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1.
Transplant Cell Ther ; 2022 Oct 21.
Article in English | MEDLINE | ID: covidwho-2150218

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), disproportionately affects immunocompromised and elderly patients. Not only are hematopoietic cell transplantation (HCT) and chimeric antigen receptor (CAR) T-cell recipients at greater risk for severe COVID-19 and COVID-19-related complications, but they also may experience suboptimal immune responses to currently available COVID-19 vaccines. Optimizing the use, timing, and number of doses of the COVID-19 vaccines in these patients may provide better protection against SARS-CoV-2 infection and better outcomes after infection. To this end, current guidelines for COVID-19 vaccination in HCT and CAR T-cell recipients from the American Society of Transplantation and Cellular Therapy Transplant Infectious Disease Special Interest Group and the American Society of Hematology are provided in a frequently asked questions format.

2.
Blood Advances ; 2022.
Article in English | ScienceDirect | ID: covidwho-2162273

ABSTRACT

: Prior publications have demonstrated low rates of seroconversion to the SARS-CoV-2 mRNA vaccines in patients with chronic lymphocytic leukemia (CLL). In this national collaboration of 11 cancer centers around the United States, we aimed to further characterize and understand the vaccine-induced immune response, including T-cell responses and the impact of CLL therapeutics (NCT04852822). Eligible patients were enrolled into two cohorts: 1) at the time of the initial vaccination and 2) at the time of booster vaccination. Serologic response rates (anti-S) from the 210 patients in the initial vaccination cohort and 117 in the booster vaccination cohort were 56% (95% CI, 50-63%) and 68% (95% CI, 60-77%), respectively. Compared to patients not on therapy, those receiving B-cell-directed therapy were less likely to seroconvert (OR 0.27, 95% CI 0.15-0.49). Persistence of response was seen at 6 months;anti-S titers increased with administration of booster vaccinations. In the initial vaccination cohort, positive correlations were seen between quantitative serologic response and CD4 T-cell response for the Wuhan variant and to a lesser degree, for the Omicron variant (Spearman ρ = 0.45 for Wuhan, ρ = 0.25 for Omicron). In the booster vaccination cohort, positive correlations were seen between serologic response and CD4 T-cell responses for both variants (ρ = 0.58 Wuhan, ρ= 0.57 Omicron) and to a lesser degree for CD8 T-cell responses (ρ = 0.33 Wuhan, ρ = 0.22 Omicron). While no deaths from COVID-19 were reported after booster vaccinations, patients should use caution as newer variants emerge and escape vaccine-induced immunity.

5.
Transplant Cell Ther ; 28(11): 784.e1-784.e9, 2022 11.
Article in English | MEDLINE | ID: covidwho-2007886

ABSTRACT

Chronic graft-versus-host disease (cGVHD) and its management with immunosuppressive therapies increase the susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as well as progression to severe Coronavirus 19 disease (COVID-19). Vaccination against COVID-19 is strongly recommended, but efficacy data are limited in this patient population. In this study, responses to COVID-19 vaccination were measured at 3 time points-after the initial vaccine series, before the third dose, and after the third dose-in adults with cGVHD receiving immunosuppressive therapy. Humoral response was measured by quantitative anti-spike antibody and neutralizing antibody levels. Anti-nucleocapsid antibody levels were measured to detect natural infection. T cell response was evaluated by a novel immunosequencing technique combined with immune repertoire profiling from cryopreserved peripheral blood mononuclear cell samples. Present or absent T cell responses were determined by the relative proportion of unique SARS-CoV-2-associated T cell receptor sequences ("breadth") plus clonal expansion of the response ("depth") compared with those in a reference population. Based on both neutralizing antibody and T cell responses, patients were categorized as vaccine responders (both detected), nonresponders (neither detected), or mixed (one but not both detected). Thirty-two patients were enrolled for the initial series, including 17 (53%) positive responders, 7 (22%) mixed responders, and 8 (25%) nonresponders. All but one patient categorized as mixed responders had humoral responses while lacking T cell responses. No statistical differences were observed in patient characteristics among the 3 groups of patients categorized by immune response, although sample sizes were limited. Significant positive correlations were observed between the robustness of cellular and humoral responses after the initial series. Among the 20 patients with paired samples (pre- and post-third dose), a third vaccination resulted in increased neutralizing antibody titers. cGVHD worsened in 10 patients (26%; 6 after the initial series and 4 after the third dose), necessitating escalation of immunosuppressive doses in 5 patients, although 4 had been tapering immunosuppression and 5 had already worsening cGVHD at the time of vaccination, and a clear association between COVID-19 vaccination and cGVHD could not be drawn. Among the patients with cGVHD on immunosuppressive therapy, 72% demonstrated a neutralizing antibody response after a 2-dose primary COVID-19 vaccination, two-thirds of whom also developed a T cell response; 25% had neither a humoral nor a T cell response. A third dose further amplified the antibody response.


Subject(s)
COVID-19 , Graft vs Host Disease , Immunologic Deficiency Syndromes , Adult , Humans , COVID-19 Vaccines , SARS-CoV-2 , Antibodies, Viral , Leukocytes, Mononuclear , Vaccination/methods , Immunity, Cellular , Antibodies, Neutralizing , Immunosuppression Therapy
9.
Br J Haematol ; 197(3): 306-309, 2022 05.
Article in English | MEDLINE | ID: covidwho-1700211

ABSTRACT

Prior reports evaluating SARS-CoV-2 vaccine efficacy in chronic lymphocytic leukaemia (CLL) used semiquantitative measurements of anti-S to evaluate immunity; however, neutralization assays were used to assess functional immunity in the trials leading to vaccine approval. Here, we identified decreased rates of seroconversion in vaccinated CLL patients and lower anti-S levels compared to healthy controls. Notably, we demonstrated similar results with the Roche anti-S assay and neutralization activity. Durable responses were seen at six months; augmentation with boosters was possible in responding patients. Absence of normal B cells, frequently seen in patients receiving Bruton tyrosine kinase and B-cell lymphoma 2 inhibitors, was a strong predictor of lack of seroconversion.


Subject(s)
COVID-19 , Leukemia, Lymphocytic, Chronic, B-Cell , COVID-19/prevention & control , COVID-19 Vaccines/therapeutic use , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , SARS-CoV-2
10.
N Engl J Med ; 386(4): 305-315, 2022 01 27.
Article in English | MEDLINE | ID: covidwho-1585665

ABSTRACT

BACKGROUND: Remdesivir improves clinical outcomes in patients hospitalized with moderate-to-severe coronavirus disease 2019 (Covid-19). Whether the use of remdesivir in symptomatic, nonhospitalized patients with Covid-19 who are at high risk for disease progression prevents hospitalization is uncertain. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving nonhospitalized patients with Covid-19 who had symptom onset within the previous 7 days and who had at least one risk factor for disease progression (age ≥60 years, obesity, or certain coexisting medical conditions). Patients were randomly assigned to receive intravenous remdesivir (200 mg on day 1 and 100 mg on days 2 and 3) or placebo. The primary efficacy end point was a composite of Covid-19-related hospitalization or death from any cause by day 28. The primary safety end point was any adverse event. A secondary end point was a composite of a Covid-19-related medically attended visit or death from any cause by day 28. RESULTS: A total of 562 patients who underwent randomization and received at least one dose of remdesivir or placebo were included in the analyses: 279 patients in the remdesivir group and 283 in the placebo group. The mean age was 50 years, 47.9% of the patients were women, and 41.8% were Hispanic or Latinx. The most common coexisting conditions were diabetes mellitus (61.6%), obesity (55.2%), and hypertension (47.7%). Covid-19-related hospitalization or death from any cause occurred in 2 patients (0.7%) in the remdesivir group and in 15 (5.3%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.03 to 0.59; P = 0.008). A total of 4 of 246 patients (1.6%) in the remdesivir group and 21 of 252 (8.3%) in the placebo group had a Covid-19-related medically attended visit by day 28 (hazard ratio, 0.19; 95% CI, 0.07 to 0.56). No patients had died by day 28. Adverse events occurred in 42.3% of the patients in the remdesivir group and in 46.3% of those in the placebo group. CONCLUSIONS: Among nonhospitalized patients who were at high risk for Covid-19 progression, a 3-day course of remdesivir had an acceptable safety profile and resulted in an 87% lower risk of hospitalization or death than placebo. (Funded by Gilead Sciences; PINETREE ClinicalTrials.gov number, NCT04501952; EudraCT number, 2020-003510-12.).


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/therapeutic use , Adult , Aged , Aged, 80 and over , Alanine/adverse effects , Alanine/therapeutic use , Antiviral Agents/adverse effects , COVID-19/complications , COVID-19/mortality , Comorbidity , Disease Progression , Double-Blind Method , Female , Hospitalization/statistics & numerical data , Humans , Male , Middle Aged , Outpatients , SARS-CoV-2/drug effects , Time-to-Treatment , Viral Load
12.
Open forum infectious diseases ; 8(Suppl 1):S806-S807, 2021.
Article in English | EuropePMC | ID: covidwho-1564252

ABSTRACT

Background Remdesivir (RDV) is a potent nucleotide prodrug inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase that has demonstrated efficacy in the treatment of patients hospitalized with moderate to severe COVID-19. This Phase 3 (GS-US-540–9012) double-blind, placebo-controlled study compared the efficacy and safety of 3 days of RDV to standard of care in non-hospitalized, high-risk participants with confirmed COVID-19. Table 1. COVID-19 related hospitalization or death, COVID-19 related medically attended visits or death, and Treatment Emergent Adverse Events Methods Participants were randomly assigned 1:1 to receive intravenous (IV) RDV (200 mg on day 1, 100 mg on days 2 to 3) or placebo. The primary efficacy endpoint was composite COVID-19 hospitalization or all-cause death by day 28 and compared using Cox proportional hazards model with baseline stratification factors as covariates. The primary safety endpoint was proportion of participants with treatment-emergent adverse events. Study enrollment was terminated early for administrative reasons in light of the evolving pandemic. Results 562 patients underwent randomization and started their assigned treatment (279, RDV;283, placebo). Baseline demographics and characteristics were balanced across arms. Overall, 52% were male, 44% were Hispanic/Latino ethnicity and 30% were ≥ 60 years old. The most common comorbidities were diabetes mellitus (62%), obesity (56%;median BMI, 30.7), and hypertension (48%). Median baseline SARS-CoV-2 RNA nasopharyngeal viral load was 6.2 log10 copies/mL. Treatment with RDV significantly reduced COVID-19 hospitalization or all-cause death by day 28 (HR, 0.13;95% CI, 0.03 – 0.59;p = 0.008;Table 1) compared to placebo. Participants receiving RDV also had significantly lower risk for COVID-19-related medically attended visits or all-cause death by day 28 compared to placebo (HR, 0.19;95% CI, 0.07 – 0.56;p = 0.002;Table 1). No deaths occurred in either arm by day 28. There was no difference between arms in time-weighted average change in nasopharyngeal viral loads from baseline up to day 7. The proportion of patients with AEs was similar between arms (Table 1);the most common AEs in the RDV arm were nausea (11%), headache (6%), and diarrhea (4%). Conclusion A 3-day course of IV RDV was safe, well tolerated and highly effective at preventing COVID-19 related hospitalization or death in high-risk non-hospitalized COVID-19 patients. Disclosures Joshua A. Hill, MD, Allogene (Individual(s) Involved: Self): Consultant;Allovir (Individual(s) Involved: Self): Consultant, Grant/Research Support;Amplyx (Individual(s) Involved: Self): Consultant;Covance/CSL (Individual(s) Involved: Self): Consultant;CRISPR (Individual(s) Involved: Self): Consultant;Gilead (Individual(s) Involved: Self): Consultant, Grant/Research Support;Karius: Grant/Research Support, Scientific Research Study Investigator;Medscape (Individual(s) Involved: Self): Consultant;Octapharma (Individual(s) Involved: Self): Consultant;OptumHealth (Individual(s) Involved: Self): Consultant;Takeda (Individual(s) Involved: Self): Consultant, Grant/Research Support, Scientific Research Study Investigator Roger Paredes, MD, PhD, Gilead Sciences, Inc (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member) Carlos Vaca, MD, Gilead Sciences, Inc (Scientific Research Study Investigator) Jorge Mera, MD, Gilead Sciences, Inc (Consultant, Study Investigator (payment to employer not self)) Gilberto Perez, MD, Gilead Sciences, Inc (Scientific Research Study Investigator) Godson Oguchi, MD, Gilead Sciences, Inc (Scientific Research Study Investigator) Pablo Ryan, MD PhD, Gilead Sciences, Inc (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member) Jan Gerstoft, MD, Gilead Sciences, Inc (Other Financial or Material Support, Study Investigator (payment to employer)) Michael Brown, FRCP PhD, Gilead Sciences, Inc (Scientific Research Study Inve tigator, Investigator for numerous remdesivir trials (employer received compensation)) Morgan Katz, MD, MHS, Roche (Individual(s) Involved: Self): Advisor or Review Panel member;Skinclique (Individual(s) Involved: Self): Consultant Gregory Camus, PhD, Gilead Sciences (Employee, Shareholder) Danielle P. Porter, PhD, Gilead Sciences (Employee, Shareholder) Robert H. Hyland, DPhil, Gilead Sciences, Inc (Shareholder, Other Financial or Material Support, Employee during the conduct of this trial) Shuguang Chen, PhD, Gilead Sciences, Inc (Employee, Shareholder) Kavita Juneja, MD, Gilead Sciences, Inc (Employee) Anu Osinusi, MD, Gilead Sciences, Inc (Employee, Shareholder) Frank Duff, MD, Gilead Sciences, Inc (Employee, Shareholder) Robert L. Gottlieb, MD, Eli Lilly (Scientific Research Study Investigator, Advisor or Review Panel member)Gilead Sciences (Scientific Research Study Investigator, Advisor or Review Panel member, Other Financial or Material Support, Gift in kind to Baylor Scott and White Research Institute for NCT03383419)GSK (Advisor or Review Panel member)Johnson and Johnson (Scientific Research Study Investigator)Kinevant (Scientific Research Study Investigator)Roche/Genentech (Scientific Research Study Investigator)

14.
J Immunother Cancer ; 9(10)2021 10.
Article in English | MEDLINE | ID: covidwho-1495513

ABSTRACT

Recipients of chimeric antigen receptor-modified T (CAR-T) cell therapies for B cell malignancies have profound and prolonged immunodeficiencies and are at risk for serious infections, including respiratory virus infections. Vaccination may be important for infection prevention, but there are limited data on vaccine immunogenicity in this population. We conducted a prospective observational study of the humoral immunogenicity of commercially available 2019-2020 inactivated influenza vaccines in adults immediately prior to or while in durable remission after CD19-, CD20-, or B cell maturation antigen-targeted CAR-T-cell therapy, as well as controls. We tested for antibodies to all four vaccine strains using neutralization and hemagglutination inhibition (HAI) assays. Antibody responses were defined as at least fourfold titer increases from baseline. Seroprotection was defined as a HAI titer ≥40. Enrolled CAR-T-cell recipients were vaccinated 14-29 days prior to (n=5) or 13-57 months following therapy (n=13), and the majority had hypogammaglobulinemia and cellular immunodeficiencies prevaccination. Eight non-immunocompromised adults served as controls. Antibody responses to ≥1 vaccine strain occurred in 2 (40%) individuals before CAR-T-cell therapy and in 4 (31%) individuals vaccinated after CAR-T-cell therapy. An additional 1 (20%) and 6 (46%) individuals had at least twofold increases, respectively. One individual vaccinated prior to CAR-T-cell therapy maintained a response for >3 months following therapy. Across all tested vaccine strains, seroprotection was less frequent in CAR-T-cell recipients than in controls. There was evidence of immunogenicity even among individuals with low immunoglobulin, CD19+ B cell, and CD4+ T-cell counts. These data support consideration for vaccination before and after CAR-T-cell therapy for influenza and other relevant pathogens such as SARS-CoV-2, irrespective of hypogammaglobulinemia or B cell aplasia. However, relatively impaired humoral vaccine immunogenicity indicates the need for additional infection-prevention strategies. Larger studies are needed to refine our understanding of potential correlates of vaccine immunogenicity, and durability of immune responses, in CAR-T-cell therapy recipients.


Subject(s)
Cell- and Tissue-Based Therapy/methods , Hemagglutination Inhibition Tests/methods , Immunogenicity, Vaccine/immunology , Influenza, Human/drug therapy , Influenza, Human/immunology , Adolescent , Adult , Aged , Humans , Middle Aged , Prospective Studies , Young Adult
16.
Clin Infect Dis ; 73(2): e455-e457, 2021 07 15.
Article in English | MEDLINE | ID: covidwho-1315665
18.
Transpl Infect Dis ; 23(4): e13645, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1238475

ABSTRACT

As some of those who were lucky enough to have been mentored by Dr Francisco Marty in transplant infectious diseases, we stand with the larger medical community in mourning his untimely death and in commemorating him as a uniquely exceptional and talented physician, investigator, teacher, mentor, friend, artist, and human being.


Subject(s)
Physicians , Humans , Male
19.
J Immunother Cancer ; 9(5)2021 05.
Article in English | MEDLINE | ID: covidwho-1228897

ABSTRACT

COVID-19, the syndrome caused by the infection with SARS-CoV-2 coronavirus, is characterized, in its severe form, by interstitial diffuse pneumonitis and acute respiratory distress syndrome (ARDS). ARDS and systemic manifestations of COVID-19 are mainly due to an exaggerated immune response triggered by the viral infection. Cytokine release syndrome (CRS), an inflammatory syndrome characterized by elevated levels of circulating cytokines, and endothelial dysfunction are systemic manifestations of COVID-19. CRS is also an adverse event of immunotherapy (IMTX), the treatment of diseases using drugs, cells, and antibodies to stimulate or suppress the immune system. Graft-versus-host disease complications after an allogeneic stem cell transplant, toxicity after the infusion of chimeric antigen receptor-T cell therapy and monoclonal antibodies can all lead to CRS. It is hypothesized that anti-inflammatory drugs used for treatment of CRS in IMTX may be useful in reducing the mortality in COVID-19, whereas IMTX itself may help in ameliorating effects of SARS-CoV-2 infection. In this paper, we focused on the potential shared mechanisms and differences between COVID-19 and IMTX-related toxicities. We performed a systematic review of the clinical trials testing anti-inflammatory therapies and of the data published from prospective trials. Preliminary evidence suggests there might be a benefit in targeting the cytokines involved in the pathogenesis of COVID-19, especially by inhibiting the interleukin-6 pathway. Many other approaches based on novel drugs and cell therapies are currently under investigation and may lead to a reduction in hospitalization and mortality due to COVID-19.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , COVID-19/therapy , Cytokine Release Syndrome/drug therapy , Immunotherapy/methods , Interleukin-6/antagonists & inhibitors , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/pathology , Cytokine Release Syndrome/pathology , Humans , Immunization, Passive/methods , Immunotherapy/adverse effects , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Interleukin-1beta/blood , Interleukin-6/blood , Nitriles , Pyrazoles/therapeutic use , Pyrimidines , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Tumor Necrosis Factor-alpha/blood
20.
J Med Virol ; 93(4): 2270-2280, 2021 04.
Article in English | MEDLINE | ID: covidwho-1217379

ABSTRACT

Coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 causes substantial morbidity. Tocilizumab, an interleukin-6 receptor antagonist, might improve outcomes by mitigating inflammation. We conducted a retrospective study of patients admitted to the University of Washington Hospital system with COVID-19 and requiring supplemental oxygen. Outcomes included clinical improvement, defined as a two-point reduction in severity on a six-point ordinal scale or discharge, and mortality within 28 days. We used Cox proportional-hazards models with propensity score inverse probability weighting to compare outcomes in patients who did and did not receive tocilizumab. We evaluated 43 patients who received tocilizumab and 45 who did not. Patients receiving tocilizumab were younger with fewer comorbidities but higher baseline oxygen requirements. Tocilizumab treatment was associated with reduced C-reactive protein, fibrinogen, and temperature, but there were no meaningful differences in time to clinical improvement (adjusted hazard ratio [aHR], 0.92; 95% confidence interval [CI], 0.38-2.22) or mortality (aHR, 0.57; 95% CI, 0.21-1.52). A numerically higher proportion of tocilizumab-treated patients had subsequent infections, transaminitis, and cytopenias. Tocilizumab did not improve outcomes in hospitalized patients with COVID-19. However, this study was not powered to detect small differences, and there remains the possibility for a survival benefit.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , COVID-19/drug therapy , Aged , C-Reactive Protein/metabolism , COVID-19/metabolism , COVID-19/mortality , COVID-19/virology , Female , Fibrinogen/metabolism , Hospitalization , Humans , Immunomodulation , Inflammation/drug therapy , Inflammation Mediators/metabolism , Male , Middle Aged , Receptors, Interleukin-6/metabolism , Retrospective Studies , SARS-CoV-2/drug effects , Treatment Outcome
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