Immunogenicity of a Three-Dose Primary Series of mRNA COVID-19 Vaccines in Patients With Lymphoid Malignancies.

Background: Patients with lymphoid malignancies are at risk for poor coronavirus disease 2019 (COVID-19)-related outcomes and have reduced vaccine-induced immune responses. Currently, a 3-dose primary regimen of mRNA vaccines is recommended in the United States for immunocompromised hosts. Methods: A prospective cohort study of healthy adults (n = 27) and patients with lymphoid malignancies (n = 94) was conducted, with longitudinal follow-up through completion of a 2- or 3-dose primary mRNA COVID vaccine series, respectively. Humoral responses were assessed in all participants, and cellular immunity was assessed in a subset of participants. Results: The rate of seroconversion (68.1% vs 100%) and the magnitude of peak anti-S immunoglobulin G (IgG) titer (median anti-S IgG = 32.4, IQR = 0.48-75.0 vs median anti-S IgG = 72.6, IQR 51.1-100.1; P = .0202) were both significantly lower in patients with lymphoid malignancies compared to the healthy cohort. However, peak titers of patients with lymphoid malignancies who responded to vaccination were similar to healthy cohort titers (median anti-S IgG = 64.3; IQR, 23.7-161.5; P = .7424). The third dose seroconverted 7 of 41 (17.1%) patients who were seronegative after the first 2 doses. Although most patients with lymphoid malignancies produced vaccine-induced T-cell responses in the subset studied, B-cell frequencies were low with minimal memory cell formation. Conclusions: A 3-dose primary mRNA series enhanced anti-S IgG responses to titers equivalent to healthy adults in patients with lymphoid malignancies who were seropositive after the first 2 doses and seroconverted 17.1% who were seronegative after the first 2 doses. T-cell responses were present, raising the possibility that the vaccines may confer some cell-based protection even if not measurable by anti-S IgG.

Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine Immunogenicity among Chimeric Antigen Receptor T Cell Therapy Recipients.

Patients receiving chimeric antigen receptor T cell (CAR-T) therapy may have impaired humoral responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinations owing to their underlying hematologic malignancy, prior lines of therapy, and CAR-T-associated hypogammaglobulinemia. Comprehensive data on vaccine immunogenicity in this patient population are limited. A single-center retrospective study of adults receiving CD19 or BCMA-directed CAR-T therapy for B cell non-Hodgkin lymphoma or multiple myeloma was conducted. Patients received at least 2 doses of SARS-CoV-2 vaccination with BNT162b2 or mRNA-1273 or 1 dose of Ad26.COV2.S and had SARS-CoV-2 anti-spike antibody (anti-S IgG) levels measured at least 1 month after the last vaccine dose. Patients were excluded if they received SARS-CoV-2 monoclonal antibody therapy or immunoglobulin within 3 months of the index anti-S titer. The seropositivity rate (assessed by an anti-S assay cutoff of ≥.8 U/mL in the Roche assay) and median anti-S IgG titers were analyzed. Fifty patients were included in the study. The median age was 65 years (interquartile range [IQR], 58 to 70 years), and the majority were male (68%). Thirty-two participants (64%) had a positive antibody response, with a median titer of 138.5 U/mL (IQR, 11.61 to 2541 U/mL). Receipt of ≥3 vaccines was associated with a significantly higher anti-S IgG level. Our study supports current guidelines for SARS-CoV-2 vaccination among recipients of CAR-T therapy and demonstrates that a 3-dose primary series followed by a fourth booster increases antibody levels. However, the relatively low magnitude of titers and low percentage of nonresponders demonstrates that further studies are needed to optimize vaccination timing and determine predictors of vaccine response in this population.

SARS-CoV-2 vaccine immunogenicity among chimeric antigen receptor T-cell therapy recipients

Introduction Patients receiving chimeric antigen receptor T-cell (CAR T-cell) therapy may have impaired humoral responses to SARS-CoV-2 vaccinations due to their underlying hematologic malignancy, prior lines of therapy, and CAR T-cell-associated hypogammaglobulinemia. Comprehensive data on vaccine immunogenicity in this patient population are limited. Methods A single-center retrospective study of adults receiving CD19 or BCMA-directed CAR T-cell therapy for B-cell non-Hodgkin lymphoma or multiple myeloma was conducted. Patients received at least two doses of SARS-CoV-2 vaccinations with BNT162b2, mRNA-1273, or one dose of Ad26.COV2.S and had SARS-CoV-2 anti-spike antibody (anti-S IgG) levels measured at least one month after the last vaccine dose. Patients were excluded if they received SARS-CoV-2 monoclonal antibody therapy or immunoglobulin within three months of the index anti-S titer. The seropositivity rate (assessed by anti-S assay cutoff of ≥0.8 U/mL, Roche assay) and median anti-S IgG titers were analyzed. Results Fifty patients were included in the study. Median age was 65 years (IQR 58–70), and a majority of patients were male (68%). Thirty-two (64%) participants had a positive antibody response, with a median titer of 138.5 U/mL (IQR 11.61–2541). Receiving ≥3 vaccines was associated with a significantly higher anti-S IgG. Conclusion Our study supports current guidelines for SARS-CoV-2 vaccination among CAR T-cell recipients and demonstrates that a three-dose primary series followed by a fourth booster increases antibody levels. However, the relatively low magnitude of titers and percent of non-responders demonstrates that further studies are needed to optimize vaccination timing and determine predictors of vaccine response in this population. Graphical Image, graphical

Impact of Donor and Recipient SARS-CoV-2 Vaccination or Infection on Immunity Post Hematopoietic Cell Transplantation

Background The role of donor and recipient COVID-19 immunologic status pre-transplant has not been fully investigated for allogeneic hematopoietic stem cell transplant (HSCT) recipients. Given poor immunogenicity to vaccines in this population and severe outcomes of COVID-19, adoptive transfer of immunity may offer important insights for improved protection for this vulnerable population. Objective To evaluate the role of adoptive transfer of immunity at one month post-transplant and six months post-transplant after vaccination of the recipient, based on SARS-CoV-2 vaccination and infection exposures of both the recipient and donor prior to transplant. Study Design Using banked specimens from related donor allogeneic HSCT recipients and clinical data for both donors and recipients, anti-Spike (S) IgG titers were analyzed at one-, three-, and six-months post-transplant according to prior SARS-CoV-2 immunologic exposures. Recipients were excluded if they had received SARS-CoV-2 monoclonal antibodies or had infection in the first six months after transplant. Results Of the 53 recipient-donor pairs, 29 donors and 24 recipients had prior SARS-CoV-2 immunologic exposures. Recipient-donor pairs with no prior SARS-CoV-2 exposures (D0R0) had significantly lower anti-S IgG titers at one month as compared to recipient-donor pairs with prior exposures (D1R1) (D0R0 median 2.43, IQR 0.41-3.77;D1R1 median 8.42, IQR 5.58 – 12.20;p = 0.008). At six months, anti-S IgG titers were higher in recipients who were vaccinated at three months post-transplant in the D1R1 cohort (median IgG 148.34, IQR 92.36-204.33) as compared to the D0R0 cohort (median IgG 38.74, IQR 8.93 - 119.71). Conclusions Current strategies should be optimized to enhance SARS-CoV-2 protection for HSCT recipients, including augmentation of the immune response for both the donors and recipients prior to transplant.

Impact of Donor and Recipient SARS-CoV-2 Vaccination or Infection on Immunity after Hematopoietic Cell Transplantation.

The role of donor and recipient Coronavirus disease 2019 (COVID-19) immunologic status pre-transplantation has not been fully investigated in allogeneic hematopoietic stem cell transplantation (HSCT) recipients. Given the poor immunogenicity to vaccines in this population and the serious outcomes of COVID-19, adoptive transfer of immunity may offer important insight into improving protection for this vulnerable population. In this study, we evaluated the role of adoptive transfer of immunity at 1 month post-transplantation and 6 months post-transplantation after vaccination of recipients, based on pre-transplantation severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination and infection exposures of both recipient and donor. Using banked specimens from related donor allogeneic HSCT recipients and clinical data from both donors and recipients, anti-Spike (S) IgG titers were analyzed at 1, 3, and 6 months post-transplantation according to prior SARS-CoV-2 immunologic exposures. Recipients were excluded if they had received SARS-CoV-2 monoclonal antibodies or had infection in the first 6 months post-transplantation. Of the 53 recipient-donor pairs, 29 donors and 24 recipients had prior SARS-CoV-2 immunologic exposure. Recipient-donor pairs with no prior SARS-CoV-2 exposure (D0R0) had significantly lower anti-S IgG titers at 1 month compared to those with prior exposures (D1R1) (D0R0: median, 2.43 [interquartile range (IQR), .41 to 3.77]; D1R1: median, 8.42; IQR, 5.58 to 12.20]; P = .008). At 6 months, anti-S IgG titers were higher in recipients who were vaccinated at 3 months post-transplantation in the D1R1 cohort (median IgG, 148.34; IQR, 92.36 to 204.33) compared with the D0R0 cohort (median IgG, 38.74; IQR, 8.93 to 119.71). Current strategies should be optimized to enhance SARS-CoV-2 protection for HSCT recipients, including augmentation of the immune response for both donors and recipients prior to transplantation.

Severe Acute Respiratory Syndrome Coronavirus 2 Messenger RNA Vaccines in Allogeneic Hematopoietic Stem Cell Transplant Recipients: Immunogenicity and Reactogenicity.

The severe acute respiratory syndrome coronavirus 2 messenger RNA vaccine-induced humoral response and reactogenicity profile are described in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Findings showed that 75.0% (by Simoa assay) or 80.0% (by Roche assay) of the HSCT cohort had a positive antibody response on series completion, compared with 100% in the healthy cohort.

Immunogenicity of a three-dose primary series of mRNA COVID-19 vaccines in patients with lymphoid malignancies

Background Patients with lymphoid malignancies are at risk for poor COVID-19 related outcomes and have reduced vaccine-induced immune responses. Currently a three-dose primary regimen of mRNA vaccines is recommended in the U.S. for immunocompromised hosts. Methods A prospective cohort study of healthy adults (n = 27) and patients with lymphoid malignancies (n = 94) was conducted, with longitudinal follow-up through completion of a two or three-dose primary mRNA COVID vaccine series, respectively. Humoral responses were assessed in all participants, and cellular immunity in a subset of participants. Results The rate of seroconversion (68.1% v. 100%) and the magnitude of peak anti-S IgG titer (median anti-S IgG 32.4, IQR 0.48-75.0 v. 72.6, IQR 51.1-100.1;p = 0.0202) were both significantly lower in patients with lymphoid malignancies as compared to the healthy cohort. However, peak titers of patients with lymphoid malignancies who responded to vaccination were similar to healthy cohort titers (median anti-S IgG 64.3, IQR 23.7 - 161.5, p = 0.7424). The third dose seroconverted 7/41 (17.1%) patients who were seronegative after the first two doses. Although most patients with lymphoid malignancies produced vaccine-induced T-cell responses in the subset studied, B-cell frequencies were low with minimal memory cell formation. Conclusions A three-dose primary mRNA series enhanced anti-S IgG responses to titers equivalent to healthy adults in patients with lymphoid malignancies who were seropositive after the first two doses and seroconverted 17.1% who were seronegative after the first two doses. T-cell responses were present, raising the possibility that the vaccines may confer some cell-based protection even if not measurable by anti-S IgG.

US201 Study: A Phase 2, Randomized Proof-of-Concept Trial of Favipiravir for the Treatment of COVID-19.

BACKGROUND: Favipiravir is used to treat influenza, and studies demonstrate that it has antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We performed a randomized, open-label, multicenter, phase 2 proof-of-concept trial of favipiravir in hospitalized adult patients with polymerase chain reaction (PCR)-positive coronavirus disease 2019 (COVID-19). Patients were randomized to standard of care (SOC) or favipiravir treatment (1800mg per os twice a day [b.i.d.] on day 1, followed by 1000mg b.i.d. for 13 days). The primary end point was time to viral clearance on day 29. RESULTS: Fifty patients were enrolled and stratified by disease severity (critical disease, severe disease, or mild to moderate disease). Nineteen patients were censored from the event of viral clearance based on being SARS-CoV-2 PCR-negative at the study outset, being PCR-positive at day 29, or because of loss to follow-up. Data from the 31 remaining patients who achieved viral clearance show enhanced viral clearance in the favipiravir group compared with the SOC group by day 29, with 72% of the favipiravir group and 52% of the SOC group being evaluable for viral clearance through day 29. The median time to viral clearance was 16.0 days (90% CI, 12.0 to 29.0) in the favipiravir group and 30.0 days (90% CI, 12.0 to 31.0) in the SOC group. A post hoc analysis revealed an effect in the subgroup of patients who were neutralizing antibody-negative at randomization. Treatment-emergent adverse events were equally distributed between the groups. CONCLUSIONS: We demonstrate that favipiravir can be safely administered to hospitalized adults with COVID-19 and believe that further studies are warranted. CLINICALTRIALSGOV REGISTRATION: NCT04358549.