key: cord-1003067-7gexxgcm authors: Longlune, Nathalie; Nogier, Marie Béatrice; Miedougé, Marcel; Gabilan, Charlotte; Cartou, Charles; Seigneuric, Bruno; Del Bello, Arnaud; Marion, Olivier; Faguer, Stanislas; Izopet, Jacques; Kamar, Nassim title: High immunogenicity of a messenger RNA based vaccine against SARS-CoV-2 in chronic dialysis patients date: 2021-05-31 journal: Nephrol Dial Transplant DOI: 10.1093/ndt/gfab193 sha: c3c100ca64c60456a397ee40ff7457b1f820465b doc_id: 1003067 cord_uid: 7gexxgcm BACKGROUND: Patients with chronic kidney disease, dialysis patients and kidney-transplant patients are at high risk of developing severe coronavirus disease-19 (COVID-19). Data regarding the immunogenicity of anti-Severe Acute Respiratory Syndrome coronavirus-2 messenger RNA (anti-SARS-CoV-2 mRNA) vaccines in dialysis patients were published recently. We assessed the immunogenicity of anti-SARS-CoV-2 mRNA vaccine in dialysis patients. PATIENTS AND METHODS: One hundred-nine patients on hemodialysis (n = 85) or peritoneal dialysis (n = 24) have received two injections of 30-μg doses of BNT162b2 mRNA COVID-19 Vaccine (Pfizer-BioNTech), that were administered intramuscularly 28 days apart. Those who were still seronegative after the second dose were given a third dose one month later. Anti-SARS-CoV-2 antibodies were tested before and after vaccination. RESULTS: Ninety-one out of the 102 patients who had at least a one-month follow-up after the second (n = 97) or the third (n = 5) vaccine doses had anti-SARS-CoV-2 antibodies. The seroconversion rate was 88.7% (86 out of 97 patients) among SARS-CoV-2 seronegative patients at the initiation of vaccination. Receiving immunosuppressive therapy was an independent predictive factor for non-response to vaccination. CONCLUSION: Due to high immunogenicity and safety of mRNA vaccines, we strongly recommend prioritizing a two-doses vaccination of dialysis patients. A third dose can be required in non-responders to two doses. When possible, patients waiting for a kidney transplantation, should be offered the vaccine before transplantation. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 -The study shows a high immunogenicity and safety of mRNA vaccines in dialysis patients -It shows that patients given immunosuppresssants have a weak immunological response -It shows that a third dose vaccine may be useful in non-responders to 2-doses. -Dialysis patients should be prioritized to be vaccinated -All patients awaiting for a kidney transplantation should be offered the vaccine Nephrology Dialysis Transplantation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 we assessed the immunogenicity of anti-SARS-CoV-2 mRNA vaccine in a population of patients on hemodialysis or peritoneal dialysis given two or three doses vaccine. Since anti-SARS-CoV-2 vaccines became available in France in January 2021, they were proposed to all patients undergoing hemodialysis or peritoneal dialysis in the dialysis unit of Toulouse University Hospital, a tertiary hospital. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Eighty-eight of the 132 hemodialysis patients gave their consent to be vaccinated (66.7%) ( Figure 1 ). Of the remaining patients, 33 patients decline the vaccine, 9 patients had been infected by the SARS-CoV-2 within the last three months, and 2 patients had an ongoing medical complication requiring hospitalization. Eighty-five out the 88 patients had received at least two doses. Twenty-four of the 33 patients on peritoneal dialysis gave their consent to be vaccinated (72.7%) ( Figure 2 ). Of the remaining patients, 7 patients decline the vaccine, and 2 patients had been infected by the SARS-CoV-2 within the last three months. All 24 patients had received two doses. The characteristics of patients who received the vaccine are presented in Table 1 . According to French law (loi Jardé), anonymous retrospective studies do not require institutional review board approval. Two injections of 30-μg doses of BNT162b2 mRNA COVID-19 Vaccine (Pfizer-BioNTech), were administered intramuscularly 28 days apart. Vaccines were given at the dialysis center the day of dialysis session. A third dose vaccine was proposed to patients who were still seronegative at one month after the second dose, i.e. at one month after the second dose. After vaccination, patients were under medical surveillance for 30 minutes. Total antibodies against SARS-CoV-2 in serum samples were tested using an enzyme linked immunosorbent assay (ELISA) kit supplied by Beijing Wantai Biological Pharmacy Enterprise Co., Ltd., China, according to the manufacturer's instructions. Briefly, the ELISA for total antibodies detection was developed based on double-antigens sandwich immunoassay, using mammalian cell expressed recombinant antigen containing the receptor binding domain of the 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 6 spike protein of SARS-CoV-2 as the immobilized and HRP conjugated antigens. Samples were considered as positive if the S/Co was > 1. 1 [18] . Antibodies concentrations were also determined. Data are presented either as means (± SD) or medians (ranges). Proportions were compared by the  2 test or Fisher's exact test. Quantitative variables were compared by either Student's t-test or the Mann-Whitney test. Independent factors associated with non-response to vaccine were studied using a stepwise multivariate logistic regression model that used initial inclusion criteria that had a significance of p <0.05. A p-value of <0.05 was considered to be statistically significant. Before vaccination, anti-SARS-CoV-2 antibodies were detected in 5 out of the 88 patients (5.7%) ( Figure 1 ). All five patients had previously presented symptomatic COVID-19. After the first dose, one patient who was still seronegative developed one week after vaccination a symptomatic COVID-19 requiring hospitalization, another one who was also seronegative had undergone a heart transplantation and unfortunately deceased of multiorgan failure, and finally a third one who was seropositive (due to COVID-19 followed by a single vaccine dose) had Transplantation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 that time, anti-SARS-CoV-2 antibodies were detected in 69 patients (84.1%): 5 patients who were already positive before the first dose and 64 patients who seroconverted after vaccination. Among the 13 patients who didn't develop anti-SARS-CoV-2 antibodies after the two-doses vaccines, a third dose was offered to 12 patients. It was given one month after the second dose. The last patient died before the third dose from a cardiovascular event. All 12 patients had a one-month follow-up after the third dose. Of these 5 seroconverted. Hence, overall, anti-SARS- 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 had failed to seroconvert after two vaccine doses. Five of these patients seroconverted. This report of use of a third vaccine dose is encouraging for non-responders. Overall, anti-SARS-CoV-2 antibodies were detected in 89.2%. This high response suggests that mRNA-based vaccines targeting non-SARS-CoV2 viruses could be tested in dialysis patients. After exclusion of patients who were positive at baseline, the seroconversion rate was 88.7%. Our results are in line with those published recently in this setting [11] [12] [13] [14] [15] [16]. In the general population, the seroconversion rate was at 100% at day 21 following vaccination [7] . A lower humoral response was reported in dialysis patients compared to a control group [11] [12] . In the present study, receiving immunosuppressive therapy was an independent predictive factor for non-response to vaccination. This finding is in line with recent data showing a weak immunogenicity of mRNA vaccines after the first dose in solid-organ-transplant patients [8] [9]. Grupper et al. have shown that a low lymphocyte count was associated with a low-humoral response [13] . This study has several limitations. It is a single center in which we measured the humoral response but not the cellular one. Neutralizing antibodies were not assessed. Only the BNT162b vaccine was used. Finally, we didn't compare data in dialysis patients to a control group with normal kidney function. In conclusion, due to high immunogenicity and safety of mRNA vaccines, we strongly recommend prioritizing a two-doses vaccination of dialysis patients. A third dose can be given in non-responders. When possible, patients waiting for a kidney transplantation, should be offered the vaccine before transplantation. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 17. https://www.mesvaccins.net/textes/dgs_urgent_n43_vaccination_modalites_d_adm inistration_des_rappels.pdf. Dialysis Transplantation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Table 1 Abbreviations: M, male; F, female; Y, yes; N, no; mTOR, mammalian target of rapamycin. * Ten out of the 19 patients with history of kidney transplantation had received T-cell depleting agents. For the 19 patients, the time between kidney-allograft loss and vaccination was 36 (4-187) months. ** Four out the 5 patients who had received a non-kidney transplant had received T-cell depleting agents *** Steroids were given in non-kidney-transplant patients, patients with recent kidney allograft loss and patients with recent history auto-immune diseases. In patients with failed kidney allograft, calcineurin inhibitors and anti-metabolites were stopped at the initiation of dialysis and steroids are pursued for 6 months. Nephrology Dialysis Transplantation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 164x265mm (300 x 300 DPI) Nephrology Dialysis Transplantation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 76x251mm (300 x 300 DPI) Page 16 of 19 Nephrology Dialysis Transplantation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 Dialysis Transplantation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 157x265mm (300 x 300 DPI) Page 18 of 19 Nephrology Dialysis Transplantation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 NDT-00518-2021.R1-fig3 Patients on peritoneal dialysis N=33 Patients who received the first dose N=24 Patients who received two doses N=24 Patients with less than 1 month follow-up after the second dose N=4 Patients with 1 month follow-up after the second dose Dialysis Transplantation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 IMPact of the COVID-19 epidemic on the moRTAlity of kidney transplant recipients and candidates in a French Nationwide registry sTudy (IMPORTANT) Of Mice and Men: The Effect of Maternal Protein Restriction on Offspring's Kidney Health. Are Studies on Rodents Applicable to Chronic Kidney Disease Patients? A Narrative Review COVID-19 Among US Dialysis Patients: Risk Factors and Outcomes From a National Dialysis Provider At least 156 reasons to prioritise COVID-19 vaccination in patients receiving in-centre haemodialysis Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine Efficacy and Safety of the mRNA-1273 SARS-CoV Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates Antibody Response to 2-Dose SARS-CoV-2 mRNA Vaccine Series in Solid Organ Transplant Recipients CoV-2 Messenger RNA-Based Vaccines in Recipients of Solid Organ Transplants Practical Guide to Vaccination in All Stages of CKD, Including Patients Treated by Dialysis or Kidney Transplantation Experience with SARS-CoV-2 BNT162b2 mRNA vaccine in dialysis patients Haemodialysis patients show a highly diminished antibody response after COVID-19 mRNA vaccination compared to healthy controls Humoral Response to the Pfizer BNT162b2 Vaccine in Patients Undergoing Maintenance Hemodialysis Efficacy of the BNT162b2 mRNA Covid-19 Vaccine in a hemodialysis cohort Immunogenicity of SARS-CoV-2 Vaccine in Dialysis We thank Mrs C.Duport and Mrs A.Beaudoin for their help for having organized the vaccination, and Mr A.Bertozzi from SINED (Groupe Theradial) for his help for data extraction. The authors have no conflict of interest related to the current paper to declare.