key: cord-0706597-hb9rqr0m authors: Russo, Gianluca; Lai, Quirino; Poli, Luca; Perrone, Maria Paola; Gaeta, Aurelia; Rossi, Massimo; Mastroianni, Claudio M.; Garofalo, Manuela; Pretagostini, Renzo title: SARS‐COV‐2 vaccination with BNT162B2 in renal transplant patients: Risk factors for impaired response and immunological implications date: 2021-10-28 journal: Clin Transplant DOI: 10.1111/ctr.14495 sha: 660f32cd7fa222dd5eb3d8e846eed411f942f467 doc_id: 706597 cord_uid: hb9rqr0m Solid organ transplant patients are at a higher risk for poor CoronaVirus Disease‐2019 (COVID‐19)‐related outcomes and have been included as a priority group in the vaccination strategy worldwide. We assessed the safety and efficacy of a two‐dose vaccination cycle with mRNA‐based COVID‐19 vaccine (BNT162b2) among 82 kidney transplant outpatients followed in our center in Rome, Italy. After a median of 43 post‐vaccine days, a SARS‐CoV‐2 anti‐Spike seroprevalence of 52.4% (n = 43/82) was observed. No impact of the vaccination on antibody‐mediated rejection or graft function was observed, and no significant safety concerns were reported. Moreover, no de novo HLA‐donor‐specific antibodies (DSA) were detected during the follow‐up period. Only one patient with pre‐vaccination HLA‐DSA did not experience an increased intensity of the existing HLA‐DSA. During the follow‐up, only one infection (mild COVID‐19) was observed in a patient after receiving the first vaccine dose. According to the multivariable logistic regression analysis, lack of seroconversion after two‐dose vaccination independently associated with patient age ≥60 years (OR = 4.50; P = .02) and use of anti‐metabolite as an immunosuppressant drug (OR = 5.26; P = .004). Among younger patients not taking anti‐metabolites, the seroconversion rate was high (92.9%). Further larger studies are needed to assess the best COVID‐19 vaccination strategy in transplanted patients. Several studies on solid organ transplant patients affected by Severe Acute Respiratory Syndrome-CoronaVirus-2 (SARS-CoV-2) infection showed a higher risk for severe CoronaVirus Disease-2019 (COVID- 19) with poor outcomes. [1] [2] [3] Thus, transplanted patients are among the priority population groups for SARS-CoV-2 vaccine-based preventive activities worldwide. It should also be underlined that, in general, vaccine administration in transplanted patients may represent a nonspecific trigger factor for developing Donor-Specific Antibodies against Human Leukocyte Antigens (HLA-DSA) that are associated with acute organ rejection. 4 Moreover, response to various vaccines in transplanted patients is lower than in the general population. 5 Furthermore, transplanted patients were not included in the study population to register all approved COVID-19 vaccines, including those based on mRNA technology (BNT162b2 -Pfizer-BioNTech; mRNA1273, Moderna). 6, 7 According to real-life data, transplanted patients receiving mRNA SARS-CoV-2 vaccines show significantly lower seroconversion and anti-spike titers than the general population. 8, 9 Moreover, to date, there are insufficient data on anti-spike SARS-CoV-2 antibody levels in previously transplanted vaccinees beyond a period of one month after two-dose vaccination. The main objective of the present study is to assess the safety and efficacy of the mRNA SARS-CoV-2 vaccine (BNT162b2) after the second dose of the vaccine in a population of patients previously undergoing a specific organ transplant, namely the kidney transplantation (KT). The secondary objective is to evaluate the impact of the vaccination on rejection and graft function. According to the policy on COVID-19 vaccination in Italy, vulnerable population groups, including solid organ transplant patients, were prioritized to receive mRNA SARS-CoV-2 vaccines. Each Italian region was in charge of the voluntary vaccination of residents in its territory. All KT patients transplanted at the Polyclinic Umberto I Hospital, Rome, and resident in the Lazio region, Italy, were contacted by phone to propose the vaccination. The vaccine used was the mRNA COVID-19 vaccine (BNT162b2, Comirnaty, Pfizer-BioNTech) administered in two doses given three weeks apart. The vaccine was administered only in a hospital setting after written informed consent. Among KT vaccinees, only those already followed as outpatients at Polyclinic Umberto I Hospital, Rome, were enrolled in the present study. Routine blood tests were performed as post-transplant outpatient activity, including serum creatinine, serum electrolytes, serum level of calcineurin inhibitors, serum HLA-DSA. The search for HLA-DSA antibodies was carried out using the multianalyte bead assay with the Luminex platform (Luminex, Austin, TX, USA), including Lifecode Screen and LSA I/II (Immucor, Inc., Norcross, Georgia). The results were expressed as mean fluorescence intensity (MFI); an MFI > 1000 was considered positive. Following the second dose of the vaccine, serum anti-spike SARS-CoV-2 antibodies were also assessed. LIAISON SARS-CoV-2 S1/S2 IgG chemiluminescent assay against a recombinant Spike (S) protein (S1/S2) (DiaSorin S.p.A., Saluggia, Italy) was used according to the manufacture instructions. Results below 12.0 AU/mL were considered negative. All the post-vaccination adverse events were reported. Continuous variables were reported as medians and interquartile ranges (IQR). Binary variables were reported as numbers and percentages. No missing data were reported in the investigated population. Everolimus use was reported in 10 patients (12.2%). An antimetabolite drug (azathioprine or derivatives of mycophenolic acid) was adopted in 57 patients (69.5%). As for the analysis of the post-vaccine side effects ( As for the immunosuppressive therapy, no relevant differences were observed in terms of steroid use, steroid dosing, and use of calcineurin inhibitors. In the Undetectable Group, triple therapy (84.6 vs 60.5%; P-value .03) and antimetabolite drugs (84.6 vs 55.8%; P-value = .008) were more common. The potential variables connected with an inadequate titer response after the two-dose vaccination are reported in Supplementary Table 1 and Table 3 . At univariable logistic regression analysis, patient age In Table 3 In the present study performed on 82 KT, a seroconversion rate of 52.4% was assessed after a median period of 43 (IQR 23-63) days postsecond dose of mRNA-based COVID-19 vaccine (BNT162b2). This result is in line with previously published studies. [8] [9] [10] [11] [12] Age > 60 years and the use of anti-metabolite drugs independently increased the odds of a lower seroconversion after COVID-19 vaccination. Also in this case, the results of our study are in line with previous experiences. 8, 9 Interestingly, when both advanced age and anti-metabolites use were absent in our population, a high seroconversion rate (92.9%) was observed, suggesting the utility of a "tailored" use of the vaccine third dose. Recent studies reported the efficacy for seroconversion of the administration of a third dose (around two months after the second dose) of the COVID-19 vaccine among transplanted patients. 13, 14 Overall, the seroconversion rate measured 2-4 weeks after the third were observed in liver and heart transplant patients. 17 Larger studies are necessary to clarify this specific aspect. Overall, no significant safety concerns were reported in this study (Table 2) , similarly to what was observed in the registration trials of mRNA-based COVID-19 vaccines, 6,7 as well as in the studies assessing the efficacy of a third dose of the vaccines. 13, 14 In literature, the rate of post-vaccination infections among fully vaccinated transplanted patients has been estimated to be around .6% in two US studies. 18, 19 This datum is substantially higher than the rate of .05% reported in the general population. 20 Interestingly, antibodies to SARS-CoV-2 seem not to be a surrogate indicator of the magnitude of memory T cells 22 in immunocompetent individuals, suggesting that antibody levels alone may not be a robust indicator of protection in subjects previously infected with SARS-CoV-2. 23 Thus, a low SARS-CoV-2 antibody titer after infection or vaccination does not necessarily mean a lack of protection. However, studies focused on this specific aspect are necessary to evaluate the impact on protecting the T-cells response elicited by COVID-19 vaccines, 23 No funds have been received for the present work. The authors have no conflict of interest to declare, and any support has been received for the present study. GR and RP contributed to conception and design of the study; QL, LP, MPP, AG, and MG contributed to acquisition of data; GR and QL analyzed and interpreted the data; GR and QL drafted the article; MR, CMM, and RP critically revised the manuscript; and all authors approved the final version. The data of this study are available on request from the corresponding author. The data are not publicly available because of privacy restrictions. Gianluca Russo https://orcid.org/0000-0002-8764-7389 Quirino Lai https://orcid.org/0000-0003-1487-3235 for UW COVID-19 SOT Study Team. 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