TB biomarkers, TB correlates and human challenge models: New tools for improving assessment of new TB vaccines

SummaryThe 4th Global Forum on TB Vaccines, convened in Shanghai, China, from 21 – 24 April 2015, brought together a wide and diverse community involved in tuberculosis vaccine research and development to discuss the current status of, and future directions for this critical effort. This paper summarizes the sessions on Biomarkers and Correlates, and Human Challenge Models. Summaries of all sessions from the 4th Global Forum are compiled in a special supplement of Tuberculosis. [August 2016, Vol 99, Supp S1, S1–S30]

A dose-dependent plasma signature of the safety and immunogenicity of the rVSV-Ebola vaccine in Europe and Africa.

The 2014-2015 Ebola epidemic affected several African countries, claiming more than 11,000 lives and leaving thousands with ongoing sequelae. Safe and effective vaccines could prevent or limit future outbreaks. The recombinant vesicular stomatitis virus-vectored Zaire Ebola (rVSV-ZEBOV) vaccine has shown marked immunogenicity and efficacy in humans but is reactogenic at higher doses. To understand its effects, we examined plasma samples from 115 healthy volunteers from Geneva who received low-dose (LD) or high-dose (HD) vaccine or placebo. Fifteen plasma chemokines/cytokines were assessed at baseline and on days 1, 2 to 3, and 7 after injection. Significant increases in monocyte-mediated MCP-1/CCL2, MIP-1β/CCL4, IL-6, TNF-α, IL-1Ra, and IL-10 occurred on day 1. A signature explaining 68% of cytokine/chemokine vaccine-response variability was identified. Its score was higher in HD versus LD vaccinees and was associated positively with vaccine viremia and negatively with cytopenia. It was higher in vaccinees with injection-site pain, fever, myalgia, chills, and headache; higher scores reflected increasing severity. In contrast, HD vaccinees who subsequently developed arthritis had lower day 1 scores than other HD vaccinees. Vaccine dose did not influence the signature despite its influence on specific outcomes. The Geneva-derived signature associated strongly (ρ = 0.97) with that of a cohort of 75 vaccinees from a parallel trial in Lambaréné, Gabon. Its score in Geneva HD vaccinees with subsequent arthritis was significantly lower than that in Lambaréné HD vaccinees, none of whom experienced arthritis. This signature, which reveals monocytes' critical role in rVSV-ZEBOV immunogenicity and safety across doses and continents, should prove useful in assessments of other vaccines

Identification of T-cell antigens specific for latent mycobacterium tuberculosis infection.

BACKGROUND: T-cell responses against dormancy-, resuscitation-, and reactivation-associated antigens of Mycobacterium tuberculosis are candidate biomarkers of latent infection in humans. METHODOLOGY/PRINCIPAL FINDINGS: We established an assay based on two rounds of in vitro restimulation and intracellular cytokine analysis that detects T-cell responses to antigens expressed during latent M. tuberculosis infection. Comparison between active pulmonary tuberculosis (TB) patients and healthy latently M. tuberculosis-infected donors (LTBI) revealed significantly higher T-cell responses against 7 of 35 tested M. tuberculosis latency-associated antigens in LTBI. Notably, T cells specific for Rv3407 were exclusively detected in LTBI but not in TB patients. The T-cell IFNgamma response against Rv3407 in individual donors was the most influential factor in discrimination analysis that classified TB patients and LTBI with 83% accuracy using cross-validation. Rv3407 peptide pool stimulations revealed distinct candidate epitopes in four LTBI. CONCLUSIONS: Our findings further support the hypothesis that the latency-associated antigens can be exploited as biomarkers for LTBI

Measuring the State of Disaster Philanthropy 2016: Data to Drive Decisions

This is the third edition of the annual publication Measuring the State of Disaster Philanthropy: Data to Drive Decisions. This report analyzes funding for disasters and humanitarian crises in 2014, the most recent year for which comprehensive data are available. The report examines funding from U.S. foundations, bilateral and multilateral donors, corporations, and smaller donors who give through online platforms

Measuring the State of Disaster Philanthropy 2017: Data to Drive Decisions

Each year, the Center for Disaster Philanthropy and Foundation Center analyze global disaster-related funding from foundations, bilateral and multilateral donors, the U.S. Federal Emergency Management Agency (FEMA), corporations, and smaller donors who give through donor advised funds and online platforms. We analyze this funding according to a taxonomy that classifies giving by type of disaster and disaster assistance strategy.Philanthropic funding for disasters and humanitarian crises is situated within a large ecosystem of global aid. While assistance from governments far surpasses funding from foundations, institutional philanthropy still plays an important role. For example, foundations can choose to fill funding gaps and support underfunded areas of the disaster lifecycle. Support for disaster risk reduction and preparedness can mitigate the impact of disasters, and many communities need sustained funding for the long road to recovery. We hope this analysis will aid donors in considering how to maximize the impact of their disaster-related giving

Diagnosis of childhood tuberculosis and host RNA expression in Africa

Improved diagnostic tests for tuberculosis in children are needed. We hypothesized that transcriptional signatures of host blood could be used to distinguish tuberculosis from other diseases in African children who either were or were not infected with the human immunodeficiency virus (HIV

Measuring the State of Disaster Philanthropy 2015: Data to Drive Decisions

Jointly produced by Foundation Center and the Center for Disaster Philanthropy, Measuring the State of Disaster Philanthropy 2015: Data to Drive Decisions analyzes funding trends for disasters and humanitarian crises in 2013. In addition to examining U.S. foundation funding, this second annual report integrates other disaster-related funding data, including bilateral and multilateral aid, corporate giving, and online giving, to paint a more detailed picture of how institutional philanthropy is situated within the broader disaster funding landscape. Collectively, this report, along with the dashboard and mapping platform, provides donors, practitioners, and other stakeholders with in-depth information on funding flows for disasters and humanitarian crises. Explore more at disasterphilanthropy.org

Detailed characterization of human Mycobacterium tuberculosis specific HLA-E restricted CD8(+) T cells

Immunogenetics and cellular immunology of bacterial infectious disease

BLR1 and FCGR1A transcripts in peripheral blood associate with the extent of intrathoracic tuberculosis in children and predict treatment outcome

Biomarkers reflecting the extent of Mycobacterium tuberculosis-induced pathology and normalization during anti-tuberculosis treatment (ATT) would considerably facilitate trials of new treatment regimens and the identification of patients with treatment failure. Therefore, in a cohort of 99 Indian children with intrathoracic tuberculosis (TB), we performed blood transcriptome kinetic analysis during ATT to explore 1) the association between transcriptional biomarkers in whole blood (WB) and the extent of TB disease at diagnosis and treatment outcomes at 2 and 6 months, and 2) the potential of the biomarkers to predict treatment response at 2 and 6 months. We present the first data on the association between transcriptional biomarkers and the extent of TB disease as well as outcome of ATT in children: Expression of three genes down-regulated on ATT (FCGR1A, FPR1 and MMP9) exhibited a positive correlation with the extent of TB disease, whereas expression of eight up-regulated genes (BCL, BLR1, CASP8, CD3E, CD4, CD19, IL7R and TGFBR2) exhibited a negative correlation with the extent of disease. Baseline levels of these transcripts displayed an individual capacity >70% to predict the six-month treatment outcome. In particular, BLR1 and FCGR1A seem to have a potential in monitoring and perhaps tailoring future antituberculosis therapy