key: cord-1047268-hfb9hyly
authors: Kastritis, Efstathios; Terpos, Evangelos; Evangelakou, Zoi; Theodorakakou, Foteini; Fotiou, Despina; Manola, Maria S.; Gianniou, Despoina D.; Bagratuni, Tina; Kanellias, Nikolaos; Migkou, Magdalini; Gavriatopoulou, Maria; Trougakos, Ioannis P.; Dimopoulos, Meletios A.
title: Kinetics of anti‐SARS‐CoV‐2 neutralizing antibodies development after BNT162b2 vaccination in patients with amyloidosis and the impact of therapy
date: 2021-11-23
journal: Am J Hematol
DOI: 10.1002/ajh.26406
sha: 4d8dfbddd5ec6a65f7f8ac9c19e918e53ca55ce2
doc_id: 1047268
cord_uid: hfb9hyly

nan

dose of the vaccine). NAbs against SARS-CoV-2 were measured using an FDA approved surrogate assay (ELISA, cPass™ SARS-CoV-2 NAbs Detection Kit; GenScript, Piscataway, NJ). We used the 30% inhibition cut-off for this surrogate NAbs test as previously suggested 10 ; a titer of at least 50% is considered a clinically relevant threshold for viral inhibition. 11 The study was approved by the respective Ethical Committees in accordance At the time of vaccination, 66 (52%) patients with AL amyloidosis were on active therapy, 29 (24%) were on daratumumab-based therapy, 8 Figure 1A ).

In univariate analysis, factors associated with NAb titers on D50 included age (p < .001), lymphocyte counts (p < .001), serum albumin of those who were not on therapy. There was no difference in the baseline NAb titers among those on or off active therapy, while on D22 (i.e., after 1st dose) the NAbs titer was higher among those on therapy but statistical difference was marginal (median 30% vs. 19.6%, p = .052). Thus, after the second dose, the response among those not on therapy was substantially more robust than in patients receiving anti-clonal therapy ( Figure 1B) . Notably, on D22, NAb titers among AL patients not on active therapy were still significantly lower as compared to non-AL controls (median 27.9 vs. 46.7%, p < .001) as well as on D50 (median 91.6% vs. 95.6%, p < .001). Using receiver operating characteristic (ROC) analysis, we found that at least 3 months since the last dose of therapy were associated with significantly higher probability of ≥50% NAbs on D50 (sensitivity: 62%, specificity: 80%, AUC: 0.690, p = .001).

Among patients on treatment, there was no significant difference between those on bortezomib-based therapy (VCD) versus those on daratumumab-alone therapy, those on daratumumab with VCD or those on IMiDs, or those with current or prior use of cyclophosphamide. Active therapy containing daratumumab did not affect NAbs titers among patients on active therapy (median NAb titer was 52.1% Generalized linear models after normalization of NAb titers, were used for evaluation of multiple factors associated with D50 NAb titers (Table S3) . Specifically, at least 3 months since the last dose of anticlonal therapy (p < .001), lymphocyte counts (p = .001) and serum albumin levels at the time of vaccination (p = .020) were independent predictors of NAb titers on D50.

Focusing on significant (i.e., protective) seroconversion (defined as NAbs titer ≥50% at D50), we performed a multiple logistic regression analysis. In this analysis, >3 months of treatment-free interval (OR: 7.75, p < .001), was the strongest predictive factor associated with activation of humoral immune responses (Table S2) .

Among the patients in the study, one was infected and developed very mild symptoms after the first and before the second dose and two patients were infected but remained completely asymptomatic more than 2 weeks after the second dose (in both testing was performed because of close home contact with an infected individual).

We also compared NAbs titers of patients with ATTR wt (N = 22) to age and gender matched controls (N = 44, 1:2 matching, median vs. 94.2%, p = .546) ( Figure S1 ).

The data presented in this report indicate that patients with AL amyloidosis have an attenuated humoral response to vaccination with BNT162b2, as compared to matched controls. Our analysis indicates that the most important factor that negatively affects the development of NAbs after vaccination for COVID-19 is the administration of active anti-clonal therapy. This data point to the major immunosuppressive role of anti-plasma cell therapy but also to the immunosuppressive effect of the underlying plasma cell clone, even though the impact may be low. Thus, patients with AL amyloidosis do not differ significantly in their response to vaccination than patients with myeloma (data published from our group 5,6 and others 7, 8 ). Specifically, we recently reported that antibody response after vaccination with BNT162b2 in patients with myeloma depends on the type of antimyeloma treatment. 6 In the current study, in patients with AL amyloidosis, we observed that the use of daratumumab as part of the treatment regimen did not significantly affect antibody response, among those on active therapy, while prior exposure to daratumumab, also did not have any additive immunosuppressive effect. Data from our group in patients with myeloma indicated that daratumumabbased therapy was associated with lower NAb titers 6 ; however, myeloma patients were more heavily pretreated than patients with AL amyloidosis and with more extensive and aggressive clones. In addition, weekly bortezomib with cyclophosphamide (the most widely used regimen in AL amyloidosis) is also associated with significant immunosuppression. Time from the last dose of therapy was a significant factor to predict an adequate antibody response; however, some patients may require more time to restore a fully functional immune system. We observed that a duration of at least 3 months after last dose of anti-clonal therapy before vaccination may affect humoral immune response. In support, in an exploratory analysis, not all patients had recovered lymphocyte counts at the time of vaccination (10% of those not in therapy had lymphocyte counts <1000/μL).

Although it is recommended that a treatment-free period should pre- of concern, including the delta variant, although neutralizing serum responses may be weaker. 14, 15 In a recent paper by Rosati et al., 16 the authors found that anti-spike antibodies from the vaccine recipients (naïve and convalescent) and SARS-CoV-2 convalescent patients show a strong ability to recognize and neutralize the autologous WA1, as well as the Alpha and Delta Spike variants but that they show greatly impaired recognition of Beta, in agreement with others.

Furthermore, they found a strong direct correlation between NAbs against WA1 and Delta variant, supporting the notion that individuals with robust NAb against WA1 also strongly neutralize Delta. This data indicates that a title of NAb >50% may not be as protective against delta variant infection, but the clinically relevant threshold is difficult to define. Finally, in the current study, we did not evaluate the antiviral T and B cell memory responses after vaccination, which may also be affected in patients with AL amyloidosis, and which are also important for protection from the infection.In conclusion, patients with AL amyloidosis have a less robust response to anti-SARS-CoV-2 vaccination as compared to matched controls. Our data point to the critical role of concomitant anti-clonal therapy, which significantly reduced the probability of an adequate antibody response and protective seroconversion. Moreover, our data support the need for additional booster doses, especially for those on active therapy.

Challenges in the management of patients with systemic light chain (AL) amyloidosis during the COVID-19 pandemic

Clinical features associated with COVID-19 outcome in multiple myeloma: first results from the international myeloma society data set

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Low neutralizing antibody responses against SARS-CoV-2 in older patients with myeloma after the first BNT162b2 vaccine dose

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Humoral response rate and predictors of response to BNT162b2 mRNA COVID19 vaccine in patients with multiple myeloma

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Distinct neutralization profile of spike variants by antibodies induced upon SARS-CoV-2 infection or vaccination