key: cord-0743533-cgrpaat8 authors: Frantzen, Luc; Thibeaut, Sandrine; Moussi-Frances, Julie; Indreies, Monica; Kiener, Clotilde; Saingra, Yannick; Santini, Julien; Stroumza, Paul; El-Haik, Yohan; Cavaille, Guilhem title: COVID-19 Vaccination in Haemodialysis Patients: Good things come in threes… date: 2021-07-20 journal: Nephrol Dial Transplant DOI: 10.1093/ndt/gfab224 sha: 80ca25ef0d50d7a95b15bc7eb4d2163c1af7d21c doc_id: 743533 cord_uid: cgrpaat8 nan INTRODUCTION Dialysis patients are particularly vulnerable to SARS-CoV-2 infection, which justifies their priority access to vaccination in many countries. Even though their vaccine response level can be regarded as excellent (around 90%), several studies [1, 2, 3] have nonetheless found antibody titers significantly lower than those observed in the general population. In this context, the French National Authority for Health recommended to adjust vaccination schedules in haemodialysis patients and administer a third dose. We had already presented [4] the serological response (by quantifying antibodies directed against the Spike protein using the Elecsys® Anti SARS-CoV-2 S enzyme immunoassay) of 244 consecutive patients who had received two injections of the BNT162b2 mRNA vaccine in January and February (three weeks apart) in our dialysis centers, showing a vaccine efficacy rate of 95% one month after the second injection (V2M1). However, the vaccine response varied among patients as 58% presented antibody levels above 250 U/ml, 32% had suboptimal response (levels between 15 and 250 U/ml), 5% had insufficient response (levels between 0.8-15 U/ml) and 4% had no seroconversion (levels < 0.8 U/ml). In April, French health authorities recommended the injection of a third dose of mRNA vaccine for severely immunocompromised people, including dialysis patients. This third injection should take place at least 4 weeks after the second dose, or as soon as possible for people who have already exceeded this time. The French Speaking Society of Nephrology, Dialysis and Transplantation (SFNDT) will quickly qualify this recommendation by proposing to adapt the vaccination schedule according to the response to the first two injections. Following these recommendations, we started administering the third dose in early May to all patients with antibody titers below 250 U/ml (corresponding to a vaccination schedule M0-M1-M4) except for the patients with no seroconversion, who had already been vaccinated in early April (vaccination schedule M0-M1-M3). Since we did not have any information about the efficacy of this third injection, we have proceeded with serology testing one month after the injection (V3M1) in order to guide the management of our patients. This time we decided to dilute our reagent to allow measurements up to 25000 U/ml. We have been able to assess the response to the third injection for 88 of our 102 patients presenting antibody titers below 250 U/ml one month after the second injection. 14 patients were excluded: 1 departure, no third injection for 3 of them, lack of data for 5 of them, 1 patient suffering from SARS-CoV-2 infection in the meantime Table 1 . Vaccine tolerability was excellent with no serious adverse event during this third vaccination campaign. The results go far beyond our expectations. The third vaccine injection enabled an impressive increase of the median antibody level from 55 U/ml (V2M1) to 3897 U/ml (V3M1) (Figure 1 ). Those results are highly relevant since they apply both to the subgroup of 71 patients who had a suboptimal initial response to vaccination (between 15 and 250 UI/ml), with a median antibody level increasing from 79 to 5061 U/ml, and to the subgroup of 17 patients who had no significant vaccine response (antibody titers < 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 15U/ml or no seroconversion at all) with a median antibody level rising from 3 to 486 U/ml ( Figure 2 ). Only two patients with no seroconversion following the first two injections show no response to the third injection. These two individuals are highly immunocompromised patients (pancreas transplant and haemopathy with ongoing treatment). Before administering the third dose, we measured the antibody levels three months after the second injection (V2M3) in the 82 patients with seroconversion. There was a slight decrease in levels between V2M1 (median: 55 U/ml, IQR: 26-116) and V2M3 (median level 50 U/ml, IQR: 25-82). What about the 3rd vaccine for the other patients of our initial cohort with antibody levels above 250 U/ml after the first 2 injections ? At first glance these patients seemed to have an «optimal» vaccine response, but on closer inspection we realized that we did not know their exact antibody level (because we had not diluted the reagent above 250U/ml for our measurements at V2M1). However, the studies by Berar Yanay, Simon and Grupper [1, 2, 3] show that HD patients present highly diminished SARS-CoV-2 S antibody titers compared to a cohort of controls. Simon and al, using the same assay as our team (with a dilution allowing measurements up to 2500 U/ml), find an average antibody titer of 170 U/ml in their whole cohort after 2 injections of the BNT162b2 mRNA vaccine, widely below the average antibody titer of 3897 U/ml observed in our cohort (of initially hypo-responders…) after the third injection. It is therefore necessary to consider all dialysis patients as low responders compared to the general population. In this context, trying to assess which dialysis patients would only require 2 doses seems delicate and potentially dangerous for this particularly fragile population. This attitude would waste time and would also require control serologies (currently not reimbursed in France). There is also the question of the timing of the 3rd dose. Our work was not designed to answer this question. However, since 40% of our cohort had a suboptimal or even insufficient response, it seems lawful to offer the 3rd vaccine quickly to all dialysis patients. Based on our observations and lack of other similar studies, we feel that it makes sense to administer the 3rd vaccine 1 month after the 2nd dose. 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 Our work has methodological limitations because the initial purpose was not to conduct a scientific study but a study allowing us to design the best protocol for our local vaccination management due to a lack of clear scientific data among haemodialysis patients. We have therefore proceeded with serology testing in order to provide better guidance for our strategy and obtain maximum protection for this vulnerable population. Another limitation is the lack of knowledge regarding the correlation between the antibody level and the optimal protection level. An antibody level above 200 U/ml correlates with maximal neutralizing capacity in the neutralization assays for the Elecsys® Anti SARS-CoV-2 S test. Nonetheless, despite initial antibody levels that were sometimes low, our patients were rapidly protected after the second injection with a rapid decrease in new case occurrences in our dialysis centers two weeks after the second injection while the rest of the region was severely affected by the COVID-19 epidemic. Nevertheless, in haemodialysis, the third vaccine injection seems vital in order to obtain vaccine protection probably close to that acquired by the general population after 2 doses [2] and secure better efficacy against variants. Finally, we adopted a vaccination schedule with three doses at one month intervals (M0-M1-M2) for all our haemodialysis patients (except for those with previous SARS-CoV-2 infection). By extrapolating our biological results, this schedule will enable to achieve very robust vaccine coverage for more than 95% of our haemodialysis patients. Haemodialysis patients who have received a third dose of the BNT162b2 mRNA vaccine present a spectacular increase in anti-Spike antibodies, with levels close to those of the general population. The implementation of a three-injection vaccination schedule seems therefore crucial to ensure maximum and lasting protection in this particularly vulnerable population to SARS-CoV-2 infection. The authors declare that the results presented in this paper have not been published previously in whole or part. None of the authors does present a conflict of interest. 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 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 60 Page 10 of 15 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 Page 11 of 15 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 83x252mm (300 x 300 DPI) Page 12 of 15 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 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 90x253mm (300 x 300 DPI) Page 14 of 15 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 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 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 haemodialysis cohort