Use of Oral Antivirals Ritonavir-Nirmatrelvir and Molnupiravir in Patients with Multiple Myeloma Is Associated with Low Rates of Severe COVID-19: A Single-Center, Prospective Study.

In patients with multiple myeloma (MM), SARS-CoV-2 infection has been associated with a severe clinical course and high mortality rates due to the concomitant disease- and treatment-related immunosuppression. Specific antiviral treatment involves viral replication control with monoclonal antibodies and antivirals, including molnupiravir and the ritonavir-boosted nirmatrelvir. This prospective study investigated the effect of these two agents on SARS-CoV-2 infection severity and mortality in patients with MM. Patients received either ritonavir-nirmatrelvir or molnupiravir. Baseline demographic and clinical characteristics, as well as levels of neutralizing antibodies (NAbs), were compared. A total of 139 patients was treated with ritonavir-nirmatrelvir while the remaining 30 patients were treated with molnupiravir. In total, 149 patients (88.2%) had a mild infection, 15 (8.9%) had a moderate infection, and five (3%) had severe COVID-19. No differences in the severity of COVID-19-related outcomes were observed between the two antivirals. Patients with severe disease had lower neutralizing antibody levels before the COVID-19 infection compared to patients with mild disease (p = 0.04). Regarding treatment, it was observed that patients receiving belantamab mafodotin had a higher risk of severe COVID-19 (p < 0.001) in the univariate analysis. In conclusion, ritonavir-nirmatrelvir and molnupiravirmay prevent severe disease in MM patients with SARS-CoV-2 infection. This prospective study indicated the comparable effects of the two treatment options, providing an insight for further research in preventing severe COVID-19 in patients with hematologic malignancies.

Second Booster BNT162b2 Restores SARS-CoV-2 Humoral Response in Patients With Multiple Myeloma, Excluding Those Under Anti-BCMA Therapy.

COVID-19 vaccination leads to a less intense humoral response in patients with multiple myeloma (MM) compared with healthy individuals, whereas the SARS-CoV-2-specific immunity fades over time. The purpose of this study was to explore the kinetics of SARS-CoV-2 neutralizing antibodies (NAbs) in patients with MM after vaccination with the BNT162b2 mRNA vaccine, focusing on their response before (B4D) and at 1 month after the fourth vaccination (M1P4D). Overall, 201 patients with a median age of 67 years were included, whereas 114 (56.7%) were men. The median NAbs levels B4D were 80.0% (±3.5%) and at M1P4D they increased to a median value of 96.1% (±3.7%). The NAb values at M1P4D were similar to those at 1 month post the third dose and superior to all previous timepoints. At M1P4D, the NAbs levels of all the treatment groups increased, apart from the anti-BCMA group. A significant increase in median NAbs values was observed for those receiving CD38-based treatment (n = 43, from 71.0% B4D to 96.0% at M1P4D) and those who did not receive CD38- or BCMA-targeted therapy (n = 137, from 89.6% B4D to 96.3% at M1P4D). Regarding the patients under BCMA-based therapy (n = 21), there was no remarkable increase in NAbs values following the second booster shot (from 3.0% B4D to 4.0% at M1P4D). In conclusion, booster vaccination with the BNT162b2 results in a substantially improved humoral response against SARS-CoV-2 in patients with MM. Anti-BCMA treatment remains an adverse predictive factor for NAbs response; thus, tailored prevention measures should be considered for this patient subgroup.

SARS-CoV-2 humoral responses following booster BNT162b2 vaccination in patients with B-cell malignancies.

Patients with B-cell malignancies have suboptimal immune responses to SARS-CoV-2 vaccination and are a high-risk population for severe COVID19 disease. We evaluated the effect of a third booster BNT162b2 vaccine on the kinetics of anti- SARS-CoV-2 neutralizing antibody (NAbs) titers in patients with B-cell malignancies. Patients with NHL (n = 54) Waldenström's macroglobulinemia (n = 90) and chronic lymphocytic leukemia (n = 49) enrolled in the ongoing NCT04743388 study and compared against matched healthy controls. All patient groups had significantly lower NAbs compared to controls at all time points. 1 month post the third dose (M1P3D) NAbs increased significantly compared to previous time points (median NAbs 77.9%, p < .05 for all comparisons) in all patients. NAbs ≥ 50% were seen in 59.1% of patients, 34.5% of patients with suboptimal responses post-second dose, elicited a protective NAb titer ≥50%. Active treatment, rituximab, and BTKi treatment were the most important prognostic factors for a poor NAb response at 1MP3D; only 25.8% of patients on active treatment had NAbs ≥ 50%. No significant between-group differences were observed. Patients with B-cell malignancies have inferior humoral responses against SARS-CoV-2 and booster dose enhances the NAb response in a proportion of these patients.

Comparison of Neutralizing Antibody Responses at 6 Months Post Vaccination with BNT162b2 and AZD1222.

Along with their level of protection against COVID-19, SARS-CoV-2-specific antibodies decline over time following vaccination with BNT162b2. However, relevant data on AZD1222 are scarce. In this context, the aim of this study was to compare SARS-CoV-2 neutralizing antibody (NAb) levels at one, three and six months after second vaccination with the BNT162b2 mRNA vaccine and the ChAdOx1 (AZD1222) viral vector vaccine (NCT04743388). The measurements were performed with the GenScript's cPassTM SARS-CoV-2 NAbs Detection Kit (GenScript, Inc.; Piscataway, NJ, USA). Overall, data from 282 individuals were included (BNT162b2 n = 83, AZD1222 n = 199). Both vaccines induced strong NAbs responses at 1 month following vaccination. Interestingly, NAb activity seemed superior with BNT162b2 compared with AZD1222. A gradual decline in NAbs titers was evident at 3 and 6 months post vaccination with both vaccines. However, the superiority of NAb response with BNT162b2 over AZD1222 remained consistent at all time points examined. Furthermore, the elimination rate of the NAb titer was higher throughout during the study period for those vaccinated with AZD1222 compared with BNT162b2. Age, gender, body mass index or comorbidities did not have a significant impact on NAbs levels over time. Our results may inform public health policies regarding the timing of booster COVID-19 vaccine shots.

Predictive Factors for Neutralizing Antibody Levels Nine Months after Full Vaccination with BNT162b2: Results of a Machine Learning Analysis.

Vaccination against SARS-CoV-2 with BNT162b2 mRNA vaccine plays a critical role in COVID-19 prevention. Although BNT162b2 is highly effective against COVID-19, a time-dependent decrease in neutralizing antibodies (NAbs) is observed. The aim of this study was to identify the individual features that may predict NAbs levels after vaccination. Machine learning techniques were applied to data from 302 subjects. Principal component analysis (PCA), factor analysis of mixed data (FAMD), k-means clustering, and random forest were used. PCA and FAMD showed that younger subjects had higher levels of neutralizing antibodies than older subjects. The effect of age is strongest near the vaccination date and appears to decrease with time. Obesity was associated with lower antibody response. Gender had no effect on NAbs at nine months, but there was a modest association at earlier time points. Participants with autoimmune disease had lower inhibitory levels than participants without autoimmune disease. K-Means clustering showed the natural grouping of subjects into five categories in which the characteristics of some individuals predominated. Random forest allowed the characteristics to be ordered by importance. Older age, higher body mass index, and the presence of autoimmune diseases had negative effects on the development of NAbs against SARS-CoV-2, nine months after full vaccination.

Sustained but Declining Humoral Immunity Against SARS-CoV-2 at 9 Months Postvaccination With BNT162b2: A Prospective Evaluation in 309 Healthy Individuals.

The sustainability of coronavirus 19 (COVID-19) vaccine-induced immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical to be determined to inform public health decisions on vaccination programs and prevention measures against COVID-19. The aim of the present study was to prospectively evaluate the kinetics of neutralizing antibodies (NAbs) and anti-S-receptor binding domain (RBD IgGs) against SARS-CoV-2 after full vaccination with the BNT162b2 mRNA vaccine for up to 9 months in healthy individuals (NCT04743388). The assessments were performed at the following time points after the second vaccination: 2 weeks, 1 month, 3 months, 6 months, and 9 months. The measurements were performed with the GenScript's cPassTM SARS-CoV-2 NAbs Detection Kit (GenScript, Inc.; Piscataway, NJ) and the Elecsys Anti-SARS-CoV-2 S assay (Roche Diagnostics GmbH; Mannheim, Germany). Three hundred nine participants with a median age of 48 years were included. A gradual decline in both NAbs and anti-S-RBD IgGs became evident from 2 weeks to 9 months postvaccination. Both NAbs and anti-S-RBD IgGs levels were significantly lower at 9 months compared with the previous timepoints. Interestingly, age was found to exert a statistically significant effect on NAbs elimination only during the first-trimester postvaccination, as older age was associated with a more rapid clearance of NAbs. Furthermore, simulation studies predicted that the median NAb value would fall from 66% at 9 months to 59% and 45% at 12 and 18 months postvaccination, respectively. This finding may reflect a declining degree of immune protection against COVID-19 and advocates for the administration of booster vaccine shots especially in areas with emerging outbreaks.

Robust Neutralizing Antibody Responses 6 Months Post Vaccination with BNT162b2: A Prospective Study in 308 Healthy Individuals.

Elucidating long-term immunity following COVID-19 vaccination is essential for decision-making regarding booster shots. The aim of this study was to investigate the kinetics of neutralizing antibodies (Nabs) against SARS-CoV-2 up to six months after the second vaccination dose with the BNT162b2 mRNA vaccine. Nabs levels were measured on days 1 (before the first vaccine shot), 8, 22 (before the second shot), 36, 50, and 3 and 6 months after the second vaccination (NCT04743388). Three hundred and eight healthy individuals without malignant disease were included in this study. At six months, 2.59% of the participants had a Nabs value less than 30%, while 11.9% had Nabs values of less than 50%. Importantly, 58% of the subjects had Nabs values of more than 75%. Nabs were initially eliminated at a relatively slow rate, but after three months their elimination was 5.7 times higher. Older age was inversely associated with Nabs levels at all examined timepoints. Interestingly, a population modeling analysis estimated that half of the subjects will have Nabs values less than 73.8% and 64.6% at 9 and 12 months, respectively, post vaccination completion. In conclusion, we found a persistent but declining anti-SARS-CoV-2 humoral immunity at six months following full vaccination with BNT162b2 in healthy individuals, which was more pronounced among older persons. These data may inform the public health policies regarding the prioritization of booster vaccine shots.

Poor neutralizing antibody responses in 106 patients with WM after vaccination against SARS-CoV-2: a prospective study.

Immunocompromised patients with hematologic malignancies are more susceptible to COVID-19 and at higher risk of severe complications and worse outcomes compared with the general population. In this context, we evaluated the humoral response by determining the titers of neutralizing antibodies (NAbs) against SARS-CoV-2 in patients with Waldenström macroglobulinemia (WM) after vaccination with the BNT162b2 or AZD1222 vaccine. A US Food and Drug Administration-approved enzyme-linked immunosorbent assay-based methodology was implemented to evaluate NAbs on the day of the first vaccine shot, as well as on days 22 and 50 afterward. A total of 106 patients with WM (43% men; median age, 73 years) and 212 healthy controls (46% men; median age, 66 years) who were vaccinated during the same period at the same center were enrolled in the study (which is registered at www.clinicaltrials.gov as #NCT04743388). Our data indicate that vaccination with either 2 doses of the BNT162b2 or 1 dose of the AZD1222 vaccine leads to lower production of NAbs against SARS-CoV-2 in patients with WM compared with controls on days 22 and 50 (P < .001 for all comparisons). Disease-related immune dysregulation and therapy-related immunosuppression are involved in the low humoral response. Importantly, active treatment with either rituximab or Bruton's tyrosine kinase inhibitors was proven as an independent prognostic factor for suboptimal antibody response after vaccination. In conclusion, patients with WM have low humoral response after COVID-19 vaccination, which underlines the need for timely vaccination ideally during a treatment-free period and for continuous vigilance on infection control measures.

Myeloma patients with COVID-19 have superior antibody responses compared to patients fully vaccinated with the BNT162b2 vaccine.

Patients with multiple myeloma (MM) have a suboptimal antibody response following vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and lower seroconversion rates following coronavirus disease 2019 (COVID-19) compared with healthy individuals. In this context, we evaluated the development of neutralising antibodies (NAbs) against SARS-CoV-2 in non-vaccinated patients with MM and COVID-19 compared with patients after vaccination with two doses of the BNT162b2 vaccine. Serum was collected either four weeks post confirmed diagnosis or four weeks post a second dose of BNT162b2. NAbs were measured with a Food and Drug Administration-approved enzyme-linked immunosorbent assay methodology. Thirty-five patients with COVID-19 and MM along with 35 matched patients were included. The two groups did not differ in age, sex, body mass index, prior lines of therapy, disease status, lymphocyte count, immunoglobulin levels and comorbidities. Patients with MM and COVID-19 showed a superior humoral response compared with vaccinated patients with MM. The median (interquartile range) NAb titre was 87·6% (71·6-94%) and 58·7% (21·4-91·8%) for COVID-19-positive and vaccinated patients, respectively (P = 0·01).Importantly, there was no difference in NAb production between COVID-19-positive and vaccinated patients who did not receive any treatment (median NAb 85·1% vs 91·7%, P = 0·14). In conclusion, our data indicate that vaccinated patients with MM on treatment without prior COVID-19 should be considered for booster vaccine doses.

The neutralizing antibody response post COVID-19 vaccination in patients with myeloma is highly dependent on the type of anti-myeloma treatment.

Recent data suggest a suboptimal antibody response to COVID-19 vaccination in patients with hematological malignancies. Neutralizing antibodies (NAbs) against SARS-CoV-2 were evaluated in 276 patients with plasma cell neoplasms after vaccination with either the BNT162b2 or the AZD1222 vaccine, on days 1 (before the first vaccine shot), 22, and 50. Patients with MM (n = 213), SMM (n = 38), and MGUS (n = 25) and 226 healthy controls were enrolled in the study (NCT04743388). Vaccination with either two doses of the BNT162b2 or one dose of the AZD1222 vaccine leads to lower production of NAbs in patients with MM compared with controls both on day 22 and on day 50 (p < 0.001 for all comparisons). Furthermore, MM patients showed an inferior NAb response compared with MGUS on day 22 (p = 0.009) and on day 50 (p = 0.003). Importantly, active treatment with either anti-CD38 monoclonal antibodies (Mabs) or belantamab mafodotin and lymphopenia at the time of vaccination were independent prognostic factors for suboptimal antibody response following vaccination. In conclusion, MM patients have low humoral response following SARS-CoV-2 vaccination, especially under treatment with anti-CD38 or belamaf. This underlines the need for timely vaccination, possibly during a treatment-free period, and for continuous vigilance on infection control measures in non-responders.

Low neutralizing antibody responses in WM, CLL and NHL patients after the first dose of the BNT162b2 and AZD1222 vaccine.

Vaccination against SARS-CoV-2 is considered as the most important preventive strategy against COVID-19, but its efficacy in patients with hematological malignancies is largely unknown. We investigated the development of neutralizing antibodies (NAbs) against SARS-CoV-2 in patients with Waldenstrom Macroglobulinemia (WM), Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin Lymphoma (NHL). After the first dose of the vaccine, on D22, WM/CLL/NHL patients had lower NAb titers compared to controls: the median NAb inhibition titer was 17% (range 0-91%, IQR 8-27%) for WM/CLL/NHL patients versus 32% (range 2-98%, IQR 19-48%) for controls (P < 0.001). Only 8 (14%) patients versus 114 (54%) controls developed NAb titers ≥ 30% on D22 (p < 0.001). Our data indicate that the first dose of both BNT162b2 and AZD1222 leads to lower production of NAbs against SARS-CoV-2 in patients with WM/CLL/NHL compared to controls of similar age and gender and without malignant disease. Even though the response rates were not optimal, vaccination is still considered essential and if possible should be performed before treatment initiation. These patients with suboptimal responses should be considered to be prioritized for booster doses.

High Prevalence of Anti-PF4 Antibodies Following ChAdOx1 nCov-19 (AZD1222) Vaccination Even in the Absence of Thrombotic Events.

It is unclear whether the ChAdOx1 nCov-19 vaccine can induce the development of anti-PF4 antibodies in vaccinated individuals who have not developed thrombosis. The aim of this prospective study was to evaluate the presence of antibodies against heparin/PF4 in adults who received a first dose of the ChAdOx1 nCov-19 vaccine, and correlate them with clinical data and antibody responses to the vaccine. We detected non-platelet activating anti-PF4 antibodies in 67% (29/43) of the vaccinated individuals on day 22 following the first dose of the ChAdOx1 nCov-19 vaccine, though these were detected in low titers. Furthermore, there was no correlation between the presence of anti-PF4 IgG antibodies and the baseline clinical characteristics of the patients. Our findings suggest that the ChAdOx1 nCov-19 vaccine can elicit anti-PF4 antibody production even in recipients without a clinical manifestation of thrombosis. The presence of anti-PF4 antibodies was not sufficient to provoke clinically evident thrombosis. Our results offer an important insight into the ongoing investigations regarding the underlying multifactorial pathophysiology of thrombotic events induced by the ChAdOx1 nCov-19 vaccine.