Evaluation of SARS-CoV-2 Serum Level in Patients Vaccinated With Sinopharm/BBIBP-CorV With Kidney Transplantation.

BACKGROUND: Every year, a large number of people undergo kidney transplants because of various reasons leading to renal failure. These patients usually have low immunoglobulin levels due to the use of immunosuppressive drugs. In recent years, the COVID-19 pandemic has been a major global health risk. Patients who are immunocompromised or who have diabetes are especially at risk.
METHODS: In this study, we enrolled 156 patients who had undergone kidney transplant and had received 2 doses of Sinopharm/BIBP-CorV. The serum antibody levels against COVID-19 spike glycoprotein (immunoglobulin [Ig] G and IgM) were measured using a sandwich enzyme-linked immunosorbent assay kit to evaluate whether different immunosuppressive drugs could affect the body's response to the said vaccine.
RESULTS: We found that only patients receiving Rapamune had increased IgM secondary to COVID-19 vaccine. None of the immunosuppressive drugs in this study have shown a positive correlation with increased IgG levels. The only factor that showed a significant effect on both IgM and IgG was a positive history of COVID-19, which was correlated with increased levels of serum IgG/M.
CONCLUSIONS: Only patients treated with Rapamune showed an acute immune reaction to the vaccine in the form of positive serum IgM levels, and no rise of serum IgM antibody was observed in COVID-19-naive patients. Patients who had a previous history of COVID-19 infection showed an elevated serum IgM and IgG level, suggesting that vaccines in general and Sinopharm/BIBP-CorV in particular are not enough to ensure immunity against COVID-19 in transplant recipients. We recommend further studies using different types of vaccines and immunosuppressive drugs.

Introduction

Coronavirus disease 2019 (COVID-19) was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In 2020 COVID-19 was declared a pandemic by the World Health Organization. Vaccination against COVID-19 is one of the known ways to prevent severe forms of the disease (1, 2).

The only permanent treatment for End Stage Renal Disease (ESRD) patients is kidney transplantation. Since, the transplanted kidney is technically considered a foreign object by the body, inflammatory and immune response could be triggered by this alien tissue. Therefore, the use of various immunosuppressive drugs must be used to prevent acute rejection of such bonds (3-6).

Due to kidney transplant patients having a high risk of developing a severe form of the disease, SARS-CoV-2 vaccination is a must to prevent COVID-19 infection. As noted before these patients are immunosuppressed and thus should be given priority for vaccination. However, the innate immune response by the body to the vaccine is somewhat subdued because of the said immunosuppressive drugs(7, 8). Making the immunocompromised patients uniquely susceptible to COVID-19 infection, even if they have received prior vaccination. These patients are also at a higher risk of death and have poorer prognosis(9-11).

Studies have demonstrated that patients treated with costimulation blockade have lower immune responses after vaccination compared to other patients. Other risk factors for decreased immune response include the time passed since transplantation and lymphocyte-depleting induction therapy (12, 13).

One way to strengthen the immune response in these patients is to use an additional dose of vaccination (14). BIBP-CorV is an inactivated vaccine developed at Sinopharm's Beijing Institute in China (15). According to a study by Mijanur Rahman et al. In February 2022, 2 doses of this vaccine can be up to 78.1% effective against Delta variant (16).

There have been many studies on mRNA vaccines and their effects on lowering immunoglobulin levels in transplanted kidneys (17-19), but few studies have been performed on inactivated COVID-19 vaccines. In addition, due to the serious need for immunosuppressive drugs by patients receiving kidney transplants and the consequent susceptibility of these individuals to various infections, our aim was to evaluate the immune response and coronavirus antibody production in kidney transplant recipients and to evaluate the factors associated with reduced immunogenicity. And since immunocompromised patients are a group of high-risk individuals for many different diseases, it is vital to study and evaluate the response to vaccines and whether different treatment options could affect such response. As a consequence of the difference in genetics of our patients and the type of vaccination received from other countries, the difference in the amount of antibodies produced using different immunosuppressive drugs was examined and analyzed for the first time.

Materials and Methods

The present study is a cross-sectional study that was performed from April 2021 to January 2022 that was approved by the Tehran university of medical sciences committee of ethics (IR.TUMS.SINAHOSPITAL.REC.1400.100). Of the 1152 patients who underwent kidney transplants at Sina Hospital in Tehran, Iran, 156 patients agreed to participate in the study, signed a written informed consent, and returned for a visit of minimum 2 weeks and a maximum 6 weeks after the second dose of the vaccine(20). All of the patients had received two doses of Sinopharm/BIBP-CorV. Information on comorbid conditions and the drugs used, was collected in their medical records. Patient history was taken to determine the cause of their ESRD. Blood samples were measured for evaluation of anti-SARS-CoV-2 spike glycoprotein antibodies and immunoglobulin G or M (IgG, IgM), 2 weeks after vaccination. Patients are excluded from the study if there is no informed consent and if there isn't complete information of the patient for analysis.

5 cc of patients' blood was taken in the laboratory to test for SARS-CoV-2 spike glycoprotein antibody. To detect the subjects' serum antibodies to the SARS-CoV-2 spike glycoprotein (IgM and IgG) levels, a sandwich ELISA kit (Pishtaz Teb, Iran; lot numbers 99006 [IgM] and 99012 [IgG]) was utilized. To detect IgM, a volume of 100 μL of diluted serum (1:100) was applied to a 96-well microplate (coated with N protein). To detect IgG, the dilution factor was adjusted (1:20), and the cut-off value was changed (OD of the blank well + 0.15).

Statistical analysis was performed using SPSS 24.0 (Statistical Package for Social Science 24 for Windows). Continuous variables were described as mean with standard deviation or median with respect to data distribution. The distribution of parameters was evaluated using the Kolmogorov-Smirnov test. The groups were analyzed using independent t-test or Mann-Whitney U test. Classified variables were described as frequencies and percentages and analyzed by Fisher's Exact test. The two variables of antibody titer with other variables were tested by calculating Spearman coefficient. p <0.05 was considered statistically significant for all analyzes.

Results

A total of 156 vaccinated patients were included in the study. The median age of patients was 50 years. 41 patients were over 60 years old. Among the patients, 67% were male and the rest were female. There were several reasons for kidney transplantation, of which hypertension was the most common (32%), followed by diabetes mellitus and urological complications, respectively. The median time between the patients’ transplant and our study was 8 years. 89 (57%) of the kidneys were donated from patients with cadaver and 35% of the patients had a history of transplantation rejection and the need for a re-transplant. For 31% of patients, an increase in creatinine was reported after kidney transplantation. Regarding the patients' underlying disease, hypertension had the highest prevalence (53%) followed by diabetes (25%), CMV infection (10%) and stroke (3%). Surprisingly, all of the drugs we studied were insignificantly correlated with serum IgG levels. However, the drug Sirolimus (Rapamune®) had a significant correlation with serum IgM levels, showing how this drug could increase the odds of the patient having positive serum IgM levels after COVID-19 vaccination (odds ratio=4.00, P=0.043). A positive history of COVID-19 was significantly correlated with a high antibody titer. It was significantly correlated with an increased probability of positive serum IgM (OR=4.00, P=0.020) and IgG titer (OR=2.57, P=0.016) (Table 1 , 2 ). With Sinopharm/BIBP-CorV efficacy being around 80%(21), most of our patients showed a lower antibody titer than expected. We also found the dosage of drugs to be of no consequence in whether or not the patient develops antibodies. As such we chose not to include their data.

Table 1

Demographic and Clinical Characteristics between Kidney Transplant IgM antibody statuses

		Total n=156	IgM antibody status		P-value
			Positive n=12(8%)	Negative.n=144(92%)
Baseline characteristics
Median Age [IQR], Years		50(39,60)	45(38,58)	51(39,60)	0.456
Age ≥ 60 years, n (%)		41(26%)	2(17%)	39(27%)	0.431
Men, n (%)		105(67%)	9(75%)	96(67%)	0.554
Median BMI [IQR], Kg/m2		26(23,29)	26(25,29)	26(23,29)	0.860
Causes of KT, n (%)	HBP	50(32%)	2(17%)	48(33%)	0.066
	DM/HBP	17(11%)	4(33%)	13(9%)
	Urology	24(15%)	2(17%)	22(15%)
	Other	65(42%)	4(33%)	61(42%)
Median time after KT[IQR], Years		8(4,13)	7(4,15)	8(4,13)	0.902
Cadaver graft, n (%)		89(57%)	8(67%)	81(56%)	0.484
Re-Transplant, n (%)		16(10%)	1(8%)	15(10%)	0.819
Rejection transplantation, n (%)		54(35%)	5(42%)	49(34%)	0.593
Creatinine increasing, n (%)		48(31%)	4(33%)	44(31%)	0.841
Hypertension, n (%)		83(53%)	7(58%)	76(53%)	0.711
Cardiovascular disease, n (%)		16(10%)	0(0%)	16(11%)	0.223
Diabetes, n (%)		39(25%)	4(33%)	35(24%)	0.488
Stroke, n (%)		5(3%)	0(0%)	5(3%)	0.999
Kidney problem, n (%)		82(53%)	8(67%)	74(51%)	0.309
CMV infection, n (%)		15(10%)	2(17%)	13(9%)	0.388
Drug treatment
Cellcept (mycophenolate mofetil), n (%)		101(65%)	6(50%)	95(66%)	0.266
Tacrolimus, n (%)		63(40%)	3(25%)	60(42%)	0.258
Azathioprine, n (%)		21(13%)	1(8%)	20(14%)	0.588
Sirolimus (Rapamune), n (%)		14(9%)	3(25%)	11(8%)	0.043
Prednisolone, n (%)		148(95%)	12(100%)	136(94%)	0.402
Cyclosporine, n (%)		85(55%)	6(50%)	79(55%)	0.745
History of Covid, n (%)		68(44%)	9(75%)	59(41%)	0.020

P-values were calculated based on Mann–Whitney U, Chi-Square tests, Fisher's Exact Test or Monte Carlo method.

Table 2

Demographic and Clinical Characteristics between Kidney Transplant IgG antibody status.

		Total n=156	IgG antibody status		P-value
			Positive n=34(22%)	Negative n=122(78%)
Baseline characteristics
Median Age [IQR], Years		50(39,60)	51(40,61)	49(38,60)	0.475
Age ≥ 60 years, n (%)		41(26%)	9(27%)	32(26%)	0.977
Men, n (%)		105(67%)	26(77%)	79(65%)	0.198
Median BMI [IQR], Kg/m2		26(23,29)	26(24,29)	26(23,30)	0.746
Causes of KT, n (%)	HBP	50(32%)	6(18%)	44(36%)	0.076
	DM/HBP	17(11%)	7(21%)	10(8%)
	Urology	24(15%)	5(15%)	19(16%)
	Other	65(42%)	16(47%)	49(40%)
Median time after KT[IQR], Years		8(4,13)	7(4,11)	8(4,14)	0.647
Cadaver graft, n (%)		89(57%)	21(62%)	68(56%)	0.530
Re-Transplant, n (%)		16(10%)	1(3%)	15(12%)	0.112
Rejection transplantation, n (%)		54(35%)	11(32%)	43(35%)	0.754
Creatinine increasing, n (%)		48(31%)	10(29%)	38(31%)	0.846
Hypertension, n (%)		83(53%)	15(44%)	68(56%)	0.230
Cardiovascular disease, n (%)		16(10%)	3(9%)	13(11%)	0.755
Diabetes, n (%)		39(25%)	11(32%)	28(23%)	0.263
Stroke, n (%)		5(3%)	1(3%)	4(3%)	0.999
Kidney problem, n (%)		82(53%)	22(65%)	60(49%)	0.109
CMV infection, n (%)		15(10%)	6(18%)	9(7%)	0.072
Drug treatment
Cellcept (mycophenolate mofetil), n(%)		101(65%)	24(71%)	77(63%)	0.420
Tacrolimus, n (%)		63(40%)	11(32%)	52(43%)	0.280
Azathioprine, n (%)		21(13%)	3(9%)	18(15%)	0.370
Sirolimus (Rapamune), n (%)		14(9%)	4(12%)	10(8%)	0.520
Prednisolone, n (%)		148(95%)	31(91%)	117(96%)	0.269
Cyclosporin, n (%)		85(55%)	19(56%)	66(54%)	0.853
History of Covid, n (%)		68(44%)	21(62%)	47(39%)	0.016

P-values were calculated based on Mann–Whitney U, Chi-Square tests, Fisher's Exact Test or Monte Carlo method.

Discussion

COVID-19 pandemic is, at the time of the publication, ravaging the world. Because of the immunosuppressed situation of the posttransplant patients, they are at a unique risk of different diseases. In the setting of COVID-19 pandemic, these problems are multiplied and the transplant patients are at a very high risk of COVID-19. A very important piece of the COVID-19 immune response puzzle is the production of IgM and IgG antibodies. And the levels of serum IgG and IgM are good indications of vaccine efficacy and immunization (22-24). These antibodies could also be used to assess previous or acute infections with COVID-19 virus.

However as stated before, the immunosuppressed patients, have subdued or even completely suppressed immunogenicity and have significantly lower levels of serum immunoglobulins after receiving one or even two doses of COVID-19 vaccination, irrespective to the type of vaccine used (25, 26). With Sinopharm/BIBP-CorV being around 80% effective, our patients showing a lower-than-expected titer of antibody was also expected. Our data too, reflects this reduced immunogenicity. We also analyzed whether the different immunosuppressive drugs, comorbidities or a history of previous COVID-19 infection could change this serum immunoglobulin level.

In our study we found that among drugs used to suppress the immune system in kidney transplant patients such as Cellcept, Tacrolimus, Azathioprine, etc. the only one that seems to still allow the patient to develop humoral immunity against COVID-19 and we still see immune response in the form of IgM formation against COVID-19, was Sirolimus (also known as Rapamune®). Other studies have also been done on Rapamune's effects on COVID-19 vaccination. It's been hypothesized by Zurlo et. al, based on Rapamune's effect on the influenza vaccine, that it could help bolster the effects of COVID-19 vaccination Patients receiving Sirolimus had an odds ratio of positive serum IgM levels of 4. Which is comparable to the patient having a positive history of previous COVID-19 infection (OR=4.00). This has also been hypothesized before by other studies. Zurlo et. al. has hypothesized based on the effect of Rapamune on flu vaccine, that it could help bolster the effects of COVID-19 vaccination(27). Bischoff et. al. has also shown how Rapamycin and other mTOR inhibitors could help prevent a COVID-19 infection and or improve the mortality and morbidity of the disease (28). However, this finding was isolated to IgM and such finding could not be applicable to IgG levels. Meaning that Sirolimus mostly suppresses the long-term immunogenicity and not the acute response unit of the immune system. This finding is in line with many other studies, showing drugs such as tacrolimus(29), mycophenolate mofetil (CellCept)(30), Azathioprine(31), etc. to be correlated with a negative seroconversion. The only factor that was found to both affect the IgG and IgM production in our patients was, unsurprisingly, a positive history of previous COVID-19 infection. Meaning that no immunosuppressive therapy completely shuts down the immune system, as they shouldn't. Due to the wide distribution of vaccines in recent months in Iran and the third dose of vaccination, the need to study the level of Ig with 3 doses of vaccine is also felt.

The limitations in this study could be the heterogeneity in Iranian genetics and the sandwich ELISA kits being inaccurate. If the results seem inconclusive, we suggest redoing the tests with more accurate ELISA kits. We didn't have a baseline for serum antibody level of the patients, and many of them could have contracted COVID-19 infection and just not show any significant symptoms for the infection to be diagnosed. These patients could show a heightened serum Ig level. This study began when the delta variant was most prevalent. But by the end of 2021, with the spread of the new omicron variant, and the coincidence of the omicron outbreak and this study, Ig level may have different reaction to different variants of COVID-19. Another limitation in this study has been the rather narrow view on the vaccine used. We studied only the effect of Sinopharm/BIBP-CorV. In our patients, vaccines sorted by the number of injected doses are: Sinopharm (BIBP-CorV), Oxford – AstraZeneca (AZD1222), Sputnik V (Gam-COVID-Vac), Covexin (BBV152). It should be noted that BIBP-CorV vaccine has been injected more than twice the total of all other vaccines. Making Sinopharm/BIBP-CorV by far the most used vaccine. Therefore, our study has been solely focused on Sinopharm/BIBP-CorV. while other vaccines may have higher or lower efficacy and immunogenicity. Sinopharm/BIBP-CorV is an inactivated virus vaccine and this may impact the result with mRNA vaccines showing different results. We suggest this study be redone with patients who had received different vaccines.

Disclosure

Ethics approval and consent to participate

The study was run under the Tehran University of Medical Sciences ethical committee (IR.TUMS.SINAHOSPITAL.REC.1400.100). All patients signed the written informed consent. All the methods were in accordance with the relevant institutional or in accordance with the declaration of Helsinki.

Consent for publication

Written informed consent was obtained from patients. Written formal consent ensures that the publisher has the author's permission to publish research findings.

Availability of data and materials

The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

Author Contributions Statement

SMKA and MR are the principal investigator, RK, MGH edited the manuscript, HS, PGH and MN wrote the manuscript, SD provide data, MAP analyses the data.

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