Better Anti-Spike IgG Antibody Response to SARS-CoV-2 Vaccine in Patients on Haemodiafiltration than on Haemodialysis

Introduction: The antibody response to SARS-CoV-2 vaccine in haemodialysis (HD) patients is diminished compared to healthy subjects. The aim of this study was to compare the presence of reactive SARS-CoV-2 antibodies in patients with high-flux HD and on-line haemodiafiltration (HDF) three and 6 months after the second dose of SARS-CoV-2 vaccine since previous studies indicate that a sustained antibody response correlates with protection from disease. Methods: We included 216 HD patients of which 157 had on-line HDF and 59 high-flux HD and 46 health care workers as controls and studied the presence of reactive anti-spike IgG antibodies three and 6 months after the second dose of SARS-CoV-2 vaccine. Clinical features between the patient groups were similar, but patients with on-line HDF had significantly higher Kt/V. Results: The percentage of participants with reactive antibodies was significantly lower in patients compared to controls, both three and 6 months after the second dose of vaccine. Furthermore, the proportion of patients with reactive anti-spike IgG ≥1.0 6 months after the second dose of vaccine was significantly higher in patients with on-line HDF compared to in patients with high-flux HD. In logistic regression analyses adjusted for several clinical features, the variables associated with presence of reactive anti-spike IgG at 3 months after the second dose of vaccine were lower age, HDF treatment, not being obese and not having a previous solid organ transplant. The two variables with the strongest influence on the presence of reactive anti-spike IgG levels 6 months after the second dose of vaccine were treatment with on-line HDF and not having immunosuppressive therapy. Conclusion: This is the first study to show that on-line HDF preserves the antibody response better than high-flux HD after vaccination with SARS-CoV-2 vaccine. Treatment strategies that sustain the vaccine response are essential to apply in this vulnerable group of patients.

© 2023 S. Karger AG, Basel

Introduction

Patients on in-centre haemodialysis (ICHD) have a higher risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) than the general population and worse clinical outcomes after coronavirus disease 2019 (COVID-19) [1]. The pandemic has been a particular threat to patients on ICHD as they need to attend thrice-weekly treatments to which they are often transported by shared cars or public transport. Compounding these risks, HD patients tend to be elderly and are often from ethnic and socioeconomically underprivileged groups with a high comorbidity burden [2].

Consequently, there is an imperative need to effectively immunize HD patients and to take actions to maintain optimal antibody titres over time. The humoral immune responses to SARS-CoV-2 are mediated by IgG antibodies directed against viral surface glycoproteins, mainly the spike glycoprotein and the nucleocapsid protein. Recent studies have shown that antibody titres after vaccination against SARS-CoV-2 are diminished in HD patients as compared to the general population with an incomplete, delayed humoral immune response, and a blunted cellular immune response [3]. The immunological mechanisms are not fully understood.

Studies have shown that HD patients also have an impaired immune response to vaccines against hepatitis B [4], pneumococcal capsular polysaccharide vaccine [5], and influenza [6], with lower seroconversion rates and waning titres with time. The reduced efficacy of these vaccines in HD patients has been attributed to a variety of factors such as retention of uremic solutes, age, gender, body weight, nutritional status, seropositivity for antibodies against hepatitis C virus or human immunodeficiency virus, low serum albumin, possession of the major histocompatibility complex haplotypes, blood transfusion history, volume overload, and the acceleration of immunosenescence induced by chronic inflammation [79].

For most infective agents, the current view is that neutralizing antibody levels serve as an immune correlate of protection from infection [10]. Data obtained from vaccine trials demonstrate a strong correlation between neutralizing antibody levels and protective efficacy [10], suggesting the higher the antibody levels, the better the protection from infection.

The retention of waste products of metabolism in patients with kidney failure leads to reduced function of the immune system: both innate and adaptive immunity are compromised [10]. Haemodiafiltration (HDF) increases middle molecule azotemic toxin clearances compared to HD and may reduce systemic inflammation and this may lead to improved immunological responsiveness [11].

Indeed, studies have indicated that dialysis membrane flux influences the immunological response to vaccines against hepatitis B and influenza [12, 13]. The primary objective of the present study was to investigate if the antibody response to SARS-CoV-2 vaccine is better sustained in patients on HDF than in patients on high-flux HD.

Materials and MethodsStudy Population – Patients on Haemodialysis and Health Care Workers

In January 2021, the Portuguese health authority declared HD patients as well as healthcare workers to be in a high-risk category for infection and a priority for SARS-Cov-2 vaccination. This presented a unique opportunity to investigate the outcomes of a real-life programme of simultaneous vaccination of all ICHD patients in a single DaVita haemodialysis unit in Leiria, Portugal.

This study aimed to evaluate the antibody response following a mRNA COVID-19 vaccination programme in patients receiving either on-line HDF (n = 156) or high-flux HD (n = 59). The most common dialysers used in our clinic are FX CorDiax (Fresenius Medical Care). Dialysis time is 4 h in both groups and the convection volume for HDF patients is ≥23 L per session, mean (standard deviation, SD) 26.7 ± 2.1 L independently of body weight. Health care workers (n = 46) were included as controls.

Laboratory Studies

Serum tubes (BD Vacutainer) were used for blood sampling. Samples were transported to the laboratory at 2–8°C within 2 h. On arrival, specimens were centrifuged at 1,300 g (RCF) for 10 min according to the manufacturers’ instructions, aliquoted and stored at −20°C.

All samples were tested for the presence of IgG antibodies against SARS-CoV-2 with two commercially available serological assays: the Elecsys® Anti-SARS-CoV-2 electrochemiluminescence immunoassay, from Roche Diagnostics, measuring IgG against SARS-CoV-2 N-protein (anti-nucleocapsid antibodies), and the Atellica® IM SARS-CoV-2 IgG chemiluminescence assay, from Siemens Healthineers, measuring IgG against SARS-CoV-2 S-protein (anti-spike protein antibodies).

To ensure that all participants were correctly allocated to the with and without previous SARS-CoV-2 infection groups, anti-N antibody tests were performed 21 days after each vaccine dose, and at three and 6 months after the full vaccination.

SARS-CoV-2 IgG titres (index) were calculated automatically by the immunoassay analysers based on relative light units (RLU) because the viral antibody titre is positively associated with RLU. According to both manufacturers’ instructions, the cut-off value for a positive SARS-CoV-2 IgG result is 1.0 (index value). Traceability to the first WHO 20/136 has been demonstrated by manufacturer studies which concluded that the cut-off of 1.00 index on the Atellica IM assay is equivalent to a WHO binding antibody units (BAU)/mL value of 21.8. This traceability allows comparison of different studies or results in BAU/mL obtained from different assays, once they have the same protein targets (in this case, anti-S1 RDB IgG assays. All antibody tests in this study were performed by the same doctor. Patient and treatment characteristics and biochemical data, leucocyte count, lymphocyte count, and C-reactive protein (CRP) were collected during routine clinical practice and laboratory analyses were performed in accordance with validated and recommended routine procedures.

Statistical Analysis

Statistical analyses were performed using IBM SPSS v.27. Descriptive data are presented as mean values and SD. χ2 test or Fisher’s exact test was used for comparisons of categorical variables and Student’s t test for continuous variables. Unadjusted multiple logistic regression analysis and analyses with conditional backward selection were used to determine variables associated with the occurrence of reactive (≥1.0) anti-spike IgG antibodies 3 months and 6 months after the second dose of SARS-Cov-2 vaccination. Data were expressed as odds ratio and 95% confidence interval. Statistical significance was considered at a p value <0.05.

Results

Anti-spike protein IgG antibody titres and anti-nucleocapsid antibodies to SARS-CoV-2 were analysed after the first and second dose of BNT162b2 (Pfizer-BioNTech) vaccine in 216 HD patients, mean age 69 ± 13 years, 63% males, 41% diabetes mellitus, 20% obese (BMI ≥30 kg/m2) and in 46 health care workers, mean age 49 ± 15 years, 15% males, 2% diabetes mellitus, 0% obese. 156 (73%) of the HD patients had on-line HDF and 59 (27%) patients had high-flux HD.

Reactive antibodies (IgG anti-spike ≥1.0) were detected in 94% of all HD patients and in 100% of controls (NS) 3 weeks after the second dose (Table 1). Three months and 6 months after the second dose the corresponding figures were 87% versus 100% (p < 0.01) and 75% versus 100% (p < 0.001), respectively (Table 1). There were no significant differences in anti-nucleocapsid antibodies between HD patients and controls (data not shown).

Table 1.

Reactive (≥1.0) anti-spike IgG antibodies (%) after the first and second dose of COVID-19 vaccine in haemodialysis patients and health care workers

HD patients n = 216Health care workers n = 46p value*mean (SD)mean (SD)Age, years69 (±13)49 (±15)<0.001aFirst dose of vaccine (January 2021)Reactive antibodies after 3 weeksN (%)N (%)p value*No131 (61)3 (7)<0.001Yes85 (39)43 (93)Second dose of vaccine (February 2021)Reactive antibodies after 3 weeksN (%)N (%)p value*No13 (6)0 (0)NSYes200 (94)46 (100)(May 2021)Reactive antibodies after 3 monthsN (%)N (%)p value*No26 (13)0 (0)<0.01fYes178 (87)46 (100)(August 2021)Reactive antibodies after 6 monthsN (%)N (%)p value*No49 (25)0 (0)<0.001Yes147 (75)42 (100)

Table 2 shows patient characteristics at baseline before vaccination, leukocyte count, lymphocyte count, and CRP levels 6 months after vaccination and reactive (≥1.0) anti-spike IgG 3 months at 6 months after vaccination in patients on high-flux HD (n = 59) and on-line HDF (n = 156), respectively. Clinical features between the groups were similar, but patients with on-line HDF had significantly higher Kt/V (Table 2). The proportion of patients with reactive anti-spike IgG ≥1.0 6 months after the second dose of vaccine was significantly higher in patients with on-line HDF compared to patients with high-flux HD (Table 2).

Table 2.

Patient characteristics, leukocyte count, and CRP levels 6 months after vaccination and reactive (≥1.0) anti-spike IgG 3 months at 6 months after vaccination in patients on high-flux HD and on-line HDF, respectively

High-flux HD n= 59On-line HDF n= 157p value*Gender (female), %4137NSAge, years, SD68 (±13)70 (±13)NSbKt/V (SD)1.7 (±0.3)2.0 (±0.3)<0.001bConvection volume (HDF) (L/session, SD)26.7 (±2.1)Diabetes, %3444NSHypertension, %9390NSChronic heart failure, %4651NSIschemic heart disease, %1717NSCerebrovascular disease, %2935NSPeripheral vascular disease, %4650NSChronic obstructive pulmonary disease, %1715NSObesity (BMI >30 kg/m2), %1522NSLiver disease, %2738NSActive neoplasia, %5.12.6NSPrevious solid organ transplant, %1.71.3NSImmunosuppressive state, %1914NSCOVID-19 before vaccination, %1.73.8NSCOVID-19 after vaccination, %5.10.6NSfActive smoking, %104NSPositive HBsAg, %1.71.3NSLeucocyte count, ×109/L7.4 (±3.7)6.4 (±1.74)NSbNeutrophil count, ×109/L4.4 (±2.2)4.0 (±1.42)NSbLymphocyte count, ×109/L2.1 (±2.9)1.5 (±0.53)NSbCRP, mg/L1.3 (±1.8)1.1 (±1.6)NSbReactive anti-spike IgG at 3 months, %8188NSReactive anti-spike IgG at 6 months, %60770.01

Table 3 shows unadjusted logistic regression analysis for the presence of reactive anti-spike antibody levels (≥1.0) at 3 months and 6 months after the second dose of vaccine. Treatment with on-line HDF and not being in an immunosuppressive state were associated with significantly higher odds (57% and 62%, respectively) of having reactive anti-spike IgG 6 months after vaccination.

Table 3.

Unadjusted logistic regression analysis, OR for reactive anti-spike protein levels (≥1.0) at 3 months and 6 months after the second dose of vaccine

3 months6 monthsORCIp valueORCIp valueGendera1.740.75–4.010.1901.220.63–2.350.555Age0.970.93–1.000.0910.990.96–1.020.515Dialysis modalityb0.480.2–1.130.0850.430.22–0.860.016Kt/V1.850.55–6.420.3241.830.71–4.890.216Diabetesc0.650.42–0.980.0420.890.64–1.250.496Chronic obstructive pulmonary diseasec0.570.22–1.680.2720.540.24–1.310.162Hypertensionc1.240.27–4.050.7510.840.23–2.500.775Chronic heart failurec0.930.41–2.150.8721.060.55–2.020.869Ischemic heart diseasec0.550.22–1.510.2181.050.45–2.650.912Peripheral vascular diseasec0.530.22–1.220.1450.680.35–1.300.249Cerebrovascular diseasec0.730.32–1.770.4771.290.65–2.680.482Active neoplasiac0.570.08–11.480.6271.000.12–20.481.000Obesity (BMI ≥30)0.380.16–0.930.0290.810.38–1.840.606Liver diseasec0.610.26–1.420.2410.880.45–1.780.725Previous solid organ transplantationc0.060.00–0.700.0280.160.01–1.680.135Immunosuppressive statec0.420.17–1.180.0810.380.16–0.880.022RAAS blockade (No vs. any ACE, ARB)1.440.61–3.670.4220.640.33–1.240.813

In adjusted logistic regression analysis with conditional backward selection, the variables associated with presence of reactive anti-spike IgG at 3 months after the second dose of vaccine were lower age, HDF treatment, not being obese, and not having a previous solid organ transplant (data not shown). The two variables with the strongest influence on the presence of reactive anti-spike IgG levels 6 months after the second dose of vaccine were treatment with on-line HDF and not having immunosuppressive therapy (Table 4).

Table 4.Full model (adjusted)Backward selection step 14Backward selection step 15ORCIp valueORCIp valueORCIp valueGendera1.590.66–3.800.296Age0.980.94–1.010.2060.980.95–1.010.186Dialysis modalityb0.520.23–1.230.1340.440.22–0.890.0220.450.23–0.910.025Kt/V1.350.33–5.540.672Diabetesc1.030.66–1.630.910Chronic obstructive pulmonary diseasec0.630.24–1.750.360Hypertensionc0.910.22–3.180.886Chronic heart failurec1.610.70–3.850.272Ischemic heart diseasec1.370.47–4.260.573Peripheral vascular diseasec0.890.39–2.060.785Cerebrovascular diseasec1.870.80–4.630.162Active neoplasiac1.630.17–37.810.699Obesity (BMI ≥30)0.780.29–2.200.632Liver diseasec1.110.49–2.590.807Previous solid organ transplantationc0.220.01–3.570.293Immunosuppressive statec0.440.16–1.260.1200.350.14–0.850.0200.400.17–0.960.036RAAS blockade (No vs. any ACE, ARB)0.610.28–1.320.210Conclusion

The most important findings in this prospective observational cohort study are that adjusted logistic regression analyses showed that the clinical factors most strongly associated with a continued humoral immune response in HD patients 3 months after COVID-19 vaccination were lower age, not being obese, not having a previous solid organ transplant and being treated with on-line HDF rather than high-flux HD. Moreover, a continued presence of reactive antibodies to SARS-CoV-2 BNT162b2 after 6 months was significantly associated with not having immunosuppressive therapy and being treated with on-line HDF, as opposed to high-flux HD.

The impact of on-line HDF in preserving reactive antibody response in HD patients following vaccination for COVID-19 is new and clinically important information, as the current understanding is that persisting neutralizing antibody titres correlate with protection from infection [10]. It is of note that naturally acquired anti-SARS-CoV-2 IgG positivity in patients with end-stage kidney disease is associated with lower risk of subsequent COVID-19 [2]. Furthermore, a correlation between the level of IgG antibodies to the receptor-binding domain of the S1 spike antigen of SARS-CoV-2 and viral neutralization levels have been demonstrated [14].

Patients treated with HD have a higher risk of COVID-19 and poorer clinical outcomes, with more hospital admissions and more extended hospital stays than many other groups of patients and the general population [1, 15]. Consequently, prioritizing HD patients for SARS-CoV-2 vaccination has been at the forefront in international vaccination programs [16].

In the present study, patients on HD had lower IgG anti-spike antibody titres after a second vaccination against SARS-CoV-2, compared to the healthy subjects. Previous studies in HD patients have also demonstrated an incomplete and delayed humoral immune response and a blunted cellular response after vaccination against SARS-CoV-2, compared to the general population [3, 8, 17]. Independent predictors of the immune response in these studies of HD patients include age, body mass index, previous COVID-19 experience, vaccine type, use of immunosuppressive drugs, serum albumin, lymphocyte count, immunoglobulin G levels, hepatitis B vaccine nonresponder status, dialysis vintage, iron status, and calcitriol treatment [1720]. It remains unclear whether the more rapid decrease in antibody titres is caused by the impaired immune system in frail HD patients or the accumulation of uremic toxins [15, 21, 22]. Experience following a third dose of SARS-CoV-2 vaccine in HD patients is emerging [23].

The groups of patients on high-flux HD or on-line HDF in the present study had similar clinical and laboratory features apart from the significantly higher Kt/V in patients receiving on-line HDF. This accord with the ROMANOV study [24] in which dialysis adequacy was associated with a better response to SARS-CoV-2 vaccination, suggesting that uremic toxins could potentially have a detrimental impact on the humoral response [24]. It has also been proposed that the uremic milieu in HD patients may be associated with impaired function of antibodies [25]. One might speculate that the response to vaccines in HD patients could be improved by optimizing uremic toxin elimination; this accords with data showing that higher Kt/V values are associated with better antibody response to hepatitis B virus vaccine [26].

HD patients typically show less robust responses to vaccines, including pneumococcus, hepatitis B, and influenza vaccines, with lower seroconversion rates and a more rapid decline in antibody titres, as compared to healthy subjects [46, 27]. The underlying mechanisms remain elusive, but combined deficits in the function of antigen presenting cells, T-cell and B-cell function have been proposed [4, 5].

In the present study treatment with on-line HDF was one of the factors strongly associated with persisting antibody levels to SARS-CoV-2 both three and 6 months after a second dose of vaccine. This new finding accords with previous experiences showing an impact of dialysis membrane flux on the immune response in HD patients following vaccination against influenza and hepatitis B [12, 13, 28]. Indeed, a previous study of the effects of influenza vaccine in HD patients showed that antibody levels were better sustained in dialysis patients treated by HDF, compared to those treated by low-flux HD [13]. The retention of waste products of metabolism in HD patients leads to an impaired or dysregulated immune [29, 30] and the fact that on-line HDF leads to a substantially greater removal of middle-sized azotemic toxins compared to HD [31] may explain the better preservation of antibody titres against SARS-CoV-2 in this group of patients. However, the immunological response elicited by vaccines in patients treated by HDF has not been well characterized and needs to be further explored.

Our study has several strengths. It was a prospective observational study, and we were able to obtain serial plasma samples before and after vaccination in all patients. We also had a control group of healthy subjects against which we could compare SARS-CoV-2 antibody levels. Detailed data on patient characteristics, type of HD, comorbid conditions, and use of immunosuppressant medications were available, allowing the identification of independent predictors of the persistence of antibodies following COVID-19 vaccination.

Limitations of our study must be acknowledged. Firstly, vaccine responses were assessed in a relatively small group of individuals from a single centre, which limited statistical analyses and could induce bias. Secondly, measurement of response to vaccination was only assessed using antibody levels, without considering cellular immunity or clinical outcomes. Thirdly, there was a gender and age difference between the dialysis group and the control group of health care workers. Fourthly, the HD patients were not randomized to high-flux HD or on-line HDF, which may have resulted in selection bias. These points may hamper the generalizability of our findings.

We conclude that the antibody titres 6 months after a second dose of vaccine against SARS-CoV-2 in patients with end-stage kidney disease were significantly better preserved with on-line HDF compared with high-flux HD. Considering the devastating impact of COVID-19 on HD patients, it is imperative to use treatment strategies that maximize and sustain the vaccine response.

Acknowledgments

The authors want to thank Head Nurse Mr. Boaventura Cabecinhas for his helpful co-operation and Mr. Fredrik Johansson, medical statistician at the Department of Clinical Sciences, Karolinska Institutet, Stockholm, Sweden, for advice and for statistical analyses of deidentified data. Grateful thanks to Prof. Jonathan G. Fox (Glasgow, UK) for assistance with language editing.

Statement of Ethics

The study adhered to the Declaration of Helsinki and was reviewed and approved by the Portuguese Research DaVita Ethics Committee on February 8th, 2021. Written informed consent was obtained from participants prior to the study.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

The laboratory costs of this study were supported by DaVita Portuguese Research Fund.

Author Contributions

Fernando Carrera and Stefan Jacobson designed the study, analysed and interpreted the results, and drafted the manuscript. Joana Costa and Francisco Ferrer collected the data and reviewed the manuscript. Marco Marques conducted the laboratory tests and reviewed the manuscript. All of the authors read and approved the final manuscript.

Data Availability Statement

All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author. The datasets used during the current study are available from the corresponding author on reasonable request.

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