Immunogenicity of COVID‐19 mRNA vaccines in hemodialysis patients: Systematic review and meta‐analysis

Abstract Background and Aims Vaccine response is a concern in hemodialysis patients. Given that hemodialysis patients were not included in clinical trials, we aimed to synthesize the available evidence on the immunogenicity of coronavirus disease 2019 (COVID‐19) mRNA vaccines in hemodialysis patients. Methods We searched Scopus, PubMed, Sciencedirect, and finally google scholar databases for studies on COVID‐19 mRNA‐vaccines immunogenicity in hemodialysis patients up to December 1, 2021. Eligible articles measured antibodies against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) spike or Receptor‐Binding Domain Antibody (S/RBD) postimmunization with COVID‐19 mRNA vaccines. The immunogenicity of the vaccine was evaluated using seroconversion rates measured between 21 and 30 days after the first immunization and between 14 and 36 days post the second dose. We included studies including participants without a history of COVID‐19 before vaccination. Healthy controls or health‐care workers served as the control groups. After selecting eligible articles, the data were finally extracted from included articles. We used a random effects model to estimate the pooled seroconversion rate after COVID‐19 mRNA vaccine administration. We assessed the heterogeneity between studies with the I 2 statistical index. Result We selected 39 eligible citations comprising 806 cases and 336 controls for the first dose and 6314 cases and 927 controls for the second dose for statistical analysis. After the first dose of mRNA vaccines, the seroconversion rate was 36% (95% confidence interval [CI]: 0.24–0.47) and 68% (95% CI: 0.45–0.91) in hemodialysis patients and the control group, respectively. While seroconversion rate after the second dose of mRNA vaccines was 86% (95% CI: 0.81–0.91) and 100% (95% CI: 1.00–1.00) in hemodialysis patients and the control group, respectively. Conclusion Although the immune response of hemodialysis patients to the second dose of the SARS‐CoV‐2 mRNA vaccine is very promising, the seroconversion rate of dialysis patients is lower than healthy controls. Periodically assessment of antibody levels of hemodialysis patients at short intervals is recommended.


| INTRODUCTION
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was detected in late 2019 in Wuhan, China. 1,2 Coronavirus disease 2019  is one of the most critical health problems in the world right now. [3][4][5] Several vaccines have been licensed for emergency use. 6,7 Vaccination remains an essential part of preventive care due to the high infection rate in hemodialysis patients. As kidney function decreases, the antibody response to the vaccine is impaired. Different methods have been used to improve response to influenza A and hepatitis B vaccines, such as higher vaccine doses and more frequent booster vaccinations. 8 Vaccine efficacy in clinical trials has been determined for the general population. However, its efficacy has not been evaluated for vulnerable populations such as hemodialysis patients.
Hemodialysis patients are at high risk in the COVID-19 pandemic due to increased average age, immunosuppression, renal failure, and frequent visits to dialysis centers. The mortality rate of COVID-19 in these patients is much higher than in the general population, and up to 32% has been reported. 8,9 Including patients with kidney disease in the COVID-19 vaccine, clinical trials are low. In most trials, people with "severe" or "chronic" kidney disease and people using/undergoing immunosuppression have been excluded. There is not much information about the effectiveness of COVID-19 vaccines in hemodialysis patients.
On the other hand, the effectiveness of previous vaccines such as hepatitis B and influenza in hemodialysis patients has been less than in the general population. The seroconversion rate after influenza virus vaccination is about 33%-80% in hemodialysis patients. 10 The combination of this evidence has raised concerns about the vaccine's efficacy in this group and raised questions: The efficacy of COVID-19 vaccines and the rate of postvaccination seroresponse in hemodialysis patients has not been fully determined; the duration of immune protection after vaccination is unknown. Seroconversion is related to immune protection from many pathogens, and there is increasing evidence that the same is true for SARS-CoV-2. Some studies have found a strong correlation between spike1 antibody titer and neutralization ability, innate immunity and the recruitment of T-cellspecific SARS-CoV-2 responses. 11 Our objective was to synthesize the available evidence on the immunogenicity of COVID-19 mRNA vaccines in hemodialysis patients compared with healthy controls.  Healthy controls or health-care workers served as the control groups.

| Eligibility criteria and study selection
The title and abstract of the articles were read. In the next step, the full text of the articles was evaluated for eligibility. After selecting the relevant studies, the reference list of each article was searched manually. Finally, all eligible articles were included in the study.

| Data extraction
Two researchers independently recorded the following data: first author, year of study, country, type of study, number of cases, number of positive cases, number of the control group, number of positive controls, vaccine type, antibody type, timing post first/second dose (days). Discrepancies among the researchers were resolved through discussions or additional consultations with the third author.

| Statistical analysis
The heterogeneity of studies was assessed using Cochran's Q test and the I 2 index. Due to the high heterogeneity, the random effect model was selected for meta-analysis. Meta-regression analysis was used to investigate the relationship between vaccine type and seroconversion rate. We used STATA version 11(STATA Corporation) for the analysis.
All levels of significance tests were two-sided and p-values less than 0.05 was considered significant.

| RESULTS
In the first research phase, a total of 2407 relevant articles were  Anti-S1 IgG

| DISCUSSION
The mRNA-based vaccines showed more than 90% efficacy in preventing COVID-19 disease. 25,48 Patients with severe kidney disease were not present in clinical trials; therefore, the vaccine's efficacy in this high-risk group has not been evaluated. been actively monitored in the study population; these people were excluded from the study or located in a separate group. 15,27,28,51 The limitations of this study include: the small sample size, and also our study includes articles that assessed the efficacy of mRNAbased vaccines by antibody titer. seroconversion and antibody titer is an easy method to evaluate the immunological response to vaccination, but it is not equivalent to complete protection. 52 Also, the antibody levels required to protect against COVID- 19 have not yet been determined. 53 However, to assess vaccine responses, it is recommended to assess both humoral and cellular responses. 54 However, due to limited data on vaccine-mediated cellular immunity, this study focused on investigating humoral immune responses after vaccination.
F I G U R E 3 Forest plot for the seroconversion rate after the second dose of mRNA-based vaccines, (A) Cases, (B) Controls Although the seroconversion rate is high, many studies have reported that the antibody level of hemodialysis patients after being vaccinated with the COVID-19 vaccine is lower than that of the control group; as a result, a shorter period of immune protection can be assumed. Therefore, it is necessary to periodically assess the antibody levels of hemodialysis patients at short intervals and renew their vaccination when necessary.

| CONCLUSION
Although the immune response of hemodialysis patients to the second dose of SARS-CoV-2 mRNA vaccine is very promising, the seroconversion rate of dialysis patients is lower than healthy controls. As a result, it is necessary to pay more attention to the vaccination programs of this population, periodically assess the antibody levels of hemodialysis patients at short intervals and renew their vaccination when necessary.

CONFLICT OF INTEREST
The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
Data sharing does not apply to this article as no datasets were generated or analyzed during the current study.

TRANSPARENCY STATEMENT
The lead author Azra Kenarkoohi affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.