Resistance-WATCH

Resistance watch (Re-WATCH) is a genomics-based platform for accurate diagnosis and surveillance of drug-resistant tuberculosis in South Africa. 

Dr Frederick Clasen, Bioinformatician and Entrepreneur, CEO of Gigabiome Ltd and Researcher at King's College London. 

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is second only to COVID-19 for the number of deaths caused by an infectious agent. In 2020 almost 10 million people contracted TB and it caused 1.5 million deaths due to resistance to antibiotics. This makes drug-resistant TB (DR-TB) one of the biggest health-economic problems globally. In low- and middle-income countries (LMIC), such as South Africa that is listed in all three high TB burden country lists by the WHO, accurate surveillance and diagnosis are the biggest challenges faced by the public health sector. Current estimates show that as much as one-third of new cases (~3 million) remains unknown to the health system, and most are not receiving proper treatment. 

Whole genome-sequencing (WGS) of MTB has progressed to be a useful tool for diagnosis and management of TB in public health surveillance. Its implementation is a problem in South Africa (and other LMICs) because of a lack of technical expertise and infrastructure which we aim to address with our solution. 

Our solution will primarily serve the 60 million public citizens of South Africa who are directly affected by DR-TB. Successful implementation of our solution will also pave the way for further deployment across the continent and potentially elsewhere in the world. More directly, our project supports the Department of Health of South Africa and healthcare systems to address the threat of DR-TB and the burden it has on the economy and healthcare system. Our project therefore aligns well with the END-TB 2035 program of the WHO.

As part of our solution, we will also engage with two groups of people key to our solution to understand their needs and how to support them to deliver our solution and beyond. Firstly, we will engage with healthcare providers to pilot our diagnostic and establish how we can implement this on a larger scale. Secondly, integration of our platform into the surveillance system of the country brings extensive engagement with scientists and developers on the best ways to improve current practices how we can ensure sustainability, longevity, and accuracy of the solution. The latter will be achieved by continuous training and collaboration between project partners.

Improved surveillance and diagnosis of drug resistant TB through our technology are directly contributing to the improvement of public health to combat the deaths that are a direct and indirect consequence of AMR in South Africa. That will be the biggest contribution to public good.

We are also committed to generate broader public goods by the following:

1. Knowledge-sharing: It is vital to implement these types of platforms for surveillance and diagnosis across the world. Our team is therefore committed to assist other countries on the continent. As such, one of team leads, Dr Shaheed Omar (Head of CTB), is extensively involved with programs of the WHO to implement WGS in other African countries and elsewhere in the world.
2. Data-sharing and publications: We will seek to aggregate patterns and insights from our datasets to make it available to other researchers and public health departments through, for example, peer-review and white-paper publications. The codebase of our platform is also open source.
3. Policy briefs: Our team is extensively involved in policy making in South Africa and the continent. We will therefore engage with these stakeholders and issue policy briefs to advise on best practices and policy gaps.

Re-WATCH aims to have a major public health impact with policy guidance and directly impact management of DR-TB by reducing the spread of drug resistance TB and associated deaths.

Timely and accurate transmission surveillance serves as a crucial early warning system for high-risk clusters of drug resistant TB that creates tangible impact for healthcare systems by alerting them and implementing appropriate measures to stop further spread. Further, understanding the prevalence of drug resistance can guide standardized regimen use and effectiveness. For example, in a previous case using our G-RES platform the Centre for TB was able to identify smaller subclusters of a resistant outbreak because of the higher resolution it provides compared to other methods. Together with geospatial mapping this was narrowed down to a ~2km radius and the value of transmission surveillance with WGS was demonstrated. This has real tangible impact on public health authorities and healthcare providers.

By working closely with stakeholders in South Africa and across Africa and establishing more collaborations our solution will continue to create tangible impact by further development and implementation.

Our G-RES platform has had measurable impact on drug resistant TB surveillance in South Africa. We must now focus on implementing the platform as part of the standard of care and designing a deployable targeted NGS (tNGS) diagnostic.

Over the next year, we will focus on:

• Integrating the platform into the current surveillance system of drug resistant TB in South Africa and developing a comprehensive resource for drug resistant TB 

Over the next three years, we will focus on:

• To roll out the integrated surveillance dashboard to include all 4700 health care facilities in the NHLS network.
• Engaging and partnering with relevant stakeholders in the private and public sector to build a tNGS diagnostic that can scale easily into different healthcare settings.
• Making accessible data to the research community including academia to leverage off the genomic data for research purposes.
• Scale the platform to other pathogens for a more holistic pathogen surveillance system.

Improving surveillance and early drug resistance detection saves lives and prevents large economic damages. Having tangible impact is therefore at the core of our team's ethos. 

We focus on the following impact areas to evaluate implementation of our platform:

Platform measurements

• System performance: we measure the ability of the platform to increase in scale (number of samples) by optimisation of algorithms
• Platform validation: comparing drug resistance predictions against standard of care

Other direct and indirect measurements

• Healthcare impact: we measure quantitatively and qualitatively how improved surveillance reduced spread of resistance by comparison against previous outbreaks when the system has not been implemented
• Economic impact: comparison against historical data of drug resistant TB outbreaks, we measure economic benefit of reduced outbreaks because of improved surveillance 
• Socio-Economic Impact: we measure the social return on investment (SROI) for monitoring impact on social, economic, and environmental levels. This focuses on the positive or negative fluctuations of these components, which will indicate the project’s direction. 

The biggest barriers for implementation of novel technology, especially NGS-based, for surveillance in high TB-burden areas such as LMICs are related to a lack of technical expertise and infrastructure.

Technical expertise

We believe that the involvement of Gigabiome based in the UK together with team members in South Africa will significant to help overcome this. The world-class technical expertise of Gigabiome's team will be crucial for success of Re-WATCH.

The team can further provide the necessary training to teams based in South Africa.

Infrastructure

The necessary infrastructure for WGS and surveillance are available for pilot work through the NICD. However, large-scale implementation of a tNGS platform in public healthcare will remain a significant barrier. Continued close collaboration with Department of Health will be critical for this success. The NICD is ideally positioned for this.

Innovation in the AMR space is complex, in particular when it comes to implementation of these solutions. In addition, although AMR poses such a great problem, fundraising in the sphere remains difficult, especially equity investment through classical fundraising routes. This is even more true for earlier-stage technology such as we build at Gigabiome.

We mentioned two barriers for AMR innovation (which we also face): technical expertise and infrastructure. The Trinity Challenge will help us overcome this by providing the funding necessary to expand our team to provide the technical expertise for this solution. We think we are also ideally located in the UK to make use of the larger technical expertise network that would otherwise be difficult to get in a LMIC. Secondly, this challenge will allow us to start building the infrastructure and network needed to implement this on a wider scale. We hope that directly measuring the impact of our solution will showcase to local, national and global authorities that this is not just an unmet need but also possible.

There are several collaborators that we will benefit from either through partnerships or collaboration:

• Wellcome Trust & Bill and Melinda Gates Foundation: Engagement with these organisations will be key to scale our solution from South Africa to other countries. In particular for additional funding applications.
• GSK: To accelerate development of a tNGS based assay
• University of Oxford: Team members at the NICD has previously had collaboration with Oxford, which we would continue to accelerate our solution.