ABSTRACT
Epstein-Barr virus (EBV) is a human herpes virus that infects over 90% of the world's population and is linked to development of cancer. In immune-competent individuals, EBV infection is mitigated by a highly efficient virus-specific memory T-cell response. Risk of EBV-driven cancers increases with immune suppression (IS). EBV-seronegative recipients of solid organ transplants are at high risk of developing post-transplant lymphoproliferative disease (PTLD) due to iatrogenic IS. While reducing the level of IS may improve EBV-specific immunity and regression of PTLD, patients are at high risk for allograft rejection and need for immune-chemotherapy. Strategies to prevent PTLD in this vulnerable patient population represents an unmet need. We have previously shown that BZLF1-specific cytotoxic T-cell (CTL) expansion following reduced IS correlated with immune-mediated PTLD regression and improved patient survival. We have developed a vaccine to bolster EBV-specific immunity to the BZLF1 protein and show that co-culture of dendritic cells (DCs) loaded with a αDEC205-BZLF1 fusion protein with peripheral blood mononuclear cells (PMBCs) leads to expansion and increased cytotoxic activity of central-effector memory CTLs against EBV-transformed B-cells. Human-murine chimeric Hu-PBL-SCID mice were vaccinated with DCs loaded with αDEC205-BZLF1 or control to assess prevention of fatal human EBV lymphoproliferative disease. Despite a profoundly immunosuppressive environment, vaccination with αDEC205-BZLF1 stimulated clonal expansion of antigen-specific T-cells that produced abundant IFNγ and significantly prolonged survival. These results support preclinical and clinical development of vaccine approaches using BZLF1 as an immunogen to harness adaptive cellular responses and prevent PTLD in vulnerable patient populations.
ABSTRACT
INTRODUCTION: Isoniazid preventive therapy (IPT) is a proven means to prevent tuberculosis (TB) disease among people living with HIV (PLHIV). However, there is a concern that patients often develop tuberculosis disease while receiving IPT, defined here as breakthrough tuberculosis, which may affect treatment outcome. In this study, we assessed the magnitude and determinants of breakthrough tuberculosis. METHODS: A multisite retrospective longitudinal study from the year 2005 to 2014 involving 11 randomly selected hospitals from the Addis Ababa, SNNPR (Southern Nations Nationalities and Peoples Region), and Gambela regions of Ethiopia was carried out to assess the occurrence of breakthrough tuberculosis. Cox regression analysis was used to study factors associated with breakthrough TB. RESULTS: 4,484 patients in chronic HIV care received IPT. Eighty percent of the same number received antiretroviral therapy (ART). Tuberculosis developed in 88 of 4,484 (2%) patients of which 24 (0.5%) were diagnosed while receiving IPT. Breakthrough TB incidence was 1106 per 100,000 person-years (PY) (95% CI: 742-1651) while TB incidence after completing IPT was 624 per 100,000 PY (95% CI: 488-797). Seven of the 24 (29%) breakthrough TB cases were diagnosed within the first month of IPT initiation. Of 15 patients who developed breakthrough TB while on ART, nine (60%) were diagnosed within the first six months of ART initiation. Having high CD4 cell count and being on ART were associated with having lower risk of developing TB and breakthrough TB. CONCLUSION: Breakthrough TB was uncommon in the study setting. Even then, taking ART reduced the risk of its occurrence. Slightly more than a quarter of the cases of breakthrough TB occurred in the first month of treatment and may be existing undiagnosed TB cases which were missed during diagnostic work-up.
