key: cord-1048226-9mgdoyr8 authors: Matejak-Górska, Marta; Zielonka, Michał; Górska, Hanna; Durlik, Marek title: Covid-19 vaccines in pancreatic transplant patients – a single-center observative study date: 2022-03-15 journal: Transplant Proc DOI: 10.1016/j.transproceed.2022.03.002 sha: 7f789bc2e9b743af68abc43d622c47b4d8c19749 doc_id: 1048226 cord_uid: 9mgdoyr8 The Sars-CoV-2 pandemic was a real test for the doctors’ ability to adapt and respond to the patients’ needs. The course of infection varied from influenza-like symptoms to severe infections with multi-organ failure and death. Therefore, the possibility of vaccination against the Covid-19 virus brought great hope. Since 2004, 240 pancreas - pancreas with kidney (SPK, PAK, PTA) transplants were performed in our center. Currently, 130 transplant patients are under the care of the Transplant Clinic. All patients were informed about the possibility of vaccination against Sars-CoV-2with the mRNA vaccine. The aim of the study was to evaluate the development of antibodies to Sars-CoV-2 in patients who had previously undergone transplantation. 53 patients were vaccinated with the full double dose. 37 patients received an additional third dose. The level of antibodies in the IGM and IGG classes was assessed in the serum of the patients. The level of antibodies was assessed before administration of the vaccine and then after administration of the 1st and 2nd doses. Most patients had no response to vaccination after one dose of the vaccine. 21 patients achieved therapeutic antibody levels after the full dose of vaccination. However, the highest titer of immunoglobulins was found in recipients who received the third dose. The use of vaccinations is safe and can protect the group of patients after pancreas transplantation from serious complications of Sars-CoV-2 infection despite the use of immunosuppressive drugs. The aim of the study was to evaluate the development of antibodies to Sars-CoV-2 in patients who had previously undergone transplantation. 53 patients were vaccinated with the full double dose. 37 patients received an additional third dose. The level of antibodies in the IGM and IGG classes was assessed in the serum of the patients. The level of antibodies was assessed before administration of the vaccine and then after administration of the 1st and 2nd doses. Most patients had no response to vaccination after one dose of the vaccine. 21 patients achieved therapeutic antibody levels after the full dose of vaccination. However, the highest titer of immunoglobulins was found in recipients who received the third dose. The use of vaccinations is safe and can protect the group of patients after pancreas transplantation from serious complications of Sars-CoV-2 infection despite the use of immunosuppressive drugs. A steady increase in the number of transplants, as well as an increase in the reporting of potential organ donors, was observed in Poland before the covid-19 pandemic. In the course of the covid-19 pandemic, many hospitals were converted into COVID hospitals and therefore could not carry out transplantation activities. The data from 2020 showed that the number of reported organ donors and the number of organ transplants significantly decreased [ Table 1 ]. In March 2020, the Polish Transplantation Society issued recommendations limiting the possibility of pancreatic transplantation due to the lack of urgent indications for this organ transplant, and at the same time, the need to use depressive immunosuppression, which potentially causes a long-lasting reduction in immune immunity. In May 2021, the system of care for patients with covid-19 changed in Poland, the COVID hospitals ceased to function and returned to the full range of activities. Despite this, the number of reported organ donors and organ transplants performed only slightly increased. At the same time, the Polish Society of Transplantation recommended administering covid-19 vaccinations to patients after organ transplantation and to dialysis patients awaiting transplantation. Chronic dialysis patients with end-stage renal disease are known to have a lower response to vaccination than immunocompetent individuals, but this response is believed to be better in comparison to immunity after organ transplantation. After transplantation, antibodies produced after vaccination disappear faster, so optimally patients awaiting transplantation should be vaccinated. Post-transplant vaccination should be performed about 4 weeks after surgery, or after 3-6 months if depleting immunosuppression was used. Live vaccines are contraindicated after transplantation. The vaccines against Sars-Cov-2 infection currently available on the market are inactivated vaccines and can be used in patients after organ transplantation [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] . The aim of this study was to analyze the safety and efficiency of anti-COVID19 vaccination in a group of patients after pancreas transplantation. Prospective observation of all patients after pancreas transplantation was performed. Out of 240 patients, 53 were fully vaccinated. The choice of vaccination was done regarding guidelines of the Polish Ministry of Health. Patients after organ transplantation are recommended to receive an mRNA vaccine. 2 recipients were excluded from the study, due to adenovirus vaccination. One was vaccinated with double dose (Vaxzevria, AstraZeneca) according to the occupation (Adenovirus vaccines were sooner available and recommended for teachers). One patient received a single dose of Adenovirus vaccine (Jansen/JNJ)) outside our Centre. At the beginning of the observation, there was no selection of vaccines due to limitations in delivery. Second and third doses were administrated according to the product used for the first time. The analysis of time from the transplant, age and sex was performed. We also gathered information about SARS-CoV-2 infection, before and after vaccination. The level of serum antibodies in the IGM and IGG classes was assessed in the serum of the patients (Anty-SARS-CoV-2 QuantiVac ELISA IgG, BAU/ml). The level of antibodies was assessed before administration of the vaccine and then after administration of the 1st and 2nd doses after 3 weeks after vaccination. We also collected data about side effects like fatigue, muscle pain, fever, and possible adverse events after each vaccine. Our surgical technique was described in pour previous articles [11] [12] [13] [14] . We perform a double layer duodenojejunal anastomosis, reconstruct pancreas graft's arterial blood supply into a Y-graft from the iliac artery of the donor anastomosed to the supra mesenteric and splenic arteries and perform a singlelayer continuous anastomosis to common iliac artery. In most cases, we do not perform a portal vein reconstruction. Most often we use a left kidney and a retroperitoneal approach. In our clinic, we prefer regular visits of patients -clinical examination and laboratory tests every 2-3 weeks in the first quarter after transplantation. We use a three-drug immunosuppression scheme with induction with polyclonal antibodies thymoglobulin -in a total dose of 1.5 mg/kg. We start with a lowmolecular-weight heparin (LMWH) in a single or double dose. Three months after the transplant, hospitalization with CT and laboratory tests is planned. LMWH is changed to75 mg of acetylsalicylic acid daily. In the next quarter, visits are made approximately every 6-8 weeks on an outpatient basis. Another hospitalization one year after the transplant. In subsequent years, outpatient visits every 3 months. During outpatient examinations, we always perform peripheral blood counts, electrolytes, creatinine levels, eGfr, pancreatic enzymes, urinalysis, C-peptide levels, HBA1, and the concentration of immunosuppressants. Depending on the patient's condition or test results, we can additionally perform imaging tests, e.g. ultrasound. Once a year, we measure the level of tumor markers (CEA, PSA, CA 125, CA 19-9) and CMV DNA. A dermatological evaluation is required at least once a year due to the increased risk of skin cancer after organ transplantation. To our knowledge, it is one of the first observative studies of pancreas recipients vaccinated with a third dose. Italian group reported analysis of 25 PTA and SPK patients who underwent two doses of COVID-19 vaccine. They did not find significant differences in the analyzed parameters: graft function, inflammation, or autoimmune re-activation. 7 patients were found to present elevated d-dimer and 12 increase in C3 factor [15] . Even though the risk of lethal complications from COVID-19 among pancreas transplant recipients was well known, the availability of the vaccine was limited and the onset of vaccinating was delayed. Such trend was not only observed in our cohort. Only two of our patients were vaccinated in January 2021 when the governmental program started, and vaccination was available for healthcare providers and the elderly. Also, patients' hesitation was an important cause of delay in immunization. Tsapepas in a retrospective study analyzed solid organs recipients (kidney or pancreas) who were willing to be vaccinated. 110 out of 320 reached patients were not interested in vaccination. Recipients willing to get the vaccine were older, p<0.001 [16] . Data regarding pancreas recipients is limited. There are however several studies that prove safety among kidney recipients. One adverse event, manifested with the development of donor-specific antibodies, was reported by Massa after the second dose [17] . No cases of graft loss or clinical signs of rejection were observed [17] . We did not observe any serious adverse events and those reported did not differ from side effects reported by healthy vaccinated. Anti-COVID vaccines were designed to develop effective immunity, both humoral based on the production of antibodies against SarsCov-2 and cellular immunity formed by T-lymphocytes. The humoral response, despite being only one part of the immunity, is the easiest to detect and devaluate due to the wide spread use and standardization of tests. IgM antibodies are the first to be detectable in human blood and prove the initial stages of infection. They usually appear in the blood between 3 and 6 days after the beginning of the infection. Around day 8, IgG antibodies that persist after infection and vaccination against COVID-19 can be detected [18] . In our center, antibodies were determined by chemiluminescence. It is based on the measurement of chemiluminescence in the collected blood. It also uses spike protein(S), which in its structure contains a receptor-binding protein (RBD). This domain guarantees the virus gets into the host cell. Antibodies directed against this protein neutralize the virus. The purpose of vaccination is to produce antibodies directed against protein S. Accurate measurement of the post-vaccination humoral response allows to predict whether people are protected from infection. However, it should be remembered that the development of the post-vaccination response is influenced by many individual factors, and it also depends on the type of used vaccine. Antibody values above 33.8 BAU/ml (Binding Affinity Units/ml) were considered positive whereas below 33.8 BAU/ml were considered negative [18] . Vaccination does not prevent healthy volunteers from SarsCoV-2 infection, and patients on immunosuppression seem to be at a higher risk. There are data suggesting that solid graft recipients did not develop sufficient humoral immunization after two doses of the BNT162b2 vaccine and still remained at risk of infection [19, 20] . Even up to 75% of kidney recipients did not have an optimal response [21] . The suboptimal response might be due to immunosuppressive agents [22] . Mycophenolate mofetil (MMF) decreases the proliferation of helper CD+T lymphocytes and interfere with antibody production by lymphocytes B [22] and the exact response of specific SARS-CoV-2 T-cell after vaccination is still not fully proven [23] . Long-term care for patients after organ transplantation involves the need to respond to various population situations -such as pandemics, changes in the availability of immunosuppressive drugs, but also individual -such as planning procreation and the need to modify and change immunosuppressive drugs. Caillard et al. basing on preliminary results debated the impact of lowering the dose of MMF or replacement with belatacept [22] . The findings of Cucchiari et al. showed that half of the patients with negative antibodies after vaccine developed humoral response and the absence of antibodies does not mean lack of immunity [24] . Dialysis might be responsible for impairment of cellular and humoral response in course of SARS-CoV-2 infection [25] . There is data that the third dose of vaccination provides a sufficient immunization of pancreas and kidney recipients [26, 27] . Also, in our cohort, patients after the third dose were less likely to undergo COVID-19 infection. We excluded patients after Adenovirus vaccinations from the study group, as there were no recommendations from Polish Health Ministry and patients were vaccinated outside our Clinic. What is more, there is some data that adenovirus vaccines (Jansen) provide a worse humoral immunity than mRNA vaccines [21] . of Oxford-Astra Zeneca vaccine and two after BBV152 (Covaxin) [28] . We have previously described the course of COVID-19 in kidney recipients [29] . In our cohort recipients after two doses or three had a mild course of the infection. mRNA vaccines are safe and should be recommended to patients after pancreas transplantation. We observed no severe side effects after vaccination. A third dose should also be considered, as our data as well as other observations, prove that immunization gained after an additional dose seems to be sufficient to prevent infection. Legend Figure Figure 1 Distribution of the type of vaccination, dose I and/or II ASTS: Transplant Capacity in the COVID-19 Era and Early Vaccine Recommendations Guidance from the International Society of Heart and Lung Transplantation regarding the SARS CoV-2 pandemic REVISED COVID-19 Vaccination in Our Transplant Recipients: The Time is Now; Saima Aslam COVID-19 Vaccine FAQ Sheet American Society of Transplantation: COVID-19 Vaccine FAQ Sheet (released 12/8/2020) SARS-CoV-2 vaccination in patients with liver disease: responding to the next big question Guidance Focused Review: SARS-CoV-2 Vaccines in Transplant Recipients. 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Transplantation The Course of SARS-CoV-2 in a Patient After a Recent Kidney Transplant: A Literature Review on COVID-19 Therapy Patients who had lower IGGs after second dose more often developed SARS-CoV-2 infection in further coursep<0,001