Dialysis patients are particularly vulnerable to sudden acute respiratory syndrome coronavirus 2 (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 (~90%), several studies [1–3] have nonetheless found antibody titres significantly lower than those observed in the general population. In this context, the French National Authority for Health recommends adjusting vaccination schedules in haemodialysis (HD) patients and administer a third dose. We have already presented [4] the serological response by quantifying antibodies directed against the Spike protein using the Elecsys Anti-SARS-CoV-2 S enzyme immunoassay (Roche Diagnostics, Mannheim, Germany) of 244 consecutive patients who had received two injections of the BNT162b2 messenger RNA (mRNA) vaccine in January and February (3 weeks apart) in our dialysis centres, showing a vaccine efficacy rate of 95% 1 month after the second injection (V2M1). However, the vaccine response varied among patients, as 58% presented antibody levels >250 U/mL, 32% had suboptimal response (levels between 15 and 250 U/mL), 5% had insufficient response (levels between 0.8 and 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) quickly qualified this recommendation by proposing to adapt the vaccination schedule according to the response to the first two injections. Following these recommendations, we started administering a third dose in early May to all patients with antibody titres <250 U/mL (corresponding to a vaccination schedule Month 0-Month 1-Month 4), except for patients with no seroconversion, who had already been vaccinated in early April (vaccination schedule Month 0-Month 1-Month 3). Since we did not have any information about the efficacy of this third injection, we proceeded with serology testing 1 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 25 000 U/mL. We have been able to assess the response to the third injection for 88 of our 102 patients presenting antibody titres <250 U/mL 1 month after the second injection. Fourteen patients were excluded: one departure, three with no third injection, five with a lack of data, one suffering from SARS-CoV-2 infection in the meantime and four deaths, with three deaths of various causes (exacerbation of chronic obstructive pulmonary disease, septic shock of undetermined origin, heart surgery complications) and one death from SARS-CoV-2 infection in a patient presenting a very weak vaccinal response with an antibody titre of 1 U/mL after two doses. Among the 88 remaining patients, 71 patients initially presented a suboptimal response with antibody levels between 15 and 250 U/mL and 17 with an insufficient response to vaccination. In this last group, 11 patients had a very weak seroconversion (titres <15 U/mL) and six had no seroconversion (levels <0.8 U/mL). It is also worth noting that none of the 88 patients had had any previous coronavirus disease (COVID) infection. The six patients not showing seroconversion were vaccinated 2 months after the second vaccine (schedule Month 0-Month 1-Month 3), while all the other patients (n = 82) received the third dose 3 months after the second vaccine (schedule Month 0-Month 1-Month 4). The clinical characteristics of those patients and their serology responses are presented in Table 1. Patient characteristics and immune response after two and three doses of the BNT162b2 mRNA COVID-19 vaccine Descriptive statistics included the percentages for categorical variables and medians (IQRs) for continuous variables. Comparisons between the two groups according to the presence or absence of a significant antibody level for continuous variables were made using the Student’s t-test or the Mann–Whitney test, according to the variable distribution. Comparisons between the two groups for categorical variables were made using the Pearson’s chi-square test or Fisher’s exact test. A P-value <0.05 was considered significant (shown in bold). The statistical analysis was conducted using R: A language and environment for statistical computing (R Foundation for Statistical Computing, Vienna, Austria). Pancreatic graft. With ongoing treatment. Patient characteristics and immune response after two and three doses of the BNT162b2 mRNA COVID-19 vaccine Descriptive statistics included the percentages for categorical variables and medians (IQRs) for continuous variables. Comparisons between the two groups according to the presence or absence of a significant antibody level for continuous variables were made using the Student’s t-test or the Mann–Whitney test, according to the variable distribution. Comparisons between the two groups for categorical variables were made using the Pearson’s chi-square test or Fisher’s exact test. A P-value <0.05 was considered significant (shown in bold). The statistical analysis was conducted using R: A language and environment for statistical computing (R Foundation for Statistical Computing, Vienna, Austria). Pancreatic graft. With ongoing treatment. Vaccine tolerability was excellent with no serious adverse events 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). Evolution of the antibody level after the second and third vaccine. 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 titres <15 U/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 showed no response to the third injection. These two individuals are highly immunocompromised patients (pancreas transplant and haemopathy with ongoing treatment). Evolution of the vaccine response according to the response after the second dose. Before administering the third dose we measured the antibody levels 3 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 [interquartile range (IQR) 26–116]} and V2M3 [median 50 U/mL (IQR 25–82)]. What about the third vaccine for the other patients of our initial cohort with antibody levels >250 U/mL after the first two 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 >250 U/mL for our measurements at V2M1). However, the studies by Berar Yanay et al. [1], Simon et al. [2] and Grupper et al. [3] show that HD patients present highly diminished SARS-CoV-2 S antibody titres compared with a cohort of controls. Simon et al. [2], using the same assay as our team (with a dilution allowing measurements up to 2500 U/mL), found an average antibody titre of 170 U/mL in their whole cohort after two injections of the BNT162b2 mRNA vaccine, considerably less than the average antibody titre of 3897 U/mL observed in our cohort (of initially hyporesponders) after the third injection. It is therefore necessary to consider all dialysis patients as low responders compared with the general population. In this context, trying to assess which dialysis patients would only require two 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 third 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 reasonable to offer the third 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 third vaccine 1 month after the second dose. 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 HD 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 >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 decrease in new case occurrences in our dialysis centres 2 weeks after the second injection while the rest of the region was severely affected by the COVID-19 epidemic. Nevertheless, in HD, the third injection seems vital in order to obtain vaccine protection probably close to that acquired by the general population after two doses [2] and secure better efficacy against variants. Finally, we adopted a vaccination schedule with three doses at 1-month intervals (Month 0-Month 1-Month 2) for all our HD patients (except for those with previous SARS-CoV-2 infection). By extrapolating our biological results, this schedule will enable us to achieve very robust vaccine coverage for >95% of our HD patients. HD 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. Therefore, the implementation of a three-injection vaccination schedule seems crucial to ensure maximum and lasting protection in this particularly vulnerable population. None declared.
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