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Genome-based diagnostics for mapping, monitoring and management of insecticide resistance in major African malaria vectors

Award Number: R01AI116811
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Malaria is a major cause of mortality and morbidity in Sub-Saharan Africa (SSA) and one of the biggest impediments to the economic development. The major method for controlling these malaria-transmitting mosquitoes is through the use of chemical insecticides but resistance has emerged and is a major threat to the recent reductions in both deaths and malaria infections. A major challenge facing malaria control program managers is knowing to what extent insecticide resistance is impacting control and when to take action eg by switching to a new intervention. In the first cycle of this award we exploited the advent of population genomic technologies to develop an improved understanding of the evolution and distribution of insecticide resistance mechanisms. In this proposal we describe how we will integrate this resistance marker discovery work with new functional genomic approaches and large vector control trials to demonstrate how genomic surveillance can be used to guide vector control. We will leverage our work on two large vector control trials in East Africa. In Uganda we embedded a cluster- randomised control trial (RCT) of long-lasting insecticidal nets (LLINs) with, and without, the synergist PBO into a countrywide distribution campaign. In Kenya together with KEMRI we are conducting an RCT of novel intervention, Attractive Targeted Sugar Baits. We will use whole genome sequencing of the three major malaria vectors Anopheles gambiae, An. funestus and An. arabiensis from these trial sites to identify genomic regions that are associated with insecticide resistance. We will then develop two contrasting models of the genetics of resistance. The first that assumes that we can accurately describe the likelihood of mosquito being insecticide resistant to by examining a small number of well characterised markers. This model capitalises on our recent developments in CRISPR/Cas9 transformation of Anopheles. The second model uses a polygenic score approach that requires a far larger number of markers, significantly-associated with resistance, but with no need for an understanding of causal mechanisms. By screening mosquito collections from the clusters within the RCTs and by, re-analysing the epidemiological data with the inclusion of the two resistance models, we will quantify the impact of resistance on the intervention efficacy. We will test whether the model based on a small number of genetic variants has sufficient predictive power for resistance monitoring or whether a larger number of loci provides superior predictive power. The former would aid widespread adoption of genetic surveillance of programmes. Finally through two modelling approaches we will 1. deliver predictions of molecularly-defined resistance at the administrative unit level in East Africa and 2. integrate these resistance data into transmission models of falciparum malaria to inform decisions on what is the optimal type of vector control to deploy.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $485,347 )
2023	2023	LIVERPOOL SCHOOL OF TROPICAL MEDICINE	PEMBROKE PL	LIVERPOOL	MERSEYSIDE			GBR	Allergy and Infectious Diseases Research	001	7	4/25/2023	NON-COMPETING CONTINUATION	$485,347
2023	2022	LIVERPOOL SCHOOL OF TROPICAL MEDICINE	PEMBROKE PL	LIVERPOOL	MERSEYSIDE			GBR	Allergy and Infectious Diseases Research	000	6	1/25/2023	COMPETING CONTINUATION	$0
2023	2020	LIVERPOOL SCHOOL OF TROPICAL MEDICINE	PEMBROKE PLACE	LIVERPOOL				GBR	Allergy and Infectious Diseases Research	002	5	5/15/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $485,347

Issue Date FY: 2022 ( Subtotal = $496,799 )
2022	2022	LIVERPOOL SCHOOL OF TROPICAL MEDICINE	PEMBROKE PL	LIVERPOOL	MERSEYSIDE			GBR	Allergy and Infectious Diseases Research	000	6	5/31/2022	COMPETING CONTINUATION	$496,799
														Subtotal = $496,799

Issue Date FY: 2020 ( Subtotal = $442,853 )
2020	2020	LIVERPOOL SCHOOL OF TROPICAL MEDICINE	PEMBROKE PL	LIVERPOOL	MERSEYSIDE	L3 5QA		GBR	Allergy and Infectious Diseases Research	000	5	1/13/2020	NON-COMPETING CONTINUATION	$442,853
														Subtotal = $442,853

Issue Date FY: 2019 ( Subtotal = $453,961 )
2019	2019	LIVERPOOL SCHOOL OF TROPICAL MEDICINE	PEMBROKE PL	LIVERPOOL	MERSEYSIDE	L3 5QA		GBR	Allergy and Infectious Diseases Research	000	4	1/7/2019	NON-COMPETING CONTINUATION	$453,961
														Subtotal = $453,961

Issue Date FY: 2018 ( Subtotal = $474,427 )
2018	2018	LIVERPOOL SCHOOL OF TROPICAL MEDICINE	PEMBROKE PL	LIVERPOOL	MERSEYSIDE	L3 5QA		GBR	Allergy and Infectious Diseases Research	000	3	1/29/2018	NON-COMPETING CONTINUATION	$474,427
														Subtotal = $474,427

Issue Date FY: 2017 ( Subtotal = $486,646 )
2017	2017	LIVERPOOL SCHOOL OF TROPICAL MEDICINE	PEMBROKE PL	LIVERPOOL	MERSEYSIDE	L3 5QA		GBR	Allergy and Infectious Diseases Research	000	2	1/24/2017	NON-COMPETING CONTINUATION	$486,646
														Subtotal = $486,646

Issue Date FY: 2016 ( Subtotal = $497,509 )
2016	2016	LIVERPOOL SCHOOL OF TROPICAL MEDICINE	1 TITHEBARD STEET	LIVERPOOL, UK				GBR	Allergy and Infectious Diseases Research	000	1	2/9/2016	NEW	$497,509
														Subtotal = $497,509

Grand Total All Awards = $3,337,542

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Genome-based diagnostics for mapping, monitoring and management of insecticide resistance in major African malaria vectors

Award Number: R01AI116811

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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