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Multi-scale mathematical modelling of parasite, drug and vaccine interactions: optimising public health and disease elimination strategies

English title Multi-scale mathematical modelling of parasite, drug and vaccine interactions: optimising public health and disease elimination strategies
Applicant Penny Melissa
Number 170702
Funding scheme SNSF Professorships
Research institution Department of Epidemiology and Public Health Swiss Tropical and Public Health Institute Universität Basel
Institution of higher education University of Basel - BS
Main discipline Infectious Diseases
Start/End 01.07.2017 - 31.08.2021
Approved amount 1'531'636.00
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All Disciplines (2)

Discipline
Infectious Diseases
Mathematics

Keywords (6)

mathematical modelling; parasite dynamics; drugs; vaccines; neglected tropical diseases; malaria

Lay Summary (German)

Lead
Mathematische Modellierung der Entwicklung und optimierte Verteilung neuer Medikamente sowie Impfungen zur Malaria-Elimination.
Lay summary

In den letzten Jahrzehnten wurden enorme Fortschritte in der Malariabekämpfung erzielt. Von 2000 bis 2015 ermöglichten die Erhöhung von Kontrolle und Interventionen eine Reduktion um 60% der Todesrate, sowie eine Abnahme um 40% der klinischen Erkrankungen. Trotz dieser Erfolge stehen wir vor erheblichen Herausforderungen, wenn wir Malaria ausrotten wollen. Um einen Rückgang in der Übertragung von Malaria zu erreichen, braucht es Programme, welche direkt auf die unterversorgte Bevölkerung zugeschnitten sind. Gleichzeitig wird die Wirksamkeit der aktuellen Malaria Interventionen durch die Resistenzverbreitung von Moskitos und Parasiten bedroht. Die Erreichung der Eliminationsziele erfordert neue Instrumente, priorisiert nach der nachhaltigen Reduktion der Übertragung.

Mathematische Modellierung kann helfen, die Dynamiken und Interaktionen zwischen Interventionen und Parasiten, Menschen und Moskitos zu verstehen. Modelle können auch dazu beitragen, neue Interventionen über klinische Studien hinaus zu beurteilen. Durch die Kombination verschiedener Modelle mit frühen klinischen Daten können wir beurteilen, wie wahrscheinlich diese Instrumente die Ziele erreichen und auch definieren, wie sie am besten eingesetzt werden können. Bisher wurden Modelle nicht auf diese Weise verwendet.

Wir werden Daten vom Schweizerischen Tropen und Public Health Instituts und Partnern kombinieren, um mathematische Modelle zu erstellen, die die Entwicklung neuer Malaria Medikamente und Impfstoffe unterstützen. Insbesondere wollen wir untersuchen, wie man diese Instrumente zur Malariaelimination einsetzt, insbesondere angesichts der Medikamentenresistenz. Dieses Projekt wird einen Beitrag leisten, um Entscheidungen im Bereich der Medikamenten- und Impfstoffentwicklung zu beschleunigen.

Direct link to Lay Summary Last update: 20.05.2017

Lay Summary (English)

Lead
Mathematical modelling for the development and delivery optimisation of new drugs and vaccines for malaria elimination
Lay summary

Tremendous progress has been made over the last decades in controlling malaria. From 2000 to 2015 scale-up of control and curative interventions enabled a 60% reduction in malaria death rates and a 40% reduction in rate of clinical disease. Despite these gains, we face significant challenges if we are to eliminate malaria entirely. Changing malaria epidemiology that accompanies transmission decline requires programs to direct efforts toward populations historically underserved by the health sector. Reaching these communities with services is difficult and expensive. At the same time the efficacy of current malaria interventions is threatened by spreading resistance of mosquitos to insecticides and of malaria parasites to drugs. Succeeding toward elimination targets requires new tools, and we should prioritize tools that are best able to reduce and halt malaria transmission.

Mathematical modelling can help understand malaria dynamics and interactions between malaria tools and the malaria parasite, human and mosquito hosts. Models can also help assess new tools such as vaccines beyond clinical trials. Combining different models with early clinical data from new drugs and vaccines we are able to assess how likely these tools will achieve health goals and also define how best to deploy them. Until now, models have not been used in this way. 

We will combine preclinical and clinical data from the Swiss Tropical and Public Health Institute and partners to build mathematical models to inform development of new malaria drugs and vaccines. Specifically, we aim to define which type and how to use these tools within populations for malaria elimination, especially in light of drug resistance. This project will yield evidence to accelerate decisions in drug and vaccine development.

Direct link to Lay Summary Last update: 20.05.2017

Responsible applicant and co-applicants

Employees

Publications

Publication
Mechanistic within-host models of the asexual Plasmodium falciparum infection: a review and analytical assessment
Camponovo Flavia, Lee Tamsin E., Russell Jonathan R., Burgert Lydia, Gerardin Jaline, Penny Melissa A. (2021), Mechanistic within-host models of the asexual Plasmodium falciparum infection: a review and analytical assessment, in Malaria Journal, 20(1), 309.
Parasite-host dynamics throughout antimalarial drug development stages complicate the translation of parasite clearance
Burgert Lydia, Zaloumis Sophie, Dini Saber, Marquart Louise, Cao Pengxing, Cherkaoui Mohammed, Gobeau Nathalie, McCarthy James, Simpson Julie A., Möhrle Jörg J., Penny Melissa A. (2021), Parasite-host dynamics throughout antimalarial drug development stages complicate the translation of parasite clearance, in Antimicrobial Agents and Chemotherapy, 65(4), e01539.
Proteome-wide analysis of a malaria vaccine study reveals personalized humoral immune profiles in Tanzanian adults.
Camponovo Flavia, Campo Joseph J, Le Timothy Q, Oberai Amit, Hung Christopher, Pablo Jozelyn V, Teng Andy A, Liang Xiaowu, Sim B Kim Lee, Jongo Said, Abdulla Salim, Tanner Marcel, Hoffman Stephen L, Daubenberger Claudia, Penny Melissa A (2020), Proteome-wide analysis of a malaria vaccine study reveals personalized humoral immune profiles in Tanzanian adults., in eLife, 9, e53080.
Future use-cases of vaccines in malaria control and elimination
Penny Melissa A., Camponovo Flavia, Chitnis Nakul, Smith Thomas A., Tanner Marcel (2020), Future use-cases of vaccines in malaria control and elimination, in Parasite Epidemiology and Control, 10, e00145.
Ensemble modeling highlights importance of understanding parasite-host behavior in preclinical antimalarial drug development.
Burgert Lydia, Rottmann Matthias, Wittlin Sergio, Gobeau Nathalie, Krause Andreas, Dingemanse Jasper, Möhrle Jörg J, Penny Melissa A (2020), Ensemble modeling highlights importance of understanding parasite-host behavior in preclinical antimalarial drug development., in Scientific reports, 10(1), 4410.
Mass campaigns combining antimalarial drugs and anti-infective vaccines as seasonal interventions for malaria control, elimination and prevention of resurgence: a modelling study.
Camponovo Flavia, Ockenhouse Chris F, Lee Cynthia, Penny Melissa A (2019), Mass campaigns combining antimalarial drugs and anti-infective vaccines as seasonal interventions for malaria control, elimination and prevention of resurgence: a modelling study., in BMC infectious diseases, 19(1), 920-920.
Identifying key factors of the transmission dynamics of drug-resistant malaria
Lee Tamsin E., Penny Melissa A. (2019), Identifying key factors of the transmission dynamics of drug-resistant malaria, in Journal of Theoretical Biology, 462, 210-220.
Emulator-based Bayesian optimization for efficient multi-objective calibration of an individual-based model of malaria
Reiker Theresa, Golumbeanu Monica, Shattock Andrew, Burgert Lydia, Smith Thomas, Filippi Sarah, Cameron Ewan, Penny Melissa, Emulator-based Bayesian optimization for efficient multi-objective calibration of an individual-based model of malaria, in Nature Communications, x.

Collaboration

Group / person Country
Types of collaboration
Idorisa Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Industry/business/other use-inspired collaboration
Infectious Disease Modelling Unit Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Hainan Medical University,Laboratory of Tropical Environment and health, Haikou, Hainan China (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Theoretical biology/ Institute of Integrative Biology/ETHZ Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Clinical Pharmacology group, The Mahidol Oxford Tropical Medicine Research Unit Thailand (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
The Clinical Tropical Medicine Laboratory, QIMR Berghofer Australia (Oceania)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
PATH: Malaria Vaccine Initiative United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Industry/business/other use-inspired collaboration
Liverpool School of Tropical Medicine Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Clinical Immunology Unit, Swiss Tropical and Public Health Institute Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Medicines for Malaria Venture Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Industry/business/other use-inspired collaboration
Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Northwestern University, Chicago United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Virtual Seminar Series, Swiss TPH Individual talk The Science Behind COVID-19: Interpreting Epidemiological Trends and Models 14.04.2021 Basel, Switzerland Penny Melissa;
International Society for Environmental Epidemiology Young 2021 Talk given at a conference Mathematical modelling to address contemporary issues in infectious diseases and global health 18.02.2021 Basel, Switzerland Penny Melissa;
PAMCA-VectorBase Virtual meeting Talk given at a conference Quantifying the effect of vector bionomics on the impact of vector control interventions against malaria 01.12.2020 Washington, United States of America Golumbeanu Monica;
American Society of Tropical Medicince and Hygiene annual meeting 2020 Poster Model informed target product profiles of long acting injectables a160 for use as seasonal malaria prevention 01.12.2020 virtual, United States of America Penny Melissa; Burgert Lydia;
American Society of Tropical Medicince and Hygiene annual meeting 2020 Poster Investigation of parasite-host dynamics in antimalarial drug development reveals a disconnect in experimental endpoints 01.12.2020 virtual, United States of America Penny Melissa; Burgert Lydia;
BRCCH "Insights Into COVID-19 Research" Webinar series Individual talk Modelling and machine learning to optimise interventions and strategies for COVID-19 09.09.2020 online, Switzerland Penny Melissa;
DayOne Basel DeepDive Individual talk Infectious Disease Modelling and Excellence in Global Health 19.08.2020 Basel, Virtual, Switzerland Penny Melissa;
Swiss Vector Entomology Group Annual Scientific Meeting Talk given at a conference Quantifying the effect of vector bionomics on the impact of vector control interventions against malaria 16.01.2020 Basel, Switzerland Golumbeanu Monica;
Innovative Vector Control Tech Bite Individual talk Harnessing machine learning and disease transmission models to evaluate target product profiles of novel malaria interventions 12.12.2019 Liverpool, Great Britain and Northern Ireland Penny Melissa;
EPIDEMICS conference Poster Investigation of parasite-host dynamics in antimalarial drug development reveals a disconnect in experimental endpoints 06.12.2019 Charleston, United States of America Burgert Lydia;
Heidelberg DZIF Seminar Series Individual talk Development and deployment of novel malaria interventions: the role of modelling and simulation 01.12.2019 Heidelberg , Germany Penny Melissa;
American Society of Tropical Medicine and Hygiene Poster Machine learning and mathematical models guiding decisions on innovation and strategies for malaria control and elimination 20.11.2019 National Harbour, United States of America Golumbeanu Monica;
American Society of Tropical Medicine and Hygiene Annual Meeting, November 20 2019 Talk given at a conference Machine learning and mathematical models guiding decisions on innovation and strategies for malaria control and elimination 20.11.2019 National Harbour, United States of America Golumbeanu Monica;
Keystone Symposia: The Malaria Endgame: Innovation in Therapeutics, Vector Control and Public Health Tools Talk given at a conference Models and machine learning to inform Target Product Profiles of new tools 30.10.2019 Addis Ababa, Ethiopia Penny Melissa;
Keystone Symposia: The Malaria Endgame: Innovation in Therapeutics, Vector Control and Public Health Tools Talk given at a conference Quantifying the effect of vector bionomics on the impact of vector control interventions against malaria transmitted by Anopheles mosquitoes 30.10.2019 Addis Ababa, Ethiopia Penny Melissa; Golumbeanu Monica;
Malaria Modelling Consortium Public forum: Using Models to Guide Public Health Policy: Community-Defined Standards Individual talk Malaria model comparisons Insights and lessons learnt from RTS,S malaria vaccin 18.09.2019 Seattle, United States of America Penny Melissa;
QIMR Berghofer Seminar series Individual talk Modelling and simulation for decisions on novel malaria interventions 05.07.2019 Brisbane, Australia Penny Melissa;
Malaria Gordon Research Conference Translational Malaria Research in Patients and Populations Poster Malaria drug resistance and competition dynamics 01.07.2019 Les Diablerets, Switzerland Lee Tamsin; Penny Melissa;
Gordon Research Seminar: Translational Malaria Research in Patients and Populations Talk given at a conference Understanding Minimal Tool Properties Versus Operational Factors of New Malaria Interventions for Elimination: A Modelling Study 29.06.2019 Les Diablerets, Switzerland Golumbeanu Monica;
Modelling Ecology & Evolution Zurich Individual talk Informing decisions on novel interventions for malaria elimination Malaria drug resistance and competition dynamics (public health perspective) 27.06.2019 Zurich, Switzerland Penny Melissa;
Malaria Vaccine for the World conference Talk given at a conference Modelling and simulations to investigate alternative use of vaccines for malaria control, elimination and prevention of resurgence 08.05.2019 Oxford, Great Britain and Northern Ireland Camponovo Flavia;
Malaria Vaccine for the World conference Talk given at a conference Modelling and simulations to investigate alternative use of vaccines for malaria control, elimination and prevention of resurgenc 05.05.2019 Oxford, Great Britain and Northern Ireland Camponovo Flavia; Penny Melissa;
at Institute of Disease Modelling Symposium Talk given at a conference Malaria drug resistance and competition dynamics 15.04.2019 Bellevue, United States of America Lee Tamsin;
WHO working group for the Malaria Vaccine Implementation Program Individual talk Modelling 03.12.2018 Geneva, Switzerland Penny Melissa;
Monoclonal convening Individual talk Modelling evidence to support decisions on novel interventions for malaria 26.11.2018 Seattle, United States of America Penny Melissa;
American Society of Tropical Medicine and Hygiene conference Poster Identifying key factors of the transmission dynamics of drug-resistant malaria 28.10.2018 New Orleans, United States of America Penny Melissa; Lee Tamsin;
UniBasel UKBB research day Individual talk Decision making for novel health interventions: combining data, modelling and expert opinion 23.10.2018 Basel, Switzerland Penny Melissa;
Basellife Talk given at a conference Informing decisions on novel interventions for malaria elimination, Mathematical Modelling towards Efficient Product Development 14.09.2018 Basel, Switzerland Penny Melissa;
Multilateral Initiative on Malaria Conference Talk given at a conference Defining minimal profiles of new malaria interventions for elimination: a modelling study 15.04.2018 Dakar, Senegal Penny Melissa;
Multilateral Initiative on Malaria Conference Poster Pre-erythrocytic malaria vaccines as seasonal intervention tools: a model based assessment 14.04.2018 Dakar, Senegal Penny Melissa; Camponovo Flavia;
Multilateral Initiative on Malaria Conference Poster Drug resistance modelling discussion 14.04.2018 Dakar, Senegal Lee Tamsin;
American Society of Tropical Medicine and Hygiene conference Individual talk Discussion on malaria vacines and product development with Bill and Melinda Gates Foundation and product developer 05.11.2017 Baltimore, United States of America Penny Melissa;
American Society of Tropical Medicine and Hygiene conference Poster Proteome microarray profiling of malaria antibodies in Tanzanian adult male volunteers undergoing a dose escalated radiation attenuated Plasmodium falciparum sporozoite vaccine trial 05.11.2017 Baltimore, United States of America Camponovo Flavia; Penny Melissa;


Self-organised

Title Date Place
Swiss TPH and Paediatric Pharmacology Group UKBB joint discussions 2017 05.12.2017 UKBB Basel university, Switzerland
Multiple meetings with product developers and collaborators on mathematical model use for malaria elimination 01.11.2017 Basel (and other), Switzerland

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
DayOne Health care innovation event Talk 07.05.2019 Basel, Switzerland Penny Melissa;
Multiple meetings with product developers and collaborators on mathematical model use for malaria elimination Talk 01.09.2018 Basel, Switzerland Camponovo Flavia; Lee Tamsin; Burgert Lydia; Penny Melissa;


Self-organised

Title Date Place
Multiple meetings with product developers and collaborators on mathematical model use for malaria elimination 01.11.2017 Basel (and many), Switzerland

Communication with the public

Communication Title Media Place Year
Media relations: radio, television Radio SRF – Echo der Zeit: “Massnahmen gegen die Pandemie - Was Computermodelle können – und was nic SRF German-speaking Switzerland 2020
Media relations: print media, online media Video by Dr Tamsin Lee: What drives the spread of drug resistant malaria? you tube public video International 2018

Awards

Title Year
Tuition scholarship only: 12th Annual Summer Institute in Statistics and Modeling in Infectious Diseases (SISMID), department of biostatistics, Washington University 2020
Admittance to competitive graduate training: PharMetrX Graduate Research Training program: Pharmacometrics and computational disease modeling in Berlin 2018
Tuition scholarship only: 10th Annual Summer Institute in Statistics and Modeling in Infectious Diseases (SISMID), department of biostatistics, Washington University 2018
Travel grant:Problem Workshop-UK QSP Network in Warwick 2017 (funds covered accomodation and workshop food only) 2017

Associated projects

Number Title Start Funding scheme
203450 Multi-scale mathematical modelling of pathogen, drug and vaccine interactions: optimising public health and disease elimination strategies 01.09.2021 SNSF Professorships

Abstract

Following years of investment in strategies to control malaria, elimination is becoming tangible. But optimal delivery strategies and profiles for drug and vaccines for elimination differ from those of disease control. This is because disease and immunity dynamics change as elimination approaches. Individual-level variations in immune responses and pharmacokinetics-dynamics, variations between parasites in ability to evade interventions, and the alignment of the profiles of new drugs and vaccines with the delivery capacity of health systems, all become more important. Ignoring these factors and their influence on the drop off from efficacy in trials to the effectiveness of interventions in real life will result in, at best, the roll out of inefficient tools, and, at worst, wasted investment and failure to achieve elimination.Mathematical modelling has been essential to understand complex interactions in malaria transmission between mosquito and human hosts and is gaining a greater role in clinical development of drugs and vaccines. But models to date have generally been used at very specific stages (e.g. pharmacometric modelling of drugs in human clinical trials; assessing public health impact of vaccines in Phase 3), rather than in generating evidence for decision-making along the whole pathway from pre-clinical to clinical, through to population, health systems and environmental contexts. Strategic use of novel mathematical models that identify key determinants of intervention impact, could make resource allocation much more efficient. The comprehensive model framework developed in this project will identify these key determinants and integrate them with data on variation in vaccine response and drug dynamics to predict intervention effectiveness, and optimise strategies for elimination and avoidance of drug resistance and vaccine insensitivity. Building on the applicant’s experience in malaria modelling and public health, we specifically aim to:(1)Elucidate the link between preclinical malaria parasite-drug dynamics and host-parasite-drug dynamics in early human clinical testing. Through model development and use of extensive preclinical and clinical data we will explore predictability of pharmaco-kinetic and -dynamic determinants in preclinical models for optimal human dosing. (2)Understand and optimise malaria vaccine immunogenicity and protection combining early clinical data and newly developed mathematical models. Through simulation of parasite and immune kinetic models, fitted to individual level data, we will evaluate kinetics resulting in longer protection;(3)Determine key vaccine, operational, population, and epidemiological determinants of public health impact when targeting malaria control and elimination, by linking models of individual immunity with population-scale models;(4)Optimise the role of new drugs and intervention strategies for malaria elimination and mitigation of drug resistance. Through development of new models of evolution of malaria drug resistance, we will elucidate drug properties, operational and health system factors that limit drug resistance and assist in malaria elimination.As an overarching aim we will bring these building blocks together by:(5) Synthesising evidence from the global community and from aims 1-4 to influence the models and to guide profiles of drugs and vaccines for malaria control and elimination Thus ensuring integration of the findings of the model-based research into a systematic framework for the innovation of new tools from preclinical stages to delivery.The research benefits from access to unique resources, with models developed and validated with data from historical, and on-going laboratory and clinical studies with Swiss TPH participation. The research builds on the applicant’s previous research and proven networks of partners within or affiliated with Swiss TPH and ETHZ, with expertise ranging from statistics, mathematical modelling, immunology, vaccine and drug development, epidemiology to health systems. The comprehensive model framework and evidence compiled in this proposal, will improve malaria drug and vaccine development and public health policy by linking basic science innovations through to application, via a novel holistic approach distinct from existing mathematical-epidemiological models or industry efforts. The multi-dimensional approach and the new mathematical models will be significant advances for epidemiological modelling and understanding of parasite, host and population interactions. Of most immediate relevance for malaria eradication, the project will also inform efforts to eliminate other neglected tropical diseases, while sustaining the positions of the applicant, Swiss TPH, ETHZ and Switzerland as global leaders in malaria and neglected disease research and control.
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