Periodic Reporting for period 2 - TB-RECONNECT (Reconnecting transmission to global tuberculosis control by mapping pathogen transmission events to host infection status)
Reporting period: 2023-01-01 to 2024-06-30
The annual decline in tuberculosis (TB) incidence is not greatly different from that of the ‘90s, when no coordinated efforts in global tuberculosis control were in place. The failure of current TB control programmes to accelerate TB elimination has multiple causes, including losses of TB cases at the different steps of the TB care cascade, and a chronic lack of funding hampering innovation. From 2020 to 2050 and based on current estimates (now disrupted by COVID-19) almost 30 million people will die of tuberculosis (Silva et al Lancet Global Health). It is estimated that this figure correspond to an economic loss of 17 trillion dollars. If the Sustainable development Goals for tuberculosis are met by 2030 then three trillion dolars will be saved. But the goal will not be achieved if we not advance in TB controls with innovations in healthcare. In particular, we have failed to halt transmission in many settings, as we have failed to incorporate our improved understanding of transmission in TB control programmes. Our current approach to controlling TB is focused on a narrow view of who is transmitting the disease (symptomatically active TB cases), while there is a growing consensus that the traditional latent/active dichotomy is no longer valid, and that asymptomatic individuals with active TB signatures are also likely to be transmitting the disease. There is a critical lack of high-resolution data from different settings on the contribution to the transmission burden of cases with different infection statuses. To fill this evidence gap, TB-RECONNECT propose synergizing three recent TB research developments; We can now use host blood transcriptomics to discriminate between infection status within the latent pool of individuals. We can now quantify transmission at a resolution not previously available, using pathogen genome sequencing. We can now use phylogenetic and epidemiological models to identify when transmission has happened. Combining these three key developments with TB cohorts from multiple settings, and available tools from bacterial population genetics, high-throughput functional genomics and infection biology, we will be in a key position to answer these burning questions about the nature of TB transmission and the host and pathogen biology behind this. More importantly, we will reconnect transmission to TB control, to inform major shifts in global and local control strategies. Our project can have a major impact at the societal level. By cutting transmission we can help to i) Break the poverty/tuberculosis vicious circle. Tuberculosis is a poverty disease and low- and middle-income countries are disproportionally affected by tuberculosis. In fact poverty and tuberculosis form a vicious cycle in continuous flux. The reason is that poverty influence tuberculosis through limited healthcare, sanitation, education, malnutrition and combordities like HIV or diabetes. Tuberculosis influences poverty through a devastating almost chronic disease including post-TB sequalae that impact the countries productivity. And to reduce ii) Individual financial burden. Household suffer of major reduction in income due to TB illness. For example, in a study in India the mean number of work days lost was 88 with mounting debts due to treatment costs and household financial burdens. To the point that in some countries leads to situations like the household income relying on children of school age. Therefore TB has a major societal impact which can be ameliorated if new ways to control TB are incorporated in global TB control estrategies. At least until a low-cost, effective vaccine is developed and make it to clinical settings.
TB-RECONNECT is composed of four different objectives all of them aiming to understand TB transmission beyond our current understanding and integrate that improved understanding in global TB control. To do that TB-RECONNECT studies transmission from different perspectives: i. Using genomic epidemiology to quantify transmission in TB settings, thus recognizing the heterogeneity of transmission across settings and comorbidities; ii. By identifying who is transmitting whom and when; iii. By linking the information from ii. to the host infection status to identify cases of subclinical transmission; iv. By identifying pathogen determinants of transmission and finally by v. understanding the role of local genotypes in transmission burden. Each one of the approaches will fill a knowledge gap on transmission, all together will reveal how our improved understanding of transmission can be incorporated in global TB Control.
Results. Our project has already generated evidence that TB burden and transmission is unlinked by comparing genomic epidemiology data across three different countries (eLife 2022) as well as transmission and drug resistance in two of the countries where we focus Spain (The Lancet Microbe 2023) and Mozambique (Mgen 2022, Clinical Infectious Diseases 2023). We are now extending the approach to 29 different settings and 30,000 isolate genomes. At the same time we have generated long-term cohorts (>5 years) of pathogen genomic data in Mexico and Spain that will allow us to test who is transmitting to whom and when at a resolution not available before. In parallel, we have already developed statistical ways to link genes to transmission and other phenotypes like virulence and drug resistance (PNAS 2022). One of the targets identified is being studied in a parallel project as a new way to treat TB. Finally we have identified more than 100 local genotypes which we are testing for their role in local transmission (see a proof of concept for Mozambique Mgen 2022) and local co-adaptation both using wet and dry approaches.
Importantly, during the first two years of the ERC the COVID-19 pandemic was on-going. Thanks to ERC preparedness we had the chance to lead genomic surveillance efforts of SARs-CoV-2 in Spain directly reporting to authorities. We applied ERC developments to understand SARS-CoV-2 in Spain. As a result we generated capital evidence for public health later published in Nature Genetics (first wave), Nature (second wave, including Europe) as well many other collaborations with Spanish research groups on waste water surveillance or vaccine effectiveness. We also applied the approaches learned to the other major countries where we do TB work, Mozambique, showing the impact of non-pharmaceutical interventions (The LancetGH2023).
Results. Our project has already generated evidence that TB burden and transmission is unlinked by comparing genomic epidemiology data across three different countries (eLife 2022) as well as transmission and drug resistance in two of the countries where we focus Spain (The Lancet Microbe 2023) and Mozambique (Mgen 2022, Clinical Infectious Diseases 2023). We are now extending the approach to 29 different settings and 30,000 isolate genomes. At the same time we have generated long-term cohorts (>5 years) of pathogen genomic data in Mexico and Spain that will allow us to test who is transmitting to whom and when at a resolution not available before. In parallel, we have already developed statistical ways to link genes to transmission and other phenotypes like virulence and drug resistance (PNAS 2022). One of the targets identified is being studied in a parallel project as a new way to treat TB. Finally we have identified more than 100 local genotypes which we are testing for their role in local transmission (see a proof of concept for Mozambique Mgen 2022) and local co-adaptation both using wet and dry approaches.
Importantly, during the first two years of the ERC the COVID-19 pandemic was on-going. Thanks to ERC preparedness we had the chance to lead genomic surveillance efforts of SARs-CoV-2 in Spain directly reporting to authorities. We applied ERC developments to understand SARS-CoV-2 in Spain. As a result we generated capital evidence for public health later published in Nature Genetics (first wave), Nature (second wave, including Europe) as well many other collaborations with Spanish research groups on waste water surveillance or vaccine effectiveness. We also applied the approaches learned to the other major countries where we do TB work, Mozambique, showing the impact of non-pharmaceutical interventions (The LancetGH2023).
Our project has already provided novel insights into the evolution, epidemiology and also actionable results for public health. On one hand we have shown the disconnection between country TB burden and transmission. Counterintuitively, we show that low burden countries can bear high transmission rates. Long term analysis of transmission suggests that differences among countries of similar profiles are driven by the capacity of the countries to halt local transmission in the past. We have also developed new ways to identify genetic associations to virulence and transmission and use that to identify novel determinants of drug resistance and adaptation to host. We are now following some of these leads to identify new compounds. Finally, we have provided seminal data to show that the diversity observed in the sputum of TB patients is mirrored in the culture in most of the cases, validating the large body of work based on analyzing culture positive cases in TB.