The aim of this project is to assess the facilitators and barriers to scale-up of two proven active TB case finding and comprehensive patient care models in Vietnam and Nepal as examples of these low and lower-middle income country settings. We will use these data to develop an evidence-based framework for scale-up of implementation by the respective National TB Programs in consultation with relevant stakeholders and governments. This will facilitate programmatic adoption of realistic and optimised active case finding strategies by national TB control programmes. We will compare two alternative implementation strategies in each country appropriate to the local level of current service delivery. For Vietnam, we will compare implementation using salaried employees with volunteer counsellors. For Nepal, we will compare two diagnostic testing strategies as a component of active case finding: traditional smear microscopy or the novel Xpert Omni molecular testing. We will determine the health economic impact of active case detection under the different models and model the long-term epidemiologic impact and cost-effectiveness. The research seeks to achieve the following objectives: 1) Implementation of active case finding with comprehensive patient support in 6 districts of Ho Chi Minh City, Vietnam detecting 1,450 additional cases in 2 years. 2) Implementation of active case finding with comprehensive patient support in 4 districts of the Central Development Region of Nepal, detecting 1,050 additional cases in 2 years. 3) Health economic evaluation of alternative implementation models in low (Nepal) and middle income (Vietnam) scenarios to inform policy. 4) Consultation with policy makers, stakeholders and end-users to evaluate facillatators and barriers to scale-up at health system and individual level and development of an evidence-based framework for scale-up for each country. 5) Transmission modelling of epidemic impact and long-term cost-effectiveness.

The main aim of the proposed project is to use genomic epidemiology of tuberculosis, malaria and emerging and re-emerging pathogens in Africa as to better understand disease etiology, dynamics of disease transmission, and evolution of drug-resistant pathogens. The study also aims to increase Africa's capacity in bioinformatics, genomics, genomics data management, biobanking, and promote data sharing. Our goal is to improve the health of Africans with innovations in disease surveillance, equip the next generation of African scientists with cutting edge skills and strengthening south-south research collaborations. We propose the following hypotheses: 1. Increased capacity in genomic epidemiology will enable more effective disease surveillance in Africa. 2. Increased capacity in biobanking and genomics data management and analysis in Africa will enhance regional surveillance of infectious diseases and encourage timely and effective responses to emerging pathogens. 3. Regional whole genome sequence-based surveillance will improve the detection of DR-TB and inform the development of more sensitive and specific rapid diagnostics for the detection and surveillance of DR-TB in Africa and elsewhere. 4. Regional genomic surveillance of malaria parasites will inform a pre-emptive detection of emerging DR parasites and measure the impact of programmatic interventions for a data driven decision making by policy makers. 5. Implementation of harmonized genomic data analysis tools will allow the creation of continent-wide surveillance networks able to identify cross-border spread of DR variants and emerging pathogens. To achieve this, PANGenS will develop genomic epidemiology capacity across Africa by establishing a collaborative framework that brings together all expertise to perform trainings and implementation in all relevant components ranging from wet lab to bioinformatics, and establish proof-of-concept studies for TB and malaria in in selected partner countries

Current anti-tuberculosis (TB) drug regimens face serious limitations at times of increasing antimicrobial drug resistance. Fortunately, for the first time for centuries, several novel anti-TB compounds are available for clinical evaluation. As the traditional approach to testing these in multiple combination regimens is too slow and inefficient new approaches of clinical phase 2 study designs are required if we are to meet the targets of the WHO EndTB strategy to save the lives of millions into the near future. Our consortium brings together a unique group of European and international leaders in TB research and leading industry partners. Together we will provide the necessary comprehensive range of expertise to meet the demands of the UNITE4TB scientific research agenda. Specifically, we will develop a new global standard for phase 2 TB clinical trial designs, utilising simulation tools to identify optimal doses in phase 2A trials and apply a multi-arm multi-stage adaptive randomised controlled 2B/C trial design capable of rapid and simultaneous evaluation of the best candidate regimens. Our innovative phase 2 trials will be performed to the highest regulatory standards, incorporating state-of-the-art microbiology, biomarker investigation and clinical pharmacology. We will take advantage of existing global TB clinical trial networks with the capacity to enrol patients at an unprecedented pace and number across four continents. Artificial intelligence/machine learning technologies will be applied to validate state-of-the art molecular and imaging tools as treatment decision biomarkers with the aim of establishing new, real-time outcome measures. Our consortium will evaluate 3-5 new chemical entities (NCEs) at phase 2A and up to 17 novel combination regimens in phase 2B/C. Our objective is to identify those that have the greatest chance of success in subsequent definitive phase 3 clinical trials and of becoming the global gold-standard TB regimens of the future.