Periodic Reporting for period 5 - ARBODYNAMIC (Coupling dynamic population immunity profiles and host behaviours to arboviral spread)
Período documentado: 2024-04-01 hasta 2024-12-31
Viruses transmitted by mosquitoes (arboviruses) continue to be a major threat to public health. This project studied the mechanisms that drive arbovirus transmission, using dengue virus in Thailand as a case study. All four serotypes of dengue virus have circulated endemically in Thailand for decades. We used historic serotype distributions and measures of antigenicity from novel cartographic methods to reconstruct the changing immune profile of the population. Further, we used detailed data on the historical genetic make-up of viruses that circulated in the country by sequencing isolates from each dengue serotype for each year over 50 years from the country. We then used measures of human behaviours (mixing patterns and mobility) obtained from mobile phone and questionnaire data as well as mosquito distributions to develop an integrative analytical framework that can bring together these different datasets and explore the consistency of different hypotheses of viral spread. This project allowed valuable insights into long-term drivers of virus spread with key implications for public health. Finally, as the peak of the COVID-19 pandemic occurred during the middle of the project, we quickly expanded our project to also include understanding SARS-CoV-2 burden and spread. In such a way we were able to support the French government on their COVID-19 response.
Our project found that the specific virus that infects an individual determines their future infection and disease risk. This means that an individual’s first dengue infection (or vaccine) in life determines their immune response to that pathogen and is important to consider as we start vaccinating young individuals around the world who won’t have seen dengue before. We further quantified the underlying risk of infection for different arboviruses, which is useful as we look to target interventions in the most appropriate way possible.
We used new mathematical models applied to geolocated dengue genomes to quantify the respective roles of human mobility, local immunity and mosquito levels in spreading the virus. We showed that those involved in transmission (often children) moved around less than adults, limited the short term movement of the virus. However, the occasional long distance movement by infected individuals was sufficient to result in long range virus movement in the medium term, although rarely between countries.
Our study also helped identify an immune correlate of protection for chikungunya virus, another arbovirus transmitted by the same mosquitoes. These findings have helped lead to the licensure of the first chikungunya vaccine through an unusual route that relies on immune correlates, rather than traditional large vaccine trials.
Our project found that the specific virus that infects an individual determines their future infection and disease risk. This means that an individual’s first dengue infection (or vaccine) in life determines their immune response to that pathogen and is important to consider as we start vaccinating young individuals around the world who won’t have seen dengue before. We further quantified the underlying risk of infection for different arboviruses, which is useful as we look to target interventions in the most appropriate way possible.
We used new mathematical models applied to geolocated dengue genomes to quantify the respective roles of human mobility, local immunity and mosquito levels in spreading the virus. We showed that those involved in transmission (often children) moved around less than adults, limited the short term movement of the virus. However, the occasional long distance movement by infected individuals was sufficient to result in long range virus movement in the medium term, although rarely between countries.
Our study also helped identify an immune correlate of protection for chikungunya virus, another arbovirus transmitted by the same mosquitoes. These findings have helped lead to the licensure of the first chikungunya vaccine through an unusual route that relies on immune correlates, rather than traditional large vaccine trials.
We sequenced thousands of dengue viruses from Thailand, and also geocoded their home location. This allowed us to link the genetic diversity of the pathogen with spatial spread. We developed mathematical models to use this new information to understand how dengue moves around the country, highlighting the critical role of human mobility and immunity in determining where the virus moves.
We also used mathematical models to understand the changing immune profile of the population. We demonstrated that the an individual’s risk of getting really sick from dengue is linked to both the specific antigenic properties of the dengue virus that first infected them (but probably didn’t make them very ill at the time) and the properties of the second virus they were exposed (which often did make them very sick). This highlighted for the first time the role of historic pathogen circulation patterns in driving disease risk. These results have important implications for vaccines as they start to be rolled out in places with high historic levels of infection.
We developed a tool (‘Phylowave’) that uses pathogen sequences to quickly identify fitness changes in the circulating pathogens, and to identify how the pathogen is changing to become more successful. We demonstrated that this tool has wide applicability to different pathogens, and works when there are few sequences available, which is often the case in low income settings.
Finally, in our work supporting the COVID-19 response, we developed models that predicted the changing burden on healthcare infrastructure in France, including providing regular predictions of intensive care bed requirements. We also estimated the impact of the lockdown on cases and deaths in the country. We also used models to generate some of the earliest estimates of the risk of severe disease and death by age and sex in different countries and highlighted the key burden in retirement homes in many Western countries and the likely many missed COVID-19 deaths in lower income countries. We later demonstrated that patterns of severe disease by age and sex seen in SARS-CoV-2 followed a very similar pattern as other pathogens, suggesting a common immune mechanism.
We also used mathematical models to understand the changing immune profile of the population. We demonstrated that the an individual’s risk of getting really sick from dengue is linked to both the specific antigenic properties of the dengue virus that first infected them (but probably didn’t make them very ill at the time) and the properties of the second virus they were exposed (which often did make them very sick). This highlighted for the first time the role of historic pathogen circulation patterns in driving disease risk. These results have important implications for vaccines as they start to be rolled out in places with high historic levels of infection.
We developed a tool (‘Phylowave’) that uses pathogen sequences to quickly identify fitness changes in the circulating pathogens, and to identify how the pathogen is changing to become more successful. We demonstrated that this tool has wide applicability to different pathogens, and works when there are few sequences available, which is often the case in low income settings.
Finally, in our work supporting the COVID-19 response, we developed models that predicted the changing burden on healthcare infrastructure in France, including providing regular predictions of intensive care bed requirements. We also estimated the impact of the lockdown on cases and deaths in the country. We also used models to generate some of the earliest estimates of the risk of severe disease and death by age and sex in different countries and highlighted the key burden in retirement homes in many Western countries and the likely many missed COVID-19 deaths in lower income countries. We later demonstrated that patterns of severe disease by age and sex seen in SARS-CoV-2 followed a very similar pattern as other pathogens, suggesting a common immune mechanism.
The Phylowave approach will provide scientists and public health officials with a means to quickly identify emerging lineages and to identify the genetic changes associated with these changes. It is especially as it is both widely applicable (i.e to a range of viruses and bacteria) and works even in situations of limited and biased sequence availability, which is especially problematic in low income countries.
Measuring the antigenic distance between circulating viruses and demonstrating that antigenic distance between sequentially infecting viruses is key to biological understanding of disease. It is becoming clear that for many pathogens, an individual’s first exposure in life is critical to determining their future immunity and ability to respond to future challenges (the concept of immune imprinting). However, our paper was one of the first to demonstrate this explicitly for a highly endemic pathogen. These findings also have important implications for dengue vaccines, and demonstrate that the impact of the vaccine may differ between countries.
Finally, understanding the risk of death, the burden on ICU and quantifying the impact of the lockdown was critical to the COVID-19 response. Our papers were a very important part of obtaining these estimates.
Measuring the antigenic distance between circulating viruses and demonstrating that antigenic distance between sequentially infecting viruses is key to biological understanding of disease. It is becoming clear that for many pathogens, an individual’s first exposure in life is critical to determining their future immunity and ability to respond to future challenges (the concept of immune imprinting). However, our paper was one of the first to demonstrate this explicitly for a highly endemic pathogen. These findings also have important implications for dengue vaccines, and demonstrate that the impact of the vaccine may differ between countries.
Finally, understanding the risk of death, the burden on ICU and quantifying the impact of the lockdown was critical to the COVID-19 response. Our papers were a very important part of obtaining these estimates.