Biology subjects

Selinger, C.

Publications and source records attributed to Selinger, C..

5 recordsLinked to original sources

bioRxiv2019

Using multiple infection history to infer contact network structure

Interactions within a population shape the spread of infectious diseases but contact patterns between individuals are difficult to access. We hypothesised that key properties of these patterns can be inferred from multiple infection data in longitudinal follow-ups. We developed a simulator for epidemics with multiple infections on networks and analysed the resulting individual infection time series by introducing the concept of infection barcodes. We find that, depending on infection multiplicity and network sampling, infection barcode summary statistics can recover network properties such as degree distribution. Furthermore, we show that by mining infection barcodes for multiple infection patterns, one can detect immunological interference between pathogens (i.e. the fact that past infections in a host condition future probability of infection). The combination of individual-based simulations and barcode analysis of infection histories opens promising perspectives to infer and validate transmission networks and immunological interference for infectious diseases from longitudinal cohort data. Author summaryInfectious disease dynamics are constrained both by between-host contacts and pathogen interactions within a host. Furthermore, multiple parasites circulate such that hosts are infected (sometimes simultaneously) by a variety of strains or species. We hypothesise that multiple infection history can inform us about the networks on which parasites are transmitted, but also on within-host interactions such as immunological interference. We developed a simulator for multiple infections on networks. By combining intuitive novel metrics for multiple infection events and established tools from computational data analysis, we show that similarity in infection history between two hosts correlates with their proximity in the contact network. By analysing pathogens co-occurrence patterns within hosts, we also recover immunological interference at the population level. The demonstrated robustness of our results in terms of observability, network clustering, and pathogen diversity opens new perspectives to extract host contact and between-pathogen immunity information from longitudinal cohort data.

ecology↗

bioRxiv2019

The future of a partially effective HIV vaccine: assessing limitations at the population level

ObjectivesMathematical models have unanimously predicted that a first-generation HIV vaccine would be useful and cost-effective to roll out, but that its overall impact would be insufficient to reverse the epidemic. Here, we explore what factors contribute most to limiting the impact of such a vaccine.\n\nMethodsRanging from a theoretical ideal to a more realistic regimen, mirroring the one used in the currently ongoing trial in South Africa (HVTN 702), we model a nested hierarchy of vaccine attributes such as speed of roll-out, efficacy, and retention of booster doses.\n\nResultsThe predominant reasons leading to a substantial loss of vaccine impact on the HIV epidemic are the time required to scale up mass vaccination, limited durability and waning of efficacy.\n\nConclusionsA partially effective HIV vaccine will be a critical milestone for the development of a highly effective, durable, and scalable next-generation vaccine. Accelerated development, expedited vaccine availability, and improved immunogenicity are the main attributes of a vaccine that could dramatically reverse the course of the epidemic in highly endemic countries.

epidemiology↗

bioRxiv2018

Targeting and Vaccine Durability Are Key for Population-level Impact and Cost-Effectiveness of a Pox-Protein HIV Vaccine Regimen in South Africa

BackgroundRV144 is to date the only HIV vaccine trial to demonstrate efficacy, albeit rapidly waning over time. The HVTN 702 trial is currently evaluating in South Africa a similar vaccine formulation to that of RV144 for subtype C HIV with additional boosters (pox-protein regimen). Using a detailed stochastic individual-based network model of disease transmission calibrated to the HIV epidemic, we investigate population-level impact and maximum cost of an HIV vaccine to remain cost-effective.\n\nMethodsConsistent with the original pox-protein regimen, we model a primary series of five vaccinations meeting the goal of 50% cumulative efficacy 24 months after the first dose and include two-yearly boosters that maintain durable efficacy over 10 years. We simulate vaccination programs in South Africa starting in 2027 under various vaccine targeting and HIV treatment and prevention assumptions.\n\nResultsOur analysis shows that this partially effective vaccine could prevent, at catch-up vaccination with 60% coverage, up to 941,000 (15.6%) new infections between 2027 and 2047 assuming current trends of antiretroviral treatment. An impact of up to 697,000 (11.5%) infections prevented could be achieved by targeting age cohorts of highest incidence. Economic evaluation indicates that, if treatment scale-up was achieved, vaccination could be cost-effective at a total cost of less than $385 and $62 per 10-year series (cost-effectiveness thresholds of $5,691 and $750).\n\nConclusionsWhile a partially effective, rapidly waning vaccine could help to prevent HIV infections, it will not eliminate HIV as a public health priority in sub-Saharan Africa. Vaccination is expected to be most effective under targeted delivery to age groups of highest HIV incidence. Awaiting results of trial, the introduction of vaccination should go in parallel with continued innovation in HIV prevention, including studies to determine the costs of delivery and feasibility and further research into products with greater efficacy and durability.

epidemiology↗

bioRxiv2018

A novel role for the HLH protein Inhibitor of Differentiation 4 (ID4) in the DNA damage response in basal-like breast cancer.

Basal-like breast cancer (BLBC) is a poorly characterised, heterogeneous disease. Patients are diagnosed with aggressive, high-grade tumours and often relapse with chemotherapy resistance. Detailed understanding of the molecular underpinnings of this disease is essential to the development of personalised therapeutic strategies. Inhibitor of Differentiation 4 (ID4) is a helix-loop-helix transcriptional regulator required for mammary gland development. ID4 is overexpressed in a subset of BLBC patients, associating with a stem-like poor prognosis phenotype, and is necessary for the growth of cell line models of BLBC, through unknown mechanisms. Here, we have defined a molecular mechanism of action for ID4 in BLBC and the related disease highgrade serous ovarian cancer (HGSOV), by combining RIME proteomic analysis and ChIP-Seq mapping of genomic binding sites. Remarkably, these studies have revealed novel interactions with DNA damage response proteins, in particular, mediator of DNA damage checkpoint protein 1 (MDC1). Through MDC1, ID4 interacts with other DNA repair proteins ({gamma}H2AX and BRCA1) at fragile chromatin sites. ID4 does not affect transcription at these sites, instead binding to chromatin following DNA damage and regulating DNA damage signalling. Clinical analysis demonstrates that ID4 is amplified and overexpressed at a higher frequency in BRCA1-mutant BLBC compared with sporadic BLBC, providing genetic evidence for an interaction between ID4 and DNA damage repair pathways. These data link the interactions of ID4 with MDC1 to DNA damage repair in the aetiology of BLBC and HGSOV.

cancer biology↗

bioRxiv2016

How polio vaccination affects poliovirus transmission

The oral polio vaccine (OPV) contains live-attenuated polioviruses that induce immunity by causing low virulence infections in vaccine recipients and their close contacts. Widespread immunization with OPV has reduced the annual global burden of paralytic poliomyelitis by a factor of ten thousand or more and has driven wild poliovirus (WPV) to the brink of eradication. However, in instances that have so far been rare, OPV can paralyze vaccine recipients and generate vaccine-derived polio outbreaks. To complete polio eradication, OPV use should eventually cease, but doing so will leave a growing population fully susceptible to infection. If poliovirus is reintroduced after OPV cessation, under what conditions will OPV vaccination be required to interrupt transmission? Can conditions exist where OPV and WPV reintroduction present similar risks of transmission? To answer these questions, we built a multiscale mathematical model of infection and transmission calibrated to data from clinical trials and field epidemiology studies. At the within-host level, the model describes the effects of vaccination and waning immunity on shedding and oral susceptibility to infection. At the between-host level, the model emulates the interaction of shedding and oral susceptibility with sanitation and person-to-person contact patterns to determine the transmission rate in communities. Our results show that inactivated polio vaccine is sufficient to prevent outbreaks in low transmission rate settings, and that OPV can be reintroduced and withdrawn as needed in moderate transmission rate settings. However, in high transmission rate settings, the conditions that support vaccine-derived outbreaks have only been rare because population immunity has been high. Absent population immunity, the Sabin strains from OPV will be nearly as capable of causing outbreaks as WPV. If post-cessation outbreak responses are followed by new vaccine-derived outbreaks, strategies to restore population immunity will be required to ensure the stability of polio eradication.\n\nAuthor SummaryOral polio vaccine (OPV) has played an essential role in the elimination of wild poliovirus (WPV). OPV contains attenuated yet transmissible viruses that can spread from person-to-person. When OPV transmission persists uninterrupted, vaccine-derived outbreaks occur. After OPV is no longer used in routine immunization, as with the cessation of type 2 OPV in 2016, population immunity will decline. A key question is how this affects the potential of OPV viruses to spread within and across communities. To address this, we examined the roles of immunity, sanitation, and social contact in limiting OPV transmission. Our results derive from an extensive review and synthesis of vaccine trial data and community epidemiological studies. Shedding, oral susceptibility to infection, and transmission data are analyzed to systematically explain and model observations of WPV and OPV circulation. We show that in high transmission rate settings, falling population immunity after OPV cessation will lead to conditions where OPV and WPV are similarly capable of causing outbreaks, and that this conclusion is compatible with the known safety of OPV prior to global cessation. Novel strategies will be required to ensure the stability of polio eradication for all time.

epidemiology↗