https://orcid.org/0000-0002-8884-4579
Figures
Abstract
Due to the nature of the disease, end-stage renal disease (ESRD) patients suffer from dysfunction of the adaptive immune system, which leads to a poorer response to vaccination. Accordingly, it is crucial to evaluate the efficacy and safety of management strategies, including vaccinations, which could potentially reduce the risk of respiratory diseases, such as pneumonia, influenza, or COVID-19, and its associated outcomes. We searched PubMed, CENTRAL, ScienceDirect, Scopus, ProQuest, and Google Scholar databases using designated MeSH keywords. The risk of bias was assessed using ROBINS-I. The quality of evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. Relative risk (RR) and 95% confidence interval (CI) were calculated. Heterogeneity was investigated using forest plots and I2 statistics. This systematic review included a total of 48 studies, with 13 studies of influenza (H1N1 and H3N2) vaccination and 35 studies of COVID-19 vaccination. H1N1 vaccination in ESRD patients undergoing hemodialysis induced lower seroconversion rates (RR 0.62, 95% CI: 0.56–0.68, p <0.00001) and lower seroprotection rates (RR 0.76, 95% CI: 0.70–0.83, p <0.00001) compared to controls. H3N2 vaccination in ESRD patients undergoing hemodialysis yielded lower seroconversion rates (RR 0.76, 95% CI: 0.68–0.85, p <0.00001) and lower seroprotection rates (RR 0.84, 95% CI: 0.77–0.90, p <0.00001) compared to controls. Twenty-nine studies demonstrate significantly lower antibody levels in ESRD patients undergoing hemodialysis compared to the controls following COVID-19 vaccination. This review presents evidence of lower seroconversion and seroprotection rates after vaccination against viral respiratory diseases in patients with ESRD undergoing hemodialysis. Since hemodialysis patients are more susceptible to infection and severe disease progression, a weakened yet substantial serological response can be considered adequate to recommend vaccination against respiratory diseases in this population. Vaccination dose, schedule, or strategy adjustments should be considered in stable ESRD patients on maintenance hemodialysis.
Trial registration: Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021255983, identifier: CRD42021255983.
Citation: Puspitasari M, Sattwika PD, Rahari DS, Wijaya W, Hidayat ARP, Kertia N, et al. (2023) Outcomes of vaccinations against respiratory diseases in patients with end-stage renal disease undergoing hemodialysis: A systematic review and meta-analysis. PLoS ONE 18(2): e0281160. https://doi.org/10.1371/journal.pone.0281160
Editor: Etsuro Ito, Waseda University: Waseda Daigaku, JAPAN
Received: October 6, 2022; Accepted: January 16, 2023; Published: February 9, 2023
Copyright: © 2023 Puspitasari et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: Data of extraction table is accessible on Open Science Framework (OSF) portal through this link: https://osf.io/es2ma/.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
1. Introduction
According to the International Society of Nephrology’s (ISN) 2019 Global Kidney Health Atlas (GKHA), from 79 countries worldwide, the average number of new end-stage renal disease (ESRD) diagnoses was 144 individuals per million general population. In this population, hemodialysis is the most common technique of predominant renal replacement therapy (RRT) [1]. ESRD patients requiring dialysis are identified as high-risk patients for the severe form of respiratory infections, including pneumonia, influenza, and coronavirus disease 2019 (COVID-19), due to their frequent contact with health care providers and other patients, high burden of comorbid conditions, and altered immune responses [2–5]. Approximately 20% of infections in ESRD patients are attributable to pulmonary causes. The mortality rate of respiratory infections in dialysis patients is 14 to 16-fold higher than in the general population [6].
The high incidence, morbidity, and mortality rate of respiratory infections in ESRD patients have rendered vaccination a vital measure to prevent life-threatening complications. However, ESRD patients mount lower responses to vaccination than healthy individuals due to dysfunction of the adaptive immune system [5, 7, 8]. Furthermore, end-stage renal disease patients have been largely excluded from vaccine trials for safety reasons. Therefore, more convincing evidence regarding the efficacy and safety of vaccinations against respiratory infections is required. This systematic review and meta-analysis aimed to evaluate and summarize the available evidence on the efficacy and safety of vaccination against respiratory infections in ESRD patients undergoing hemodialysis and its associated outcomes to help guide clinical practice and vaccination recommendations.
2. Materials and methods
2.1 Protocol registration
The protocol of this systematic review has been registered and accepted in PROSPERO with the registration number CRD42021255983 available at https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021255983 (S1 Protocol).
2.2 Search strategy and eligibility criteria
We searched PubMed, The Cochrane Central Register of Controlled Trials (CENTRAL), ScienceDirect, Scopus, ProQuest, and Google Scholar for interventional (non-randomized or randomized controlled trials [RCTs]) and observational studies from inception until 20 October 2022. Electronic searches were complemented by manually searching all reference lists of identified studies and reviews for additional studies. We used the MeSH-related keywords such as “end-stage renal disease” AND “hemodialysis” AND (“pneumococcal vaccines” OR “influenza vaccines” OR “COVID-19 vaccines”), as well as their common synonyms. Restrictions involved non-English language and animal studies. The complete search strategy is shown in S1 Appendix.
One reviewer conducted the initial searches. After removing duplicates, three reviewers first scanned all remaining articles by title and abstract. Then, two independent reviewers read the full text of potentially eligible items and decided on which studies to include. Discrepancies were resolved by discussion.
Studies had to meet the following inclusion criteria: (i) original report on the efficacy and safety within six weeks after vaccination against respiratory diseases (pneumococcal, influenza, and COVID-19 vaccines) in adult patients with ESRD undergoing hemodialysis, and (ii) control participants had to be clinically healthy populations who received vaccination against respiratory diseases. We excluded studies in which participants with ESRD in the intervention arm underwent peritoneal dialysis or renal transplant.
2.3 Data extraction
Four authors performed data extraction independently using a standardized data extraction form [9]. The following information was extracted from eligible studies: first author, year of publication, study registration, setting, study design, inclusion and exclusion criteria, participant numbers and characteristics, vaccine type, dose, timing and route of administration, outcome definition, and outcome proportion in each arm for dichotomous data or mean and standard deviation (SD) for continuous data. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were applied to the search strategy (S1 Checklist) [10]. The complete data extraction table is accessible on the Open Science Framework (OSF) portal via this link: https://osf.io/es2ma/?view_only=87b0e57246704617aa094219a60ba73b.
2.4 Risk of bias and quality of evidence assessment
The risk of bias was independently assessed by two authors using a tool for assessing the risk of bias in non-randomized studies of interventions (ROBINS-I) [11]. The tool views each study as an attempt to emulate a hypothetical pragmatic randomized trial and covers seven distinct domains through which bias might be introduced. The judgments within each domain are carried forward to an overall risk of bias judgment across domains for the assessed outcome. The categories for risk of bias judgments are “Low risk”, “Moderate risk”, “Serious risk”, and “Critical risk” of bias. The “No information” category should be used only when insufficient data are reported to permit a judgment. Discrepancies were resolved by discussion. Funnel plots were constructed to check for publication bias in studies included in meta-analyses.
The quality (certainty) of evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) framework. The quality of the overall evidence was rated as one of four levels: very low, low, moderate, and high, based on the assessment of the domains for risk of bias, imprecision, inconsistency, indirectness, and publication bias [12].
2.5 Data synthesis and statistical analysis
We examined dichotomous outcomes and expressed results as risk ratio (RR) with a 95% confidence interval (CI). From the included studies, we used the data of seroconversion rate, seroprotection rate, and adverse events rate for meta-analysis. Whenever available, we extracted the data of antibody titer. The analysis was separated between each type of vaccine group. Statistical analysis and generation of forest plots were conducted using Review Manager (RevMan) 5.4 software, with p<0.05 deemed statistically significant.
The variability across studies due to heterogeneity was investigated using forest plots and I2 statistics, with I2 values of 0% to 40%, 30% to 60%, 50% to 90%, and 75% to 100% corresponding to not important, moderate, substantial and considerable levels of heterogeneity, respectively [9].
3. Results
3.1 Characteristics of included studies
During the initial search, we identified 1080 records from electronic databases, 58 records from Google Scholar, and four additional records from manual searching. After further screening, we included 48 eligible studies (Fig 1). The included studies mostly have cohort design [13–53], five studies are of case-control design [30, 54–57], two studies are of cross-sectional design [58, 59], and 1 study is an open-label clinical trial [60].
Among thirteen studies, eleven provide data on the H1N1 influenza vaccine [15, 21, 30, 32, 42, 49, 50, 55, 57, 58, 60], and 11 studies on the H3N2 influenza vaccine [15, 21, 26, 42, 49, 50, 55–58, 60]. Most of them used hemagglutination-inhibiting (HI) assay to measure seroconversion and seroprotection. Meanwhile, thirty-five studies on COVID-19 vaccines [13, 16–20, 24, 25, 27–29, 31, 33–41, 43–48, 51–54, 59] used various vaccine platforms (including mRNA-based, inactivated, viral vector, and heterologous vaccines) and various units of measurement for IgG levels and neutralizing antibodies (NAbs) percentage (%) of inhibition. We could not find any studies on pneumococcal vaccines. The outcome of seroconversion and seroprotection rates were assessed for all studies. Table 1 summarizes the characteristics of included studies.
3.2 Risk of bias assessment
The risk of bias assessment in each individual study is summarized in Fig 2. We rated the overall risk of bias on the outcome of seroconversion and seroprotection rates to be high risk of bias in two studies and unclear risk of bias in six of thirteen observational studies investigating influenza vaccinations in patients with ESRD undergoing hemodialysis. These risks of bias arise from each domain. Two studies by Versluis in 1985 and 1988 [50, 57] was considered to have high risks of bias due to selection bias in sequence generation and selective reporting (reporting bias). From thirty-five included observational studies of COVID-19 vaccinations for patients with ESRD undergoing hemodialysis, twenty-one studies showed an unclear risk of bias due to bias in sequence generation (selection bias) [13, 16, 22–24, 34, 40, 41, 48, 52], blinding of participants and personnel (performance bias) [29, 35, 36, 41, 47], blinding of outcome assessment (performance bias) [33], incomplete outcome data (attrition bias) [13, 20, 54], or selective reporting (reporting bias) [17, 51, 59]. Funnel plots to assess publication bias in studies included for meta-analyses were also constructed and displayed in S2 Appendix.
(a) Influenza vaccine and (b) COVID-19 vaccine studies (green: low risk, yellow: moderate risk, red: serious risk, black: critical risk).
3.3 Outcome
This section discusses the outcomes of vaccination in patients with ESRD undergoing hemodialysis consisting of efficacy and adverse events outcomes in included studies.
3.3.1 H1N1 vaccine.
For the H1N1 vaccine, vaccination in ESRD patients undergoing hemodialysis showed lower seroconversion and seroprotection rates compared to controls. Ten of the included studies reported the outcome of seroconversion rate. H1N1 vaccination in patients with ESRD undergoing hemodialysis induced lower seroconversion rates (Fig 3A, with 10 studies, 1191 participants: RR 0.62, 95% CI: 0.56–0.68, p<0.00001) with substantial heterogeneity (I2 = 81%). One study by Labriola in 2011 utilized a seroneutralization assay to measure antibody level and reported a significantly lower seroconversion rate in HD patients (64,2%) compared to controls (93,8%) (p = 0.002) [30]. Seroprotection rate was lower in ESRD patients receiving H1N1 vaccines compared to controls (Fig 3B, with 7 studies, 1001 participants: RR 0.76, 95% CI: 0.70–0.83, p<0.00001) with considerable heterogeneity (I2 = 96%). There was only one study reporting adverse events following vaccinations of H1N1 with 2 of 53 patients with ESRD experiencing moderate local pain at the site of injection with no adverse events observed in the control group [30].
(a) seroconversion rate and (b) seroprotection rate after H1N1 vaccination in patients with ESRD undergoing hemodialysis.
3.3.2 H3N2 vaccine.
H3N2 vaccination in patients with ESRD undergoing hemodialysis produced lower rates of seroconversion compared to controls (Fig 4A, with 10 studies, 1012 participants: RR 0.76, 95% CI: 0.68–0.85, p < 0.00001) with moderate heterogeneity (I2 = 43%) and lower rates of seroprotection (Fig 4B, with 6 studies, 754 participants: RR 0.84, 95% CI: 0.77–0.90, p <0.00001) with considerable heterogeneity (I2 = 85%). A study by Nikoskelainen in 1982 determined the antibody responses with single radial hemolysis (SRH) technique and demonstrated a higher seroconversion rate in HD patients (92%) compared to controls (88%) [56]. In terms of adverse events, ESRD patients undergoing hemodialysis experienced lower adverse events rated compared to the control group (HD: 22% vs control: 56%, p = 0.003) [60]. ESRD patients developed fewer local symptoms and had fewer symptoms of generalized myalgia and headache.
(a) seroconversion rate and (b) seroprotection rate (below) after H3N2 vaccination in patients with ESRD undergoing hemodialysis.
3.3.3 COVID-19 vaccine.
Thirty-five studies investigated the antibody responses after COVID-19 vaccination in ESRD patietns undergoing hemodialysis compared to healthy controls. These studies used various vaccine platforms (including mRNA, inactivated, viral vector and heterologous vaccines) as well as different units of measurements. Table 2 summarizes the comparison of IgG levels between HD and control groups following COVID-19 vaccination obtained from the 30 studies [16–20, 22–25, 27–29, 31, 33–36, 38–40, 43, 44, 46–48, 51, 53, 54, 59]. Overall, twenty-nine studies demonstrated lower IgG levels after COVID-19 vaccination in HD patients compared to healthy controls, whereas only one study by Panizo showed a contrary finding [36].
A study by Haase in 2022 reported higher spike IgG levels in HD patients receiving heterologous vaccination with ChAd/BNT (1744 [267–2840] BAU/mL) compared to HD patients receiving homologous vaccination with BNT/BNT (361 [120–936] BAU/mL), ChAd/ChAd (100 [41–346] BAU/mL), and healthy controls (650 [217–1402] BAU/mL). However, the study did not differentiate the spike IgG levels between different vaccine platforms combinations in the control group [25]. Lesny 2021 showed a lower mean IgG level in HD patients (1.6 [0–14.5] AU/mL) compared to controls (73.1 [16.1–1324.5] AU/mL) after only the first dose of vaccination. This study also reported a lower ACE 2 receptor binding inhibition capacity in HD patients (5.0% [3.1–10.4]) compared to healthy controls (10.5% [6.0–40.9]) [33].
ESRD patients undergoing hemodialysis presented with a lower number of adverse events compared to the control group (Fig 5, with 5 studies, 677 participants: RR 0.34, 95% CI: 0.27–0.42, p < 0.00001) with substantial heterogeneity (I2 = 88%) [13, 20, 25, 40, 51].
4. Discussion
4.1 H1N1 vaccine
In this present study, the intensity of immune response to vaccinations for viral respiratory diseases such as influenza (H1N1 and H3N2) and COVID-19 was inferior in patients with ESRD undergoing hemodialysis compared to healthy subjects. Serological conversion following influenza vaccinations was determined as the outcome measure of efficacy due to the unavailability of hemagglutination-inhibiting antibody titers in most included studies. Ten heterogenous studies were used to generate pooled estimates of seroconversion rate after H1N1 vaccination in patients with ESRD receiving hemodialysis and healthy controls. Except for two studies by Versluis in 1985 and Song in 2006, all investigations found a significant reduction in seroconversion rate in patients with ESRD on hemodialysis compared to healthy controls. The pooled estimates showed a 38% decrease in seroconversion rate in patients with ESRD undergoing hemodialysis. This result is consistent with previous literature reviews in which patients with CKD and ESRD experience significant dysregulation in the adaptive immunity, including T cells and B cells, which impairs vaccine response. The B cells changes in patients with CKD/ESRD include a decrease in the number of B cells, B-cell activating factor, B-cell lymphoma 2 (Bcl-2), and an increase in apoptosis. All of these changes result in the depletion of serological response [5]. The insignificant results of Versluis in 1985 could be related to the small sample size [50]. However, the power of this study (weighted at 0.6%) is insufficient to alter the outcome of our analysis. The limitation of the study by Song in 2006 was that a previous vaccination history was not considered and there was a considerable number of dropouts—which might affect the seroconversion rate [42].
Pooled estimates of seroprotection rate after H1N1 vaccination were derived from seven studies with considerable heterogeneity (I2 = 96%). Five of the seven studies showed a significant reduction in seroprotection rate in patients with ESRD on hemodialysis compared to healthy controls, which is consistent with a previous literature review of adaptive immune dysfunction in patients with CKD/ESRD [5]. The study by Scharpe in 2009 demonstrated an insignificantly higher seroprotection rate in hemodialysis patients compared to healthy controls, both in subjects with and without baseline seroprotection before vaccination. We assume that this is attributable to (1) a higher seroprotection rate in hemodialysis patients due to more frequent immunizations the previous year and (2) the role of recent dialysis procedural improvements and therapeutic drug advancements [60]. However, only further studies with a larger number of patients will be able to confirm or refute this hypothesis. As mentioned before, the study by Song in 2006 had several limitations that might have affected the outcomes [42].
We found only one study that measured the adverse events after H1N1 influenza vaccination as an outcome. Labriola in 2011 reported that 2 out of 53 hemodialysis patients presented with moderate local pain at the site of injection. No other side effects associated with the vaccination were observed in hemodialysis patients. However, the number of hemodialysis patients included in the study was small. The results were limited in generalizability due to a larger Caucasian population in the study group. In addition, the intensity and types of local adverse reactions were not characterized [30]. As a result, further studies with larger sample sizes and more diverse subjects are required to evaluate adverse events following H1N1 vaccination in hemodialysis patients.
4.2 H3N2 vaccine
Pooled estimates of seroconversion rate after H3N2 vaccination in patients with ESRD undergoing hemodialysis were derived from 10 studies with moderate heterogeneity. Our findings showed a 24% decrease in seroconversion rate in hemodialysis patients, indicating impaired serological response compared to healthy subjects, which is consistent with a recent literature review [5]. In six of the ten studies, the seroconversion rates of hemodialysis patients were shown to be significantly lower than healthy controls.
Scharpe et al. reported a lower seroconversion rate, but with an insignificant difference, in hemodialysis patients compared to healthy controls, indicating a similar immune response to healthy subjects. In addition, the seroconversion rate is independently related to the baseline seroprotection rate. It is detailed that the baseline seroprotective rate is affected by the frequencies of past immunizations and higher ferritin levels. This study, however, is underpowered to detect a significant difference in immune responses between healthy subjects and hemodialysis patients, with a post hoc power analysis finding that indicated an unrealistically large number of patients would be necessary to achieve an 80% power [60].
Three studies reported an insignificantly higher seroconversion rate in patients with ESRD undergoing hemodialysis than in healthy individuals [26, 50, 58]. However, all three studies are also underpowered (each weighted at 4.6%, 2.6%, and 0.3%) to affect the pooled estimates due to the small number of participants. In addition, one study by Hodges in 1979 still utilized a bivalent split-virus vaccine containing A/New Jersey/76 and A/Victoria/75 instead of a trivalent influenza vaccine [26].
Six studies with considerable heterogeneity were analyzed to generate pooled estimates of the seroprotection rate after H3N2 vaccination in patients with ESRD undergoing hemodialysis. Our study demonstrated a significant decrease of 16% in seroprotection rate in hemodialysis patients compared to healthy subjects. Four of the six studies reported a significantly lower seroprotection rate in patients with ESRD undergoing hemodialysis compared to healthy subjects. Furthermore, Eiselt et al. also found a lower seroprotection rate in patients with ESRD undergoing hemodialysis, although the difference was not statistically significant. Nevertheless, Scharpé et al. reported a slightly higher seroprotection rate in hemodialysis patients. Similar to the response to H1N1 influenza vaccination, the higher seroprotection rate might be caused by a higher baseline seroprotection rate in hemodialysis patients due to more frequent immunizations the previous year and the impact of recent advancements in dialysis technology and therapeutic drugs [60].
We found only one study by Scharpé in 2009, which evaluated the safety of H3N2 influenza vaccinations as an outcome. In this study, neither hemodialysis patients nor healthy subjects experienced adverse side effects. Compared to healthy controls, the number of mild adverse events was considerably lower in hemodialysis patients. Hemodialysis patients demonstrated fewer local symptoms, fewer generalized myalgia, and fewer headache symptoms [60]. This finding indicates a more potent immune reaction in healthy subjects compared to hemodialysis patients.
4.3 COVID-19 vaccine
Since COVID-19 is a novel disease and numerous different vaccine platforms are currently used, studies investigating immune responses after COVID-19 vaccinations in the HD population also utilize various methods and units of measurement and different vaccine platforms and combinations. Of the included 35 studies investigating COVID-19 vaccination in this systematic review, 30 studies provided data on SARS-CoV-2 IgG antibody response following vaccination (Table 2). Most studies demonstrated lower antibody response in HD patients compared to healthy controls after COVID-19 vaccination, except for one study (i.e., Panizo 2022).
This finding suggests that dialysis patients have a poorer overall antibody response than healthy subjects. As a result, dialysis patients are less likely to be able to neutralize the SARS-CoV-2 virus even after two homologous vaccine doses, no matter the vaccine platform. Thus, vulnerable populations such as hemodialysis patients are more susceptible to infection and severe disease progression [61]. Meanwhile, an interesting finding by Haase et al. 2022 demonstrated higher spike IgG levels in HD patients receiving heterologous vaccination with ChAd/BNT compared to HD patients receiving homologous vaccination with BNT/BNT, ChAd/ChAd, and healthy controls. However, the study did not differentiate the spike IgG levels between different vaccine platforms combinations in the control group. With these findings, a prompt consideration for vaccination dose or schedule adjustment and the administration of heterologous vaccines in ESRD patients on maintenance hemodialysis should be made as done with different vaccines in the past [62].
Meanwhile, a study by Panizo et al. revealed the opposite result. This study demonstrated a higher median anti-RBD IgG level among HD patients (1146 [0–2500] BAU/mL) compared to controls (641 [0–2500] BAU/mL) 15 days after completion of the vaccination schedule with the mRNA-1273 vaccine. This finding might be caused by the larger proportion of seropositive HD patients (12.5%) compared to controls (7%) before vaccination. The participants who were seropositive at baseline might have had a recent COVID-19 infection before vaccination. However, antibody measurement three months after the vaccination showed a waning of antibody levels and a reversal between the two groups (HD: 388 [0–2500] BAU/mL vs. Control: 477 [5.9–2500] BAU/mL). The more pronounced decline in HD patients suggests accelerated kinetics of antibody waning in this population [36].
Even though the gold standard to measure the neutralizing capacity of patients’ serum antibodies is a plaque reduction neutralization test [63], the anti-SARS-CoV-2 S antibody has been shown to have a high correlation with a direct virus neutralization test and a surrogate neutralization assay [64]. Therefore, the anti-SARS-CoV-2 antibody can be used as a surrogate marker for vaccine-induced immunity.
This review demonstrated that, generally, patients with ESRD undergoing hemodialysis have a blunted early serological response to SARS-CoV-2 vaccination. The dynamics of humoral immune response to different SARS-CoV-2 vaccines in this population may be affected by several factors, such as the use of immunosuppressive medications, dialysis vintage, and previous history of COVID-19 vaccination. A multivariate analysis from a prospective cohort study conducted by Van Praet et al. revealed that COVID-19 experience, immunosuppressive drugs use, and dialysis vintage represent independent predictors of humoral immune responses (Van Praet 2021). However, not all included studies in this review provided the data on immunosuppressive drugs and dialysis vintage (extracted data available in https://osf.io/es2ma/?view_only=87b0e57246704617aa094219a60ba73b).
Pooled estimates of the adverse events rate after COVID-19 vaccination were derived from five studies with substantial heterogeneity (I2 = 88%). Four studies showed a significantly lower number of adverse events in ESRD patients undergoing hemodialysis compared to healthy controls. The pooled estimates in our study demonstrated a 66% lower percentage of adverse events rate in ESRD patients undergoing hemodialysis. This result represents a more potent and noticeable immune reaction in cellular and humoral arms in healthy individuals. The correlation of adverse events with the amount of immunosuppression and whether the number of AEs can indirectly predict response to vaccination are potential research topics to be explored in the future. Further studies are needed to determine the potential causal relationship between adverse events and immune response in patients with ESRD on hemodialysis.
To our knowledge, this review is the first to investigate vaccination against respiratory diseases in ESRD patients undergoing hemodialysis. The overall quality of evidence for seroconversion and seroprotection rate after both H1N1 and H3N2 vaccination and the adverse events rates in COVID-19 vaccination was assessed using the GRADE framework (S1 Table).
There are several limitations of our study. In the absence of RCT data, serological conversion represents the most appropriate surrogate for efficacy despite not being a true measure. Antibody titer data were extracted. However, due to heterogeneous measurement methods, pooled analyses could not be performed. Secondly, due to a lack of available data, our discussion on vaccine safety was limited. In addition, data on immunosuppressive medications, the onset of dialysis, the glomerular filtration rate, and other predictors potentially influencing the immunogenicity outcomes were also inadequate.
5. Conclusions
Our systematic review demonstrates evidence of lower seroconversion and seroprotection rates after vaccinations against viral respiratory diseases in ESRD patients undergoing hemodialysis. We consistently found a lower incidence of minor adverse events and no reported serious adverse events in hemodialysis patients after vaccination. Considering that hemodialysis patients are more susceptible to infection and severe disease progression, a weakened yet substantial serological response can be considered adequate for the recommendation of vaccination against respiratory diseases vaccination in this population. Vaccination dose, schedule, or strategy adjustments should be considered in ESRD patients undergoing hemodialysis.
Supporting information
S2 Appendix. Funnel plots of studies included in the meta-analyses.
https://doi.org/10.1371/journal.pone.0281160.s004
(PDF)
S1 Table. Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria for studies included in the meta-analyses.
https://doi.org/10.1371/journal.pone.0281160.s005
(PDF)
Acknowledgments
Authors express gratitude to the staff of Klinik Bahasa in the Office of Research and Publication, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia for the English language and grammar editing of the manuscript.
References
- 1. Thurlow JS, Joshi M, Yan G, Norris KC, Agodoa LY, Yuan CM, et al. Global epidemiology of end-stage kidney disease and disparities in kidney replacement therapy. Am J Nephrol. 2021;52: 98–107. pmid:33752206
- 2. Guo H, Liu J, Collins AJ, Foley RN. Pneumonia in incident dialysis patients—The United States Renal Data System. Nephrol Dial Transplant. 2008;23: 680–686. pmid:18029368
- 3. Cho J-H, Do J-Y, Kim S-H, Kim J-Y, Seo J-J, Choi J-Y, et al. Impact of Dialysis Modality on the Incidence of 2009 Pandemic H1N1 Influenza in End-Stage Renal Disease Patients. 2011;31: 347–350. pmid:21555416
- 4. Naicker S, Yang CW, Hwang SJ, Liu BC, Chen JH, Jha V. The Novel Coronavirus 2019 epidemic and kidneys. Kidney Int. 2020;97: 824–828. pmid:32204907
- 5. Syed-Ahmed M, Narayanan M. Immune Dysfunction and Risk of Infection in Chronic Kidney Disease. Adv Chronic Kidney Dis. 2019;26: 8–15. pmid:30876622
- 6. Sarnak MJ, Jaber BL. Pulmonary infectious mortality among patients with end-stage renal disease. Chest. 2001;120: 1883–1887. pmid:11742917
- 7. Kato S, Chmielewski M, Honda H, Pecoits-Filho R, Matsuo S, Yuzawa Y, et al. Aspects of immune dysfunction in end-stage renal disease. Clin J Am Soc Nephrol. 2008;3: 1526–1533. pmid:18701615
- 8. Eleftheriadis T, Antoniadi G, Liakopoulos V, Kartsios C, Stefanidis I. Disturbances of acquired immunity in hemodialysis patients. Semin Dial. 2007;20: 440–451. pmid:17897251
- 9. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane handbook for systematic reviews of interventions. John Wiley & Sons; 2019.
- 10. Moher D, Liberati A, Tetzlaff J, Altman DG. Academia and Clinic Annals of Internal Medicine Preferred Reporting Items for Systematic Reviews and Meta-Analyses: Ann Intern Med. 2009;151: 264–269.
- 11. Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: A tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355: 4–10. pmid:27733354
- 12. Guyatt GH. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. 2008;336. pmid:18436948
- 13. Ahmed MF, Ahmed AO, Ahmed AM, El-Hameed ARA. Assessment of Immune Response to the COVID-19 Vaccination in Egyptian Patients Undergoing Maintenance Hemodialysis. Egypt J Hosp Med. 2022;88: 3457–3463.
- 14. Antonen JA, Pyhälä R, Hannula PM, Ala-Houhala IO, Santanen R, Ikonen N, et al. Influenza vaccination of dialysis patients: Cross-reactivity of induced haemagglutination-inhibiting antibodies to H3N2 subtype antigenic variants is comparable with the response of naturally infected young healthy adults. Nephrol Dial Transplant. 2003;18: 777–781. pmid:12637648
- 15. Beyer WEP, Versluis DJ, Kramer P, Diderich PPMN, Weimar W, Masurel N. Trivalent influenza vaccine in patients on haemodialysis: Impaired seroresponse with differences for A-H3N2 and A-H1N1 vaccine components. Vaccine. 1987;5: 43–48. pmid:3577356
- 16. Boongird S, Chuengsaman P, Setthaudom C, Nongnuch A, Assanatham M, Phanprasert S, et al. Short-Term Immunogenicity Profiles and Predictors for Suboptimal Immune Responses in Patients with End-Stage Kidney Disease Immunized with Inactivated SARS-CoV-2 Vaccine. Infect Dis Ther. 2021;11: 351–365. pmid:34859359
- 17. Boongird S, Chuengsaman P, Phanprasert S, Kitpermkiat R, Assanatham M, Nongnuch A, et al. Anti–SARS-CoV-2 spike protein S1 receptor-binding domain antibody after vaccination with inactivated whole-virus SARS-CoV-2 in end-stage kidney disease patients: an initial report. Kidney Int. 2021;100: 1136–1138. pmid:34419552
- 18. Bruminhent J, Setthaudom C, Kitpermkiat R, Kiertiburanakul S, Malathum K, Assanatham M, et al. Immunogenicity of ChAdOx1 nCoV-19 vaccine after a two-dose inactivated SARS-CoV-2 vaccination of dialysis patients and kidney transplant recipients. Sci Rep. 2022;12: 1–9.
- 19. Danthu C, Hantz S, Dahlem A, Duval M, Ba B, Guibbert M, et al. Humoral response after SARS-CoV-2 mRNA vaccination in a cohort of hemodialysis patients and kidney transplant recipients. J Am Soc Nephrol. 2021;32: 2153–2158. pmid:34135083
- 20. Dheir H, Tocoglu A, Toptan H, Pinar M, Demirci T, Koroglu M, et al. Short and mid‐term SARS‐CoV‐2 antibody response after inactivated COVID‐19 vaccine in hemodialysis and kidney transplant patients. J Med Virol. 2022;94: 3176–3183. pmid:35277975
- 21. Eiselt J, Kielberger L, Rajdl D, Racek J, Pazdiora P, Malánová L. Previous vaccination and age are more important predictors of immune response to influenza vaccine than inflammation and iron status in dialysis patients. Kidney Blood Press Res. 2016;41: 139–147. pmid:26914585
- 22. Fu C, Tsai K, Kuo W, Wu C, Yu C, You H. The Waxing, Waning, and Predictors of Humoral Responses to Vector-Based SARS-CoV-2 Vaccine in Hemodialysis Patients. 2022; 1–15. pmid:36146615
- 23. Fucci A, Giacobbe S, Guerriero I, Suzumoto Y, D’Andrea EL, Scrima M, et al. The DiaCoVAb study in South Italy: immune response to Sars-CoV-2 vaccination in dialysis patients. Kidney Blood Press Res. 2022. pmid:35318291
- 24. Grupper A, Sharon N, Finn T, Cohen R, Israel M, Agbaria A, et al. Humoral response to the Pfizer BNT162b2 vaccine in patients undergoing maintenance hemodialysis. Clin J Am Soc Nephrol. 2021;16: 1037–1042. pmid:33824157
- 25. Haase M, Lesny P, Anderson M, Cloherty G, Stec M, Haase-Fielitz A, et al. Humoral immunogenicity and tolerability of heterologous ChAd/BNT compared with homologous BNT/BNT and ChAd/ChAd SARS-CoV-2 vaccination in hemodialysis patients: A multicenter prospective observational study. J Nephrol. 2022;35: 1467–1478. pmid:35084719
- 26. Hodges GR, Davis JW, Lewis HD Jr, Whittier FC Jr, Siegel CD, Chin TD, et al. Response to influenza A vaccine among high-risk patients. South Med J. 1979;72: 29–32. pmid:366766
- 27. Jahn M, Korth J, Dorsch O, Anastasiou OE, Sorge-Hädicke B, Tyczynski B, et al. Humoral response to SARS-CoV-2-vaccination with BNT162b2 (Pfizer-BioNTech) in patients on hemodialysis. Vaccines. 2021;9: 360. pmid:33918085
- 28. Kim DK, Jung SW, Moon J-Y, Jeong KH, Hwang HS, Kim JS, et al. Severe Acute Respiratory Syndrome Coronavirus 2 Antibody Response After Heterologous Immunizations With ChAdOx1/BNT162b2 in End-Stage Renal Disease Patients on Hemodialysis. Front Immunol. 2022;13. pmid:35734170
- 29. Kolb T, Fischer S, Müller L, Lübke N, Hillebrandt J, Andrée M, et al. Impaired immune response to SARS-CoV-2 vaccination in dialysis patients and in kidney transplant recipients. Kidney360. 2021;2: 1491. pmid:35373105
- 30. Labriola L, Hombrouck A, Maréchal C, Van Gucht S, Brochier B, Thomas I, et al. Immunogenicity of an adjuvanted 2009 pandemic influenza A (H1N1) vaccine in haemodialysed patients. Nephrol Dial Transplant. 2011;26: 1424–1428. pmid:21273236
- 31. Labriola L, Scohy A, Van Regemorter E, Robert A, Clerbaux G, Gillerot G, et al. Immunogenicity of BNT162b2 SARS-CoV-2 vaccine in a multicenter cohort of nursing home residents receiving maintenance hemodialysis. Am J Kidney Dis. 2021;78: 766–768. pmid:34364905
- 32. Lertdumrongluk P, Changsirikulchai S, Limkunakul C. Safety and immunogenicity of a 2009 influenza A (H1N1) vaccine in hemodialysis patients. Vaccine. 2012;30: 1108–1114. pmid:22178515
- 33. Lesny P, Anderson M, Cloherty G, Stec M, Haase-Fielitz A, Haarhaus M, et al. Immunogenicity of a first dose of mRNA-or vector-based SARS-CoV-2 vaccination in dialysis patients: a multicenter prospective observational pilot study. J Nephrol. 2021;34: 975–983. pmid:34050904
- 34. Matsunami M, Suzuki T, Terao T, Kuji H, Matsue K. Immune response to SARS-CoV-2 vaccination among renal replacement therapy patients with CKD: a single-center study. Clin Exp Nephrol. 2022;26: 305–307. pmid:34746991
- 35. Murt A, Altiparmak MR, Yadigar SS, Yalin SF, Ozbey D, Yildiz Z, et al. Antibody Responses to the SARS-CoV-2 Vaccines in Hemodialysis Patients: Is inactivated vaccine effective? Ther Apher Dial. 2021; 769–774. pmid:34741418
- 36. Panizo N, Albert E, Giménez-Civera E, Puchades MJ, D’Marco L, Gandía-Salmerón L, et al. Dynamics of SARS-CoV-2-Spike-reactive antibody and T-cell responses in chronic kidney disease patients within 3 months after COVID-19 full vaccination. Clin Kidney J. 2022;15: 1562–1573. pmid:35880064
- 37. Park J-S, Minn D, Hong S, Jeong S, Kim S, Lee CH, et al. Immunogenicity of COVID-19 Vaccination in Patients With End-Stage Renal Disease Undergoing Maintenance Hemodialysis: The Efficacy of a Mix-and-Match Strategy. J Korean Med Sci. 2022;37. pmid:35698835
- 38. Piotrowska M, Zieliński M, Tylicki L, Biedunkiewicz B, Kubanek A, Ślizień Z, et al. Local and Systemic Immunity Are Impaired in End-Stage-Renal-Disease Patients Treated With Hemodialysis, Peritoneal Dialysis and Kidney Transplant Recipients Immunized With BNT162b2 Pfizer-BioNTech SARS-CoV-2 Vaccine. Front Immunol. 2022;13. pmid:35935974
- 39. Schrezenmeier E, Bergfeld L, Hillus D, Lippert J-DD, Weber U, Tober-Lau P, et al. Immunogenicity of COVID-19 tozinameran vaccination in patients on chronic dialysis. Front Immunol. 2021;12: 690698. pmid:34276681
- 40. Simon B, Rubey H, Treipl A, Gromann M, Hemedi B, Zehetmayer S, et al. Hemodialysis patients show a highly diminished antibody response after COVID-19 mRNA vaccination compared to healthy controls. MedRxiv. 2021;36: 1709–1716.
- 41. Smith RM, Cooper DJ, Doffinger R, Stacey H, Al-Mohammad A, Goodfellow I, et al. SARS-COV-2 vaccine responses in renal patient populations. BMC Nephrol. 2022;23. pmid:35641961
- 42. Song JY, Cheong HJ, Ha SH, Kee SY, Jeong HW, Kim WJ. Active Influenza Immunization in Hemodialysis Patients: Comparison between Single-Dose and Booster Vaccination. Am J Nephrol. 2006;26: 206–211. pmid:16699258
- 43. Speer C, Schaier M, Nusshag C, Töllner M, Buylaert M, Kälble F, et al. Longitudinal humoral responses after covid-19 vaccination in peritoneal and hemodialysis patients over twelve weeks. Vaccines. 2021;9. pmid:34696238
- 44. Speer C, Göth D, Benning L, Buylaert M, Schaier M, Grenz J, et al. Early humoral responses of hemodialysis patients after COVID-19 vaccination with BNT162b2. Clin J Am Soc Nephrol. 2021;16: 1073–1082. pmid:34031181
- 45. Speer C, Benning L, Töllner M, Nusshag C, Kälble F, Reichel P, et al. Neutralizing antibody response against variants of concern after vaccination of dialysis patients with BNT162b2. Kidney Int. 2021;100: 700–702. pmid:34265359
- 46. Strengert M, Becker M, Ramos GM, Dulovic A, Gruber J, Juengling J, et al. Cellular and humoral immunogenicity of a SARS-CoV-2 mRNA vaccine in patients on haemodialysis. EBioMedicine. 2021;70: 103524. pmid:34391096
- 47. Tillmann F, Figiel L, Ricken J, Still H, Korte C, Plassmann G, et al. Evolution of SARS-CoV-2-Neutralizing Antibodies after Two Standard Dose Vaccinations, Risk Factors for Non-Response and Effect of a Third Dose Booster Vaccination in Non-Responders on Hemodialysis: A Prospective Multi-Centre Cohort Study. 2021. pmid:34768631
- 48. Van Praet J, Reynders M, De Bacquer D, Viaene L, Schoutteten MK, Caluwé R, et al. Predictors and dynamics of the humoral and cellular immune response to SARS-CoV-2 mRNA vaccines in hemodialysis patients: a multicenter observational study. J Am Soc Nephrol. 2021;32: 3208–3220. pmid:34588184
- 49. Vogtländer NPJ, Brown A, Valentijn RM, Rimmelzwaan GF, Osterhaus ADME. Impaired response rates, but satisfying protection rates to influenza vaccination in dialysis patients. 2004;22: 2199–2201. pmid:15149777
- 50. Versluis DJ, Beyer WEP, Masurel N, Weimar W. Influenza vaccination in dialysis and transplant patients. Antiviral Res. 1985;5: 289–292. pmid:3909959
- 51. Wang H, Wu J, Chang M, Wu H, Ho L, Chi P, et al. Antibody Response and Adverse Events of AZD1222 COVID-19 Vaccination in Patients Undergoing Dialysis: A Prospective Cohort Study. Vaccines. 2022;10: 1460. pmid:36146538
- 52. Yau K, Abe KT, Naimark D, Oliver MJ, Perl J, Leis JA, et al. Evaluation of the SARS-CoV-2 Antibody Response to the BNT162b2 Vaccine in Patients Undergoing Hemodialysis. JAMA Netw Open. 2021;4: e2123622–e2123622. pmid:34473256
- 53. Zhao T, Nishi-Uchi T, Omata F, Takita M, Kawashima M, Nishikawa Y, et al. Humoral response to SARS-CoV-2 vaccination in haemodialysis patients and a matched cohort. BMJ Open. 2022;12: 1–7. pmid:36351730
- 54. Piscitani L, Del Pinto R, Basili A, Tunno M, Ferri C. Humoral Immune Response to COVID-19 Vaccination in Hemodialysis Patients: A Retrospective, Observational Case–Control Pilot Study. High Blood Press Cardiovasc Prev. 2022;29: 163–167. pmid:34978702
- 55. Mastalerz-Migas A, Bujnowska-Fedak M, Brydak LB. Immune efficacy of first and repeat trivalent influenza vaccine in healthy subjects and hemodialysis patients. Adv Exp Med Biol. 2015;836: 47–54. pmid:25248348
- 56. Nikoskelainen J, Väänänen P, Forsström J, Kasanen A. Influenza vaccination in patients with chronic renal failure. Scand J Infect Dis. 1982;14: 245–251. pmid:7163777
- 57. Versluis DJ, Beyer WEP, Masurel N, Diderich PPNM, Kramer P, Weimar W. Intact humoral immune response in patients on continuous ambulatory peritoneal dialysis. Nephron. 1988;49: 16–19. pmid:3380215
- 58. Krairittichai U, Chittaganpitch M. Efficacy of the trivalent influenza vaccination in Thai patients with hemodialysis or kidney transplant compared with healthy volunteers. J Med Assoc Thailand = Chotmaihet Thangphaet. 2013;96: S1–7. pmid:23682516
- 59. Bai S, Dhrolia M, Qureshi H, Qureshi R, Nasir K, Ahmad A. Comparison of COVID-19 Inactivated Virus Vaccine Immunogenicity Between Healthy Individuals and Patients on Hemodialysis: A Single-Center Study From Pakistan. 2022;14. pmid:35582560
- 60. Scharpé J, Peetermans WE, Vanwalleghem J, Maes B, Bammens B, Claes K, et al. Immunogenicity of a standard trivalent influenza vaccine in patients on long-term hemodialysis: an open-label trial. Am J kidney Dis. 2009;54: 77–85. pmid:19339089
- 61. Francis A, Baigent C, Ikizler TA, Cockwell P, Jha V. The urgent need to vaccinate dialysis patients against severe acute respiratory syndrome coronavirus 2: a call to action. Kidney Int. 2021;99: 791–793. pmid:33582109
- 62. Centers for Disease Control and Prevention. CDC Updated Vaccine Guideline for Dialysis and Chronic Kidney Disease Patients. Centers for Disease Control and Prevention; 2021.
- 63. Muruato AE, Fontes-Garfias CR, Ren P, Garcia-Blanco MA, Menachery VD, Xie X, et al. A high-throughput neutralizing antibody assay for COVID-19 diagnosis and vaccine evaluation. Nat Commun. 2020;11: 1–6.
- 64. Tan CW, Chia WN, Qin X, Liu P, Chen MI-C, Tiu C, et al. A SARS-CoV-2 surrogate virus neutralization test based on antibody-mediated blockage of ACE2–spike protein–protein interaction. Nat Biotechnol. 2020;38: 1073–1078. pmid:32704169