key: cord-0771947-ovkkhwn1
authors: Dheir, Hamad; Tocoglu, Aysel; Toptan, Hande; Pinar, Musa; Demirci, Taner; Koroglu, Mehmet; Yaylaci, Selcuk; Genc, Ahmed Bilal; Genc, Ahmed Cihad; Firat, Necattin; Karabay, Oguz; Sipahi, Savas
title: Short and mid‐term SARS‐CoV‐2 antibody response after inactivated COVID‐19 vaccine in hemodialysis and kidney transplant patients
date: 2022-03-22
journal: J Med Virol
DOI: 10.1002/jmv.27714
sha: d4a8e0caf82bf4b27dcaf214dc3389123e8f30eb
doc_id: 771947
cord_uid: ovkkhwn1

The efficacy of the inactivated severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccine has not been fully elucidated across the whole spectrum of patients on kidney replacement therapy. We aimed to characterize the long‐term antibody response of inactivated SARS‐CoV‐2 vaccine administered in kidney transplant recipients (KTRs) and hemodialysis (HD) patients. We performed this prospective observational study in 50 HD, 64 KTR, and 41 healthy control groups (HG) given two doses of CoronaVac. We measured anti‐Spike antibodies after 28 days of every vaccine dose, 3rd and 6th months after the first dose, and compared them between cohorts. After two doses, an anti‐spike immunoglobulin G of ≥50 AU/ml was present in HD, KTR, and HG as 44%, 7.2%, and 58.5%, respectively (p < 0.001). Furthermore, the proportion of antibody titers peaked at 86.5%, 23%, and 97.6% (p < 0.001) at the 3rd month and decreased significantly at the 6th month in most HD and HG participants, whereas this effect was not observed in KTRs from basal until the 6th month (p < 0.001). During the follow‐up, the incidence of coronavirus disease 2019 disease was higher (p < 0.003) in KTRs compared to the other groups, but there was no requirement for an intensive care unit and no death was recorded. We found a negative correlation between antibody seroconversion and age (p < 0.016). The antibody response following inactivated vaccine in dialysis patients is almost comparable to controls for 6 months. In contrast, kidney transplant patients have a poor response. These findings reinforce the need to discuss the vaccination strategy in immunocompromised patients, including the third dose with homologous or heterologous vaccines.

The new type of coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) threatens global public health by undergoing different mutations over time. Before the emergence of COVID-19 vaccines, wearing face masks, social distancing, and contact tracing were the cornerstones of health policies to reduce or prevent viral spread among people. 1, 2 With these measures, it has been clearly demonstrated that the COVID-19 disease can be controlled after the emergence of different effective and safe vaccines in the normal population. 3, 4 So far, messenger RNA (mRNA)-based COVID-19 vaccines have proven to be the most protective vaccine type against COVID-19 disease in the normal population and in different chronic kidney diseases (CKDs). 3, [5] [6] [7] CKD and kidney transplantation are important independent risk factors for severe COVID-19 disease. [8] [9] [10] In addition, COVID-19 disease-related mortality rates are higher in patients receiving renal replacement therapy (RRT) than in the normal population. [11] [12] [13] Therefore, health authorities emphasize that vaccination approaches against COVID-19 should be a priority in CKD and kidney recipients. However, the efficacy of COVID-19 vaccines in immunocompromised kidney transplant patients was found to be significantly lower than in other populations. 5, 6 At the beginning of the COVID-19 pandemic, it was not understood how effective the vaccines were in these patient groups, as the phase III studies against COVID-19 did not include CKD, dialysis, or kidney recipients and focused only on normal individuals.

However, in studies conducted after the administration of vaccines over time, it has been found that antibody responses are weaker in uremic and immunosuppressive patients. 14 Studies have reported varying results in antibody response rates of approximately 5%-50% after two doses of mRNA vaccine in kidney recipients and up to >90% in dialysis patients for short periods of time. 5, 15 The long-term efficacy rates of the antibody response of the mRNA vaccine in dialysis patients were found at 1, 3, and 6 months after the second vaccine dose, respectively; 94%, 78%, and 73%. 16 Studies investigating the long-term efficacy of mRNA vaccine in RRT patients are ongoing (ClinicalTrials.gov NCT04741386). 17 With respect to inactivated vaccines; anti-spike immunoglobulin G (IgG) antibody response was detected in more than 80% of dialysis patients, but lower than 20% of kidney recipients after two doses of CoronaVac vaccines. [18] [19] [20] These results reflect an 8-week time course and lead to debates about antibody response and its protection in RRT patients in the long term.

We did not find any comprehensive research investigating the effectiveness of inactivated COVID-19 vaccines administered to different kidney patients for a long time. Our aim was to characterize the long-term antibody response of inactivated SARS-CoV2 vaccine administered in kidney transplant recipients (KTRs) and hemodialysis (HD) patients.

Patients who preferred only inactivated SARS-CoV-2 vaccine (CoronaVac ® ) between January 30 and June 30, 2021, were included in this study. Other inclusion criteria; (1) being >18 years old, (2) No history of COVID-19 disease, (3) History of kidney transplant or HD for at least 6 months, and (4) Approval of informed consent to the study. As exclusion criteria; (1) being <18 years old, (2) having a history of COVID-19 disease, (3) having a history of malignancy, (4) having a previous history of allergy to any inactivated vaccine, and (5) having an unexplained 37.5°C fever or any symptoms of infection has been determined. CoronaVac ® vaccine was administered intramuscularly in two doses, 28 days apart, in all participants. 

Statistical analyses were performed using SPSS version 22 software.

The suitability of the variables to normal distribution was examined using visual (histogram and probability graphs) and analytical methods (Kolmogorov-Smirnov). The continuous variables were expressed as mean and standard deviation or as median and interquartile range (IQR), depending on the normality of their distribution. Categorical variables were described as frequencies and percentages. Categorical features and relationships between groups were assessed using an appropriate chi-square test. Variables that were not normally distributed were compared using the Kruskal-Wallis test. When binary comparisons were required, the Mann-Whitney U test was used. Normally distributed variables were compared using a one-way analysis of variance test. When an overall significance was observed, pairwise post hoc tests were performed using Tukey's test. Levene test was used to assess the homogeneity of the variances. Whether there is a difference between the binary groups (such as groups formed according to MFF doses) in terms of numerical variables;

If parametric test conditions were fulfilled, independent groups were examined by t test and if not, Mann-Whitney U test was used. While investigating the associations between nonnormally distributed and/ or ordinal variables, the correlation coefficients and their significance were calculated using the Spearman test. The statistically significant two-tailed p value was considered as <0.05.

The tests were performed blindly by the only authorized microbiologist in the laboratory of our university. After the peripheral blood samples taken from the patient were centrifuged at 4000 rpm/ 10 min, the serums were stored at −80°C until the quantitative SARS-CoV-2 IgG test was run. Quantitative SARS-CoV-2 IgG test 

The study included 50 HD patients, 64 KTRs, and 41 HG. Forty-five patients were excluded due to antibody positivity in the serum samples obtained before vaccination or having exclusion criteria set in the study. All HD patients were undergoing HD three times a

week. All KTRs were receiving triple maintenance therapy with corticosteroids, tacrolimus, and mycophenolate mofetil (MMF). The median (IQR) age of the individuals was 54 (44.75-58), 47 (37-55.75), and 40 years (26.5-50.5) (p < 0.001), respectively, with a significant difference between KTR versus HG (p = 0.011) and HD versus HG (p < 0.001) were detected. There was no difference between the groups in terms of gender distribution (p = 0.056). There was no significant difference between the groups in terms of comorbid diseases such as diabetes mellitus, hypertension, atherosclerotic heart disease, and chronic obstructive pulmonary disease (p > 0.05). Other descriptive demographic characteristics and baseline laboratory results are summarized in Table 1 . The median (IQR) HD duration in HD patients was 37.5 (24-52.25) months and ranged from 13 to 133 months. In the KTR group, the median (IQR) time between the first vaccine and transplantation was 18.9 (10.7-34.0) months and ranged from 0.7 to 208.8 months (min-max). The rate of living kidney transplantation among KTRs was 86% (no = 55).

The antibody seroconversion rates after the first and second vaccination were compared between the groups. After the first vaccine dose, there was no significant increase in anti-spike IgG antibody levels between the groups (p = 0.440). However, after the second vaccine dose, in HD, KTR, and HG, respectively; 44%, 7.2%, and 58.5% higher anti-spike IgG antibody levels were detected (p < 0.001). The significant difference was due to transplant recipients and was not significant between HD patients and HG. Likewise, the seroconversion rates of anti-spiked IgG antibodies at the 3rd month after vaccination peaked, respectively; 86%, 23.4%, and 97.6% The relationship between antibody titer after the 2nd dose and age, body mass index (BMI), lymphocyte count, neutrophillymphocyte ratio, vitamin D dose, 3rd-month antibody titer, and 6th-month antibody levels were analyzed by Spearman correlation analysis; there was a significant positive correlation between the 3rd and 6th-month anti-spike antibody titers (p < 0.001) and negative correlation with age (p < 0.016). The relationship between the other parameters was not significant (Table 2 ). There was no significant correlation between transplantation time and anti-spike IgG antibody levels in the KTR group. vaccines has proven high efficacy in CKD and dialysis patients (>80%), but not in kidney recipients [22] [23] [24] However, the efficacy of the inactivated SARS-CoV-2 vaccine in different kidney diseases has not been fully elucidated. In a study on HD patients, the seroconversion rates (80%) and neutralizing antibody levels (median 39.8 BAU/ml) were significantly lower in patients who received inactivated vaccines, whereas mRNA vaccines had better immunogenicity.

However, both vaccines could be protected from symptomatic COVID-19 disease when seropositivity was achieved. 19 In another study, IgG antibody response after two doses of inactivated vaccine administered to HD and peritoneal dialysis patients was 88%,

whereas it was 100% in the healthy group. The results of whether antibody titers remained high after the 2-month period were not reported. 20 To the best of our knowledge, we have not found any study investigating the long-term antibody response of inactivated COVID-19 vaccine in patients undergoing RRT. In the present study, antibody response after two doses of CoronaVac was 97.6% in the healthy group and 86.0% in HD patients consistent with the literature.

In addition, we observed that the antibody seropositivity in the study population peaked at the 3rd month but decreased significantly from the 3rd month to the 6th month. Similarly, a study in the normal population showed that the initial antibody response from two doses of CoronaVac declined at or below the lower limit of seropositivity As an important observation; a significant antibody response was observed in 49% of cases when a third dose of vaccine was administered to kidney recipients without anti-Spike IgG antibody response after two doses of mRNA vaccine. 29 However, we need controlled studies investigating the efficacy of more than two inactivated COVID-19 vaccines, especially in kidney transplant patients.

In the present study, no irreversible CoronaVac adverse events were recorded among the participants. We found the most common side effects such as local pain at the injection site, fatigue, and headache. These results were found to be similar to the side effects seen in the normal population reported in the literature. 30, 31 In one small study; old age, high ferritin level, and low absolute lymphocyte count were independently associated with poor humoral immune responses after two doses of inactivated vaccine in HD patients compared with the healthy control group. 20 Age and serum creatinine elevation in KTRs has been reported as independent factors for vaccine unresponsiveness. 18 We detected a significant negative correlation with

age, but not with other factors. In logistic regression analysis, we did not find any predictive factor that affects poor antibody seroconversion after CoronaVac vaccination. We are of the opinion that randomized controlled and larger studies are needed on this subject.

The main strength of our study is the prospective design with the inclusion of different cohorts of kidney patients as well as a control cohort for a long time. The study also has some limitations. First, we included a relatively small number of patients and included different age groups, which could affect antibody titers between groups.

However, the ages of all the cases included in the study were under 60 years old. Second, all participants received the same inactivated vaccine, which prevented obtaining and comparing results regarding response to other types of vaccines. In fact, different vaccines are being investigated in the same normal population to increase their efficacy. 32 The issue of administering different vaccines to the same RRT patients has not yet been clarified. Third, we excluded patients who previously experienced COVID-19 to have a uniform, immunologically naïve patient group. However, we have not been able to learn the antibody responses we obtained, how much the post-vaccine antibody responses increased after suffering COVID-19 disease, and how long they lasted. As antibody responses were observed after COVID-19 in patients receiving RRT, we could not learn that higher seroconversion rates can be obtained after additional vaccination in these patients. Fourth, cellular immunity was not evaluated in the present study. However, assessment of cellular immunity is unlikely to be routinely available in all centers in the near future. Fifth, we included patients with HD and transplantation periods of at least 6 months. This calls for caution in extrapolating these outcomes to patients who received RRT less than 6 months ago.

In conclusion, the rate of anti-Spike antibody development was low in KTRs in the short and long term after vaccination. It was sufficient in HD patients and healthy individuals in the short term, whereas it was low in all groups in the long term; suggesting that KTRs require persistent isolation measures. These findings reinforce the need to discuss the vaccination strategy in immunocompromised populations, including the third dose with homologous or heterologous vaccines.

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The authors declare no conflicts of interest.

The data that support the findings of this study are available from the corresponding author upon reasonable request.