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Clinical update on the efficacy of anti-SARS-CoV-2 mRNA vaccines in patients on the waiting list for liver transplantation and in liver transplant recipients

2021; Elsevier BV; Volume: 53; Issue: 10 Linguagem: Inglês

10.1016/j.dld.2021.07.019

1878-3562

Pierluigi Toniutto, Alessio Aghemo, Paolo Grossi, Patrizia Burra, Paola Carrai, Maria Francesca Donato, Valerio Giannelli, Silvia Martini, Maria Cristina Morelli, Francesca Romana Ponziani,

Viral gastroenteritis research and epidemiology

The efficacy of full course of anti-SARS-CoV-2 mRNA vaccines (BNT162b2 e mRNA-1273) in protecting immunocompetent patients from symptomatic-severe Coronavirus disease-2019 (COVID19) is documented in more than 95% of cases [1Polack F.P. Thomas S.J. Kitchin N. et al.Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.N Engl J Med. 2020; 383: 2603-2615Crossref PubMed Scopus (9627) Google Scholar,2Baden L.R. El Sahly H.M. Essink B. et al.Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.N Engl J Med. 2021; 384: 403-416Crossref PubMed Scopus (6647) Google Scholar]. However, in patients on the waiting list for liver transplantation and in liver transplant recipients, the efficacy of anti-SARS-CoV-2 vaccination seems to be inadequate in a consistent proportion of cases. This document, drafted by the expert panel of transplant hepatologists appointed by the Italian Association for the Study of the Liver (AISF), aims to present the updated scientific data on the efficacy of anti-SARS-CoV-2 mRNA vaccines in patients on the waiting list or after liver transplantation. Furthermore, the panel's expert opinion about several critical questions regarding the timing of administration of the second dose of vaccine after liver transplantation in subjects who received the first dose during the waiting list period, the vaccination of patients undergoing liver transplantation with a previous recovered COVID-19, and the possible option to administer a third "booster" vaccination dose in patients without antibody response at the end of the full vaccination course will be presented. At the time of preparation of this report, 5 research articles exploring the antibody response to a full schedule (two-doses) of anti-SARS-CoV-2 vaccination in patients undergoing solid organ transplantation have been published [3Boyarsky B.J. Werbel W.A. Avery R.K. et al.Antibody response to 2-dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients.JAMA. 2021; 325: 2204-2206Crossref PubMed Scopus (752) Google Scholar, 4Rabinowich L. Grupper A. Baruch R. et al.Low immunogenicity to SARS-CoV-2 vaccination among liver transplant recipients.J Hepatol. 2021; 75: 435-438Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 5Peled Y. Ram E. Lavee J. et al.BNT162b2 vaccination in heart transplant recipients: clinical experience and antibody response.J Heart Lung Transplant. 2021; 40: 759-762https://doi.org/10.1016/j.healun.2021.04.003Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 6Shostak Y. Shafran N. Heching M. et al.Early humoral response among lung transplant recipients vaccinated with BNT162b2 vaccine.Lancet Respir Med. 2021; 9: e52-ee3Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 7Grupper 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: 2719-2726Crossref PubMed Scopus (282) Google Scholar]. However, only two of them evaluated the antibody response at the end of the full course of BNT162b2 or mRNA-1273 antiSARS-CoV-2 vaccines, in a total of 158 liver transplant recipients [3Boyarsky B.J. Werbel W.A. Avery R.K. et al.Antibody response to 2-dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients.JAMA. 2021; 325: 2204-2206Crossref PubMed Scopus (752) Google Scholar,4Rabinowich L. Grupper A. Baruch R. et al.Low immunogenicity to SARS-CoV-2 vaccination among liver transplant recipients.J Hepatol. 2021; 75: 435-438Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar] (Table 1). The cumulative data derived from these studies, showed that a reduced antibody response following the full course of vaccination, ranging from 31% to 47.5%, was observed in liver transplant recipients. In the study by Boyarsky et al. [3Boyarsky B.J. Werbel W.A. Avery R.K. et al.Antibody response to 2-dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients.JAMA. 2021; 325: 2204-2206Crossref PubMed Scopus (752) Google Scholar], the antibody response was significantly higher following the mRNA-1273 vaccine compared to the BNT162b2 vaccine (22% vs 8%, p 12 in 90% of casesBNT162b2Abbott®———14-2118%• Younger age• Immunosuppression without mycophenolate and/or mTORGrupper et al. 7Grupper 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: 2719-2726Crossref PubMed Scopus (282) Google ScholarKidney13658.639.2BNT162b2Liason S1/S2 IgG®———14-2137.5%• Younger age• Immunosuppression without mycophenolate and/or mTOR• Low dose of steroidsSOT: solid organ transplantations; LT: liver transplanted; S1/S2 IgG: immunoglobulin G antibodies against subunits S1 and S2 of the SARS-CoV-2 spike protein; IgG anti RBD: Immunoglobulin G antibodies against Receptor Binding Domain of the SARS-CoV-2 spike protein; ELISA: enzyme-linked immunosorbent assay; mTOR: mammalian target of rapamycin. Open table in a new tab SOT: solid organ transplantations; LT: liver transplanted; S1/S2 IgG: immunoglobulin G antibodies against subunits S1 and S2 of the SARS-CoV-2 spike protein; IgG anti RBD: Immunoglobulin G antibodies against Receptor Binding Domain of the SARS-CoV-2 spike protein; ELISA: enzyme-linked immunosorbent assay; mTOR: mammalian target of rapamycin. It has been demonstrated that patients treated with azathioprine, methotrexate, or mycophenolate mofetil, developed a lower antibody response to the second vaccination dose of mRNA anti-SARS-CoV-2 vaccines, compared to patients on monotherapy with calcineurin or mammalian target rapamycin (mTOR) inhibitors. In the study by Boyarsky et al. [3Boyarsky B.J. Werbel W.A. Avery R.K. et al.Antibody response to 2-dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients.JAMA. 2021; 325: 2204-2206Crossref PubMed Scopus (752) Google Scholar], among the 473 patients treated with mycophenolate, 38 (8%) had antibody response after the first dose and 268 (57%) had no antibody response after the second dose of vaccine. Of the 185 participants who did not receive immunosuppression with mycophenolate or mTOR inhibitors, 60 patients (32%) had an antibody response after the first dose and 72% after the second dose of vaccine. Therefore, in transplanted patients receiving anti-SARS-CoV-2 vaccination, it can be assumed that for those treated with mycophenolate mofetil, azathioprine, high-dose of steroids (prednisone > 40 mg/daily for more than 15 days) or treated with chemotherapy causing lymphopenia, a vaccination schedule based on three doses of vaccine rather than two standard doses may be advisable. Some European scientific societies have proposed a 4-week interval between the second and third dose of the BNT162b2 and mRNA-1273 vaccines [10Sociétè Nationale Francaise de Gastro-Entérologie, Groupe d'Etude Thérapeutique des Affections Inflammatoires du Tube Digestif, d'Hépatologie. FFdCDSF. Recommandations de la SNFGE, du GETAID, de la FFCD et de l'AFEF pour la vaccination contre le SARS-CoV-2 des patients atteints de maladies chroniques de l'appareil digestif. 2021; http://www.snfge.org.Google Scholar]. In the Canadian clinical trial currently under enrollment (clinicalTrials.gov NCT04885907) a third dose of mRNA-1273 vaccine is planned 8 weeks after the second dose for all patients, regardless of the type of anti-rejection therapy. To date, there are no indications as to whether it is advisable or not to suspend/reduce the dose of immunosuppressive drugs, particularly mycophenolate, in the periods preceding and/or immediately following the administration of the booster dose of the vaccine, as this strategy may be potentially associated with an increased risk of graft rejection. A very recent report [11Werbel W.A. Boyarsky B.J. Ou M.T. et al.Safety and immunogenicity of a third dose of SARS-CoV-2 vaccine in solid organ transplant recipients: a case series.Ann Intern Med. 2021; (Jun 15:L21-0282)https://doi.org/10.7326/L21-0282Crossref Scopus (253) Google Scholar] evaluated the efficacy of the third administration of anti-SARS-CoV-2 vaccine on a series of 30 solid organ transplanted patients (3 liver transplanted), who had either a suboptimal or lack of antibody response to the previous vaccination course with two doses of mRNA vaccines. In 25/30 patients, immunosuppressive therapy was maintained with cyclosporine or tacrolimus in combination with mycophenolate, while steroids were maintained in 24/30 patients. The third dose of anti-SARS-CoV-2 vaccine (in 15 patients with Ad26.COV2.S viral vector vaccine, in 9 with mRNA-1273 vaccine and in 6 with BNT162b2 vaccine) was administered at a mean interval of 67 days after the second dose, and the evaluation of the antibody response was performed at a median interval of 14 days. In the 6 patients who presented a low antibody response to the previous two doses of vaccine, the administration of the third dose was associated with a significant increase of antibody response. On the contrary, the third dose of vaccine elicited an antibody response in only 6/24 (25%) of the patients in whom the two doses of vaccine did not induce the antibody response. In 2/24 (8%) patients, only a weak antibody response, and in 16/24 (67%) patients no antibody response was recorded. It should be noted that in this study the type of vaccines used was very heterogeneous, and the small number of patients enrolled did not allow to evaluate the independent predictors of the development of antibody response following the third dose of vaccine. Moreover, no clear indications to identify a potential higher efficacy of a vaccine over others can be deduced. The antibody response to three doses of an mRNA anti-SARS-CoV-2 vaccine has been also recently evaluated in a group of 101 solid organ transplant recipients (12 liver transplanted) [12Kamar N. Abravanel F. Marion O. et al.Three doses of an mRNA Covid-19 vaccine in solid-organ transplant recipients.N Engl J Med. 2021; (Jun 23:NEJMc2108861)https://doi.org/10.1056/NEJMc2108861Crossref PubMed Scopus (628) Google Scholar]. The mean time interval between transplantation and vaccination was 97 months. In 87% of patients immunosuppression included steroids, in 79% calcineurin inhibitors, in 63% mycophenolic acid, in 30% mTOR inhibitors, and belatacept in 12% of cases. The antibody response was detectable in 40% of the patients before the third dose of vaccine and in 68% of the patients 4 weeks after the third dose. Among the 59 patients who had been seronegative before the third dose, 26 (44%) became seropositive 4 weeks after the third dose. Older recipient age, higher levels of immunosuppression, and a lower estimated glomerular filtration rate, were the independent factors associated with poor antibody response to the third dose of vaccine. The aforementioned studies demonstrated that the third dose of anti-SARS-CoV-2 vaccine in solid organ transplant recipients, who do not have a clinically significant antibody response to the full course of vaccination, may increase the percentage of patients developing a significant antibody response by approximately 44%. Mycophenolate therapy remains an independent predictor of failure to develop an antibody response after vaccination. This suggests that the modification of immunosuppressive therapy in the immediate pre and post vaccination period may be hypothesized in the future to increase the number of recipients who can benefit from anti-SARS-CoV-2 vaccination. At the present time, the available data justify the administration of a third dose of anti-SARS-CoV-2 vaccine, especially in liver transplant recipients who have had a weak or absent antibody response to the full two-doses of vaccination course. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.