Introduction of birth dose of hepatitis B virus vaccine to the immunization program in Ethiopia: An economic evaluation

Background Hepatitis B virus (HBV) infection is an important cause of morbidity and mortality with a very high burden in Africa. The risk of developing chronic infection is marked if the infection is acquired perinatally, which is largely preventable through a birth dose of HBV vaccine. We examined the cost-effectiveness of a birth dose of HBV vaccine in a medical setting in Ethiopia. Methods We constructed a decision analytic model with a Markov process to estimate the costs and effects of a birth dose of HBV vaccine (the intervention), compared with current practices in Ethiopia. Current practice is pentavalent vaccination (DPT-HiB-HepB) administered at 6, 10 and 14 weeks after birth. We used disability-adjusted life years (DALYs) averted to quantify the health benefits while the costs of the intervention were expressed in 2018 USD. Analyses were based on Ethiopian epidemiological, demographic and cost data when available; otherwise we used a thorough literature review, in particular for assigning transition probabilities. Results In Ethiopia, where the prevalence of HBV among pregnant women is 5%, adding a birth dose of HBV vaccine would present an incremental cost-effectiveness ratio (ICER) of USD 110 per DALY averted. The estimated ICER compares very favorably with a willingness-to-pay level of 0.31 times gross domestic product per capita (about USD 240 in 2018) in Ethiopia. Our ICER estimates were robust over a wide range of epidemiologic, vaccine effectiveness, vaccine coverage and cost parameter inputs. Conclusions Based on our cost-effectiveness findings, introducing a birth dose of HBV vaccine in Ethiopia would likely be highly cost-effective. Such evidence could help guide policymakers in considering including HBV vaccine into Ethiopia’s essential health services package.publishedVersio

Multifaceted role of BTLA in the control of CD8+ T cell fate after antigen encounter

Purpose: Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown an overall clinical response rate 40%–50% in metastatic melanoma patients. BTLA (B-and-T lymphocyte associated) expression on transferred CD8+ TILs was associated with better clinical outcome. The suppressive function of the ITIM and ITSM motifs of BTLA is well described. Here, we sought to determine the functional characteristics of the CD8+BTLA+TIL subset and define the contribution of the Grb2 motif of BTLA in T-cell costimulation. Experimental Design: We determined the functional role and downstream signal of BTLA in both human CD8+ TILs and mouse CD8+ T cells. Functional assays were used including single-cell analysis, reverse-phase protein array (RPPA), antigen-specific vaccination models with adoptively transferred TCR-transgenic T cells as well as patient-derived xenograft (PDX) model using immunodeficient NOD-scid IL2Rgammanull (NSG) tumor-bearing mice treated with autologous TILs. Results: CD8+BTLA? TILs could not control tumor growth in vivo as well as their BTLA+ counterpart and antigen-specific CD8+BTLA? T cells had impaired recall response to a vaccine. However, CD8+BTLA+ TILs displayed improved survival following the killing of a tumor target and heightened “serial killing” capacity. Using mutants of BTLA signaling motifs, we uncovered a costimulatory function mediated by Grb2 through enhancing the secretion of IL-2 and the activation of Src after TCR stimulation. Conclusions: Our data portrays BTLA as a molecule with the singular ability to provide both costimulatory and coinhibitory signals to activated CD8+ T cells, resulting in extended survival, improved tumor control, and the development of a functional recall response. Clin Cancer Res; 23(20); 6151–64. ©2017 AACR

Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression

Abstract Purpose: VEGF-targeted therapies have modest efficacy in cancerpatients, butacquiredresistance iscommon. Themechanisms underlying such resistance are poorly understood. Experimental Design: To evaluate the potential role of immune cells in the development of resistance to VEGF blockade, we first established a preclinical model of adaptive resistance to anti-VEGF therapy. Additional in vitro and in vivo studies were carried out to characterize the role of macrophages in such resistance. Results: Using murine cancer models of adaptive resistance to anti-VEGF antibody (AVA), we found a previously unrecognized roleofmacrophagesinsuchresistance.Macrophageswereactively recruited to the tumor microenvironment and were responsible for the emergence of AVA resistance. Depletion of macrophages following emergence of resistance halted tumor growth and prolonged survival of tumor-bearing mice. In a macrophagedeficient mouse model, resistance to AVA failed to develop, but could be induced by injection of macrophages. Downregulation of macrophage VEGFR-1 and VEGFR-3 expression accompanied upregulation of alternative angiogenic pathways, facilitating escape from anti-VEGF therapy. Conclusions: These findings provide a new understanding of the mechanisms underlying the modest efficacy of current antiangiogenesis therapies and identify new opportunities for combinationapproachesforovarianandothercancers. ClinCancerRes; 23(22); 7034–46. �2017 AACR

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Biology of Xanthopimpla stemmator (Thunberg) (Hymenoptera:Ichneumonidae), a pupil parasite of stalkborers (Lepidoptera:Pyralidae)

Due to the character of the original source materials and the nature of batch digitization, quality control issues may be present in this document. Please report any quality issues you encounter to [email protected], referencing the URI of the item.Includes bibliographical references.Not availabl

Introduction of birth dose of hepatitis B virus vaccine to the immunization program in Ethiopia: An economic evaluation

Background Hepatitis B virus (HBV) infection is an important cause of morbidity and mortality with a very high burden in Africa. The risk of developing chronic infection is marked if the infection is acquired perinatally, which is largely preventable through a birth dose of HBV vaccine. We examined the cost-effectiveness of a birth dose of HBV vaccine in a medical setting in Ethiopia. Methods We constructed a decision analytic model with a Markov process to estimate the costs and effects of a birth dose of HBV vaccine (the intervention), compared with current practices in Ethiopia. Current practice is pentavalent vaccination (DPT-HiB-HepB) administered at 6, 10 and 14 weeks after birth. We used disability-adjusted life years (DALYs) averted to quantify the health benefits while the costs of the intervention were expressed in 2018 USD. Analyses were based on Ethiopian epidemiological, demographic and cost data when available; otherwise we used a thorough literature review, in particular for assigning transition probabilities. Results In Ethiopia, where the prevalence of HBV among pregnant women is 5%, adding a birth dose of HBV vaccine would present an incremental cost-effectiveness ratio (ICER) of USD 110 per DALY averted. The estimated ICER compares very favorably with a willingness-to-pay level of 0.31 times gross domestic product per capita (about USD 240 in 2018) in Ethiopia. Our ICER estimates were robust over a wide range of epidemiologic, vaccine effectiveness, vaccine coverage and cost parameter inputs. Conclusions Based on our cost-effectiveness findings, introducing a birth dose of HBV vaccine in Ethiopia would likely be highly cost-effective. Such evidence could help guide policymakers in considering including HBV vaccine into Ethiopia’s essential health services package

Viral infection transiently induces sIL-15 complexes <i>in vivo</i> independent of IFN signaling.

<p>A) Serum levels of sIL-15 complexes in Wt mice, at indicated times post VSV infection (1x10⁶ PFU/ mouse, i.v.) (n = 2–5 mice/group), one representative experiment of five total is shown. B,C) Cell surface IL-15 expression in myeloid cells one day after VSV infection or Poly I:C injection (150 μg/mouse, i.p.) as determined by immunofluorescence staining and flow cytometry. Histograms depict representative staining with control Ig (black histogram) and anti-IL-15 Ab (grey histograms) in macrophages (lineage-CD11b+CD11c+F480+). Graph shows average MFI of IL-15 expression in DCs (lineage-CD11b+/-CD11c+F480), macrophages, and monocyte (lineage-CD11b+CD11c-F480-) of indicated mice. n = 3 mice/group, one representative of three experiments shown. D) Levels of sIL-15 complexes in serum from WT and IFNAR-/- mice one day post VSV infection. n = 3–4 mice/group; data is representative of three experiments. * indicates p<0.05.</p

Type I IFN signaling is required for increasing sIL-15 complexes after total body irradiation.

<p>Serum was isolated 24 hours after treating WT mice with varying levels of total body irradiation. Levels of sIL-15 complexes in serum were measured using ELISA. n = 3–4 mice/group. Induction of sIL-15 complexes after TBI has been observed in at least 8 experiments. (B) IFN-α levels were measured in serum isolated from WT mice 24hours after treatment with 1000 RADs of total body irradiation. One of two experiments is shown. (C) Serum was isolated from WT and IFNAR1-/- mice 24 hours after treatment with TBI (1000 RADs). Levels of sIL-15 complexes in serum were measured using ELISA. n = 3–4 mice/group; data is representative of 4 experiments. * indicates p<0.05.</p