UNIVERSITY OF CALIFORNIA IRVINE MALARIA INITIATIVE
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A promising newly-emerging strategy for combating malaria is based on harnessing gene drive systems to spread anti-malarial genes throughout mosquito populations rendering them unable to transmit the parasites. The James laboratory (UC Irvine) developed highly-effective anti-malarial gene cassettes that can result in a 100% block of P. falciparum, the most deadly human malaria parasite, in mosquitoes (Isaacs et al., 2011, 2012). Working in collaboration with Ethan Bier and Valentino Gantz (UC San Diego), these effector gene cassettes coupled to a gene-drive system based on CRISPR/Cas9 biology were shown to spread with 99.5% efficiency in An. stephensi, the major malarial vector mosquito in urban India (Gantz et al., 2015). We will adapt this new technology to a major African vector, An. gambiae, and perform a confined field trial in a well-chosen site to demonstrate proof-of-principle for how this system will eliminate malaria locally. If successful, this strategy then could be incorporated as part of a broader initiative to achieve malaria elimination throughout Africa within the following decade.
Goals and activities
The primary goal of UCIMI is to achieve local elimination of malaria caused by P. falciparum transmitted by An. gambiae in a well-chosen field site. The proposed trial is based on a phased approach outlined in WHO guidelines (WHO 2014) and contains specific ‘go/no-go’ evaluation points and milestones. The overall timetable for this effort is to produce a field-ready alteration gene-drive strain (year one); test it in the laboratory population cages (year 2), and if required, in enclosed outdoor spaces containing the mosquito vector in a more natural setting (year 3). Finally, pending community and regulatory approval, to release the alteration-drive mosquitoes into the environment and follow the course of transgene spread and parasite reduction over the course of two consecutive seasons (years 4 and 5). Once this objective is met, mosquitoes carrying the validated alteration-drive could be scaled to a capacity appropriate for use in conjunction with current anti-malarial strategies to eliminate malaria regionally and ultimately throughout Africa.
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Organizational Structure of UCIMI
Three interacting organizational components are established for the proposed project: 1) an administrative core, 2) a laboratory component, and 3) a field component. A single principal investigator (PI, Anthony A. James, UC Irvine) acts as the overall director of the activities. Research supervision may be delegated to project coordinators (PC) based on their expertise.
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Analysis of remotely sensing data for 13 potential field sites.
For each of the 13 potential field sites under consideration, the time series (or static values, for topography) of several environmental variables will be extracted from remote sensing observations and from model reanalysis (specifically, NASA's MERRA-2). The analysis will quantify the spatial variability of the environment in potential field site, as well as the intra-annual and inter-annual variability at the spatial resolution of each variable. Using a set of well-defined criteria we will select four sites as candidate field sites for this program. The results will provide objective spatio-temporal selection criteria, and will inform the timing of site visits to facilitate mosquito collection.
Decision point 3.2.2a. Completion Date: 6/1/17, Reporting date: 6/30/17; Review date: Annual meeting. Written report with maps and graphics on the environmental data for each of 13 potential field sites.
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Select, based on set criteria, four candidate sites.
Based on the compiled reports of entomology, epidemiology and environmental data, four candidate sites will be selected. Temporal remote sensing data will be used to determine the timing of site visits to maximize Anopheles collections.
Decision point 3.2.3a. Completion Date: 6/30/17, Reporting date: 6/30/17; Review date: Annual meeting. Four sites and a tentative schedule for site visits will be determined.
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Lanzaro, and Cornel - Starts 5/1/17
Establish mosquito rearing protocols & insectary at UC Davis
Applications for the appropriate live mosquito import permits (e.g. CDC and USDA) will be initiated. Appropriate insectary set up will be prepared prior to USDA inspection. Appropriate mosquito rearing supplies will be ordered.
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Lanzaro, Cornel and Lee - Starts 10/1/17
Assess ease of colonization for An. gambiae for each site.
Gravid females will be collected and placed individually in microtubes with water and filter paper for oviposition. Egg clutches separated by single females will be transported back to UC Davis as checked baggage or via shipping. Egg numbers, hatching rate, emergence rate, sex ratio, mating status in cage (spermatheca dissections), feeding preference (and whether they laid eggs in cage conditions) and adult longevity will be recorded for each strain.
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Lanzaro, Cornel, Marshall and Lee - Starts 11/2/18
Prepare a written evaluation of each of the four candidate sites.
Candidate sites will be evaluated on the basis of the following criteria:
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Lanzaro and James - Starts 2/1/19
Make final decision on the project field site(s)
A team meeting will be organized at UC Davis to present the progress toward site evaluation and make recommendations for a field site to PI (James).
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