key: cord-0766683-95fcz3mp authors: Boudhabhay, Idris; Serris, Alexandra; Servais, Aude; Planas, Delphine; Hummel, Aurélie; Guery, Bruno; Parize, Perrine; Aguilar, Claire; Dao, Myriam; Rouzaud, Claire; Ferriere, Elsa; Knebelmann, Bertrand; Sakhi, Hamza; Leruez, Marianne; Joly, Dominique; Schwartz, Olivier; Lanternier, Fanny; Bruel, Timothée title: COVID-19 outbreak in vaccinated patients from a hemodialysis unit: antibody titers as a marker of protection from infection date: 2022-02-01 journal: Nephrol Dial Transplant DOI: 10.1093/ndt/gfac016 sha: 32ff240c6d550b52b439b202edecad2095190ba2 doc_id: 766683 cord_uid: 95fcz3mp BACKGROUND: Patients on maintenance hemodialysis have an increased risk of severe COVID-19 and a reduced response to vaccines. Data are needed to identify immune correlates of protection in this population. METHODS: Following a COVID-19 outbreak among vaccinated patients in a hemodialysis unit, clinical data and serological response to BNT162b2 vaccine were retrospectively recorded. RESULTS: Among fifty-three patients present in the dialysis room, fourteen were infected by SARS-CoV-2 alpha variant (COVID_Pos) and 39 were not. In comparison to uninfected patients, COVID_Pos patients more frequently had additional causes of immunosuppression (50% vs 21%, p = 0.046), and were more often scheduled on the Monday-Wednesday-Friday (MWF) shift (86% vs 39%, p = 0.002). Moreover, COVID_pos had lower anti-Spike IgG titers than uninfected patients (24 BAU/ml [3–1163] vs 435 BAU/mL [99–2555], p = 0.001) and lower neutralization titers (108 [17–224] vs 2483 [481–43 908], p = 0.007). Anti-Spike and neutralization antibody titers are correlated (r = 0.92, p < 0.001). In multivariable analysis, MWF schedule (OR = 10.74 (1.9–93.5), p = 0.014) and anti-spike IgG titers one month before the outbreak (<205 BAU/ml: OR = 0.046 (0.002–0.29), p = 0.006) were independently associated with COVID-19 infection. None of the patients with anti-Spike IgG above 284 BAU/mL got infected. Ten out of fourteen COVID_Pos patients were treated with Casirivimab and Imdevimab. No patient developed severe disease. CONCLUSIONS: Anti-spike IgG titer measured prior to exposure correlates to protection from SARS-CoV-2 infection in hemodialysis patients. BNT162b2 vaccination alone or in combination with monoclonal antibodies prevented severe COVID-19. patients. 1 Patients on hemodialysis are vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (coronavirus disease 2019 ), with reported mortality rates over 20%. [2] [3] [4] Consequently, patients on dialysis were among the first to be vaccinated against SARS-CoV-2 in France. However, the effectiveness of vaccination is often lower in these patients as compared to healthy subjects. 5, 6 After two injections of BNT162b2, between 79 and 90% of hemodialysis patients seroconvert, a rate above kidney transplant recipient's, but below the general population's. [7] [8] [9] [10] [11] Moreover, real-world data on vaccine efficacy or immune correlates of protection are not yet available for this particular population. Thus, the retrospective investigation of breakthrough infections in vaccinated dialyzed patients is of critical importance to optimize prophylactic and therapeutic interventions in ESRD patients. Here, we described an epidemic cluster of SARS-CoV-2 alpha variant in our dialysis unit, two months after the end of the vaccination campaign. We report patient's outcomes, provide our feedback on the epidemic management, and identify a correlate of protection for this outbreak. We performed a retrospective mono-centric study in the hemodialysis unit of Necker Hospital, Paris, France, following an outbreak of SARS-CoV-2 alpha variant infections among patients. In April 2021, 53 patients, rotating in two shifts, either Monday-Wednesday-Friday (MWF) or Tuesday-Thursday-Saturday (TTS), were undergoing hemodialysis in our unit. The dialysis unit is a single room containing 14 hemodialysis stations (Figure 1) Lymphopenia was defined as a lymphocyte count <1 G/L. Humoral response against SARS-CoV-2 was assessed on sera collected before vaccination (referred to as M-3), one month after the second vaccine dose (M-1), and at the beginning of the outbreak (M0). The outbreak occurred one month after the M-1 timepoint. Anti-SARS-CoV-2 IgG antibodies directed against the spike protein and the RBD domain of the S1 subunit were measured using CMIA (chemiluminescent microparticle immunoassay) (Figure 2) . (Table 1) , and in accordance with the local recommendations, we decided to treat 10 out of the 14 COVID_Pos patients with monoclonals antibodies (mAbs) (Casirivimab (1200mg) and Imdevimab (1200mg) (120 mg/mL, Roche)). Six patients were hospitalized because of COVID-19 (including one patient who refused vaccination), but none required more than 3 L per min of oxygen ( Table 1) . None of the COVID_Pos patients died. Of note, one patient developed hypotension after the mAb infusion, which resolved quickly after crystalloid infusion. Most of the cases were diagnosed on the MWF shift (86% of the COVID_Pos patients). There was no statistically significant difference between COVID_Pos and COVID_Neg patients Table 2 ) and on the MWF schedule than in the TTS schedule (46% vs 11%, p=0.01) ( Table 3) . Anti-S IgG and neutralization titers of the vaccinated patients were retrospectively measured at the peak of humoral response to vaccination, i.e. one month after the last vaccine dose 3E ). Evolution of neutralization titers overtime showed that in the COVID_Neg group, titers wanned, whereas antibody titers rose in the COVID_Pos group, to reach levels comparable to those of the COVID_Neg group ( Figure 3F) . In multivariable analysis, MWF schedule (OR=10.74 (1.9-93.5), p=0.014) and M-1 anti-spike (S) antibodies levels (>205 BAU/ml: OR=0.046 (0.002-0.29), p=0.006) were independently associated with COVID-19 infection ( Table 4) . Here, we report an outbreak of SARS-CoV-2 alpha variant in a dialysis unit, two months after the end of the vaccination campaign, showing that neutralizing titers and anti-S IgG levels can be correlated with the risk of infection. Our data further support the protecting effect of vaccination either alone or in combination with mAb therapy in this population. Identifying immune correlates of protection from SARS-CoV-2 is critical to forecast individual protection and determine if/when a booster dose is needed. Currently, detection of neutralizing antibodies is considered as the best predictive factor of protection against SARS-CoV-2 infection. [14] [15] [16] It has been suggested that the peak neutralizing titer (measured in the month following complete vaccination) is a marker of the overall immune response and is more predictive of protection than the peri-infection neutralizing titer. 17 infection. Indeed, anti-N IgGs wane faster than anti-S. 22 . Serological assay using N as target are thus slightly less sensitive than those using S. 22 Our study would also have been enriched by studying cellular immunity. The lack of viral genome sequencing may mislead our interpretation of the outbreak, as previously observed. 24 Finally, our findings may not be generalizable to more recent variants such as Omicron. Indeed, emergence of variants harboring mutations within epitopes targeted by neutralizing antibodies is associated with increase in breakthrough infection. On one hand it confirms the link between neutralization and vaccine efficacy, on the other hand, it stresses the need to reevaluate of correlate of protection as new variants emerged. Importantly, the concept of an humoral correlate of protection will likely remains valid regardless of variant, but it is also likely that the levels of antibodies required for protection will rise as new variants emerged. Thus, an update of vaccine to elicit broadly neutralizing antibodies may be needed. In addition, the most recent variant Omicron escapes most of therapeutic monoclonal antibodies, including Casirivimab and Imdevimab used in our study. 25 Thus, the strategy presented here is predicted to be ineffective against Omicron. 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All variables with a P value <0.2 in univariable analysis were included in the multivariable analysis. Stepwise backward selection based on the Akaike information criterion was used for the final multivariable model We thank William Henry Bolland for critical reading of the manuscript and members of the Virus and Immunity Unit for discussions and help.