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Table of Contents
ORIGINAL ARTICLE
Year : 2022  |  Volume : 16  |  Issue : 4  |  Page : 397-404

Human leukocyte antigen association with anti-SARS-CoV-2 spike protein antibody seroconversion in renal allograft recipients - An observational study


Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Submission26-Feb-2022
Date of Acceptance06-Sep-2022
Date of Web Publication30-Dec-2022

Correspondence Address:
Prof. Narayan Prasad
Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_28_22

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  Abstract 


Cellular and humoral responses are required for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) eradication. Antigen-presenting cells load SARS-CoV-2 peptides on human leukocyte antigen (HLA) with different avidities and present to T- and B-cells for imposing humoral and cellular responses. Due to immunosuppression, renal transplant recipient (RTR) patients are speculated to poorly form the antibody against the SARS-CoV-2. Therefore, determining the association of specific HLA alleles with anti-SARS-CoV-2 spike protein antibody formation will be helpful in managing the RTR having specific HLA alleles from SARS-CoV-2 infection and vaccination. Materials and Methods: In this study, anti-SARS-CoV-2 spike protein antibody in 161 RTRs was determined by the chemiluminescent microparticle immunoassay methods, and HLA alleles were determined by the polymerase chain reaction-single-strand oligonucleotide methods and analyzed to study the HLA allele association with anti-SARS-CoV-2 spike protein-specific humoral response and severity of COVID-19 symptoms in recently SARS-CoV-2-infected RTRs. Results: The anti-SARS-CoV-2 spike protein specific antibody seroconversion rate in RTRs was 90.06% with a median titer of 751.80 AU/ml. The HLA class I alleles, A*11 in 22.1%, A*24 in 21.37%, A*33 in 20.68%, HLA B*15 in 11%, B*07 in 8.27%, HLA-C*30 in 20.93%, C*70 in 23.25% and HLA Class II alleles, DRB1*07 in 18.62%, DRB1*04 in 13.8%, HLA-DRB1*10 in 14.48%, HLA-DQA1*50 in 32.55% of RTRs were associated with the seroconversion. The mean SARS-CoV-2 clearance time was 18.25 ± 8.14 days. Conclusions: RTRs with SARS-CoV-2 infection developed a robust seroconversion rate of 90.0% and different alleles of HLA-B, DRB1, and DQA1 were significantly associated with the seroconversion.

Keywords: Anti- SARS-CoV-2 antibody, Human Leucocyte antigen, home quarantine, Seroconversion


How to cite this article:
Yadav B, Prasad N, Yadav D, Singh A, Gautam S, Kushwaha R, Patel MR, Bhadauria D, Behera MR, Yachha M, Kaul A. Human leukocyte antigen association with anti-SARS-CoV-2 spike protein antibody seroconversion in renal allograft recipients - An observational study. Indian J Transplant 2022;16:397-404

How to cite this URL:
Yadav B, Prasad N, Yadav D, Singh A, Gautam S, Kushwaha R, Patel MR, Bhadauria D, Behera MR, Yachha M, Kaul A. Human leukocyte antigen association with anti-SARS-CoV-2 spike protein antibody seroconversion in renal allograft recipients - An observational study. Indian J Transplant [serial online] 2022 [cited 2023 Feb 8];16:397-404. Available from: https://www.ijtonline.in/text.asp?2022/16/4/397/364617




  Introduction Top


Human leukocyte antigens (HLAs) are highly polymorphic molecules expressed on all nucleated cells, required for imposing immunogenic response against the microbial infection and differentiation of self from nonself-components.[1] As HLA molecules are highly polymorphic, each individual has a unique set of these molecules. Broadly, there are two major classes of HLA. HLA classes I and II. HLA-I comprises A, B, and C, expressed by all the nucleated cells, adopted for presenting intracellular pathogens to cytotoxic CD8+ T-cells. HLA class II comprises to DP, DQ, DR, are expressed by the professional antigen-presenting cell and adopted for presenting extracellular antigen to CD4+ T-cell for the effector and memory immunogenic response.[2]

During viral infections, both innate and adaptive immune cells contribute to an effective immune response for viral clearance.[3] Natural killer (NK) cells can respond quickly to eliminate pathogens and infected cells and suppress dissemination to other tissues. Subsequently, activation of virus-specific CD8+ cytotoxic T-cells results in the specific killing of infected cells, and activation of virus-specific CD4+ T-cells further supports the immune response. HLAs play an essential role in the activation of both NK and T-cells.[3] In the recent COVID-19 pandemic, there was remarked variability in triggering immunogenic response against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.[4],[5] Even after anti-SARS-CoV-2 vaccination, people from different ethnicities responded differently to vaccines, suggesting the association of genetic factors with COVID-19.[6],[7],[8] One of the factors for this variability may be the polymorphism of HLA-alleles. Other than the virulence of the organisms, the varied host response may be because of the different intensity of humoral and cellular immunogenic responses, which depends primarily on the binding affinity of HLA with SARS-CoV-2 peptides.[9],[10] A stronger interaction of virus antigen peptide and HLA may impose a greater cellular response, leading to the formation of anti-SARS-CoV-2 antigen specific antibody and responses to the virus, thus may alter the disease outcome and transmission.[11],[12] The binding affinity of different HLA alleles also varies remarkably for the different HLA alleles, suggesting the genetic susceptibility of an individual holding specific set of alleles for SARS-CoV-2 infection and seroconversion.[13] Studies from different ethnicities have shown a link of HLA with SARS-CoV-2 infection susceptibility.[14],[15],[16] It is evident that ethnic variability in the composition of specific HLA allele set may affect the genetic susceptibility of the individual for acquiring viral infection. Allele HLA-B*4601 is associated with severe SARS-CoV-2 infection in Taiwanese,[14] B*27:07, DRB1*15:01, and DQB1*06:02 in Italian,[15] and HLA-A*11, C*01, and DQB1*04 in the Spanish population.[16] Furthermore, the immunogenicity response in renal transplant recipients (RTRs) remains compromised due to immunosuppressive drugs used by the patients to prevent allograft rejection. Therefore, an adequate humoral response to anti-SARS-CoV-2 infection is less likely to develop,[17] which is ratified by the data emerging from the Western countries.[6],[7],[18] There is lack of data on the seroconversion rate in RTRs who acquired SARS-CoV-2 infection and its association with HLA from this part of the world.

Therefore, in the current study, we aimed to determine the association of specific HLA alleles with anti-SARS-CoV-2 spike protein seroconversion in RTRs, who had at least one episode of reverse transcription polymerase chain reaction (RT-PCR)-confirmed SARS-CoV-2 infection within 6 months.


  Materials and Methods Top


Patient recruitment and blood sample collection

A total of 161 RTRs who developed RT-PCR-confirmed SARS-CoV-2 infection, live-related transplantation, <18 years of age were included in the study. The patients with prior 6-month history and within 2 weeks of SARS-CoV-2 infection, deceased associated transplantation, and history of any dose of vaccination were excluded. The demographic profiles and clinical characteristics of the patients were recorded. Patients were categorized as mild, moderate, and severe as per the Revised Guidelines on Clinical Management of COVID-19, Ministry of Health and Family Welfare, the Government of India.[19] The disease was classified as mild when symptoms were present without features of viral pneumonia on imaging (X-ray chest or high-resolution computed tomography [HRCT] scans), moderate if manifestation were present, while severe disease refers to the presence of hypoxia with respiratory rate >30 breaths/min, severe respiratory distress, and SpO2 <90% on room air including acute respiratory distress syndrome. Based on the need for hospitalization, patients were categorized as home quarantine (HQ) or hospitalization (HSP).

Patients were further categorized into two groups with and without seroconversion. Seroconversion was defined as when a patient had anti-SARS-CoV-2 spike antibody (IgG) titer >50 AU/ml, and those who had anti-SARS-CoV-2 spike protein IgG titer <50 AU/ml were considered negative seroconversion. An IgG titer cutoff value ≥50 AU/ml was reported to neutralize the SARS-CoV-2 infection in VERO cell lines in in vitro assay.[20] A 5 ml blood sample in K2EDTA vials was collected for the plasma separation and anti-SARS-CoV-2 titer measurement from the patients visiting the Routine Transplant Outpatient Department of Nephrology, SGPGIMS, Lucknow, India, between June 1 and July 31, 2021.

Anti-severe acute respiratory syndrome coronavirus 2 spike protein antibody titer determination

K2EDTA blood was centrifuged at 2000 RPM for 10 min, and plasma was collected. Plasma was stored at −20°C till analysis. All the samples were analyzed within a month after collection. Anti-SARS-CoV-2 spike protein antibody titer was measured by a commercially available platform based on chemiluminescent microparticle immunoassay methods.

HLA profiling

HLA allele profiles of HLA classes I and II were retrospectively collected from the patient's electronic medical record details of the hospital information system of the Institute. All HLA allele profiles were determined by the PCR-single-strand oligonucleotide methods using LIFECODES HLA Typing Kits (Immucor, Diagnostic, USA) on the Xponent Luminex technology platform. All samples were typed at the allele group level.

Statistical analysis

Variables were analyzed using IBM® SPSS® software platform SPSS20 version (IBM, corporation, Armonk, NY, USA). Continuous variables were expressed as mean with standard deviation. An independent sample t-test was used to compare the mean values between the groups. The categorical variables were expressed in terms of numbers and percentages. The Chi-square test and Fisher's exact test were applied to compare the categorical values as per the application required. The association of seroconversion and COVID-19 severity with the HLA alleles was analyzed. Graphs were plotted with GraphPad 8.0 software. P < 0.05 was considered statistically significant.

Declaration of patient consent

The patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that the names and initials would not be published, and all standard protocols will be followed to conceal their identity.

Ethics statement

This study is approved by the institutional Ethics committee. IEC code: 2021- 229-IP-EXP-42. The study was performed according to the guidelines in Declaration of Helsinki.


  Results Top


Demographic and clinical characteristics of patients

Baseline clinical characteristics of patients were similar in both the seroconversion and nonseroconversion groups, except for tacrolimus level and post-COVID-19 recovery time, which were significantly higher in the nonseroconversion group. The estimated glomerular filtration rate was tended to be lower in the nonseroconversion group [Table 1]. Out of 161 SARS-CoV-2-infected patients, 145 (90.0%) developed anti-SARS-CoV-2 spike protein IgG antibody. The median titer in the IgG seroconversion group was (median, 751.80 AU/ml, 95% confidence interval [CI], 1347.71-2221.37) compared to the nonseroconversion group (median, 16.20 AU/ml, 95% CI, 9.47-23.70; P = 0.001) [Figure 1]a.
Table 1: Baseline demographic and clinical characteristics of patients

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Figure 1: (a) Anti-SARS-CoV-2 spike protein antibody titer in the seroconversion and nonseroconversion groups. (b) Antibody titer in patients with home quarantine (mild COVID-19 symptoms) and hospitalized (severe COVID-19 symptoms). SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2

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Association of class I HLA antigen alleles with seroconversion rate

Overall, there was no statistically significant difference between the seroconversion and nonseroconversion groups for HLA-A alleles (P = 0.058). However, HLA-A*11 alleles were associated with seroconversion in 22.1%, A*24 in 21.37%, A*33 in 20.68%, and A*68 in 8.27% of patients. HLA-B1 allele was significantly associated with seroconversion rate compared to the nonseroconversion group (P < 0.001). HLA-B alleles B*35 and B*40 were associated with seroconversion in 21.37% and 20% of patients, respectively, following B*15 in 11%, B*07 in 8.27%, B*27 in 6.9%, B*37, and B*44 in 4.13% of patients. In contrast, HLA-B*04, B*52, and B*55 were significantly associated with nonseroconversion in 18.75%, 12.5%, and 6.25% of patients, respectively (P < 0.05). HLA-C*30 in 20.93% and C*70 in 23.25% of RTRs were observed in seroconversion group, while HLA-C*07, C*12, and C*30 in 16.6% of patients and C*60 in 33.3% of RTRs were associated with nonseroconversion [Table 2].
Table 2: Association of human leukocyte antigen alleles with seroconversion in severe acute respiratory syndrome coronavirus 2-infected patients

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Association of class II HLA alleles with seroconversion rate

HLA class II, DRB1, and DQA1 alleles were significantly associated with seroconversion (P < 0.05). HLA-DRB1*07 was associated in 18.62%, HLA-DRB1*04 in 13.8%, HLA-DRB1*10 in 14.48%, and HLA-DRB1*13 in 8.27% of patients with seroconversion. HLA-DRB1*01 and HLA-DRB1*03 in 12.5% and DRB1*70 in 6.25% of patients were associated with nonseroconversion. Similarly, HLA-DQA1*50 was associated with seroconversion in 32.55%, and HLA-DQA1*02 and DQA1*30 were associated with nonseroconversion in 14.2% and 42.8% of patients [Table 3].
Table 3: Association of human leukocyte antigen alleles with seroconversion in severe acute respiratory syndrome coronavirus 2-infected patients

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Association of HLA classes I and II with the severity of COVID-19

Out of 161 patients, 30 (18.63%) patients had severe COVID-19 and were hospitalized. Overall, there was no statistically significant difference of the HLA association between corona severity and nonseverity based on hospitalization. However, some alleles like A*24 in 24.42% were associated with HQ and HLA alleles A*11 in 37.5%, A*30 in 18.75%, and A*20, A*26, A*68 in 12.5% of patients were associated with HSP. Alleles HLA-C*60 in 16.6% and C*40 in 11.1% of patients were associated with HQ, and HLA-C*70 in 38.46% of patients was associated with hospitalization. HLA-DRB1*04 and DRB1*15 were associated with HQ in 15.26% and 8.3% of patients, respectively. HLA DRB1 alleles DRB1*10 and DRB1*11 were associated with severe COVID-19 and HSP in 23.33% and 16.66% of patients, respectively. The HLA alleles DQA1*60 in 13.15% of RTRs were associated with HQ, while HLA-DQA1*20 in 33.3% and DQA1*50 in 25% of RTRs were associated with HSP [Table 4] and [Table 5]. Hospitalized patients had moderate-to-severe COVID-19 and recovered completely. The anti-SARS-CoV-2 spike antibody titer was not different between mild-to-moderate and severe groups of COVID-19 [Figure 1]b.
Table 4: Association of human leukocyte antigen alleles with the severity of COVID-19 disease

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Table 5: Association of human leukocyte antigen class II alleles with the severity of COVID-19 disease

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  Discussion Top


There are marked variability in SARS-CoV-2 infection, severity of COVID-19 outcome, and seroconversion after vaccination, across the different ethnicities around the world. It has been observed that genetic factors (HLAs) are the main determinant for the virus infection and clearances even in other viral infections.[21],[22] Although, none of the HLA alleles is specifically associated with the susceptibility for SARS-CoV-2 infection and eradication. SARS-CoV-2 enters to cells through the ACE-2 receptors. A few studies have shown ACE and HLA gene polymorphism may be a genetic determinant for infection, severity of COVID-19, and its outcome.[14],[15],[23] Although, there is high variability in HLA allele frequencies across the different ethnicity worldwide.[14],[15] It has been seen that the anti-SARS-CoV-2 neutralizing antibody is important for the clearance of the virus and reducing the risk of disease severity and mortality.[11],[24] Therefore, vaccination becomes a main drive for active antibody formation for protection from subsequent SARS-CoV-2 infection. Antibody formation requires activation of the adoptive response which is primarily determined by the SARS-CoV-2 peptide presentation to T- and B-cells through the HLA. Different HLA alleles bind to viral peptides differentially and impose cellular responses differently.[12] Thus, the presence of certain alleles may determine the overall outcome of COVID-19.

In this study, we have found an association of different HLA alleles HLA-A*11, A*24, A*33, A*68, B*15, B*40, B*35, C*30, C*70, DRB1*04, DRB1*07, DRB1*10, and DQA1*50 with the higher seroconversion rate in SARS-CoV-2 infected in RTR patients [Figure 2]. While HLA-B*04, B*52, and B*55 were significantly associated with nonseroconversion. HLA-A*46 and B*54 have been linked with severe SARS-CoV-2 infection in the Taiwanese population,[17] although these alleles were absent in our cohort of RTRs with COVID-19. In the Italian population, DRB1*15:01, DQB1*06:02, and B*27:07 alleles were associated with severe COVID-19.[15] However, in our cohort, we found that HLA-DRB1*15 was similar in both the seroconversion and nonconversion groups of patients, and the majority of the patients were HQ in the Indian population having mild symptoms. DRB1*01 and DRB1*03 were associated with nonseroconversion in 12.5% of patients, and these patients had mild COVID-19 and were in HQ. DRB1*01 alleles were negatively associated with COVID-19-related fatality in the Mexican population.[25] However, in our population, DRB1*01 was associated with seroconversion in 12.5% of patients and associated with 6.87% of patients with mild COVID-19 symptoms.[25] These results suggest that seroconversion is important for recovery and prevention from the hospitalization. We have also observed that severe COVID-19 patients had a slightly lower antibody titer and had taken a longer duration in recovery from COVID-19. More importantly, HLA-B*04, B*52, and B*55 were significantly associated with nonseroconversion in 18.75%, 12.5%, and 6.25% of patients, respectively.
Figure 2: Algorithm of the study

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Moreover, RTRs have poor immunity because of immunosuppression and remain highly susceptible to acquiring an infection and mortality.[26] Studies from the Western countries show a poor seroconversion rate after vaccination and SARS-CoV-2 infection among RTRs even after the third dose of vaccination as compared to the general population.[27],[28] Although, they did not study the HLA association with seroconversion. We have also observed a relatively longer viral clearance time (18.25 ± 8.14 days) in RTRs than in the general population with COVID-19 (7-17 days).[29] All patients in our cohort were on triple immunosuppression calcineurin inhibitor, mycophenolate mofetil, and prednisolone. The nonseroconversion group had a slightly higher tacrolimus level. MMF and tacrolimus drastically inhibit antibody formation, as reported in Western renal transplant patients.[6] Further, the short half-life of the antibody remains another challenge for the protection from the subsequent infection.[9],[30] In our study, we found a 90.06% seroconversion rate in patients having IgG titer > 50 AU/ml, which was similar to the seroconversion rate in other renal transplant studies.[31],[32] Although, antibody titer and cutoff values of antibody vary significantly in different studies,[31],[33] and there is no defined threshold antibody titer to predict protection from COVID-19. The median titer in our study was 751.80 AU/ml.

For the antibody generation, the viral peptide binds to the HLA pocket for the presentation to T- and B-cells for inducing an adoptive cellular response. However, the presence of certain amino acids in the binding pocket of HLA dramatically affects the SARS-CoV-2 peptide and HLA interaction, thus affecting the potency of the cellular immune response.[12],[14] Both in vivo and in silico studies have shown that HLA-B*46:01 and HLA-B*54:01 had fewer SARS-CoV-2 binding sites, leading to poor immune response generation, resulting in poor SARS-CoV-2 clearance, in contrast to HLA-B*15:03 mounting a strong immune response and more SARS-CoV-2 clearance.[14],[34] Although, in our population, HLA-B*46 and B*54 alleles were absent, and HLA-B*15 was associated with seroconversion in 5.3% of patients and also associated with mild COVID-19 symptoms.

Limitation of the study

Although, we have retrospectively analyzed the HLA alleles, which is of low resolution up to allele level. A high-resolution HLA allele (up to peptide and amino acid level) frequency determination will be required to exactly conclude the role of HLA in seroconversion in these groups of patients.


  Conclusions Top


RTRs with recent SARS-CoV-2 infection show a 90.06% seroconversion rate with a median titer of 751.80 AU/ml. HLA-B*15 in 11%, DRB1*07 in 18.62%, and DQA1*50 in 32.55% of RTRs were associated with seroconversion. The mean SARS-CoV-2 clearance time was 18.25 ± 8.14 days.

Acknowledgment

Brijesh Yadav acknowledges the Young Scientist Research Grant (Grant No: YSS/2020/000202/PRCYSS) support of the Department of Health Research, New Delhi, India.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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Abstract
Introduction
Materials and Me...
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