RESUMEN
BACKGROUND: The burden of herpes zoster (shingles) virus and associated complications, such as post-herpetic neuralgia, is higher in older adults and has a significant impact on quality of life. The incidence of herpes zoster and post-herpetic neuralgia is increased in people living with HIV (PLWH) compared to an age-matched general population, including PLWH on long-term antiretroviral therapy (ART) with no detectable viremia and normal CD4 counts. PLWH - even on effective ART may- exhibit sustained immune dysfunction, as well as defects in cells involved in the response to vaccines. In the context of herpes zoster, it is therefore important to assess the immune response to varicella zoster virus vaccination in older PLWH and to determine whether it significantly differs to that of HIV-uninfected healthy adults or younger PLWH. We aim at bridging these knowledge gaps by conducting a multicentric, international, non-randomised clinical study (SHINGR'HIV) with prospective data collection after vaccination with an adjuvant recombinant zoster vaccine (RZV) in two distinct populations: in PLWH on long-term ART (> 10 years) over 50 years of and age/gender matched controls. METHODS: We will recruit participants from two large established HIV cohorts in Switzerland and in France in addition to age-/gender-matched HIV-uninfected controls. Participants will receive two doses of RZV two months apart. In depth-evaluation of the humoral, cellular, and innate immune responses and safety profile of the RZV will be performed to address the combined effect of aging and potential immune deficiencies due to chronic HIV infection. The primary study outcome will compare the geometric mean titer (GMT) of gE-specific total IgG measured 1 month after the second dose of RZV between different age groups of PLWH and between PLWH and age-/gender-matched HIV-uninfected controls. DISCUSSION: The SHINGR'HIV trial will provide robust data on the immunogenicity and safety profile of RZV in older PLWH to support vaccination guidelines in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT05575830. Registered on 12 October 2022. Eu Clinical Trial Register (EUCT number 2023-504482-23-00).
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Infecciones por VIH , Vacuna contra el Herpes Zóster , Herpes Zóster , Neuralgia Posherpética , Humanos , Persona de Mediana Edad , Anciano , Neuralgia Posherpética/prevención & control , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Calidad de Vida , Herpes Zóster/epidemiología , Herpesvirus Humano 3 , Vacunas Sintéticas , Inmunidad , Estudios Multicéntricos como AsuntoRESUMEN
PURPOSE OF REVIEW: Double-stranded DNA (dsDNA) viruses remain important causes of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). As treatment options are limited, adoptive therapy with virus-specific T cells (VST) is promising in restoring immunity and thereby preventing and treating virus infections. Here we review current evidence and recent advances in the field of VST for dsDNA viruses in allogeneic HCT recipients. RECENT FINDINGS: Four different protocols for VST generation are currently used in clinical trials, and various products including multivirus-specific and off-the-shelf products are under investigation for prophylaxis, preemptive therapy or treatment. Data from nearly 1400 dsDNA-VST applications in allogeneic HCT patients have been published and demonstrated its safety. Although Epstein-Barr virus, cytomegalovirus, and adenovirus-specific T-cell therapy studies have predominated over the past 25âyears, additional human herpes viruses were added to multivirus-specific T cells over the last decade and clinical evidence for polyomavirus-specific VST has just recently emerged. Response rates of around 70-80% have been reported, but cautious interpretation is warranted as data are predominantly from phase 1/2 studies and clinical efficacy needs to be confirmed in phase 3 studies. SUMMARY: Investigation on the 'ideal' composition of VST is ongoing. Several products recently entered phase 3 trials and may allow widespread clinical use in the near future.
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Infecciones por Virus de Epstein-Barr , Trasplante de Células Madre Hematopoyéticas , Infecciones por Virus de Epstein-Barr/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Herpesvirus Humano 4 , Humanos , Huésped Inmunocomprometido , Receptores de TrasplantesRESUMEN
Contemporary data on infections after intensive chemotherapy for acute myeloid leukemia (AML) are scarce. Cladribine, high-dose cytarabine, G-CSF, and dose-escalated mitoxantrone ("CLAG-M") may result in higher remission rates than standard-dose cytarabine plus anthracycline ("7 + 3") but may result in more infections. We compared moderate to severe infections occurring up to 90 days after the first induction cycle for AML or other high-grade myeloid neoplasms in patients receiving CLAG-M for newly diagnosed (n = 196) or relapsed/refractory disease (n = 131) or 7 + 3 for newly diagnosed disease (n = 115). For newly diagnosed disease, microbiologically documented infections were more frequent after CLAG-M compared to 7 + 3 (adjusted rate ratio, 1.65 [95% CI, 1.06-2.58]; P = 0.03), with a cumulative incidence of 27.8% and 16.5% by day 90, respectively. Patients receiving CLAG-M for relapsed/refractory disease had the highest cumulative incidence of 50.7%. Bacterial bloodstream infections were the most frequent followed by respiratory tract infections. Among 29 patients (7%) who died, infection was a primary or contributing cause of death in 59%. These data indicate that infections continue to cause substantial morbidity in patients treated for AML, especially those treated for relapsed/refractory disease, and are more common with newer, more myelosuppressive regimens such as CLAG-M. Improved strategies for infection prevention are needed.
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Protocolos de Quimioterapia Combinada Antineoplásica , Infecciones , Leucemia Mieloide Aguda , Mitoxantrona , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cladribina/administración & dosificación , Cladribina/efectos adversos , Citarabina/administración & dosificación , Citarabina/efectos adversos , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Mitoxantrona/administración & dosificación , Mitoxantrona/efectos adversos , Infecciones/inducido químicamente , Infecciones/etiología , Infecciones del Sistema Respiratorio/inducido químicamente , Infecciones del Sistema Respiratorio/etiología , Sepsis/inducido químicamente , Sepsis/etiología , Sepsis/microbiología , Infecciones Bacterianas/inducido químicamente , Infecciones Bacterianas/etiología , Antraciclinas/administración & dosificación , Antraciclinas/efectos adversos , Leucemia Mieloide/tratamiento farmacológico , Leucemia Mieloide/patologíaRESUMEN
INTRODUCTION: The unprecedented success of chimeric antigen receptor (CAR)-T-cell therapy in the management of B-cell malignancies comes with a price of specific side effects. Healthy B-cell depletion is an anticipated 'on-target' 'off-tumor' side effect and can contribute to severe and prolonged hypogammaglobulinemia. Evidence-based guidelines for the use of immunoglobulin replacement therapy (IGRT) for infection prevention are lacking in this population. AREAS COVERED: This article reviews the mechanisms and epidemiology of hypogammaglobulinemia and antibody deficiency, association with infections, and strategies to address these issues in CD19- and BCMA-CAR-T-cell recipients. EXPERT OPINION: CD19 and BCMA CAR-T-cell therapy result in unique immune deficits due to depletion of specific B-lineage cells and may require different infection prevention strategies. Hypogammaglobulinemia before and after CAR-T-cell therapy is frequent, but data on the efficacy and cost-effectiveness of IGRT are lacking. Monthly IGRT should be prioritized for patients with severe or recurrent bacterial infections. IGRT may be more broadly necessary to prevent infections in BCMA-CAR-T-cell recipients and children with severe hypogammaglobulinemia irrespective of infection history. Vaccinations are indicated to augment humoral immunity and can be immunogenic despite cytopenias; re-vaccination(s) may be required. Controlled trials are needed to better understand the role of IGRT and vaccines in this population.
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Agammaglobulinemia , Neoplasias , Receptores Quiméricos de Antígenos , Agammaglobulinemia/etiología , Agammaglobulinemia/terapia , Antígeno de Maduración de Linfocitos B , Tratamiento Basado en Trasplante de Células y Tejidos , Niño , Humanos , Inmunoterapia Adoptiva/efectos adversos , Receptores Quiméricos de Antígenos/uso terapéuticoRESUMEN
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.
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Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Pruebas de Inhibición de Hemaglutinación/métodos , Inmunogenicidad Vacunal/inmunología , Gripe Humana/tratamiento farmacológico , Gripe Humana/inmunología , Adolescente , Adulto , Anciano , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Adulto JovenRESUMEN
BACKGROUNDLittle is known about pathogen-specific humoral immunity after chimeric antigen receptor-modified T (CAR-T) cell therapy for B cell malignancies.METHODSWe conducted a prospective cross-sectional study of CD19-targeted or B cell maturation antigen-targeted (BCMA-targeted) CAR-T cell therapy recipients at least 6 months posttreatment and in remission. We measured pathogen-specific IgG against 12 vaccine-preventable infections and the number of viral and bacterial epitopes to which IgG was detected ("epitope hits") using a serological profiling assay. The primary outcome was the proportion of participants with IgG levels above a threshold correlated with seroprotection for vaccine-preventable infections.RESULTSWe enrolled 65 children and adults a median of 20 months after CD19- (n = 54) or BCMA- (n = 11) CAR-T cell therapy. Among 30 adults without IgG replacement therapy (IGRT) in the prior 16 weeks, 27 (90%) had hypogammaglobulinemia. These individuals had seroprotection to a median of 67% (IQR, 59%-73%) of tested infections. Proportions of participants with seroprotection per pathogen were comparable to population-based studies, but most individuals lacked seroprotection to specific pathogens. Compared with CD19-CAR-T cell recipients, BCMA-CAR-T cell recipients were half as likely to have seroprotection (prevalence ratio, 0.47; 95% CI, 0.18-1.25) and had fewer pathogen-specific epitope hits (mean difference, -90 epitope hits; 95% CI, -157 to -22).CONCLUSIONSeroprotection for vaccine-preventable infections in adult CD19-CAR-T cell recipients was comparable to the general population. BCMA-CAR-T cell recipients had fewer pathogen-specific antibodies. Deficits in both groups support the need for vaccine and immunoglobulin replacement therapy studies.FUNDINGSwiss National Science Foundation (Early Postdoc Mobility grant P2BSP3_188162), NIH/National Cancer Institute (NIH/NCI) (U01CA247548 and P01CA018029), NIH/NCI Cancer Center Support Grants (P30CA0087-48 and P30CA015704-44), American Society for Transplantation and Cellular Therapy, and Juno Therapeutics/BMS.
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Agammaglobulinemia/inmunología , Anticuerpos Antibacterianos/inmunología , Anticuerpos Antivirales/inmunología , Inmunidad Humoral/inmunología , Inmunoglobulina G/inmunología , Inmunoterapia Adoptiva , Leucemia de Células B/terapia , Linfoma de Células B/terapia , Receptores Quiméricos de Antígenos , Enfermedades Prevenibles por Vacunación/prevención & control , Adolescente , Adulto , Anciano , Antígenos CD19 , Antígeno de Maduración de Linfocitos B , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Lactante , Leucemia Linfocítica Crónica de Células B/terapia , Masculino , Persona de Mediana Edad , Mieloma Múltiple/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Estudios Prospectivos , Enfermedades Prevenibles por Vacunación/inmunología , Adulto JovenRESUMEN
Recipients of chimeric antigen receptor-modified T (CAR-T) cell therapies for B-cell malignancies are immunocompromised and at risk for serious infections. Vaccine immunogenicity is unknown in this population. We conducted a prospective observational study of the humoral immunogenicity of 2019-2020 inactivated influenza vaccines (IIV) in children and adults immediately prior to (n=7) or 13-57 months after (n=15) CD19-, CD20-, or BCMA-targeted CAR-T-cell therapy, as well as controls (n=8). Individuals post-CAR-T-cell therapy were in remission. We tested for antibodies to 4 vaccine strains at baseline and ≥1 time point after IIV using neutralization and hemagglutination inhibition assays. An antibody response was defined as a ≥4-fold titer increase from baseline at the first post-vaccine time point. Baseline A(H1N1) titers in the CAR-T cohorts were significantly lower compared to controls. Antibody responses to ≥1 vaccine strain occurred in 2 (29%) individuals before CAR-T-cell therapy; one individual maintained a response for >3 months post-CAR-T-cell therapy. Antibody responses to ≥1 vaccine strain occurred in 6 (40%) individuals vaccinated after CAR-T-cell therapy. An additional 2 (29%) and 6 (40%) individuals had ≥2-fold increases (at any time) in the pre- and post-CAR-T cohorts, respectively. There were no identified clinical or immunologic predictors of antibody responses. Neither severe hypogammaglobulinemia nor B-cell aplasia precluded antibody responses. 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. Larger studies are needed to determine correlates of vaccine immunogenicity and durability in CAR-T-cell therapy recipients. KEY POINTS: Influenza vaccination was immunogenic pre- and post-CAR-T-cell therapy, despite hypogammaglobulinemia and B-cell aplasia.Vaccination with inactivated vaccines can be considered before CAR-T-cell therapy and in individuals with remission after therapy.