Key words : Coronavirus disease 2019, Immunoglobulin G antibody, Severe acute respiratory syndrome coronavirus 2

Introduction

The COVID-19 pandemic has led to unexpected effects on health care systems particularly for fields such as solid-organ transplant (SOT).¹ At the beginning of the pandemic, transplant operations were suspended and performed almost only for life-saving situations. Mortality rates of 13% to over 30% were reported among SOT recipients.² These high rates necessitated meticulous follow-up both in the pretransplant period, ie, donor and recipient screening, and thereafter, ie, prevention and management of COVID-19. Solid-organ transplant recipients have a higher risk for COVID-19 because of chronic immunosuppressive treatment and other medical comorbidities.

Vaccination is a main method of treatment against COVID-19 along with nonpharmacological inter-ventions. Most vaccine trials have not included SOT patients in phase 2 or phase 3 studies. Also, there have been only a few records of real-world experiences of SOT recipients with these vaccines.³ Although mRNA-based vaccines are highly effective; the immune response is expected to be lower among immunocompromised patients including SOT recipients. The immune responses and the vaccination schedules for SOT recipients were reported via observational studies.^4-8

As of September 2021, there were 11 widely used vaccines worldwide, and 7 of these were in phase 4.⁹ In Turkey, 2 vaccines are presently in use (both phase 4): the mRNA-based vaccine of Pfizer-BioNTech (Comirnaty) and the inactivated vaccine of Sinovac (CoronaVac). The aim of this study was to evaluate the antibody response and adverse effects of vaccines in SOT recipients.

Materials and Methods

This prospective observational study included 10 liver and 38 kidney transplant recipients vaccinated with 2 doses of inactivated SARS-CoV-2 vaccine (CoronaVac, Sinovac) or BNT162b2 vaccine (Comirnaty, Pfizer-BioNTech) from April to June 2021. Via telephone, we contacted 38 liver transplant recipients and 88 kidney transplant recipients living in Ankara, Turkey, and 53 agreed to hospital admission for serological tests and were included in the study. There were 33 patients vaccinated with 2 doses of inactivated SARS-CoV-2 vaccine (Sinovac) given 4 weeks apart and 18 patients vaccinated with 2 doses of mRNA-based vaccine (BioNTech) given 4 to 6 weeks apart, according to the patients’ vaccine preferences. One patient did not complete the study and was excluded, and 2 patients were excluded from the study because of a positive test for immunoglobulin G (IgG) in their prevaccination serum samples. The study also included 56 health care workers who were vaccinated with 2 doses of Sinovac vaccine, and these served as the healthy control group. Reasons for exclusion were age younger than 18 years, previous infection with COVID-19, SARS-CoV-2 IgG positivity in the prevaccination serum sample, and acute COVID-19 infection during the study period.

We collected demographic data, as well as details of adverse events following the vaccination and immunosuppressive regimen. There were 37 recipients of grafts from living donors and 11 recipients of grafts from deceased donors. All living donors were blood relatives or interspousal. Three samples were collected from every patient at the following times: before the first dose of vaccine, 4 weeks after the first dose, and 4 to 6 weeks after the second dose. The SARS-CoV-2 IgG II Quant assay (Abbott) was used for quantitative measurement of IgG antibodies against the spike protein of SARS-CoV-2. A test was considered positive if IgG was detected at or above 50 AU/mL, according to the manufacturer’s instructions.¹⁰

The conformity of numerical variables to normal distribution was examined with the Shapiro-Wilk test of normality, and descriptive statistics are presented as mean values ± SD, numerical variables as median values (with minimum-maximum), and categorical variables as number of patients (with percent of total). The Pearson chi-square test was used for independent categorical data, the generalized Fisher (Fisher-Freeman-Halton) exact test was used when the Pearson chi-square test was not suitable, and the Mann-Whitney U test was used to determine statistical differences between the vaccine groups in terms of the distribution of numerical variables. Type I error probability was determined as α = .05 in all statistical analyses, and all analyses were performed with SPSS software (version 25).

This study was approved by the Baskent University Institutional Review Board. Informed consent was obtained from all participants.

Results

We analyzed the demographic data, antibody responses, and adverse events of 38 kidney and 10 liver transplant recipients after 2 doses of SARS-CoV-2 vaccine and compared the immune responses with our healthy cohort. The median age of the patients was 36.5 years (range, 18-62 years), and 45.8% of the patients were 24 to 44 years old. In the healthy cohort, the median age was 37.5 years (range, 22-52 years). Of the SOT recipients, 35 (72.7%) were male. Age and sex distributions were homogenous in both vaccine groups (P < .05). The median time from transplant to vaccination was 8 years (range, 1-21 years), and 32% were in the range of 5 to 9 years. The proportion of patients receiving immunosuppression regimens containing antimetabolites was 72%, whereas the proportion of immunosuppression-treated patients not receiving antimetabolites was 28%.

Distributions of demographic data, comorbidities, transplant and donor type, time period elapsed after transplant, consanguinity status, and immunosup-pressive regimens of the 2 vaccine groups are shown in Table 1.

Seropositivity was significantly higher in the healthy group than in transplant recipients after Sinovac vaccine (100% vs 67.5%; P = .001). However, there was no significant difference between Sinovac and BioNTech groups in terms of seropositivity after each of the 2 doses in the transplant recipients. When the median SARS-CoV-2 IgG levels were compared, there was no statistically significant difference between the Sinovac and BioNTech groups after the first dose (P = .077). However, the median SARS-CoV-2 IgG level after the second dose was significantly higher in the BioNTech group (1388.6 AU/mL) than in the Sinovac group (136.6 AU/mL) (P = .012). When we compared men versus women, there was no significant difference in seropositivity after each of the 2 doses between the 2 vaccine groups. However, the median antibody level was significantly higher after the second dose in male patients (P = .043). In female patients, higher antibody levels were obtained at both serum levels in the BioNTech group (P = .05 and P =.05, respectively). Between the donor types, serum antibody levels in living donor transplant patients were higher in the BioNTech group versus the Sinovac group, and the difference was statistically significant (P = .010). In terms of age, we only found a significant difference between the 2 vaccine groups in seropositivity in the patients who were 24 to 44 years old (P = .040).

When the 2 vaccine groups were compared in terms of immunosuppressive regimens with and without antimetabolites, the BioNTech group had higher seropositivity and serum antibody levels, but the difference was not statistically significant (P < .05). After 2 doses of BioNTech vaccine, the group seropositivity was 100% in patients with immuno-suppression regimens without antimeta-bolites, whereas in the Sinovac group it was 76.9%. The median SARS-CoV-2 level after 2 doses was 1007 AU/mL in the BioNTech group and 2487 AU/mL in the Sinovac group.

Comparisons of antibody responses to vaccine groups according to the demography, comorbidity, transplant and donor type, time period elapsed after transplant, and immunosuppressive regimen are given in Table 2.

Table 3 shows the distribution of negative side effects in both vaccine groups as well as the overall study group. The distribution of side effects in the vaccine groups differed significantly (P = .001). The rate of occurrence of at least 1 side effect was 82.4% (n = 14) in the BioNTech group and 32.3% (n = 10) in the Sinovac group, and 50.0% (n = 24) in the total cohort. A significant difference was discovered for arm pain as a side effect. Arm pain at the vaccine injection site was reported in 76.5% (n = 13) of the BioNTech group and 19.4% (n = 6) of the Sinovac group.

Discussion

Solid-organ transplant recipients are at risk for COVID-19 and related complications. Vaccination against SARS-CoV-2 is a promising way to reduce complications and mortality. Generally, the effectiveness of vaccines among SOT recipients is reduced by the inhibition of lymphocyte activation, interaction with antigen-presenting cells, and reduction in B-cell memory responses, all of which have been associated with immunosuppressive therapy.^11,12 The influenza vaccine, one of the most commonly used vaccines, has been reported to result in lower antibody and cell-mediated immune responses in transplant recipients compared with that shown in the general population; despite this, the influenza vaccine has been associated with reduction of influenza-associated complications in SOT recipients.^13,14 This experience may offer guidance for the vaccination efforts against SARS-CoV-2.

Data for vaccination among SOT recipients are accumulating, but many questions remain unanswered. The pre-approval vaccine trials were not designed to gather data about SOT recipients. Presently, SOT recipients are recommended to receive any vaccine available because none of them is a live vaccine. The immunization schedule (for example, the number of doses and durations between the doses, possible need for booster doses, vaccine preferences in SOT recipients) is not clear. These and other issues await clarification in the context of well-designed clinical trials.

In this study, we compared the seropositivity rates and antibody levels after vaccination with the 2 vaccines available in Turkey (Sinovac and BioNTech) in SOT recipients . Although there are studies that compare the vaccine response in SOT patients with the general population, there is no study in the literature that compares the responses between these 2 vaccines, both of which are administered according to patient preference in Turkey.

We found no significant difference in the seropositivity rates between the 2 vaccines after each of 2 doses; however, median SARS-CoV-2 IgG levels were significantly higher in the BioNTech group after the second dose. Recently, seropositivity rates after the mRNA-based vaccine have been between 2% and 17% after a single dose and between 34% and 54% after the second dose.^5,8,15-18 Neutralizing antibody was detected in only 47.5% of 80 liver transplant recipients following the BioNTech vaccine schedule.⁶

For inactivated SARS-CoV-2 vaccines, there are few clinical studies in SOT patients and no peer-reviewed articles about the serological response or effectiveness of the Sinovac vaccine among SOT recipients. In patients who received Sinovac, Medina-Pestana and colleagues have found the serocon-version rate to be 15.2% and median IgG value to be 477 AU/mL at 28 days after the first dose in kidney and pancreas-kidney recipients. In our study, seropositivity rates for the Sinovac vaccine were 38.7% after the first dose and 67.7% after the second dose. All seropositivity rates and antibody levels were found to be significantly lower compared with the general population in previous studies.¹¹ The seropositivity rates after Sinovac vaccine in this study were lower than the seropositivity rates of health care workers recently reported from the same center.¹⁹

The antibody levels obtained in this study were higher than reported in previous studies for the BioNTech and Sinovac groups. In previous studies, older age and a higher intensity of immunosup-pression, particularly the use immunosuppression with antimetabolites, were defined as risk factors for poor antibody responses.^5,20 Median age in all previous studies was more than 50 years. However, in our study, nearly half of the patients were 24 to 44 years old, with the median age in the Sinovac group of 39 years (range; 18-62 years) and in the BioNTech group of 32 years (range, 21-57 years). This difference could be explained by the younger age group of participants in the study. However, the small size of the study group should be considered as well.

We found no statistically significant difference in antibody levels in terms of organ type. Results were similar for both the Sinovac and the BioNTech vaccines. Against this, Medina-Pestana and colleagues reported that combined kidney-pancreas transplants had lower seroconversion rates than kidney transplants after Sinovac vaccine.²⁰ Boyarsky and colleagues found no significant difference between organ types after the first dose of BioNTech vaccine; however, after the second dose, liver transplant recipients were found to have higher seroconversion rates than recipients of other organ types.^12,15,20

Immunosuppression regimens were suspected to be another parameter for poor humoral immune response in SOT recipients. Crucially, antimetabolite-containing regimens have been associated with reduced antibody responses in previous studies.^8,12,18,20 In this study, patients who received immunosuppression with antimetabolites had lower seropositivity and lower antibody levels than patients who received immuno-suppression regimens without antimetabolites, similar to the results from other studies; however, the differences were not statistically significant.

In the present study, the adverse events after the Pfizer-BioNTech vaccine (Comirnaty) were more common than after the Sinovac vaccine. No severe adverse reactions were observed after either vaccine. The most common adverse event was local pain at the vaccination site for both vaccines, and this finding was similar to recent studies on healthy populations and SOT recipients.^5,6,12,20

There was a single episode of acute T-cell-related rejection 2 weeks after the BioNTech vaccination in a liver recipient, and he showed complete recovery of hepatic function after treatment with methylprednisone. Similarly, Medina-Pestana and colleagues have reported acute cellular rejection after inactivated SARS-CoV-2 vaccination in a kidney recipient who recovered after treatment with methylprednisone and antithymocyte globulin.²⁰ It is not appropriate to comment on the risk of rejection for both vaccines because the number of cases of rejection was extremely low.

Routine use of serological tests is presently not recommended for evaluation of patient responses to the vaccines because of the lack of approved cut-offs for protection and methodological variations of the available serological tests.²¹ The question of whether the immunocompromised patients are provided sufficient protection is a primary concern for clinicians, and antibody levels are presently considered to be the only reliable indicator for serological responses; there are a growing number of studies about this issue despite many unknown factors, such as the lack of serological cut-off or lack of any tool to determine the cellular immunity.

Recent studies have reported low seroconversion rates after the second dose in SOT recipients who received mRNA-based SARS-CoV-2 vaccines, and, in response, the French National Authority for Health has recommended administration of a third vaccine dose for immunosuppressed patients who do not respond after 2 doses. Of 159 renal transplant recipients who had received the third dose of the mRNA-1273 vaccine (Moderna), a serological response was detected in 49% of patients; however, 51% did not develop anti-SARS-CoV-2 antibodies after a third dose, particularly those patients under triple immunosuppression.⁷

Similar results were obtained from a group of 101 consecutive SOT recipients who had been vaccinated with 3 doses of the Pfizer-BioNTech vaccine (78 kidney, 12 liver, 8 lung or heart, and 3 pancreas transplant recipients). The first 2 doses were given 1 month apart, and the third dose was given 61 ± 1 days after the second dose. Among the 59 patients who were seronegative before the third dose, 44% were observed to be seropositive at 4 weeks after the third dose.8

Limitations of our study are the small number of cases and the lack of real-world experience and the lack of a worldwide established threshold levels for antibody protection.

As mentioned in previous reports, vaccination does not replace basic control measures such as hand hygiene, use of facemasks, and physical distancing. Vaccination of household contacts should be also encouraged for vaccination.

Conclusions

Vaccine responses in SOT recipients are inadequate compared with healthy controls, with an increased risk of complications and mortality. Furthermore, immune responses may differ among vaccines. As a result, in addition to additional vaccine doses, strict control measures must be maintained.

References:

1. Boyarsky BJ, Po-Yu Chiang T, Werbel WA, et al. Early impact of COVID-19 on transplant center practices and policies in the United States. Am J Transplant. 2020;20(7):1809-1818. doi:10.1111/ajt.15915
   CrossRef - PubMed
   
2. Azzi Y, Bartash R, Scalea J, Loarte-Campos P, Akalin E. COVID-19 and solid organ transplantation: a review article. Transplantation. 2021;105(1):37-55. doi:10.1097/TP.0000000000003523
   CrossRef - PubMed
   
3. Dagan N, Barda N, Kepten E, et al. BNT162b2 mRNA Covid-19 vaccine in a nationwide mass vaccination setting. N Engl J Med. 2021;384(15):1412-1423. doi:10.1056/NEJMoa2101765
   CrossRef - PubMed
   
4. Aslam S, Adler E, Mekeel K, Little SJ. Clinical effectiveness of COVID-19 vaccination in solid organ transplant recipients. Transpl Infect Dis. 2021; 23(5):e13705. doi:10.1111/tid.13705
   CrossRef - PubMed
   
5. Rozen-Zvi B, Yahav D, Agur T, et al. Antibody response to SARS-CoV-2 mRNA vaccine among kidney transplant recipients: a prospective cohort study. Clin Microbiol Infect. 2021;27(8):1173.e1-1173.e4. doi:10.1016/j.cmi.2021.04.028
   CrossRef - PubMed
   
6. Rabinowich L, Grupper A, Baruch R, et al. Low immunogenicity to SARS-CoV-2 vaccination among liver transplant recipients. J Hepatol. 2021;75(2):435-438. doi:10.1016/j.jhep.2021.04.020
   CrossRef - PubMed
   
7. Benotmane I, Gautier G, Perrin P, et al. Antibody response after a third dose of the mRNA-1273 SARS-CoV-2 vaccine in kidney transplant recipients with minimal serologic response to 2 doses. JAMA. 2021; 326(11):1063-1065. doi:10.1001/jama.2021.12339
   CrossRef - PubMed
   
8. Kamar N, Abravanel F, Marion O, Couat C, Izopet J, Del Bello A. Three doses of an mRNA Covid-19 vaccine in solid-organ transplant recipients. N Engl J Med. 2021;385(7):661-662. doi:10.1056/NEJMc2108861
   CrossRef - PubMed
   
9. World Health Organization. COVID-19 vaccine tracker and landscape. Updated November 2, 2021. https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines
   CrossRef - PubMed
   
10. United States Food and Drug Administration. AdviseDx SARS-CoV-2 IgG II chemiluminescent microparticle immunoassay: instructions for use (ARCHITECT). February 2021. https://www.fda.gov/media/146371/download
    CrossRef - PubMed
    
11. Giannella M, Pierrotti LC, Helantera I, Manuel O. SARS-CoV-2 vaccination in solid-organ transplant recipients: what the clinician needs to know. Transpl Int. 2021;34(10):1776-1788. doi:10.1111/tri.14029
    CrossRef - PubMed
    
12. Boyarsky BJ, Werbel WA, Avery RK, et al. Antibody response to 2-dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients. JAMA. 2021;325(21):2204-2206. doi:10.1001/jama.2021.7489
    CrossRef - PubMed
    
13. Hequet D, Pascual M, Lartey S, et al. Humoral, T-cell and B-cell immune responses to seasonal influenza vaccine in solid organ transplant recipients receiving anti-T cell therapies. Vaccine. 2016;34(31):3576-3583. doi:10.1016/j.vaccine.2016.05.021
    CrossRef - PubMed
    
14. Kumar D, Ferreira VH, Blumberg E, et al. A 5-year prospective multicenter evaluation of influenza infection in transplant recipients. Clin Infect Dis. 2018;67(9):1322-1329. doi:10.1093/cid/ciy294
    CrossRef - PubMed
    
15. Boyarsky BJ, Werbel WA, Avery RK, et al. Immunogenicity of a single dose of SARS-CoV-2 messenger RNA vaccine in solid organ transplant recipients. JAMA. 2021;325(17):1784-1786. doi:10.1001/jama.2021.4385
    CrossRef - PubMed
    
16. Grupper A, Rabinowich L, Schwartz D, et al. Reduced humoral response to mRNA SARS-CoV-2 BNT162b2 vaccine in kidney transplant recipients without prior exposure to the virus. Am J Transplant. 2021;21(8):2719-2726. doi:10.1111/ajt.16615
    CrossRef - PubMed
    
17. Benotmane I, Gautier-Vargas G, Cognard N, et al. Weak anti-SARS-CoV-2 antibody response after the first injection of an mRNA COVID-19 vaccine in kidney transplant recipients. Kidney Int. 2021;99(6):1487-1489. doi:10.1016/j.kint.2021.03.014
    CrossRef - PubMed
    
18. Chavarot N, Ouedrani A, Marion O, et al. Poor anti-SARS-CoV-2 humoral and T-cell responses after 2 injections of mRNA vaccine in kidney transplant recipients treated with belatacept. Transplantation. 2021;105(9):e94-e95. doi:10.1097/TP.0000000000003784
    CrossRef - PubMed
    
19. Yalcin TY, Topcu DI, Dogan O, et al. Immunogenicity after two doses of inactivated virus vaccine in healthcare workers with and without previous COVID-19 infection: prospective observational study. J Med Virol. 2022;94(1):279-286. doi:10.1002/jmv.27316
    CrossRef - PubMed
    
20. Medina-Pestana J, Cristelli MP, Viana LA, et al. Clinical impact, reactogenicity, and immunogenicity after the first CoronaVac dose in kidney transplant recipients. Transplantation. 2021. doi:10.1097/TP.0000000000003901
    CrossRef - PubMed
    
21. Manuel O. COVID-19 vaccination in solid-organ transplant recipients: generating new data as fast as possible, but taking clinical decisions as slow as necessary. Clin Microbiol Infect. 2021;27(8):1070-1071. doi:10.1016/j.cmi.2021.06.018
    CrossRef - PubMed