Human Herpesvirus-6 Reactivation and Disease Are Infrequent in Chimeric Antigen Receptor T-cell Therapy Recipients.

Human herpesvirus-6B (HHV-6B) reactivation and disease are increasingly reported after CAR-T-cell therapy (CARTx). HHV-6 reactivation in the CAR-T-cell product was recently reported, raising questions about product and patient management. Due to overlapping manifestations with immune effector cell-associated neurotoxicity syndrome, diagnosing HHV-6B encephalitis is challenging. We provide two lines of evidence assessing the incidence and outcomes of HHV-6B after CARTx. First, in a prospective study with weekly HHV-6B testing for up to 12 weeks post-infusion, HHV-6B reactivation occurred in eight of 89 participants; three had chromosomally integrated HHV-6 and were excluded, resulting in a cumulative incidence of HHV-6B reactivation of 6% (95% confidence interval (CI), 2.2-12.5%). HHV-6B detection was low level (median peak, 435 copies/mL; IQR, 164-979) and did not require therapy. Second, we retrospectively analyzed HHV-6B detection in blood and/or cerebrospinal fluid (CSF) within 12 weeks post-infusion in CARTx recipients. Of 626 patients, 24 had symptom-driven plasma testing with detection in one. Among 34 patients with CSF HHV-6 testing, one patient had possible HHV-6 encephalitis for a cumulative incidence of 0.17% (95% CI, 0.02-0.94%), although symptoms improved without treatment. Our data demonstrate that HHV-6B reactivation and disease are infrequent after CARTx. Routine HHV-6 monitoring is not warranted.

Late Cytomegalovirus Disease after Hematopoietic Cell Transplantation: Significance of Novel Transplantation Techniques.

Pre-emptive therapy (PET) and letermovir prophylaxis are effective in preventing CMV disease within the first 100 days after allogeneic hematopoietic cell transplantation (HCT) but are associated with late-onset CMV disease. We retrospectively examined the clinical manifestations, risk factors, prevention algorithm, and outcome of late CMV disease in CMV seropositive day 100 survivors transplanted between 2001-2017 (PET cohort) and 2018-2021 (letermovir cohort). There were 187 episodes of late CMV disease among 2469 day 100 survivors and the estimated cumulative incidence of first late CMV disease was 6.7% (95% CI 5.6-%-7.6%) with no difference between the PET 6.7% (95% CI 5.7%-7.8%) and the letermovir group 5.4% (95% CI 3.2%-8.3%). 32 (1.3%) patients had a second episode of late CMV disease. In multivariable Cox regression models, post-transplant cyclophosphamide was associated with an increased risk of gastrointestinal CMV disease. CMV viremia detected before day 100, corticosteroid treatment after day 100 at dose ≥1mg/kg, acute and chronic GvHD, lymphopenia, HLA mismatched related donors status and recipient age were also associated with late CMV disease. HLA mismatched donor status and late use of corticosteroids (≥1 mg/kg) were risk factors for late CMV disease recurrence. Late CMV disease occurred most frequently in a setting of prolonged low-level untreated viremia and was independently associated with death by year two after HCT. In summary, late CMV disease continues to occur in the current era. Improved prevention strategies for late CMV disease are needed.

Cytomegalovirus (CMV) Reactivation and CMV-Specific Cell-Mediated Immunity After Chimeric Antigen Receptor T-Cell Therapy.

BACKGROUND: The epidemiology of cytomegalovirus (CMV) after chimeric antigen receptor-modified T-cell immunotherapy (CARTx) is poorly understood owing to a lack of routine surveillance. METHODS: We prospectively enrolled 72 adult CMV-seropositive CD19-, CD20-, or BCMA-targeted CARTx recipients and tested plasma samples for CMV before and weekly up to 12 weeks after CARTx. We assessed CMV-specific cell-mediated immunity (CMV-CMI) before and 2 and 4 weeks after CARTx, using an interferon γ release assay to quantify T-cell responses to IE-1 and pp65. We tested pre-CARTx samples to calculate a risk score for cytopenias and infection (CAR-HEMATOTOX). We used Cox regression to evaluate CMV risk factors and evaluated the predictive performance of CMV-CMI for CMV reactivation in receiver operator characteristic curves. RESULTS: CMV was detected in 1 patient (1.4%) before and in 18 (25%) after CARTx, for a cumulative incidence of 27% (95% confidence interval, 16.8-38.2). The median CMV viral load (interquartile range) was 127 (interquartile range, 61-276) IU/mL, with no end-organ disease observed; 5 patients received preemptive therapy based on clinical results. CMV-CMI values reached a nadir 2 weeks after infusion and recovered to baseline levels by week 4. In adjusted models, BCMA-CARTx (vs CD19/CD20) and corticosteroid use for >3 days were significantly associated with CMV reactivation, and possible associations were detected for lower week 2 CMV-CMI and more prior antitumor regimens. The cumulative incidence of CMV reactivation almost doubled when stratified by BCMA-CARTx target and use of corticosteroids for >3 days (46% and 49%, respectively). CONCLUSIONS: CMV testing could be considered between 2 and 6 weeks in high-risk CARTx recipients.

Human herpesvirus-6 reactivation and disease after allogeneic haematopoietic cell transplantation in the era of letermovir for cytomegalovirus prophylaxis.

OBJECTIVES: Letermovir for cytomegalovirus (CMV) prophylaxis in allogeneic haematopoietic cell transplant (HCT) recipients has decreased anti-CMV therapy use. Contrary to letermovir, anti-CMV antivirals are also active against human herpesvirus-6 (HHV-6). We assessed changes in HHV-6 epidemiology in the post-letermovir era. METHODS: We conducted a retrospective cohort study of CMV-seropositive allogeneic HCT recipients comparing time periods before and after routine use of prophylactic letermovir. HHV-6 testing was at the discretion of clinicians. We computed the cumulative incidence of broad-spectrum antiviral initiation (foscarnet, (val)ganciclovir, and/or cidofovir), HHV-6 testing, and HHV-6 detection in blood and cerebrospinal fluid within 100 days after HCT. We used Cox proportional-hazards models with stabilized inverse probability of treatment weights to compare outcomes between cohorts balanced for baseline factors. RESULTS: We analysed 738 patients, 376 in the pre-letermovir and 362 in the post-letermovir cohort. Broad-spectrum antiviral initiation incidence decreased from 65% (95% CI, 60-70%) pre-letermovir to 21% (95% CI, 17-25%) post-letermovir. The cumulative incidence of HHV-6 testing (17% [95% CI, 13-21%] pre-letermovir versus 13% [95% CI, 10-16%] post-letermovir), detection (3% [95% CI, 1-5%] in both cohorts), and HHV-6 encephalitis (0.5% [95% CI, 0.1-1.8%] pre-letermovir and 0.6% [95% CI, 0.1-1.9%] post-letermovir) were similar between cohorts. First HHV-6 detection occurred at a median of 37 days (interquartile range, 18-58) in the pre-letermovir cohort and 27 (interquartile range, 25-34) in the post-letermovir cohort. In a weighted model, there was no association between the pre-versus post-letermovir cohort and HHV-6 detection (adjusted hazard ratio, 1.08; 95% CI, 0.44-2.62). DISCUSSION: Despite a large decrease in broad-spectrum antivirals after the introduction of letermovir prophylaxis in CMV-seropositive allogeneic HCT recipients, there was no evidence for increased clinically detected HHV-6 reactivation and disease.

Respiratory syncytial virus and other respiratory virus infections in residents of homeless shelters - King County, Washington, 2019-2021.

Respiratory syncytial virus (RSV) causes disproportionate morbidity and mortality in vulnerable populations. We tested residents of homeless shelters in Seattle, Washington for RSV in a repeated cross-sectional study as part of community surveillance for respiratory viruses. Of 15 364 specimens tested, 35 had RSV detected, compared to 77 with influenza. The most common symptoms for both RSV and influenza were cough and rhinorrhea. Many individuals with RSV (39%) and influenza (58%) reported that their illness significantly impacted their ability to perform their regular activities. RSV and influenza demonstrated similar clinical presentations and burden of illness in vulnerable populations living in congregate settings.

Impact of GVHD prophylaxis on CMV reactivation and disease after HLA-matched peripheral blood stem cell transplantation.

The kinetics of early and late cytomegalovirus (CMV) reactivation after hematopoietic cell transplantation using various methods of graft-versus-host-disease (GVHD) prophylaxis are poorly defined. We retrospectively compared CMV reactivation and disease among 780 seropositive patients given HLA-matched peripheral blood stem cell (PBSC) grafts and calcineurin inhibitor plus posttransplantation cyclophosphamide (PTCy; n = 44), mycophenolate mofetil (MMF; n = 414), or methotrexate (MTX; n = 322). Transplantation occurred between 2007 and 2018; CMV monitoring/management followed uniform standard practice. Hazards of CMV reactivation at various thresholds were compared. Spline curves were fit over average daily viral load and areas under the curve (AUC) within 1 year were calculated. PTCy and MMF were associated with an increased risk of early (day ≤100) CMV reactivation ≥250 IU/mL after multivariate adjustment. The viral load AUC at 1 year was highest with MMF (mean difference = 0.125 units vs MTX group) and similar between PTCy and MTX (mean difference = 0.016 units vs MTX group). CMV disease risk was similar across groups. There was no interaction between GVHD prophylaxis and CMV reactivation on chronic GVHD risk. Despite PTCy-associated increased risk of early CMV reactivation, the CMV disease risk by 1 year was low in HLA-matched PBSC transplant recipients. In contrast, MMF was associated with higher overall CMV viral burden in the 1 year posttransplant. Although different mechanisms of immunosuppressive agents may affect CMV reactivation risk, effective prevention of GVHD may reduce corticosteroid exposure and mitigate infection risk over time.

Structure, receptor recognition, and antigenicity of the human coronavirus CCoV-HuPn-2018 spike glycoprotein.

The isolation of CCoV-HuPn-2018 from a child respiratory swab indicates that more coronaviruses are spilling over to humans than previously appreciated. We determined the structures of the CCoV-HuPn-2018 spike glycoprotein trimer in two distinct conformational states and showed that its domain 0 recognizes sialosides. We identified that the CCoV-HuPn-2018 spike binds canine, feline, and porcine aminopeptidase N (APN) orthologs, which serve as entry receptors, and determined the structure of the receptor-binding B domain in complex with canine APN. The introduction of an oligosaccharide at position N739 of human APN renders cells susceptible to CCoV-HuPn-2018 spike-mediated entry, suggesting that single-nucleotide polymorphisms might account for viral detection in some individuals. Human polyclonal plasma antibodies elicited by HCoV-229E infection and a porcine coronavirus monoclonal antibody inhibit CCoV-HuPn-2018 spike-mediated entry, underscoring the cross-neutralizing activity among ɑ-coronaviruses. These data pave the way for vaccine and therapeutic development targeting this zoonotic pathogen representing the eighth human-infecting coronavirus.

Pathogen-Specific Humoral Immunity and Infections in B Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy Recipients with Multiple Myeloma.

Chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA-CARTx) is an emerging treatment for relapsed or refractory multiple myeloma (R/R MM). Here we characterize the epidemiology of infections, risk factors for infection, and pathogen-specific humoral immunity in patients receiving BCMA-CARTx for R/R MM. We performed a retrospective cohort study in 32 adults with R/R MM enrolled in 2 single-institution phase 1 clinical trials of BCMA-CARTx administered after lymphodepleting chemotherapy alone (n = 22) or with a gamma secretase inhibitor (GSI). We tested serum before and up to approximately 180 days after BCMA-CARTx for measles-specific IgG and for any viral-specific IgG using a systematic viral epitope scanning assay to describe the kinetics of total and pathogen-specific IgG levels pre- and post-BCMA-CARTx. We identified microbiologically documented infections to determine infection incidence and used Poisson regression to explore risk factors for infections within 180 days after BCMA-CARTx. Most individuals developed severe neutropenia, lymphopenia, and hypogammaglobulinemia after BCMA-CARTx. Grade ≥3 cytokine release syndrome (CRS; Lee criteria) occurred in 16% of the participants; 50% of the participants received corticosteroids and/or tocilizumab. Before BCMA-CARTx, 28 of 32 participants (88%) had an IgG <400 mg/dL, and only 5 of 27 (19%) had seropositive measles antibody titers. After BCMA-CARTx, all participants had an IgG <400 mg/dL and declining measles antibody titers; of the 5 individuals with baseline seropositive levels, 2 remained above the seroprotective threshold post-treatment. Participants with IgG MM (n = 13) had significantly fewer antibodies to a panel of viral antigens compared with participants with non-IgG MM (n = 6), both before and after BCMA-CARTx. In the first 180 days after BCMA-CARTx, 17 participants (53%) developed a total of 23 infections, of which 13 (57%) were mild-to-moderate viral infections. Serious infections were more frequent in the first 28 days post-treatment. Infections appeared to be more common in individuals with higher-grade CRS. Individuals with R/R MM have substantial deficits in humoral immunity. These data demonstrate the importance of plasma cells in maintaining long-lived pathogen-specific antibodies and suggest that BCMA-CARTx recipients need ongoing surveillance for late-onset infections. Most infections were mild-moderate severity viral infections. The incidence of early infection appears to be lower than has been reported after CD19-directed CARTx for B cell neoplasms, possibly due to differences in patient and disease characteristics and regimen-related toxicities.

Antibodies against vaccine-preventable infections after CAR-T cell therapy for B cell malignancies.

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.

A human coronavirus evolves antigenically to escape antibody immunity.

There is intense interest in antibody immunity to coronaviruses. However, it is unknown if coronaviruses evolve to escape such immunity, and if so, how rapidly. Here we address this question by characterizing the historical evolution of human coronavirus 229E. We identify human sera from the 1980s and 1990s that have neutralizing titers against contemporaneous 229E that are comparable to the anti-SARS-CoV-2 titers induced by SARS-CoV-2 infection or vaccination. We test these sera against 229E strains isolated after sera collection, and find that neutralizing titers are lower against these "future" viruses. In some cases, sera that neutralize contemporaneous 229E viral strains with titers >1:100 do not detectably neutralize strains isolated 8-17 years later. The decreased neutralization of "future" viruses is due to antigenic evolution of the viral spike, especially in the receptor-binding domain. If these results extrapolate to other coronaviruses, then it may be advisable to periodically update SARS-CoV-2 vaccines.

Immunogenicity of Inactivated Varicella Zoster Vaccine in Autologous Hematopoietic Stem Cell Transplant Recipients and Patients With Solid or Hematologic Cancer.

BACKGROUND: In phase 3 trials, inactivated varicella zoster virus (VZV) vaccine (ZVIN) was well tolerated and efficacious against herpes zoster (HZ) in autologous hematopoietic stem cell transplant (auto-HSCT) recipients and patients with solid tumor malignancies receiving chemotherapy (STMc) but did not reduce HZ incidence in patients with hematologic malignancies (HMs). Here, we describe ZVIN immunogenicity from these studies. METHODS: Patients were randomized to ZVIN or placebo (4 doses). Immunogenicity was assessed by glycoprotein enzyme-linked immunosorbent assay (gpELISA) and VZV interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) assay in patients receiving all 4 doses without developing HZ at the time of blood sampling. RESULTS: Estimated geometric mean fold rise ratios (ZVIN/placebo) by gpELISA and IFN-y ELISPOT ~28 days post-dose 4 were 2.02 (95% confidence interval [CI], 1.53-2.67) and 5.41 (95% CI, 3.60-8.12) in auto-HSCT recipients; 1.88 (95% CI, 1.79-1.98) and 2.10 (95% CI, 1.69-2.62) in patients with STMc; and not assessed and 2.35 (95% CI, 1.81-3.05) in patients with HM. CONCLUSIONS: ZVIN immunogenicity was directionally consistent with clinical efficacy in auto-HSCT recipients and patients with STMc even though HZ protection and VZV immunity were not statistically correlated. Despite a lack of clinical efficacy in patients with HM, ZVIN immunogenicity was observed in this population. Immunological results did not predict vaccine efficacy in these 3 populations. CLINICAL TRIAL REGISTRATION: NCT01229267, NCT01254630.

Late infectious complications in hematopoietic cell transplantation survivors: a population-based study.

Few studies have compared the incidence of infections occurring ≥2 years after hematopoietic cell transplant (HCT) with other cancer patients and the general population. In this study, ≥2-year HCT survivors who were Washington residents treated from 1992 through 2009 (n = 1792; median age, 46 years; 52% allogeneic; 90% hematologic malignancies) were matched to individuals from the state cancer registry (n = 5455, non-HCT) and driver's license files (n = 16 340; Department of Licensing [DOL]). Based on hospital and death registry codes, incidence rate ratios (IRRs; 95% confidence interval [CI]) of infections by organism type and organ system were estimated using Poisson regression. With 7-year median follow-up, the incidence rate (per 1000 person-years) of all infections was 65.4 for HCT survivors vs 39.6 for the non-HCT group (IRR, 1.6; 95% CI, 1.3-1.9) and 7.2 for DOL (IRR, 10.0; 95% CI, 8.3-12.1). Bacterial and fungal infections were each 70% more common in HCT vs non-HCT cancer survivors (IRR, 1.7; P < .01), whereas the risk for viral infection was lower (IRR, 1.4; P = .07). Among potentially vaccine-preventable organisms, the IRR was 3.0 (95% CI, 2.1-4.3) vs the non-HCT group. Although the incidences of all infections decreased with time, the relative risk in almost all categories remained significantly increased in ≥5-year HCT survivors vs other groups. Risk factors for late infection included history of relapse and for some infections, history of chronic graft-versus-host disease. Providers caring for HCT survivors should maintain vigilance for infections and ensure adherence to antimicrobial prophylaxis and vaccination guidelines.

Oral brincidofovir decreases the incidence of HHV-6B viremia after allogeneic HCT.

Human herpesvirus 6B (HHV-6B) frequently reactivates after allogeneic hematopoietic cell transplantation (HCT). There are no randomized studies of antiviral treatments to prevent HHV-6B reactivation. Brincidofovir has high in vitro activity against HHV-6B and other DNA viruses, but its in vivo activity for HHV-6B has not been demonstrated. We performed a post hoc analysis of a randomized controlled trial of twice-weekly oral brincidofovir for cytomegalovirus prophylaxis after allogeneic HCT to study the effect of brincidofovir on HHV-6B reactivation. We included patients randomized within 2 weeks of HCT and who received at least 6 consecutive doses of study drug after randomization. We tested plasma for HHV-6B through week 6 post-HCT. The cohort consisted of 92 patients receiving brincidofovir and 61 receiving placebo. The cumulative incidence of HHV-6B plasma detection through day 42 post-HCT was significantly lower among patients receiving brincidofovir (14.2%) compared with placebo (32.4%; log-rank, 0.019). In an adjusted Cox model, brincidofovir exposure remained associated with a lower hazard for HHV-6B plasma detection (hazard ratio, 0.40; 95% confidence interval, 0.20-0.80). In conclusion, brincidofovir prophylaxis reduced HHV-6B reactivation after allogeneic HCT in a post hoc analysis of a randomized controlled trial. These data support the study of intravenous brincidofovir for HHV-6B prophylaxis.

Predictive Value of Respiratory Viral Detection in the Upper Respiratory Tract for Infection of the Lower Respiratory Tract With Hematopoietic Stem Cell Transplantation.

BACKGROUND: Hematopoietic cell transplant (HCT) recipients are frequently infected with respiratory viruses (RVs) in the upper respiratory tract (URT), but the concordance between URT and lower respiratory tract (LRT) RV detection is not well characterized. METHODS: Hematopoietic cell transplant candidates and recipients with respiratory symptoms and LRT and URT RV testing via multiplex PCR from 2009 to 2016 were included. Logistic regression models were used to analyze risk factors for LRT RV detection. RESULTS: Two-hundred thirty-five HCT candidates or recipients had URT and LRT RV testing within 3 days. Among 115 subjects (49%) positive for a RV, 37% (42 of 115) had discordant sample pairs. Forty percent (17 of 42) of discordant pairs were positive in the LRT but negative in the URT. Discordance was common for adenovirus (100%), metapneumovirus (44%), rhinovirus (34%), and parainfluenza virus type 3 (28%); respiratory syncytial virus was highly concordant (92%). Likelihood of LRT detection was increased with URT detection (oods ratio [OR] = 73.7; 95% confidence interval [CI], 26.7-204) and in cytomegalovirus-positive recipients (OR = 3.70; 95% CI, 1.30-10.0). CONCLUSIONS: High rates of discordance were observed for certain RVs. Bronchoalveolar lavage sampling may provide useful diagnostic information to guide management in symptomatic HCT candidates and recipients.

Durable preservation of antiviral antibodies after CD19-directed chimeric antigen receptor T-cell immunotherapy.

The long-term effects of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy (CD19-CARTx) for B-cell malignancies on humoral immunity are unclear. We examined antiviral humoral immunity in 39 adults with B-cell malignancies who achieved durable complete remission without additional therapy for >6 months after CD19-CARTx. Despite CD19+ B-cell aplasia in all patients, the incidence of viral infections occurring >90 days post-CD19-CARTx was low (0.91 infections per person-year). Because long-lived plasma cells are CD19- and should not be direct targets of CD19-targeted chimeric antigen receptor T cells, we tested the hypothesis that humoral immunity was preserved after CD19-CARTx based on linear mixed-effects models of changes in serum total immunoglobulin G (IgG) concentration, measles IgG concentration, and the number of viruses or viral epitopes to which serum IgG was directed (the "antivirome") using the novel VirScan assay. Samples were tested pre-CD19-CARTx and ∼1, 6, and 12 months post-CD19-CARTx. Although total IgG concentration was lower post-CD19-CARTx (mean change, -17.5%), measles IgG concentration was similar (mean change, 1.2%). Only 1 participant lost measles seroprotection post-CD19-CARTx but had undergone allogeneic hematopoietic cell transplantation before CD19-CARTx. The antivirome was also preserved, with mean absolute losses of 0.3 viruses and 6 viral epitopes detected between pre- and post-CD19-CARTx samples. Most participants gained IgG to ≥2 epitopes for ≥2 viruses, suggesting that humoral immunity to some viruses may be maintained or recover after successful CD19-CARTx. These findings may differ in children. Studies of immunoglobulin replacement and vaccination after CARTx are warranted.

Effect of Recombinant Zoster Vaccine on Incidence of Herpes Zoster After Autologous Stem Cell Transplantation: A Randomized Clinical Trial.

Importance: Herpes zoster, a frequent complication following autologous hematopoietic stem cell transplantation (HSCT), is associated with significant morbidity. A nonlive adjuvanted recombinant zoster vaccine has been developed to prevent posttransplantation zoster. Objective: To assess the efficacy and adverse event profile of the recombinant zoster vaccine in immunocompromised autologous HSCT recipients. Design, Setting, and Participants: Phase 3, randomized, observer-blinded study conducted in 167 centers in 28 countries between July 13, 2012, and February 1, 2017, among 1846 patients aged 18 years or older who had undergone recent autologous HSCT. Interventions: Participants were randomized to receive 2 doses of either recombinant zoster vaccine (n = 922) or placebo (n = 924) administered into the deltoid muscle; the first dose was given 50 to 70 days after transplantation and the second dose 1 to 2 months thereafter. Main Outcomes and Measures: The primary end point was occurrence of confirmed herpes zoster cases. Results: Among 1846 autologous HSCT recipients (mean age, 55 years; 688 [37%] women) who received 1 vaccine or placebo dose, 1735 (94%) received a second dose and 1366 (74%) completed the study. During the 21-month median follow-up, at least 1 herpes zoster episode was confirmed in 49 vaccine and 135 placebo recipients (incidence, 30 and 94 per 1000 person-years, respectively), an incidence rate ratio (IRR) of 0.32 (95% CI, 0.22-0.44; P < .001), equivalent to 68.2% vaccine efficacy. Of 8 secondary end points, 3 showed significant reductions in incidence of postherpetic neuralgia (vaccine, n=1; placebo, n=9; IRR, 0.1; 95% CI, 0.00-0.78; P = .02) and of other prespecified herpes zoster-related complications (vaccine, n=3; placebo, n=13; IRR, 0.22; 95% CI, 0.04-0.81; P = .02) and in duration of severe worst herpes zoster-associated pain (vaccine, 892.0 days; placebo, 6275.0 days; hazard ratio, 0.62; 95% CI, 0.42-0.89; P = .01). Five secondary objectives were descriptive. Injection site reactions were recorded in 86% of vaccine and 10% of placebo recipients, of which pain was the most common, occurring in 84% of vaccine recipients (grade 3: 11%). Unsolicited and serious adverse events, potentially immune-mediated diseases, and underlying disease relapses were similar between groups at all time points. Conclusions and Relevance: Among adults who had undergone autologous HSCT, a 2-dose course of recombinant zoster vaccine compared with placebo significantly reduced the incidence of herpes zoster over a median follow-up of 21 months. Trial Registration: ClinicalTrials.gov Identifier: NCT01610414.

A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial of Oral Brincidofovir for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Cell Transplantation.

Cytomegalovirus (CMV) infection is a common complication of allogeneic hematopoietic cell transplantation (HCT). In this trial, we randomized adult CMV-seropositive HCT recipients without CMV viremia at screening 2:1 to receive brincidofovir or placebo until week 14 post-HCT. Randomization was stratified by center and risk of CMV infection. Patients were assessed weekly through week 15 and every third week thereafter through week 24 post-HCT. Patients who developed clinically significant CMV infection (CS-CMVi; CMV viremia requiring preemptive therapy or CMV disease) discontinued the study drug and began anti-CMV treatment. The primary endpoint was the proportion of patients with CS-CMVi through week 24 post-HCT; patients who discontinued the trial or with missing data were imputed as primary endpoint events. Between August 2013 and June 2015, 452 patients were randomized at a median of 15 days after HCT and received study drug. The proportion of patients who developed CS-CMVi or were imputed as having a primary endpoint event through week 24 was similar between brincidofovir-treated patients and placebo recipients (155 of 303 [51.2%] versus 78 of 149 [52.3%]; odds ratio, .95 [95% confidence interval, .64 to 1.41]; P = .805); fewer brincidofovir recipients developed CMV viremia through week 14 compared with placebo recipients (41.6%; P < .001). Serious adverse events were more frequent among brincidofovir recipients (57.1% versus 37.6%), driven by acute graft-versus-host disease (32.3% versus 6.0%) and diarrhea (6.9% versus 2.7%). Week 24 all-cause mortality was 15.5% among brincidofovir recipients and 10.1% among placebo recipients. Brincidofovir did not reduce CS-CMVi by week 24 post-HCT and was associated with gastrointestinal toxicity.

Inactivated varicella zoster vaccine in autologous haemopoietic stem-cell transplant recipients: an international, multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Recipients of autologous haemopoietic stem-cell transplants (auto-HSCT) have an increased risk of herpes zoster and herpes zoster-related complications. The aim of this study was to establish the efficacy and safety of an inactivated varicella zoster vaccine for the prevention of herpes zoster after auto-HSCT. METHODS: In this randomised, double-blind, placebo-controlled phase 3 trial, participants were recruited from 135 medical centres (ie, stem-cell transplant centres and hospitals) in North America, South America, Europe, and Asia. Patients were eligible if they were aged 18 years or older, scheduled to receive an auto-HSCT within 60 days of enrolment, and had a history of varicella infection or were seropositive for antibodies to varicella zoster virus, or both. Exclusion criteria included a history of herpes zoster within the previous year of enrolment, and intended antiviral prophylaxis for longer than 6 months after transplantation. Participants were randomly assigned according to a central randomisation schedule generated by the trial statistician, to receive either the inactivated-virus vaccine from one of three consistency lots, a high-antigen lot, or placebo, stratified by age (<50 vs ≥50 years) and intended duration of antiviral prophylaxis after transplantation (≤3 months vs >3 to ≤6 months). Participants, investigators, trial staff, and the funder's clinical and laboratory personnel were masked to group assignment. Participants were given four doses of inactivated vaccine or placebo, with the first dose 5-60 days before auto-HSCT, and the second, third, and fourth doses at about 30, 60, and 90 days after transplantation. The primary efficacy endpoint was the incidence of herpes zoster, confirmed by PCR or adjudication by a masked clinical committee, or both, assessed in all participants randomly assigned to the vaccine consistency lot group or placebo group who received at least one dose of vaccine and had auto-HSCT. Safety was assessed in all randomised participants who received at least one dose of vaccine and had follow-up data. A prespecified vaccine efficacy success criterion required the lower bound of the 95% CI be higher than 25% for the relative reduction of the hazard ratio of herpes zoster infection in participants given the vaccine from one of the consistency lots compared with those given placebo. This trial is registered on ClinicalTrials.gov (NCT01229267) and EudraCT (2010-020150-34). FINDINGS: Between Dec 7, 2010, and April 25, 2013, 560 participants were randomly assigned to the vaccine consistency lot group, 106 to the high-antigen lot group, and 564 to the placebo group. 249 (44%) of patients in the vaccine consistency lot group, 35 (33%) in the high-antigen lot group, and 220 (39%) in the placebo group discontinued before study end, mostly because of death or withdrawal. 51 participants were excluded from the primary efficacy endpoint analyses because they did not undergo auto-HSCT or were not vaccinated, or both (22 [4%] in the vaccine consistency lot group, and 29 [5%] in the placebo group). Mean follow-up for efficacy was 2·4 years (SD 1·3) in the vaccine consistency lot group and 2·3 years (SD 1·3) in the placebo group. 42 (8%) of 538 participants in the vaccine consistency lot group (32·9 per 1000 person-years) and 113 (21%) of 535 in the placebo group (91·9 per 1000 person-years) had a confirmed case of herpes zoster. The estimated vaccine efficacy was 63·8% (95% CI 48·4-74·6), meeting the pre-specified success criterion. For the combined vaccine groups versus the placebo group, the proportion of patients with serious adverse events (216 [33%] of 657 vs 181 [33%] of 554; risk difference 0·2%, 95% CI -5·1 to 5·5) and serious vaccine-related adverse events (five [1%] vs five [1%]; risk difference 0·1%, -1·4 to 1·1) were similar. Vaccine-related injection-site adverse events occurred more frequently in participants given vaccine than those given placebo (191 [29%] vs 36 [7%]; risk difference 22·6%, 95% CI 18·5-26·6; p<0·0001). INTERPRETATION: This study shows for the first time in a large phase 3 trial that early vaccination of auto-HSCT recipients during the peri-transplant period can be effective for the prevention of an opportunistic infection like herpes zoster and that the vaccine is well tolerated. FUNDING: Merck & Co., Inc.

Graft-Derived Reconstitution of Mucosal-Associated Invariant T Cells after Allogeneic Hematopoietic Cell Transplantation.

Mucosal-associated invariant T (MAIT) cells express a semi-invariant Vα7.2+ T cell receptor (TCR) that recognizes ligands from distinct bacterial and fungal species. In neonates, MAIT cells proliferate coincident with gastrointestinal (GI) bacterial colonization. In contrast, under noninflammatory conditions adult MAIT cells remain quiescent because of acquired regulation of TCR signaling. Effects of inflammation and the altered GI microbiota after allogeneic hematopoietic cell transplantation (HCT) on MAIT cell reconstitution have not been described. We conducted an observational study of MAIT cell reconstitution in myeloablative (n = 41) and nonmyeloablative (n = 66) allogeneic HCT recipients and found that despite a rapid and early increase to a plateau at day 30 after HCT, MAIT cell numbers failed to normalize for at least 1 year. Cord blood transplant recipients and those who received post-HCT cyclophosphamide for graft versus host disease (GVHD) prophylaxis had profoundly impaired MAIT cell reconstitution. Sharing of TCRß gene sequences between MAIT cells isolated from HCT grafts and blood of recipients after HCT showed early MAIT cell reconstitution was due at least in part to proliferation of MAIT cells transferred in the HCT graft. Inflammatory cytokines were required for TCR-dependent MAIT cell proliferation, suggesting that bacterial Vα7.2+ TCR ligands might promote MAIT cell reconstitution after HCT. Robust MAIT cell reconstitution was associated with an increased GI abundance of Blautia spp. MAIT cells suppressed proliferation of conventional T cells consistent with a possible regulatory role. Our data identify modifiable factors impacting MAIT cell reconstitution that could influence the risk of GVHD after HCT.