key: cord-0845896-hl39cdp9 authors: Terpos, Evangelos; Gavriatopoulou, Maria; Ntanasis-Stathopoulos, Ioannis; Briasoulis, Alexandros; Gumeni, Sentiljana; Malandrakis, Panagiotis; Papanagnou, Eleni-Dimitra; Migkou, Magdalini; Kanellias, Nikolaos; Kastritis, Efstathios; Trougakos, Ioannis P; Dimopoulos, Meletios A title: Booster BNT162b2 Optimizes SARS-CoV-2 Humoral Response in Myeloma Patients; the Negative Effect of anti-BCMA therapy date: 2022-01-07 journal: Blood DOI: 10.1182/blood.2021014989 sha: 9eff507dad1d952443ef04e0f51fe746e4d13bf9 doc_id: 845896 cord_uid: hl39cdp9 nan References: 24/25 The rapid development of safe and effective vaccines is imperative to attenuate the impact of COVID-19 pandemic. 1 Patients with multiple myeloma (MM) are at increased risk of infections mainly due to advanced age, immunocompromised status and concurrent comorbidities. 2, 3 Among non-vaccinated patients with MM and COVID-19, 77% experience moderate and severe symptoms, including the need for hospitalization. [3] [4] [5] Furthermore, approximately one third of MM patients with COVID-19 who require hospitalization are at high risk for death. 4, 6, 7 Recent data indicate that COVID-19 vaccination leads to a less intense humoral response in MM patients primarily in those without prior exposure to SARS-CoV-2, as reflected by a lower production of neutralizing antibodies (NAbs), compared with healthy controls. 8, 9 Active treatment with anti-BCMA regimens or anti-CD38 monoclonal antibodies that deplete B-cells, are considered as the main negative prognostic factors for antibody production after full vaccination. 9, 10 Vaccines have managed to reduce severe forms of covid-19. 11-13 However, the declining humoral immunity in time and the emergence of new SARS-CoV-2 variants have necessitated the administration of a booster vaccine dose. 14 A third BNT162b2 dose in adults aged 60 years and older was associated with significantly increased IgG titers after 10 to 19 days, with no major adverse toxicity. 15 Similar results have been reported among immunocompetent health care workers, as well as among transplant recipients. [16] [17] [18] In this context, we prospectively evaluated the development of neutralizing antibodies (NAbs) against SARS-CoV-2 in patients with MM at 30 days post vaccination with a third dose of the mRNA BNT162b2 vaccine (NCT04743388). Major inclusion criteria for the participation of patients in this study included: age above 18 years, presence of active MM according to International Myeloma Working Group criteria, 19 and eligibility for vaccination with a third dose. Major exclusion criteria included the presence of: autoimmune disorder or other active malignant disease, HIV or active hepatitis B and C infection, end-stage renal disease, and prior diagnosis of COVID-19. Dexamethasone administration was held 2 weeks before until 1 week after each vaccine shot. No other modifications in the treatment regimens were applied. The study was approved by the Institutional Ethics Committee of General Hospital Alexandra, Athens, Greece. All patients provided written informed consent prior enrollment in the study. Serum samples were collected on the date of the booster dose (just before vaccination) and 4 weeks after. NAbs against SARS-CoV-2 were measured using an FDA approved methodology (ELISA, cPass™ SARS-CoV-2 NAbs Detection Kit; GenScript, Piscataway, NJ, USA). 20 A NAb titer of ≥30% is considered as positive, whereas a NAb titer of ≥50% has been associated with clinically relevant viral inhibition. 21 All statistical analyses were performed with STATA (version 17.0, College Station, Texas). All variables were tested for normal data distribution. Non-normally distributed data were presented as the median with the interquartile range (IQR). For categorical variables, the χ2 or Fisher exact test were used to compare the distributions for the two randomized groups. The study population included 167 consecutive MM patients (58% males; median age: 68 years, IQR: 60-75 years) who were vaccinated with the booster BNT162b2 dose between September/October 2021, at the same vaccination center. All patients had been fully vaccinated with the two-dose BNT162b2, participated in the respective study for detecting NAbs after their vaccination with two vaccine doses (NCT04743388), had available NAbs titers one month after their second vaccine dose (Day 50 after the first dose) and received a booster Table 1 . The booster dose significantly improved the humoral response in MM patients. More specifically, the median (IQR) of NAbs titer reached 96.7% (52.6-97.8%) as compared with 27.1% (13.9%-65.8%) before the third dose (p<0.001) (Fig. 1, Suppl. Fig. 1 ). Overall, 114 (68%) patients had less than 50% NAb activity before the third dose. Among them, 75 (65.8%) patients increased their NAb titer to at least 50% after the third dose. Interestingly, the patients who had achieved a NAbs titer of ≥50% at one month after the second vaccine dose were more likely to achieve a NAbs titer of ≥50% at one month after the third dose, as compared with those who had inferior antibody responses after the second dose (p=0.001). Fifty-seven (34%) patients had not developed a sufficient humoral response following the second vaccination (NAbs titer <30%). All of them presented with low NAbs titers before the third dose (median 14.5% (IQR 7.2%-23.3%)). The third vaccine dose boosted the median antibody response to 38.8% (IQR 15.6%-92.3%, p<0.001). At one month after the booster dose, 32/57 (56%) patients showed a NAbs titer above the positivity threshold (≥30%) and 26/57 (45.6%) showed a NAbs titer of ≥50%. In addition to the above, the third dose improved the humoral response for patients with NAbs ≥30% after the second vaccine shot. Among these patients, the median NAb activity reached 97.56% (IQR 95.6%-97.9%) (vs. 43% (30.0%-80.0%) before the third dose, p<0.001). Similar results were shown according to the 50% cut-off value of NAbs at one month after the second dose (p<0.001 for all comparisons). Our study demonstrated that a third BNT162b2 dose in patients with MM optimized the humoral response against SARS-CoV-2, as depicted by the significant increase in NAbs at one month post the booster dose. Importantly, ~46% of patients with suboptimal NAbs responses at one month following the two-dose BNT162b2 vaccination showed NAbs titers over 50% at one month after the booster dose. These results are in accordance with the improved humoral response after a third dose of mRNA-1273 vaccine that induced 49% responses of kidney transplant recipients who did not respond after 2 vaccine doses 22 and the improved seropositivity of the third BNT162b2 dose in adults aged 60 years and older. 15 These responses have been associated with lower rates of confirmed infections and severe disease. One of the main strengths of our study is the evaluation of NAbs, which have been shown to have an important predictive value of immune protection from symptomatic COVID-19. 23, 24 Therefore, NAbs levels can be considered as significant surrogates of vaccine efficacy. The main limitations of our study include the relevant limited number of patients enrolled, the absence of 7 data on T-cell induced immune responses following booster vaccination against SARS-CoV-2 and the short follow-up period. During this time period, ie one month after the booster dose, no COVID-19 cases were reported. Thus, a longer follow-up will reveal any impact of the booster vaccination on hospitalization and deaths due to COVID-19. In conclusion, although patients with MM have an inferior humoral response against SARS-CoV-2 after vaccination with 2 doses of BNT162b2, a booster dose enhances the NAbs response significantly. However, several patients do not achieve sufficient antibody response, especially those on treatment with anti-BCMA therapeutics. Importantly, these patients should be considered for treatment with monoclonal antibodies against SARS-CoV-2 since they are at high risk for severe COVID-19. Taking also into consideration the defective immunity in patients with MM and the current COVID-19 outbreaks, self-protection measures, such as mask wearing and social distancing, remain particularly important. however, a significant increase in NAbs was evident at one month after the booster dose (p<0.001). 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The Lancet Microbe Funding: We thank SYN-ENOSIS (Greece) and IEMBITHEK (Greece) for partially funding this study.