Periodic Reporting for period 5 - SCHISTO_PERSIST (New approaches to characterise Schistosoma mansoni infections persisting despite mass drug administration)
Okres sprawozdawczy: 2022-04-01 do 2023-09-30
Over 240 million people are infected with schistosomiasis. In 2003, Uganda implemented praziquantel mass drug administration but 'hotspots’ of high transmission remain. There are no viable alternatives to praziquantel and emerging resistance would have major implications for control.
Efforts to monitor drug efficacy are impeded by an inability to differentiate between surviving worms and reinfections. As a consequence, the relative contribution of parasite (e.g. drug resistance, hybrid species) and host (e.g. immunology, pharmacokinetics) factors to transmission is unknown. To reduce transmission in hotspots it is also important to quantify the risk of reinfection from untreated individuals.
Our key objectives were to use interdisciplinary approaches to develop new diagnostic methods, optimise drug-efficacy monitoring protocols, and identify key factors that contribute to Schistosoma mansoni hotspots despite mass drug administration.
Specifically we addressed five overarching questions:
I. What is the best way to monitor schistosome infections and drug efficacy?
II. Has drug resistance been selected for?
III. What is the potential for the spread of drug resistance?
IV. What other factors drive transmission?
V. What other factors affect parasite clearance?
Our data have informed control strategies locally and building on our findings we continue to aim to reduce the global burden of schistosomiasis.
Efforts to monitor drug efficacy are impeded by an inability to differentiate between surviving worms and reinfections. As a consequence, the relative contribution of parasite (e.g. drug resistance, hybrid species) and host (e.g. immunology, pharmacokinetics) factors to transmission is unknown. To reduce transmission in hotspots it is also important to quantify the risk of reinfection from untreated individuals.
Our key objectives were to use interdisciplinary approaches to develop new diagnostic methods, optimise drug-efficacy monitoring protocols, and identify key factors that contribute to Schistosoma mansoni hotspots despite mass drug administration.
Specifically we addressed five overarching questions:
I. What is the best way to monitor schistosome infections and drug efficacy?
II. Has drug resistance been selected for?
III. What is the potential for the spread of drug resistance?
IV. What other factors drive transmission?
V. What other factors affect parasite clearance?
Our data have informed control strategies locally and building on our findings we continue to aim to reduce the global burden of schistosomiasis.
In 2017, 2018 and 2019 the SCHISTO_PERSIST team conducted eight field programmes in Mayuge District, Uganda. Field work was postponed during the Covid-19 pandemic, but field studies recommenced in 2020-2021 in Tororo District, being led remotely by the PI, and led in the field by highly skilled Ministry of Health Technicians, and in 2022 with Glasgow team members returning to Uganda for a final field study in Mayuge District.
Samples were collected from school-aged children (SAC), pre-SAC and adults from infected communities. Data on infection levels, treatment history, reasons for non treatment and illness symptoms have been collected along with blood, urine and stool samples collected for drug absorption, microbiome and immunology studies. At all time points parasites were collected for genetic analyses.
Stool samples were processed using Kato-Katz in the field and qPCR for S. mansoni and hookworm infections, PCRs for malaria detection and Luminex analyses for inflammatory markers. Urine samples where processed for antigen diagnostics in the field and the development of a new point of care circulating anodic antigen test. Blood samples were processed for malaria and anaemia in the field and qPCR for S. mansoni, Luminex for immunology, and Liquid chromatography-mass spectrometry for drug absorption and metabolism measures. Parasites were analyses using microsatellites, whole genome sequencing and ITS barcoding for sibship analyses, population dynamics and hybrid species detection.
Results
People are often labelled as systematic non-compliers but they have often not been offered the drug, meaning that outreach and improved sensitisation campaigns can improve drug uptake, rather than education programmes to change treatment views. Infection data show children are rapidly reinfected after treatment, but adults have lower infection levels post treatments. Most adults had never been treated before. MDA programmes need to reach these adults to reduce long term illness and reduce the chance of them reinfecting the children. Parasite genetics support these findings.
Infection data have being used to understand why these Ugandan communities are not clearing as expected with repeated treatments. Mathematical and statistical models highlight the limitations of current diagnostics and the importance of developing improved ones and using genetics to understand parasites dynamics post treatment. Although the drugs continue to reduce egg outputs three weeks post treatment, latent class analysis and parasite genetics indicated that several people remained infected and specific worms and worm pairs survived treatment. This raises concerns for drug resistance, but genetic analyses did not find evidence of a newly published drug resistant marker.
We have developed a point-of-care Circulating Anodic Antigen (POC-CAA) diagnostic and demonstrated that the WHO endorsed POC circulating Cathodic Antigen test (POC-CCA) shows high levels of inter-day variation and two days of testing are required to reach the WHO TPP, whilst intra-sample variation is minimal.
Additional findings including results on microbiome, immunology, and pharmacokinetics which have all been shown to affect drug efficacy, with publications in preparation, and that host blood group does not affect susceptibility to S. mansoni nor drug efficacy.
During this project my group and I have published 40 papers, 32 arising directly from this project. I have presented findings at national, international and online conferences, including the British Society for Parasitology, American Society for Tropical Medicine and Hygiene, Evolution, and International Society for Neglected Tropical Diseases. Findings have been presented and discussed at smaller meetings, with direct access to global health policy makers, such as at the World Health Organization, Bill and Melinda Gates Foundation, FIND diagnostics, British Council workshops in Rwanda and China, Coalition for Operational Research for Neglected Tropical Diseases and through the Global Schistosomiasis Alliance (GSA) Meetings.
Dissemination and Community Engagement: activities include Stakeholder meetings in the communities and districts, providing feedback to participants and other community members on project results, an Acting for Health Workshop in an endemic community, teaching courses in prisons, working with primary school aged children at local events and networks, running public engagement stalls at music festivals, giving talks at schools and in pubs, and the PI being interviewed live at a New Scientist event in London about her career, research and results.
Samples were collected from school-aged children (SAC), pre-SAC and adults from infected communities. Data on infection levels, treatment history, reasons for non treatment and illness symptoms have been collected along with blood, urine and stool samples collected for drug absorption, microbiome and immunology studies. At all time points parasites were collected for genetic analyses.
Stool samples were processed using Kato-Katz in the field and qPCR for S. mansoni and hookworm infections, PCRs for malaria detection and Luminex analyses for inflammatory markers. Urine samples where processed for antigen diagnostics in the field and the development of a new point of care circulating anodic antigen test. Blood samples were processed for malaria and anaemia in the field and qPCR for S. mansoni, Luminex for immunology, and Liquid chromatography-mass spectrometry for drug absorption and metabolism measures. Parasites were analyses using microsatellites, whole genome sequencing and ITS barcoding for sibship analyses, population dynamics and hybrid species detection.
Results
People are often labelled as systematic non-compliers but they have often not been offered the drug, meaning that outreach and improved sensitisation campaigns can improve drug uptake, rather than education programmes to change treatment views. Infection data show children are rapidly reinfected after treatment, but adults have lower infection levels post treatments. Most adults had never been treated before. MDA programmes need to reach these adults to reduce long term illness and reduce the chance of them reinfecting the children. Parasite genetics support these findings.
Infection data have being used to understand why these Ugandan communities are not clearing as expected with repeated treatments. Mathematical and statistical models highlight the limitations of current diagnostics and the importance of developing improved ones and using genetics to understand parasites dynamics post treatment. Although the drugs continue to reduce egg outputs three weeks post treatment, latent class analysis and parasite genetics indicated that several people remained infected and specific worms and worm pairs survived treatment. This raises concerns for drug resistance, but genetic analyses did not find evidence of a newly published drug resistant marker.
We have developed a point-of-care Circulating Anodic Antigen (POC-CAA) diagnostic and demonstrated that the WHO endorsed POC circulating Cathodic Antigen test (POC-CCA) shows high levels of inter-day variation and two days of testing are required to reach the WHO TPP, whilst intra-sample variation is minimal.
Additional findings including results on microbiome, immunology, and pharmacokinetics which have all been shown to affect drug efficacy, with publications in preparation, and that host blood group does not affect susceptibility to S. mansoni nor drug efficacy.
During this project my group and I have published 40 papers, 32 arising directly from this project. I have presented findings at national, international and online conferences, including the British Society for Parasitology, American Society for Tropical Medicine and Hygiene, Evolution, and International Society for Neglected Tropical Diseases. Findings have been presented and discussed at smaller meetings, with direct access to global health policy makers, such as at the World Health Organization, Bill and Melinda Gates Foundation, FIND diagnostics, British Council workshops in Rwanda and China, Coalition for Operational Research for Neglected Tropical Diseases and through the Global Schistosomiasis Alliance (GSA) Meetings.
Dissemination and Community Engagement: activities include Stakeholder meetings in the communities and districts, providing feedback to participants and other community members on project results, an Acting for Health Workshop in an endemic community, teaching courses in prisons, working with primary school aged children at local events and networks, running public engagement stalls at music festivals, giving talks at schools and in pubs, and the PI being interviewed live at a New Scientist event in London about her career, research and results.
We are undertaking innovative steps to understand the biological aspects of why schistosomiasis remains such a huge problem across several communities in Uganda. The novel analysis of family relationships in the parasite offspring to see if they are siblings or half siblings has helped us understand the effect of the drug and measure how successful the treatments have been by seeing if the eggs excreted post treatment are from new infections or worms which have survived treatment.
We have unprecedented follow up data from primary school children and have analysed these with novel mathematical methods, state-space models and latent class analyses, being the first research group to differentiate between infected and transmitting individuals using these models.
The knowledge gained on factors driving transmission and reducing drug efficacy have identified simple actions to increase treatment success, informed control programmes on drug-resistance risks, and advised national and international policy makers on how best to control this debilitating disease. At least 12 further papers are in preparation, with the impact of our research continuing to build. Results have also led to new successful funding applications including an ERC Consolidator Grant which started on the 1st March 2024.
We have unprecedented follow up data from primary school children and have analysed these with novel mathematical methods, state-space models and latent class analyses, being the first research group to differentiate between infected and transmitting individuals using these models.
The knowledge gained on factors driving transmission and reducing drug efficacy have identified simple actions to increase treatment success, informed control programmes on drug-resistance risks, and advised national and international policy makers on how best to control this debilitating disease. At least 12 further papers are in preparation, with the impact of our research continuing to build. Results have also led to new successful funding applications including an ERC Consolidator Grant which started on the 1st March 2024.