BR Biomedical Reports 2049-9434 2049-9442 D.A. Spandidos BR-20-5-01766 10.3892/br.2024.1766 Articles Effectiveness and safety of immune response to SARS‑CoV‑2 vaccine in patients with chronic kidney disease and dialysis: A systematic review and meta‑analysis LiKejia * XiaYang * YeHua * SunXian ShiBairu WuJiajun Department of Nephrology, The First People's Hospital of Jiashan, Jiaxing, Zhejiang 314100, P.R. China Correspondence to: Dr Kejia Li, Department of Nephrology, The First People's Hospital of Jiashan, 1218 Tiyu South Road, Jiaxing Zhejiang 314100, P.R. China shaoyang_w@tju.edu.cn xuyunze2012@sina.com

*Contributed equally

 05 2024 19 03 2024 20 5 78 18 10 2023 02 02 2024 Copyright: © 2024 Li et al. 2024 This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

The coronavirus disease 2019 (COVID-19) vaccination is the most effective way to prevent COVID-19. However, for chronic kidney disease patients on long-term dialysis, there is a lack of evidence regarding the efficacy and safety of the immune response to the vaccine. The present meta-analysis explores the efficacy and safety of COVID-19 vaccine in the immune response of patients with chronic kidney disease (CKD) undergoing dialysis. PubMed, Web of Science, Science Direct, and Cochrane Library databases were systematically searched from January 1, 2020, to December 31, 2022. Data analysis was performed using REVMAN 5.1s and Stata14 software. Baseline data and endpoint events were extracted, mainly including age, sex, dialysis vintage, body mass index (BMI), vaccine type and dose, history of COVID-19 infection, seropositivity rate, antibody titer, pain at injection site, headache and other safety events. The meta-analysis included 33 trials involving 81,348 patients. The immune efficacy of patients with CKD and dialysis was 80% (95 CI, 73-87%). The seropositivity rate of individuals without COVID-19 infection was 76.48% (3,824/5,000), while the seropositivity rate of individuals with COVID-19 infection was 80.82% (1,858/2,299). The standard mean difference of antibody titers in CKD and dialysis patients with or without COVID-19 infection was 27.73 (95% CI, -19.58-75.04). A total of nine studies reported the most common adverse events: Pain at the injection site, accounting for 18% (95 CI, 6-29%), followed by fatigue and headache, accounting for 8 (95 CI, 4-13%) and 6% (95 CI, 2-9%), respectively. COVID-19 vaccine benefitted patients with CKD undergoing dialysis with seropositivity rate ≥80%. Adverse events such as fatigue, headache, and pain at the injection site may occur after COVID-19 vaccination but the incidence is low.

 coronavirus disease 2019 vaccine chronic kidney disease dialysis immune response safety meta-analysis Funding: No funding was received. Introduction

The coronavirus disease 2019 (COVID-19) pandemic has caused social, economic, and political chaos worldwide (1). The effectiveness of antibody treatments varies depending on the variation of the virus strain (2). The World Health Organization (WHO) has identified α, β, γ, δ and ο as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus variants of concern (3). These variants notably decrease the effectiveness of vaccines, thus escalating the threat to global public health. Nevertheless, vaccines continue to demonstrate high efficacy in preventing severe illness, hospitalization and death against these variants (3,4). Without effective treatment, the virus can cause serious respiratory disease, similar to SARS and Middle East respiratory syndrome. Some cases of COVID-19 involve acute respiratory distress syndrome or septic shock, which causes pressure and challenges to the global medical and health system and consumes limited medical resources (5). Countries worldwide are actively responding to the COVID-19 pandemic and have formulated policies, such as wearing masks in public, social distancing and quarantining communities and cities. Despite these measures, the COVID-19 pandemic continues. Certain studies suggest vaccination may be the most effective measure to prevent COVID-19 infection (6,7). At present, most COVID-19 vaccines are based on recombinant subunit proteins, virus-like particles, messenger RNA, DNA and viral vectors (8).

Although COVID-19 infection primarily causes respiratory symptoms, the virus may also damage other organs and the kidney is one of the main sites of complications (9). Studies have shown that coronavirus infection increases serum creatinine levels and acute tubular necrosis, which may lead to impaired renal function (10,11). Clinical studies have shown that patients with COVID-19 have acute renal injury (10,12). At the same time, studies have shown that chronic kidney disease (CKD) is a risk factor for COVID-19 death (13,14). The mortality rate among patients with CKD and COVID-19 is significantly higher than that of non-nephrotic patients and non-dialysis CKD patients with COVID-19. Additionally, the severity of the disease is more pronounced in elderly patients (15-17). With the rapid mutation rate of the virus, there are still some doubts about the effectiveness and safety of existing vaccines (18-20). The present study aimed to systematically analyze the efficacy and safety of the immune response of patients with CKD receiving hemodialysis (HD) and COVID-19 vaccine.

 Materials and methods <sec> <title>Search strategy

An electronic search was performed in PubMed (pubmed.ncbi.nlm.nih.gov/), Web of Science (https://www.webofscience.com/wos/), Science Direct (https://www.sciencedirect.com/), and Cochrane Library (cochranelibrary.com/) from January 2019 until December 31, 2022, to identify eligible trials without any publication status restrictions. Data S1 shows the detailed search strategy for each database. Of the 327 identified articles, 33 fulfilled our inclusion criteria (Fig. 1).

 Study selection

Inclusion criteria were as follows: i) Prospective cohort study, randomized controlled trial or cross-sectional study; ii) reported the effectiveness of COVID-19 vaccine response and iii) studies reporting adverse events and COVID-19 vaccine safety.

 Data extraction

A total of two investigators independently performed the literature search and data selection. Discrepancies were resolved by the third reviewer. Extracted data included number of participants, occurrence of endpoints of interest, mean age at baseline, percentage of male participants, body mass index (BMI), dialysis vintage and vaccine.

 Quality assessment

The study used a Risk Of Bias In Non-randomized Studies - of Interventions (ROBINS-I) tool for bias detection (21), which includes seven component (bias due to confounding, bias in selection of participants into the study, bias in classification of Interventions, bias due to deviations from intended interventions, bias due to missing data, bias in measurement of outcomes, and bias in selection of the reported result. Overall bias was identified as low, medium or serious bias.

 Statistical analysis

The present study summarized the seropositivity rate and adverse events of patients with CKD undergoing dialysis who received the COVID-19 vaccine as outcome indicators. Heterogeneity was evaluated using the I2 statistic as follows: 0-40, no significant heterogeneity; 30-60, moderate heterogeneity; 50-90 substantial heterogeneity and 75-100%, considerable heterogeneity (22). If I2 statistic ≥50%, the random benefit model was used; otherwise, a fixed-effects model was used. Data reported as median and interquartile range were converted to mean and SD as previously described (23). Data were analyzed using Review Manager 5.1 (revman.cochrane.org/info) and STATA 18.0 (stata.com/). P<0.05 was considered to indicate a statistically significant difference.

 Results <sec> <title>Study characteristics

A total of 327 studies were initially retrieved. Of these, 294 were excluded due to lack of relevant outcomes, patients who did not have CKD or receive dialysis or COVID-19 vaccine and articles published in a language other than English. Finally, 33 trials with a total of 81,348 patients were included in the meta-analysis (24-56) and mean dialysis vintage was 2.1 years. Details of age, BMI, dialysis vintage, and vaccine name included in the analysis are presented in Table I. At baseline, the mean age was 64.9 years and the mean percentage of male participants was 59.4%.

 Quality assessment

ROBINS-I (21) was used by two independent authors to evaluate the quality of studies; the overall quality of was good. Of the 33 trials, 21 were considered low, 10 medium and two serious risk of bias (Table SI).

 Endpoints

Seropositivity rate of patients with CKD and dialysis after vaccination was 80% (95 CI, 73-87%) and the heterogeneity was I2=98.9% (Fig. 2). After removing Bielopolski et al (45) and Stumpf et al (37) due to large sample size, the sensitivity analysis found that the seropositivity rate remained unchanged but the heterogeneity was reduced (I2=96.4%; Fig. S1). Seropositivity rate of patients without a history of COVID-19 infection was lower than that of patients with a history of infection [Fig. 3; 76.48% (3,824/5,000) of uninfected and 80.82% (1,858/2,299) of patients with a history of infection]. In addition, the antibody titers of patients with CKD and dialysis who had a history of COVID-19 infection were compared; SMD was 27.73 (95% CI, -19.58-75.04), indicating no significant difference (Fig. 4).

A total of nine trials reported adverse events. Safety outcomes assessed were as follows: Pain at injection site, redness, swelling, fatigue, headache and diarrhea (Table II). Pain at injection site was the most common adverse event, accounting for 18% (95 CI, 6-29%; Fig. 5). Other common adverse events were fatigue and headache, accounting for 8 (95 CI, 4-13%) and 6% (95 CI, 2-9%), respectively (Figs. S2 and S3).

 Discussion

The present meta-analysis showed that the immune efficacy and safety of the COVID-19 vaccine in patients with CKD undergoing dialysis was good and the seropositivity rate was 80%. Individuals with a history of COVID-19 infection had higher seropositivity rate. The primary adverse events were pain at the injection site and fatigue after vaccination but the overall safety was high. Therefore, administering the COVID-19 vaccine significantly enhances protection against severe outcomes.

In recent years, CKD has become an increasingly serious global health problem (57,58). It is defined as kidney injury or glomerular filtration rate <60 ml/min/1.73 m2 for ≥3 months (59). When patients with end-stage renal disease develop uremia, they need regular dialysis to survive. Studies have shown that COVID-19 invasion of the kidney can impair renal function (60-62). Effective vaccination strategies are crucial for patients with CKD, as the decreased efficiency of the immune system impairs vaccine-induced immunization (63). The COVID-19 pandemic has prompted research on the immune response to SARS-CoV-2 vaccines in patients with CKD and kidney transplant recipients with the aim of improving efficacy (64). In patients with CKD, the seroconversion rate is reduced after two doses of SARS-CoV-2 vaccine and anti-spike antibody titers are lower than those in healthy individuals (65,66). According to Babel et al (67) in patients with CKD, immunological aging and persistent inflammation decreases the efficacy of vaccination. Patients with CKD, especially those who have renal failure, are at high risk of experiencing severe adverse effects of COVID-19(68). After receiving two doses of mRNA vaccine, most kidney transplant recipients do not establish humoral immunity despite seroconversion rates comparable to those of persons with normal renal function (69). However, some people continue to have a T cell response unique to the vaccination, which may protect against severe COVID-19. Studies have shown that elderly patients, especially men and those with cardiovascular or chronic liver disease, hypertension and CKD, are more likely to be infected with COVID-19, and the disease severity and death risk are also high (70,71). COVID-19 vaccine has a notable impact on the immune status of patients. Some studies have shown that patients undergoing renal dialysis patients may exhibit a weaker vaccine-induced immune response (72-74). According to studies, age and sex also affect immune response (75,76). Seropositivity rate of patients aged >60 years following vaccination is lower than that of those aged <60 years, which may be due to relatively strong immune system in young people leading to higher vaccine efficacy (77,78). Relevant studies have demonstrated out that sex affects seropositivity rate: The antibody response of female patients to virus infection and vaccines is usually higher than that of males (76,79,80). Studies have shown that patients who have been infected with COVID-19 have a higher seropositivity rate, indicating that history of infection can increase the concentration of antibodies (81,82). As the virus further, protective efficiency of vaccines also decrease. This can also explain why there is no significant difference between antibody levels of patients with a history of COVID-19 and those without a history of infection (83). In addition, when condition of patients with CKD is stable, COVID-19 vaccine is recommended. Studies have shown that the mRNA-1273 vaccine can induces higher antibody levels than the BNT162b2 vaccine, but the incidence of adverse events is also higher, requiring care in vaccine selection (84,85). Repeated doses of the COVID-19 vaccine improve the antibody levels and serum conversion rate of patients with kidney disease. Therefore, it is important to enhance vaccination programs, which is an important means of preventing COVID-19 infection (86-88). A recent investigation by Puspitasari et al (89) assessed the immunogenicity and safety of inactivated COVID-19 vaccines in individuals with end-stage renal disease undergoing HD. The aforementioned study observed no noteworthy distinctions in all measures of immunogenicity between 75 patients receiving HD and 71 healthy controls: The findings revealed no significant variations in anti- receptor-binding domain immunoglobulin G, neutralizing antibodies (NAbs) inhibition and seroconversion rates between the two groups. The incidence of adverse events also showed no significant difference. The study concluded that primary administration of inactivated SARS-CoV-2 vaccination generates an effective antibody response and can be safely administered to individuals undergoing HD. Moreover, a systematic review (90) examining the safety and efficacy of COVID-19 vaccination in patients with CKD undergoing maintenance HD revealed that two doses of COVID-19 vaccines were effective: Seroconversion rates for humoral response were 81-97% and T cell responses were observed in 67-100% of cases. COVID-19 vaccinations demonstrated no significant adverse effects and can be considered safe. In most HD studies, a single dose does not enhance the humoral immune response, but a double dose was improves seroconversion rates and humoral immune response (26,56). If the patient is in the stage of acute and chronic nephritis and takes hormone and immunosuppressive drugs for a long time, it is not recommended to administer the COVID-19 vaccine (91). In addition, the inactivated COVID-19 and recombinant protein vaccine are recommended for nephrotic patients; the vaccination should not be administered to patients allergic to the COVID-19 vaccine and its components (92).

Injection site pain and local injection site reactions are some of the most common reactions (93). Following COVID-19 vaccination, the body exhibits an immune response and the muscles at the injection site may become inflamed, leading to pain (94). In addition, some inactivated vaccines use aluminum hydroxide as an adjuvant to strengthen immunity. Certain scholars believe that aluminum hydroxide is related to the pain at the injection site after inoculation (95,96). The present results show that there is a fatigue reaction following injection of the COVID-19 vaccine, which may be due to brain hypoxia caused by excessive tension, which leads to muscle weakness and fatigue. If the patient has headaches after COVID-19 vaccination, the first thing to consider is psychological factors such as fear, mistrust, and conspiracy beliefs. Usually, after a few hours, the headache disappears when the individual relaxes. This is consistent with previous studies on major adverse events following COVID-19 vaccine injection (97,98).

The present study has limitations. First, most of the studies included were inpatient cases, which may not fully represent all infected people in the region, especially asymptomatic cases. In addition, the included studies did not obtain information about the characteristics, onset time, duration and acute treatment response of side effects. Finally, further research is needed to determine the protection level of naturally acquired antibodies against mutant strains and the durability of protection. Therefore, further research with a larger sample size is required, considering the specific immune and physical conditions of patients.

In conclusion, immune response of patients with CKD undergoing dialysis was effective, which indicated that COVID-19 vaccine injection can reduce the incidence of COVID-19 in patients. In addition, there were few common adverse events and there were no potentially vaccine-related serious adverse events. Therefore, the COVID-19 vaccine should be administered, considering the individual immune levels of patients.

 Supplementary Material Search strategy of electronic database. Seropositivity rate of patients with chronic kidney disease undergoing dialysis and receiving coronavirus disease 2019 vaccine after removing studies with large sample sizes. DL, DerSimonian-Laird. Forest plot of fatigue after receiving coronavirus disease 2019 vaccine. DL, DerSimonian-Laird method. Forest plot of headache after receiving coronavirus disease 2019 vaccine. DL, DerSimonian-Laird. Risk of bias assessment according to Risk of Bias in Non-randomized Studies of Interventions. Acknowledgements

Not applicable.

 Availability of data and materials

The data generated in the present study are included in the figures and/or tables of this article.

 Authors' contributions

KJ, YX and HY conceived and designed the study. XS and BS designed the search strategy and performed quality assessment. XS and BS confirm the authenticity of all the raw data All authors analyzed data and wrote the manuscript. All authors have read and approved the final manuscript.

 Ethics approval and consent to participate

Not applicable.

 Patient consent for publication

Not applicable.

 Competing interests

The authors declare that they have no competing interests.

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Flowchart of study selection for meta-analysis. CKD, chronic kidney disease; COVID-19, coronavirus disease 2019.

Forest plot of seropositivity rate of patients with chronic kidney disease undergoing dialysis receiving coronavirus disease 2019 vaccine. DL, DerSimonian-Laird.

Forest plot of seropositivity rate of patients with or without coronavirus disease 2019 infection. M-H, Mantel-Haenszel.

Forest plot of antibody titers of patients with chronic kidney disease and dialysis with or without COVID-19 infection. COVID-19, coronavirus disease 2019; IV, weighted mean difference.

Forest plot of pain at the injection site after receiving coronavirus disease 2019 vaccine.

Characteristics of the baseline population included in trials.

First author/s Year Country Sample size Population Prior COVID infection Mean age, years Male, % Mean BMI, kg/m² Mean dialysis vintage, months Vaccine Dose (Refs.)
Agur et al 2021 Israel 122 HD/PD No 71.6 33.6 26.7 39.7 BNT162b2 2 (24)
Alkadi et al 2022 Switzerland 782 HD Mixed 57.0 64.1 NR NR BNT162b2/mRNA-1273 3 (43)
Ben-Dov et al 2022 Italian 175 HD Mixed 65.1 60.0 NR 32.0 BNT162b2 2 (44)
Bielopolski et al 2022 Israel 67,861 CKD No 76.0 48.0 29.0 NR BNT162b2 2 (45)
Broseta et al 2021 Spain 78 HD No 67.1 67.9 NR 94.3 mRNA-1273 2 (25)
Butt et al 2022 USA 6,076 HD No 69.0 96.7 27.8 NR BNT162b2/mRNA-1273 2 (46)
Clavero et al 2022 Switzerland 81 HD Mixed 62.6 58.3 NR NR BNT162b2/Corona Vac 2 (56)
Cserep et al 2021 UK 83 HD No 73.0 60.0 29.5 27.0 BNT162b2 2 (36)
Davidovic et al 2022 Austria 36 HD No 66.9 66.7 NR 35.0 BNT162b2/Ad26COVS1 3 (48)
Duarte et al 2021 Portugal 67 HD/PD No 67.8 59.5 NR NR BNT162b2 2 (47)
Ducloux et al 2021 France 45 HD Mixed NR NR NR NR BNT162b2 2/3 (51)
Espi et al 2021 France 106 HD/PD No 64.9 65.0 26.5 50.7 BNT162b2 2 (52)
Fernando et al 2021 India 42 HD No NR NR NR NR ChAdOx1-nCoV-19/BBV152 2 (53)
Frantzen et al 2021 France 326 HD No 71.3 70.0 NR NR BNT162b2 2 (54)
Goupil et al 2021 Canada 131 HD Mixed 70.0 77.0 NR 45.6 BNT162b2 1 (55)
Labriola et al 2021 Belgium 79 HD Mixed 80.7 44.0 NR NR BNT162b2 2 (26)
Lesny et al 2021 Germany 23 HD No 69.3 55.6 27.9 29.7 BNT162b2/ChAdOx1-nCoV-19 1 (27)
Longlune et al 2021 France 82 HD No 64.0 68.8 NR 39.0 BNT162b2 2 (28)
Quiroga et al 2022 Spain 1,116 HD Mixed 65.0 64.0 NR NR BNT162b2/mRNA-1273/ChAdOx1-S/Ad26.COV.2 2 (49)
Rincon-Arevalo et al 2021 Germany 41 HD No 71.3 70.0 NR 66.0 BNT162b2 2 (29)
Sattler et al 2021 Germany 26 HD No 67.4 65.4 NR 82.4 BNT162b2 2 (30)
Schrezenmeier et al 2021 Germany 36 HD No 74.0 69.4 NR 64.0 BNT162b2 2 (31)
Simon et al 2021 Austria 81 HD No 67.0 55 NR NR BNT162b2 2 (32)
Speer et al 2021 Germany 30 HD No 78.7 60 25.3 37.3 BNT162b2 2 (33)
Speer et al 2021 Germany 43 HD No 83.0 63 26.0 8.0 BNT162b2 2 (34)
Strengert et al 2021 Germany 81 HD No 69.0 58 NR NR BNT162b2 2 (35)
Stumpf et al 2021 Germany 3,100 HD No 67.6 65.1 27.5 68.4 mRNA-1273/BNT162b2 2 (37)
Torreggiani et al 2021 France 132 HD No 68.9 59 NR 30.8 BNT162b2 2 (38)
Trakarnvanich et al 2022 Thailand 12 CKD No 63.1 75 22.5 NR ChAdOx1-nCoV-19 2 (50)
Tylicki et al 2021 Poland 91 HD No 69.3 61.5 25.7 36.0 BNT162b2 2 (39)
Weigert et al 2021 Portugal 156 HD No 64.0 67.8 NR NR BNT162b2 2 (40)
Yanay et al 2021 Israel 160 HD No 69.7 63 NR 40.8 BNT162b2 2 (41)
Zitt et al 2021 Austria 48 HD No 67.6 68 NR NR BNT162b2 2 (42)

HD, hemodialysis; PD, Peritoneal dialysis; CKD, Chronic kidney disease; NR, Not reported.

Adverse events after vaccination in patients with chronic kidney disease undergoing dialysis.

First author/s Year Sample size New infection (%) Death (%) Pain at the injection site (%) Redness (%) Swelling (%) Fatigue (%) Headache (%) Diarrhea (%) (Refs.)
Cserep et al 2021 83 0 (0.0) 0(0.0) NR NR 2 (2.4) 9 (10.8) 7 (8.4) 1 (1.2) (36)
Fernando et al 2021 38 2 (5.3) NR NR NR NR NR NR NR (53)
Longlune et al 2021 109 0 (0.0) NR 15 (13.8) NR NR 15 (13.8) NR NR (28)
Quiroga et al 2022 1116 NR 8 (0.7) NR NR NR NR NR NR (49)
Simon et al 2021 81 NR NR NR NR NR NR NR NR (32)
Speer et al 2021 43 NR NR 4 (9.3) NR NR 2 (4.6) 2 (4.6) NR (34)
Strengert et al 2021 81 NR NR NR NR NR NR NR NR (35)
Yanay et al 2021 160 6 (3.75) NR NR NR NR NR NR NR (41)
Zitt et al 2021 48 NR NR 16 (33.4) NR NR 2 (4.2) 2 (4.2) 1 (2.1) (42)

NR, not reported.