Safety and efficacy of coronavirus disease‐19 vaccines in chronic kidney disease patients under maintenance hemodialysis: A systematic review

Abstract Background and aims Patients on maintenance dialysis are a high‐risk, immune‐compromised population with 15%–25% coronavirus disease (COVID‐19) mortality rate that has been underrepresented in COVID‐19 vaccination clinical trials. The aim of study was to review of those studies to determine the safety and efficacy of the COVID‐19 vaccination in chronic kidney disease (CKD) patients receiving maintenance hemodialysis systematically. Methods The effectiveness was assessed by looking at the humoral and cellular responses. The humoral response is defined as de novo IgG‐ or IgA‐anti‐SpikeS1 antibody positivity. The establishment of de novo T‐cell immunity after immunization was used to measure cellular response. Adverse results were also reported of the included studies to analyze the safety of COVID‐19 vaccines. Eight previous works were included in our study. Results Two doses of COVID‐19 vaccines were shown to be effective with seroconversion rate of humoral response ranging from 81% to 97% among eight studies. The T‐cell response was shown 67% and 100% in two studies. COVID‐19 vaccines did not have notable adverse events and hence can be considered safe. Conclusion Although a single dosage has not shown to improve humoral immune response in most hemodialysis trials, a double dose has been reported to improve seroconversion rate and humoral immune response. Further research are required to observe if hemodialysis patients generate effective T‐cell responses.


| INTRODUCTION
The coronavirus 19 disease (COVID-19) caused by SARS-CoV-2 has led to loss of millions of lives across the globe since 2019. The susceptibility and complications are noted higher among immunocompromised groups. Chronic kidney disease (CKD) is one of the common immunocompromised states affecting larger population in the world. The global estimated prevalence of CKD is 13.4% (11.7%-15.1%), and patients with end-stage kidney disease (ESKD) requiring renal replacement therapy is estimated between 4.902 and 7.083 million. 1 CKD affects the morbidity and mortality through its effect on multiple organs of the body. Significant increase in number of patients of CKD and ESKD and death among these group due to poor access to renal replacement therapy has been leading to substantial financial burden for the developing countries. 1 The rate of COVID-19 infection in CKD patients is higher than the general population. 2 ESKD patients under hemodialysis are highly susceptible to COVID-19 due to other comorbidities, older age, immunocompromised status; frequent need of hospital visits for dialysis increase exposure and inability to maintain social distancing.
The reasons for increased risk of symptomatic infection are impaired immunological status, chronic inflammation, high oxidative stress, accumulated uremic toxins, and endothelial dysfunction. 3 The complications like acute respiratory distress syndrome (ARDS), acute cardiac injury, shock, and arrhythmias are higher in patients under dialysis, and mortality is reported higher 14% versus 4% in comparison to patient not infected with COVID-19. 4 Thus, to decrease the morbidity and mortality, it is essential to protect CKD patients from COVID-19 and its complications. Apart from taking various precautions to prevent COVID-19, vaccination helps to boost the immunity. However, the safety profile and the effectiveness of various COVID-19 vaccines in CKD patients are not studied adequately. 5 The aim of this study was to provide information on vaccination for COVID-19 in CKD patients under maintenance hemodialysis for prevention of infection as well as decreasing the complications which ultimately improves the morbidity and mortality.

| Study identification
The article search was conducted in the online databases PubMed, Clinical trials.gov, google scholar, and EMBASE using the keywords "COVID," "COVID-19," "SARS COV-2," "vaccine," "Chronic kidney disease," "CKD," "ESKD," "Hemodialysis," "Dialysis," "AstraZeneca," "Vero cell," "Pfizer," and "Moderna" combined with "OR" and "AND" Boolean operators. Articles after 2019 were included in the study. Additional publications were found by searching the references list of the trials and articles included in the study. Following the retrieval of citations, titles and abstracts were assessed for potential eligible studies. Following an initial screening, the complete texts of potentially eligible papers were obtained for a more comprehensive review. Manual scanning of key articles and review papers was conducted to identify additional articles missed by the search strategy. We retrieved all references in all publications for further analysis. The protocol for reviews specified in Cochrane's handbook for systematic reviews of intervention 6 and preferred reporting items for systematic reviews and meta-analysis (PRISMA) 7 was used to report the article (CRD42021282376). The first active search began on September 20, 2021, and the last was done on September 28, 2021.

| Inclusion criteria
Studies were selected on the basis of the following criteria:

| Exclusion criteria
Studies were excluded on the basis of the following criteria: (I) Patients who did not receive any vaccine.
(II) Articles that were not available in English.
(III) All other forms of articles like case reports or letter to the editor were excluded. For each of the investigations included, an adverse reaction was mentioned as per the inclusion criteria. Another author (Santosh Chhetri) double-checked the extracted data, and disagreements were resolved by discussion among the authors.

| Quality assessment
In the assessment, we looked at the following items: (1) whether the study objectives were clearly described; (2) whether the study period (start and end dates) was properly stated; (3) whether the patients selection criteria were described clearly; (4) whether the study was conducted in a multicenter setting; (5) if COVID-19 vaccine treatment dose was stated; (6) whether the baseline equivalence groups were taken into account; (7) whether the primary outcome was defined before to the study; (8) whether the follow-up period was long enough (months); (9) whether a clear hazard ratio (HR) with 95% confidence intervals (95% CI) was reported; and (10) Each study's limitations were taken into account. Quality assessment was not used as an exclusion criterion. The articles were graded based on the quality items utilized in each investigation (score range: 0-10).

| Efficacy measurement
The following subheadings were used to examine the immunogenicity of patients. ii. T-cell response: Development of de novo T-cell immunity induced by vaccination, clinical safety, and cellular immune response.

| Data synthesis
The narrative summary contained all identified studies, as well as summary tables for characteristics. In addition, descriptive statistics were used to summarize the data. For continuous variables, we used the mean, and for dichotomous variables, we used frequencies and percentages.  Table 1. There were 1826 hemodialysis patients in eight studies, with an average age of 71.1 years. The ratio of males to females was 1.78.

| Seroconversion
After reviewing the studies, we found that COVID-19 vaccination in CKD patients were effective leading to seroconversion rate in 81%-97% of the vaccinated candidates at 4-8 weeks postvaccination interval following two doses of vaccine. The T-cell response was 67% and 100% showed by the two studies which is mentioned in Table 2. However, the seroconversion rate was only 43% in one study which analyzed efficacy of a single dose of Pfizer vaccination. 8 Similarly, the trials had the low antibody titer after 1st dose of vaccination and significant rise in the titer was noted after second dose. Thus, our review suggests that the two doses of vaccination is effective leading to high seroconversion rates and antibody titers. Although the studies showed seroconversion rates and adequate antibody titers, which were low in comparison to healthy controls. 9 The nonresponders were found to be on long-term immunosuppressants for the underlying comorbidities including diabetes. 8 The studies showed no significant difference of efficacy between Pfizer and Moderna vaccine. anti-RBD IgG levels that were nondetectable, compared with 1 of 20 controls (5%, 95% CI: 1%-23%, p < 0.001). 14 By 8 weeks, none of the hemodialysis patients who had nondetectable antibodies at F I G U R E 1 Preferred reporting items for systematic reviews and meta-analysis guidelines for article identification and selection 4 weeks had produced detectable anti-RBD. Anti-RBD IgG levels were still considerably lower in patients receiving hemodialysis than in controls after 4 weeks, and they did not increase after 8 weeks. 14

| Cellular response
Cellular immune response was detected in 44% at T1 and 78% at T2 by interferon-γ release assay (IGRA) in a study by Stumpf et al. 11 Similarly in a study by Bertrand et  Hemodialysis patients had a seroconversion rate ranging from 40% to 70% after receiving hepatitis B immunization. 19 To avoid the interaction between SARS-spike CoV-2's protein and angiotensin-converting enzyme 2, vaccine-mediated immunity is developed (ACE-2). Patients with renal illness should be chosen for COVID-19 vaccination, and current evidence suggests that replication-defective viral-vectored and mRNA vaccines are safe for this population.
A virus H1N1 resulted in seroconversion rates ranging from 25% to 57%, [23][24][25][26][27] with adjuvant vaccinations having greater response rates than non-adjuvant vaccines. 28 In comparison to these findings, the robust immunogenicity of the SARS-CoV-2 vaccine reported in the studies are encouraging, and it is expected that this will translate into the prevention of clinically relevant consequences such severe   17 The presence of SARS-CoV-2-S1 IgA in dialysis patients' serum following mRNA vaccination is a noteworthy finding, as mucosal IgA is important for respiratory infection defense. 46 It is uncertain whether IgA measured in serum after vaccination is related to mucosal immunity, and more research is