7) using anti-Spike IgG titers and antibody neutralization assays. Anti-spike IgG titers were additionally quantified six months 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 predominant T cell activity in controls one week after the first vaccination dose, compared to predominant myeloid cell activity in HD at this time point. HD 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 six months 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.

Conclusion: Overall, we demonstrate differing time courses of immune responses to the BTN162b2 mRNA COVID-19 vaccination in maintenance hemodialysis subjects (HD) comparable to healthy controls (HC) 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 end stage renal disease (ESRD).

Funding: F30HD102093, F30HL151182, T32HL144909, R01HL138628This research has been funded by the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS) award UL1TR002003.

Keywords: COVID-19; Hemodialysis; RNA Sequencing; SARS-CoV-2; Vaccine; binding antibodies; neutralizing antibodies.

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Figures

Figure 1.
Figure 1.. Differentially expressed genes (DEGs) increased after second vaccination dose compared to first, and at Day 1 and 2 (D1/D2) compared to Day 7 (D7) for both controls (HC) and maintenance hemodialysis (HD).
Number of DEGs at each time point is displayed on a log scale, with DEGs for HC shown for D1 and D7 compared to pre-vaccination time point (D0), and DEGs for HD shown for D2 and D7 compared to D0. DEGs are shown independently of SARS-CoV-2 history (Top), for analysis of only subjects with no prior SARS-CoV-2 history (Middle), and for analysis of only subjects with prior SARS-CoV-2 history (Bottom). The DESeq2 R package was used to identify genes that were differentially expressed at each time point after vaccination for each subject group (p < 0.05, FDR-adjusted).
Figure 2.
Figure 2.. Controls (HC) and maintenance hemodialysis subjects (HD) with no SARS-CoV-2 history demonstrate differing longitudinal enrichments of blood transcription modules (BTMs).
(A) The most significantly enriched BTMs are shown (up to six) for Day 1 (D1) and Day 7 (D7) after each vaccination dose (V1, V2) in HC with no prior infection with SARS-CoV-2 (p < 0.05, FDR-adjusted). Density plots for each BTM represent Wald statistics from DESeq2 analysis for each membership gene, thereby representing increased or decreased expression per gene at each time point compared to baseline (V1D0 or V2D0). (B) Similarly to (A), the most significantly enriched BTMs for Day 2 (D2) and Day 7 (D7) in HD are shown.
Figure 3.
Figure 3.. Controls (HC) and maintenance hemodialysis subjects (HD) demonstrate differing time courses of blood transcription module (BTM) enrichment after each vaccination dose.
Percentage of BTMs in each BTM family with significant enrichment at each time point after each vaccination dose (V1, V2) for Day 1 (D1) and Day 7 (D7) in HC, and Day 2 (D2) and D7 for HD in subjects with no prior infection with SARS-CoV-2 (p < 0.05, FDR-adjusted). Direction of enrichment was determined using the median Wald statistic from DESeq2 analysis for each BTM membership gene, thereby representing overall increased or decreased expression of membership genes at each time point compared to baseline (V1D0 or V2D0).
Figure 4.
Figure 4.. Antibodies significantly increased in controls and maintenance hemodialysis (HD) one week after the second vaccination dose (p < 0.001) and six months after initial vaccination (p < 0.001) with the BNT162b2 mRNA COVID-19 vaccine.
(A) Anti-spike IgG levels in controls and HD subjects with and without prior SARS-CoV-2 history before vaccination (V1D0), one week after second vaccination dose (V2D7), and six months after initial vaccination (M6). (B) Antibody neutralization activity (ID50) in controls and HD subjects with and without prior SARS-CoV-2 history at V1D0 and V2D7.
Figure 5.
Figure 5.. Increased expression of multiple Blood Transcription Modules (BTMs) at V2D2 is predictive of higher anti-spike IgG at V2D7.
Of 30 enriched BTMs at V2D2, increased expression of 18 BTMs is predictive of increased anti-spike IgG at V2D7 (p< 0.05, FDR-corrected), controlling for SARS-CoV-2 history. Predictive pathways include innate immune, antigen presentation, and T cell pathways. Three examples are shown.
Figure 6.
Figure 6.. Baseline ferritin level and post-V1 white blood cell count (WBC) are clinical predictors of post-V2 antibody responses in maintenance hemodialysis patients (HD).
(A) Ferritin levels associated with lowest all-cause mortality predict the development of higher anti-spike IgG after vaccination at V2D7 (p < 0.01) and M6 (not shown, p < 0.05) in maintenance HD patients. Dashed vertical lines indicate the intermediate range of ferritin (200–1200 ng/ml) associated with lowest all-cause mortality . (B) Increased WBC after first vaccination dose is predictive of anti-spike IgG titers after vaccination at V2D7 (p < 0.01) and M6 (not shown, p < 0.05) in maintenance HD patients. Points with negative log-fold change of white blood cell counts (LFC(WBC)) and positive LFC(WBC) represent a decrease and increase, respectively, in WBC from baseline labs.
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