UNIVERSITY OF CALIFORNIA IRVINE MALARIA INITIATIVE
(UCIMI)
Project Plan (downloadable verison)
https://docs.google.com/document/d/1YmVlgwOaz_qegRmvrzZ39E8FgXZWkx_18C7w7RJTKpM/edit
Executive summary and Mission Statement
The mission of the University of California, Irvine, Malaria Initiative (UCIMI) is to promote the discovery and development of novel science for the goal of malaria eradication. This mission is accomplished by providing the necessary intellectual, resource and infrastructure support to test novel genetics-based, sustainable technologies to prevent malaria transmission. The featured activities are to develop and field-test genetically-engineered strains of malaria vector mosquitoes in collaboration with scientists and public health personnel from disease-endemic countries.
Vector population alteration strategies (also known as population replacement or modification) employ genes designed to interfere with malaria parasite transmission coupled with highly efficient gene-drive systems. These will play a crucial role in the malaria eradication agenda by providing resistance to parasite and competent vector reintroduction and allow resources to be focused on new sites while at the same time providing confidence that treated areas remain malaria-free.
Our goal is to conduct a field trial of a population alteration strain with the objective of local malaria elimination in Africa. A parrallel outcome is the capacity building that allows local and regional scientists and public health personnel to adapt and deploy population alteration strategies. Strategic development is needed in
(1) the development of population alteration mosquito strains
(2) field-site selection
(3) trial design and implementation.
The UCIMI provides the organizational structure to successfully complete these activities. Working hand-in-hand with thought-leaders, scientists, public health personnel government, we expect to lay the foundation for eradicating a disease that affects hundreds of millions of people globally every year.
TABLE OF CONTENTS
Executive summary…
Introduction and background…
Goals and activities…
Organizational Structure of UCIMI…
Project Plan Annotation…
OBJECTIVE 1: Project Administration…
Specific Aim 1.1 Recruit Project Personnel…
Specific Aim 1.2. Develop comprehensive Project Plan…
Specific Aim 1.3. Develop decision-making protocol….
Specific Aim 1.4. Develop communication strategy… .
Specific Aim 1.5. Develop central web portal… .
Specific Aim 1.6. Develop regulatory plan… .
Specific Aim 1.7. Annual meeting of project participants… .
OBJECTIVE 2. Develop and test Anopheles gambiae strains carrying autonomous gene-drive systems linked anti-pathogen effector genes….
Specific Aim 2.1 Recruit Project Personnel…
Specific Aim 2.2 Develop CRISPR/Cas9 gene-drive systems for Anopheles gambiae…
Specific Aim 2.3 Engineer additional anti-parasite effector genes…
Specific Aim 2.4 Generate transgenic mosquitoes carrying gene-drive elements and the parasite-resistance genes…
Specific Aim 2.5 Develop and maintain detailed laboratory standard operating procedures (SOPs)
Specific Aim 2.6 Test the performance characteristics of the strains (drive- and parasite-challenge assays)…
OBJECTIVE 3. Evaluate field site(s) for population alteration trials...
Specific Aim 3.1 Recruit Project Personnel…
Specific Aim 3.2 Evaluation of potential field sites for selection of four candidate sites…
Specific Aim 3.3 Evaluation of candidate field sites for selecting final field trial site…
Specific Aim 3.4. Assess “colonizability” of An. gambiae from candidate field sites…
Specific Aim 3.5. Selection of final population alteration field trial site(s)…
Introduction and background (Need to complete citations)
Malaria is a disease caused by protozoan parasites in the genus Plasmodium and is transmitted to humans by the bites of infected Anopheles mosquitoes. The World Health Organization (WHO) estimates that there are ~212 million cases and ~429,000 deaths due to malaria in 2015 (World Malaria report 2016, WHO) and more than 90% of these were in Africa. No effective vaccine exists yet for this disease, and parasite resistance to prophylactic and therapeutic drugs requires the discovery of at least one new chemical every five years.
Mosquito vector control measures have the greatest success in reducing malaria infections and deaths. Insecticide-treated nets can reduce severe disease by 60% and other vector-targeted approaches also contribute significantly. However, these measures alone are not enough to achieve eradication (Griffin et al. 2010), and new technologies are needed urgently. Among the more promising are genetic strategies that will control vector mosquitoes and block parasite transmission.
Genetic strategies seek to eliminate vector mosquitoes or reduce their densities below thresholds needed for stable parasite transmission (population suppression), or make them incapable of transmitting parasites (population alteration) (Macias and James 2016). Transgenesis technologies can produce mosquito strains that carry genes that contribute to both strategies. However, long-term, cost-effective and sustainable malaria elimination requires the development of genetic strategies that are resilient to the immigration of parasite-infected mosquitoes and people, and the lack of such tools represents a significant unmet need in the malaria eradication agenda.
Mosquito population alteration strains carrying genes conferring parasite resistance have the appropriate design features for this purpose. Wild, parasite-susceptible mosquitoes invading a region populated by an altered strain acquire the parasite-resistance genes by mating with the local insects, and persons with parasites moving into the same region cannot infect the resident vectors, and therefore are not a source of parasites for infection of other people. Population alteration also shares with other genetic control strategies the exploitation of the ability of male mosquitoes to find females, and this is expected to offer access to vector populations that would be unreachable using conventional tools. Release of a population alteration strain alone or in conjunction with other tools should make elimination possible in carefully-selected endemic areas. Population alteration strategies can be used as early as the control phase of an elimination campaign alongside other measures that reduce disease incidence. As the efforts progress, this strategy takes on a larger role and ultimately is the mainstay of the prevention of reintroduction phase. As this elimination is achieved, the released altered mosquitoes facilitate consolidation of this success by allowing resources to be moved to another region with the confidence that the area just cleared will remain so. Thus, population alteration offers a real chance to achieve sustainable elimination and therefore contributes significantly to malaria eradication.
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.
THIS DRAFT OF THE PROJECT PLAN DESCRIBES ACTIVITIES FOR THE FIRST TWO YEARS AND THESE DO NOT INCLUDE OPEN FIELD RELEASES. The activities for this period are to provide answers to the following questions:
Can we adapt coupled anti-parasite effector genes and Cas9-based, gene-drive systems for population alteration to African malaria vector mosquitoes?
Can we identify a field site in Africa at which it is possible to conduct a safe and ethically-sound release trial of a population alteration strain?
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.
Administrative component: This component is based at UC Irvine and has a highly-qualified, top-level administrator who functions as the project manager (PM) and reports to the PI. The PM carries out necessary core administrative responsibilities essential for the successful completion of the project.
Laboratory component: The laboratory component is carried out at UC Irvine, UC San Diego and UC Berkeley, and its goals are to develop new CRISPR/Cas9 gene-drive systems, engineer additional anti-parasite effector genes, generate transgenic mosquitoes carrying gene-drive elements and the parasite-resistance genes, and model and test the performance characteristics of the strains (drive- and parasite-challenge assays) in controlled laboratory settings.
Field component: The field component is led by an expert in malarial field studies (Drs. Gregory C. Lanzaro and Anthony Cornel, UC Davis) who works closely with the PI and in-country scientists and public health personnel to conduct site-selection activities. Field component will also be assisted by Dr. John Marshall (UC Berkeley) for modeling and Dr. Ziad Haddad (UCLA) for remote sensing data.
We expect to achieve elimination of malaria in the selected test site, where conditions were chosen to be optimal for success. During these activities, we will contribute to the education and infrastructure that allows us our collaborating scientists to apply this approach at our field site. This would also enhance tackling the larger and far more complex problem of malaria elimination at regional scale in Africa. This landscape is challenging in that new gene-drive systems would need to be developed to target additional mosquito species and possibly an additional parasite species, P. vivax. It will be necessary to integrate application of gene-drive population alteration systems with other well-validated anti-malarial strategies to achieve sustainable elimination of malaria at many key sites as a prelude to launching the final effort at eradication. Achieving these goals requires training of scientists both regionally and in the USA to carry out the elimination agenda.
Project Plan Annotation
Below is a synopsis of the Project Plan for the first two years including the Objectives, Specific Aims, Activities, Decision points and Milestones. Project Coordinators are listed below each Objective. There are three different dates associated with each decision point: a completion date, a reporting date and a review date. The completion dates are based on a starting date of April 1, 2017. The reporting date refers to the date that Project Coordinators must have their reports submitted for review. The review date refers to the dates that the Principal Investigator, Project Manager and Project Coordinators evaluate each Activity based on the “Decision Making Criteria.”
OBJECTIVE 1: PROJECT ADMINISTRATION
Project coordinators: Anthony A. James (UC Irvine) Principal Investigator and Sentelle Eubanks (UC Irvine) Project Manager.
This Objective provides the central administration of the project. Core operational activities include: 1) preparing budgets for the entire project (principal budget) and subcontracts for each component as well as reports and audits of these efforts; 2) communication: both proactive (e.g., establishing and maintaining an updated website describing project objectives and current status) and reactive (e.g., responding to unanticipated events impacting the project or to community concerns); 3) establishing regulatory guidelines and monitoring their implementation (which involves cycles of interaction with relevant government and local representatives, institutional review boards [IRBs], institutional biosafety committees [IBCs] and their national equivalents); 4) community engagement and consensus building (e.g., outreach to explain the project to the community, soliciting broad participation from the community for feedback on the project, addressing concerns raised by the community and if necessary revising project activities and/or goals); 5) managing legal issues (e.g., intellectual property [both project-generated and outside IP] required to meet project objectives, leases, land purchases, crisis management); 6) interaction with in-country government or research administrators, and 7) organizing participation of ancillary scientists to evaluate project outcomes in companion efforts (e.g., effects of elimination of malaria in local on education, income, political involvement).
Specific Aim 1.1 Recruit Project Personnel
This Specific Aim is to recruit the appropriate personnel for Objective 1.
James - Starts 4/1/17
Write job descriptions and job announcements to be advertised.
Finalize personnel needs and prepare draft of job descriptions. The job description for each position will be drafted to be consistent with UC approved job titles and descriptions.
Decision point 1.1.1a Completion Date: 4/15/17, Reporting date: 6/30/17; Review date: 9/30/17. Final version of job descriptions will be completed.
James - Starts 4/1/17
Advertise positions.
Job advertisements will be posted in multiple job list sites and appropriate scientific journals to maximize candidate pools.
Decision point 1.1.2a Completion Date: 4/15/17, Reporting date: 6/30/17; Review date: 9/30/17. Applications will be collected, reviewed by James and a short list of candidates will be completed.
James - Starts 4/1/17
Interview Candidates.
Candidates will be interviewed by James via an online meeting platform or in person at UCI. Interviewees will be ranked and individuals will be selected for each available position and notified.
Decision point 1.1.3a Completion Date: 5/15/17, Reporting date: 6/30/17; Review date: 9/30/17. Final list of candidates will be notified and provided with timeline to respond with their decision. All positions will remain open until filled.
James - Starts 4/1/17
Fill positions.
Administrative procedures for hiring will be completed. Each new hiree will take the required UCI training, such as lab safety, cyber security, etc. The requisite permits, visas, permissions and facility keys will be obtained.
Decision point 1.1.4a Completion Date: 9/30/17, Reporting date: 9/30/17; Review date: 9/30/17. Hiring process will be completed.
Specific Aim 1.2. Develop comprehensive Project Plan.
This Specific Aim produces and maintains the document that describes the goals, objectives and operational aspects of the UCIMI, as well as their timelines. It also includes as an Appendix I the definitions, terms and conditions of the UCIMI. Appendix II will be developed to provide in-depth information on the Specific Aims and Activities in Objectives 2 AND 3.
James - Starts 4/1/17
Activity 1.2.1. Develop draft Project Plan.
Decision point 1.2.1a: Completion date: 6/30/17; Reporting date: 6/30/17; Review date: 9/30/17.
Specific Aim 1.3. Develop decision-making protocol.
The decision-making plan is an explicit part of the comprehensive Project Plan and is included in Appendix I.
James - Starts 4/1/17
Activity 1.3.1. Develop decision-making protocol.
Decision point 1.3.1a: Completion date: 6/30/17; Reporting date: 6/30/17; Review date: 9/30/17. Have in place by the end of the first quarter a decision-making process that allows evaluation of progress towards goals.
Specific Aim 1.4. Develop communication strategy.
This Specific Aim establishes the reactive and proactive communication plans for the project.
James - Starts 4/1/17
Activity 1.4.1. Reactive plan
Develop both internal and external communication framework to give or exchange information when an unexpected event occurs.
Decision point 1.4.1a: Completion date: 6/30/17; Reporting date: Quarterly Have decided on means to communicate when an unexpected event occurs.
James - Starts 4/1/17
Activity 1.4.1. Proactive plan
Devise strategy to communicate with both within group members and outside groups.
Decision point 1.4.1a: Completion date: 6/30/17; Reporting date: Quarterly Set a long-term communication goals and decide on means to achieve those goals.
Specific Aim 1.5. Develop central web portal.
This Specific Aim provides for the UCIMI interface with the public and a private posting site for project members and documents.
James - Starts 4/1/17
Activity 1.5.1. Develop central website.
Host a website that will serve communication channel with public about UCIMI.
Decision point 1.5.1a: Completion date: 6/30/17; Reporting date: 6/30/17 Have decided on both hardware and software configurations to maximize communication aspects to the larger group and outside parties while maintaining security for confidential matters.
Milestone 1.5.1b: Completion date: 9/30/17; Reporting date: 9/30/17; Review date: Quarterly. Have in place a fully functional website.
James - Starts 10/1/17
Activity 1.5.2. Update website.
Update project progress, project personnel, contact information as needed.
Decision points 1.5.2a-c: Completion date: quarterly or as needed for duration These decision points involve evaluating the effectiveness of the website and updating it as required by progress on the project.
Specific Aim 1.6. Develop regulatory plan.
This Specific Aim provides the structure for maintaining regulatory compliance for the project.
James - Starts 4/1/17
Activity 1.6.1. Implement procedures for tracking research-related regulatory requirements.
Have system in place to keep track of research-related regulatory requirements for various agencies such as IBC, IACUC, CDC, USDA, and others.
Decision points 1.6.1a-d: Completion date: quarterly or as needed for duration Complete any necessary permits. Document the contact information, website, and process to obtain such permits. Have legal consultant(s) review documents.
James, Lanzaro and Cornel - Starts 4/1/17
Activity 1.6.2. Review and develop knowledge base for regulatory requirements for potential field sites.
Research on regulatory requirements at four potential field sites recommended by UCD.
Decision points 1.6.2a-d: Completion date: quarterly or as needed for duration Documents laws, contact information, website, and process to obtain permit to conduct genetically engineered mosquitoes in four potential field sites. Have legal consultant(s) review documents.
James, Lanzaro and Cornel - Starts 4/1/17
Activity 1.6.3. Work with field team to obtain necessary permits.
Obtain permits/permission letters needed to carry out mosquito collections in the potential field sites as well as import permits to bring mosquitoes (both live and dead) into UCI and UCD laboratories.
Decision points 1.6.3a-d: Completion date: quarterly or as needed for duration. Obtain permit, renew or resubmission as needed.
Specific Aim 1.7. Annual meeting of project participants
This Specific Aim provides for an Annual Meeting of project participants.
James - Starts 10/1/17
Activity 1.7.1. Host annual meeting.
Organize annual meeting (location to be determined) where all parties involved in the project can report their progress and discuss plans for the following year. Any revision on activity or timeline based on the current progress will be discussed.
Decision points 1.5.1a-b: Establish meeting date These decision points are the actual holding of the meeting in the last quarter of the annual cycle. These meeting will cover both scientific and administrative issues as required by the progress in the program.
Decision point 1.5.1a: Completion date: 3/30/18 Have the first annual meeting.
Decision point 1.5.1b: Completion date: 3/30/19 Have the second annual meeting.
OBJECTIVE 2. DEVELOP AND TEST ANOPHELES GAMBIAE STRAINS CARRYING AUTONOMOUS GENE-DRIVE SYSTEMS LINKED TO ANTI-PATHOGEN EFFECTOR GENES
Project coordinators: Anthony A. James (UC Irvine) Principal Investigator, Sentelle Eubanks (UC Irvine) Project Manager, Ethan Bier (UC San Diego) and John Marshall (UCB).
This component provides the Phase 1-validated insect strains for population alteration. Laboratory activities include: 1) link gene-drive systems to anti-P. falciparum effector genes and insert them in An. gambiae into fitness-neutral mosquito chromosomal loci, chromosomal loci conferring decreased mosquito fitness, and into chromosomal loci that affect parasite propagation in the vector; 2) conduct parasite challenge assays; 3) develop and test new gene-drive strategies; 4) identify new reagents to inactivate P. falciparum; 5) conduct in-depth mathematical modeling studies regarding the predicted behavior of gene-drive systems in different environmental scenarios and then test these predictions in the laboratory; and 6) develop and maintain detailed laboratory standard operating procedures, experimental records, budgets, and provide reports to appropriate components of the administrative core.
Specific Aim 2.1 Recruit Project Personnel
This Specific Aim is to recruit the appropriate personnel for Objective 1.
James and Bier - Starts 4/1/17
Write job descriptions and job announcements to be advertised.
Finalize personnel needs and prepare draft of job descriptions. The job description for each position will be drafted to be consistent with UC approved job titles and descriptions.
Decision point 2.1.1a Completion Date: 4/15/17, Reporting date: 6/30/17; Review date: Annual meeting. Final version of job descriptions will be completed.
James and Bier - Starts 4/1/17
Advertise positions.
Job advertisements will be posted in multiple job list sites and appropriate scientific journals to maximize candidate pools.
Decision point 2.1.2a Completion Date: 4/15/17, Reporting date: 6/30/17; Review date: Annual meeting. Applications will be collected, reviewed by James and Bier; a short list of candidates will be completed.
James and Bier - Starts 4/16/17
Interview Candidates.
Candidates will be interviewed by James and/or Bier via an online meeting platform or in person at UCI or UCSD. Interviewees will be ranked and individuals will be selected for each available position and notified.
Decision point 2.1.3a Completion Date: 6/30/17, Reporting date: 6/30/17; Review date: Annual meeting. Final list of candidates will be notified and provided with timeline to respond with their decision. All positions will remain open until filled.
James and Bier - Starts 4/1/17
Fill positions.
Administrative procedures for hiring will be completed. Each new hiree will take the required UCI or UCSD training, such as lab safety, cyber security, etc. The requisite permits, visas, permissions and facility keys will be obtained.
Decision point 2.1.4a Completion Date: 9/15/17, Reporting date: 9/30/17; Review date: Annual meeting. Hiring process will be completed.
Specific Aim 2.2 Develop CRISPR/Cas9 gene-drive systems for Anopheles gambiae
James and Bier - Starts 4/1/17
Activity 2.2.1 Identify and clone appropriate promoter sequences (for example, β2-tubulin, U6, vitellogenin, carboxypeptidase, G12) for expressing CRISPR/Cas9 gene-drive system components.
Multiple promoter regions will be investigated to improve the design of gRNA and/or the efficacy of anti-malarial gene expressions.
Decision point 2.2.1a Completion Date: 9/30/17, Reporting date: 9/30/17; Review date: Annual meeting. At least two promoter sequences of two different genes will be identified and cloned.
James and Bier - Starts 4/1/17
Activity 2.2.2 Identify An. gambiae fitness-neutral mosquito chromosomal loci, chromosomal loci conferring decreased mosquito fitness, and chromosomal loci that affect parasite propagation in the vector
Multiple chromosomal loci will be investigated to evaluate effects on mosquito fitness and parasite propagation in the vector.
Decision point 2.2.2a Completion Date: 9/30/17, Reporting date: 9/30/17; Review date: Annual meeting. Effects on mosquito fitness and parasite propagation by at least two different chromosomal loci will be evaluated. Preferred chromosomal integration sites defined.
James and Bier - Starts 7/1/17
Activity 2.2.3 Design and synthesize gene-drive constructs, and verify sequence.
Multiple gene-drive constructs will be tested for efficacy in gene conversion rate, mosquito fitness and parasite propagation.
Decision point 2.2.3a-c: Reporting date: every 6 months for duration. At least four different chromosomal loci will be evaluated.
Specific Aim 2.3 Engineer additional anti-parasite effector genes
James and Bier - Starts 4/1/17
Activity 2.3.1 Develop additional single-chain (scFv) immunological reagents to inactivate P. falciparum (Pfs47 with Barrillas-Mury, NIH; Pfs230 with Narum, NIH; Ashley Birkett, PATH).
Additional anti-parasite effector genes will be developed to optimize efficacy of ‘no parasite’ phenotype.
Decision point 2.3.1a-c: Completion date: every 6 months for duration. At least three different variations of candidate effector genes will be evaluated for parasite propagation.
James and Bier - Starts 4/1/17
Activity 2.3.2 Develop alternative effector molecules based on engineered synthetic receptors (SM1).
Multiple alternative effector molecules will be engineered and tested for parasite propagation.
Decision point 2.3.2a-c: Completion date: every 6 months for duration. At least three different alternative effector molecules will be engineered.
James and Bier - Starts 7/1/17
Activity 2.3.3 Make An. gambiae transgenic lines to test additional effector genes using transposon-mediated transgenesis.
Generate An. gambiae transgenic lines via transposon-mediated transgenesis to test for engineered alternative effector molecules.
Decision point 2.3.3a-c: Completion date: every 6 months for duration. At least three different alternative effector molecules will be engineered.
James and Bier - Starts 10/1/18
Activity 2.3.4 Perform challenge assays with P. falciparum to determine efficacy of novel effector constructs.
Challenge An. gambiae transgenic lines with P. falciparum parasite to determine efficacy of alternative effector molecules.
Decision point 2.3.4a-c: Completion date: every 6 months for duration. At least three different alternative effector molecules will be engineered.
Specific Aim 2.4 Generate transgenic mosquitoes carrying gene-drive elements and the parasite- resistance genes
James and Bier - Starts 7/1/17
Activity 2.4.1 Perform microinjection experiments, screen resulting insects, and validate integrated DNA to generate gene-drive lines with linked anti-parasite effector genes
Develop An. gambiae transgenic lines that contains gene-drive and two anti-Plasmodium genes.
Decision point 2.4.1a-c: Completion date: every 6 months for duration. At least two An. gambiae transgenic lines that are validated to have integrated gene-drive and multiple effector genes.
Specific Aim 2.5 develop and maintain detailed laboratory standard operating procedures, experimental records, budgets, and provide reports to appropriate components of the administrative core.
James and Bier - Starts 4/1/17
Activity 2.5.1 Develop and maintain detailed laboratory standard operating procedures (SOPs)
Decision point 2.5.1a-c: Completion date: every 6 months for duration. Have in place a fully functional project file repository. Add new SOP or update existing SOPs as required by progress on the project and upload to project file repository.
Specific Aim 2.6 Test the performance characteristics of the strains (drive- and parasite-challenge assays)
James and Bier - Starts 7/1/17
Activity 2.6.1 Conduct parasite challenge assays on transgenic An. gambiae lines
Developed strains from Activity 2.4.1 will be challenged with P. falciparum to measure the efficacy of parasite propagation and gene-drive conversion rate.
Decision point 2.6.1a-c: Completion date: every 6 months for duration. At least two An. gambiae transgenic lines will be challenged with P. falciparum and measure parasite propagation.
James, Lanzaro, Bier and Marshall - Starts 7/1/17
Activity 2.6.2 conduct in-depth mathematical modeling studies regarding the predicted behavior of gene-drive systems in different environmental scenarios and then test these predictions in the laboratory
Decision point 2.6.2a-c: Completion date: every 6 months for duration. Develop modeling framework for gene drive behavior simulation in different environmental scenarios.Generate at least two hypotheses with measurable parameters that can be tested in laboratory conditions. Test the predictions on An. gambiae transgenic strains. Revise models based on observation in laboratory experiments and devise alternative hypotheses that can be tested in laboratory conditions. Test the hypotheses on An. gambiae transgenic strains.
James and Bier - Starts 1/1/19
Activity 2.6.3 Make final recommendation for release strain(s)
Based on gene-drive success rate, fitness, and modeling results, make a short list of release strain(s) for field trial.
Milestone 2.1.4a Completion Date: 3/30/19, Reporting date: 3/30/17; Review date: Annual meeting. A short list of release strain(s) for field trial will be decided.
OBJECTIVE 3. Evaluate FIELD SITE(S) FOR POPULATION ALTERATION TRIALS.
Project coordinators: Anthony A. James (UC Irvine) Principal Investigator, Sentelle Eubanks (UC Irvine) Project Manager, Gregory C. Lanzaro (UC Davis), John Marshall (UCB) and Ziad Haddad (JPL/UCLA).
This Objective conducts the site-selection process and identifies a field trial site for evaluation of population alteration of Anopheles gambiae. The overall goal of this component is to answer the question of whether or not one or more field trial sites exist that maximize the prospects for success, minimize the risk and serve as a fair, valid and convincing test of the efficacy of the population alteration strain being evaluated.
We refer to "potential field sites" as all possible field sites; "candidate field sites" as four sites selected for closer evaluation from among the potential sites; "village" as a sub-site within a candidate site. Villages will represent the sampling units from which mosquito specimens will be collected.
Field activities in the first two years include:1) evaluate one or more sites for the field trials; 2) establish baseline data of mosquito species at the site(s) and prevalence and infectivity of Plasmodium parasites; 3) identify required facilities for laboratory aspects at the field trials and establish an on-site presence. Successful completion of these efforts is expected to be followed in subsequent years by 4) generate transgenic mosquitoes carrying gene drive; 5) production of mosquitoes to be tested in the field; 6) conduct on-site contained and open confined trials; 7) develop protocols for staged open-field releases including mitigation plans in case trials have to be halted; 8) monitor mosquito and parasite parameters during confined and full field trials; 9) report results to administrative core; 10) interact with consultants, regulatory personnel on-site, and administrative staff dedicated to regulatory responsibilities in the administrative core; 11) contribute to community engagement and interact with staff tasked with community relations in administrative core; 12) interact with the laboratory component by sending personnel to labs as necessary and communicating regularly with laboratory researchers regarding results obtained by both components.
Specific Aim 3.1 Recruit Project Personnel
Lanzaro and Cornel - Starts 4/1/17
Write job descriptions and job announcements to be advertised.
Organize meeting of Objective 3 key personnel to finalize personnel needs and prepare draft of job descriptions. The job description for each position will be drafted to be consistent with UC approved job titles and descriptions.
Decision point 3.1.1a Completion Date: 4/15/17, Reporting date: 6/30/17; Review date: Annual meeting. Final version of job descriptions will be completed.
Lanzaro and Cornel - Starts 4/1/17
Advertise positions.
Job advertisements will be posted in multiple job list sites and appropriate scientific journals to maximize candidate pools.
Decision point 3.1.2a Completion Date: 5/15/17, Reporting date: 6/30/17; Review date: Annual meeting. Applications will be collected, reviewed by Lanzaro, Cornel and Lee and a short list of candidates will be completed.
Lanzaro, Cornel and Lee - Starts 5/17/17
Interview Candidates.
Candidates will be interviewed by Lanzaro, Lee and Cornel via an online meeting platform or in person at UC Davis. Interviewees will be ranked and individuals will be selected for each available position and notified.
Decision point 3.1.3a Completion Date: 6/17/17, Reporting date: 6/30/17; Review date: Annual meeting. Final list of candidates will be notified and provided with timeline to respond with their decision. All positions will remain open until filled.
Lanzaro, Lee and Cornel - Starts 7/1/17
Fill positions.
Administrative procedures for hiring will be completed. Each new hiree will take the required UC Davis training, such as lab safety, cyber security, online sexual harassment training etc. The requisite permits, visas, permissions and facility keys will be obtained. Assistance in housing etc. will be provided.
Decision point 3.1.4a Completion Date: 8/30/17, Reporting date: 9/30/17; Review date: Annual meeting. Hiring process will be completed.
Specific Aim 3.2 Evaluation of Potential Field Sites for Selection of Four Candidate Sites
Lanzaro, Cornel and Lee - Starts 4/1/17
Literature Survey for the Evaluation of 13 Potential Field Trial Sites
We will conduct literature searches to identify geographically isolated island sites and obtain detailed information for each including: geophysical and biological features; malaria vector species and parasite species present; identify on-site university or government institutions as potential collaborators to assist with all field studies; health infrastructure and logistics of travel and shipping. Literature search will include, but will not be limited to, WHO country profile, PMI country profile, CIA handbook, US Department of State notes, Pubmed, local public health reports, and personal communications.
Decision point 3.2.1a. Completion Date: 6/1/17, Reporting date: 6/30/17; Review date: Annual meeting. Written report of information for 13 potential field sites under consideration.
Lanzaro, Haddad, and Lee - Starts 4/1/17
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.
Lanzaro, Cornel, Lee, Marshall and Haddad - Starts 6/2/17
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.
Specific Aim 3.3 Evaluation of Candidate Field Sites for Selecting Final Field Trial Site
Lanzaro, Cornel, Lee and Marshall - Starts 7/1/17
Prepare site visits to four candidate field sites and nearest mainland.
We will contact potential collaborators at each of the four candidate field sites to introduce ourselves, outline the project and schedule site visits. Travel arrangements including visa applications will be concluded prior to site visit. Potential collaborators at nearest mainland sites will also be contacted at this time for the purpose of scheduling travel and planning work.
Decision point 3.3.1a-c: Completion Date: 8/30/17, Reporting date: every 6 months for duration starting 9/30/17. Establish contacts, collaborative arrangements and site visit schedule for candidate field sites.
Lanzaro, Cornel and Lee - Starts 8/15/17
Visit villages on each candidate site and nearest mainland to collect Anopheles specimens.
An. gambiae s.l. will be collected from at least 3 villages for 9 days (3 days/village x 3 villages) at each of the four candidate field site. The ovaries from all half gravid An. gambiae s.l. will be preserved for cytogenetic analysis. The remaining carcasses and all other mosquitoes will be preserved individually in 80% ethanol with a unique accession number to track the specimen’s location (site and village) and date of collection. All mosquito specimens will be cataloged and archived at UC Davis for downstream longitudinal studies. A collection of gravid female An. gambiae will be made from each village. These will be held to collect eggs. Eggs and early stage larvae will be returned to UC Davis and reared to the adult stage to be used for insecticide susceptibility testing and to evaluate the potential for establishing colonies , as described below.
Decision point 3.3.2a. Completion Date: 9/30/17, Reporting date: 12/15/17; Review date: Annual meeting. Collections of mosquitoes from site 1 and nearest mainland. Written categorical evaluation of infrastructure, collaborators, and epidemiological data and data keeping system for each candidate site
Decision point 3.3.2b. Completion Date: 1/30/18, Reporting date: 3/30/18; Review date: Annual meeting. Collections of mosquitoes from site 2 and nearest mainland. Written categorical evaluation of infrastructure, collaborators, and epidemiological data and data keeping system for each candidate site
Decision point 3.3.2c. Completion Date: 6/30/18, Reporting date: 9/30/18; Review date: Annual meeting. Collections of mosquitoes from site 3 and nearest mainland. Written categorical evaluation of infrastructure, collaborators, and epidemiological data and data keeping system for each candidate site
Decision point 3.3.2d. Completion Date: 8/30/18, Reporting date: 12/15/18; Review date: Annual meeting. Collections of mosquitoes from site 4 and nearest mainland. Mosquito collections from 4 candidate sites and nearest mainland for a total of 2,700 adults and 2,700 larvae. Written categorical evaluation of infrastructure, collaborators, and epidemiological data and data keeping system for each candidate site.
Lanzaro, and Lee - Starts 10/1/17
Analysis of genotype data to assess entomological parameters
The divergence island SNP (DIS) assay (Lee et al. 2014, 2015) will be used for each specimen to determine species, insecticide resistance genotypes, Plasmodium species infection status (adult) and sex (larvae). DNA will be extracted from other Anopheles species to determine their malaria infection status. Maps of species composition, insecticide resistance genotypes, Plasmodium species infection status will be generated. Statistical analyses will be conducted to examine differences between indoor vs outdoor collections.
Decision point 3.3.4a-c: Completion Date: 11/1/18, Reporting date: every 6 months for duration starting 3/30/18. Genotypes of 5,400 An. gambiae s.l. specimens entered into online database. Plasmodium infection status of An. gambiae s.l. and other Anopheles species will be entered into the online database. Written report of species composition, insecticide resistance genotypes, Plasmodium infection prevalence with maps and statistical analysis.
Lanzaro, Cornel and Lee - Starts 10/1/17
Analysis of insecticide resistance
Wild An. gambiae reared from the eggs of field collected females from each of the four candidate field sites will be tested for their phenotypic susceptibility to commonly used insecticides. These tests will be conducted at UC Davis where standard susceptible An. gambiae lines are available. Mosquitoes will also be screened for target site knock-down mutations L1014S(kdr-E), L1014F(kdr-w)
Decision point 3.3.5a-c: Completion Date: 11/1/18, Reporting date: every 6 months for duration starting 3/30/18. Bottle bioassays for F1 progeny from each of the four candidate field sites. Genotype for knock-down mutations of F1 progeny from each candidate field site. Written report of insecticide resistance phenotype/genotype with maps and statistical analysis.
Lanzaro, and Lee - Starts 10/1/17
Analysis of genome data to assess degree of genetic isolation of sites
A total of 192 An. gambiae (8 mosquitoes/village x 3 villages x 8 sites) will be subjected to 150bp paired-end read HiSeq 4000 sequencing with a goal of 10X coverage per individual. Freebayes software (Garrison and Marth 2012) will be used for variant calling from 192 An. gambiae sequences. Principal Component Analysis (PCA) and SpaceMix (Bradburd et al. 2013) will be used to examine population structures and genetic isolation qualitatively. Polymorphism analysis will be conducted for known transgene insertion sites.
Decision point 3.3.6a-c: Completion Date: 11/1/18, Reporting date: every 6 months for duration starting 3/30/18. Whole genome sequences of 192 individuals at 10X coverage/sample. One sample/village (N=24) will be sequenced at 30X coverage/sample for increasing confidence in calling variants. Written report of population structure and qualitative genetic isolation test with PCA and geo-genetic map figures.
Lanzaro, and Marshall - Starts 7/1/17
Model evaluation of candidate field sites
Mathematical model frameworks will be developed to assess the suitability of candidate field sites for trials of population alteration strains with Cas9-based gene drive systems. Models will be designed to assess: (a) confinability of a transgenic release; (b) ability to measure potential trial end-points (various entomological measures, and epidemiological measures if possible); (c) feasibility of gene drive in the presence of drive-resistant alleles and local population structure; and (d) ability to remediate transgenes from the environment using insecticide-based campaigns.
Decision point 3.3.7a-c: Completion Date: 11/1/18, Reporting date: every 6 months for duration. Review date: Annual meeting. Development of the model framework for the first 6 months. Integration of data from the other activities described here, and modeling of field trials in the four candidate field sites after model development.
Specific Aim 3.4. Assess “Colonizability” of An. gambiae from Candidate Field Sites
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.
Decision point 3.4.1a-c. Completion Date: 7/1/17, Reporting date: every 6 months or as needed for duration starting 9/30/17. Review date: Annual meeting. Receive copy of CDC and/or USDA permit for live mosquito import at UC Davis insectary. Written protocol with visual aids for mosquito rearing and data record sheet to log life table for each mosquito strain.
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.
Decision point 3.4.2a-c: Completion Date: 11/1/18, Reporting date: every 6 months for duration starting 3/30/18. Review date: Annual meeting. 100 gravid females/site will be collected to ensure 2,800 mosquitoes for colony establishment. Receive eggs from 4 candidate sites. Complete species identification of females for “colonizability” tests. Written document of comparing strains from multiple locations with respect to ease of rearing efforts.
Specific Aim 3.5. Select Field Trial Site
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:
Genetic isolation from mainland
Species composition and presence of population structure within species
Degree of polymorphism present in target transgene insertion sites
“Colonizability” (ability to establish and maintain laboratory colonies)of local An.
gambiae strainLevel of insecticide resistance of local An. gambiae populations
Malaria parasite prevalence
Malaria incidence
Environmental complexity of An. gambiae habitat,
Willingness for collaboration from local institutions and collaborators
Acceptance level for genetically engineered mosquito release trials
Insectary setup or potential to set up local insectary for the project
Laboratory setup or potential for setting up laboratory dedicated for the project
Logistics of transportation between US and the field site and within the field site.
Logistics of financial transactions
Local personnel resources
Availability for housing for an on-site project manager, a junior specialist and
UCD/UCI project personnel visiting field siteAvailability of health clinic or hospital proximal to base station for on-site personnel
Security for foreign personnel for both lab and housing
Ease of communication with local personnel
Cost of running local facility and hiring project personnel
Decision point 3.5.1a Completion Date: 1/3/18, Reporting date: 3/30/19; Review date: Annual meeting. Final report on evaluation of 4 candidate sites.
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).
Milestone 3.5.2a Completion Date: 2/28/19, Reporting date: 3/30/19; Review date: Annual meeting. Decision on the field site.
APPENDIX I: UCIMI DEFINITIONS, TERMS AND CONDITIONS
Decision-Making Process
Decisions will be made by a consensus of the Principal Investigator, Project Manager and Project Coordinators. If necessary, the PI will arbitrate disputes to facilitate final decisions. Evaluation of Activity progress and project plans will be made semi-annually and be based on progress presented at the meeting, draft progress reports (in anticipation of annual reports) and discussions. The action options available are to:
1) Continue the Activity (progress is good).
2) Modify the Activity (progress is good but unanticipated outcomes or unknowns require changes in the experimental design).
3) Start a six month re-evaluation period (unsatisfactory progress which, if not remedied, will result in termination of Activity and dependent Activities).
4) Terminate the Activity even though progress was good because the specific approach no longer contributes to the ultimate goals.
5) Terminate the Activity because the progress is unsatisfactory and corrections would exceed the project’s timeline.
6) Conclude the Activity due to its successful completion.
Project Management
Administrative management is the responsibility of the principal investigator (PI, Dr. Anthony A. James - aajames@uci.edu), the project manager (Sentelle Eubanks - sentelle@uci.edu ), office personnel (Rhodell Valdez - rhodellv@uci.edu ) and the professional grants administration at UC Irvine. Bookkeeping for the subcontractors is handled by the subcontractors’ institutions, with overall review and monitoring by UC Irvine (Sentelle Eubanks). Scientific Management of Objectives 2 and 3 is carried out by the Principal Investigator, Project Manager and Project Coordinators. They are responsible for review of scientific goals and progress evaluation. Review and evaluation criteria are based on the research descriptions and timelines provided in the Project Plan. An annual meeting in which all scientists participate will facilitate the review process and provide the basis for decision-making about resource allocation. Programmatic and financial decisions are made by consensus agreement of the Principal Investigator, Project Manager and Project Coordinators with disputes mediated by Principal Investigator. Resources are allocated initially based on the budgets submitted by the Principal Investigator, Project Manager and Project Coordinators. At each annual review, progress will be indexed against budget allocations. Disparities will be corrected by reallocation of funds. The PI will communicate semiannually with designated administrative officers at UC Irvine to update progress and the project plan. Information flow among project researchers will be facilitated via the distribution of the semi-annual progress reports as well as through data posting on a secure web site (data postings are announced via email alerts). Redacted versions of the progress reports will be distributed as hard copies and posted on the secure website.
Project Management Committee
The Project Management Committee (PMC) has the responsibility of overseeing the protection of Intellectual Property (IP) matters as they develop during the course of the project. A major goal of the UCIMI is to make new technologies available to the developing world for public benefit. However, it is beyond the scope of this project to take a product to development. It is more likely that a successful outcome will be attractive and worthy of investment by the nonprofit and for-profit companies that will be better able to take the project from the trials to the next stages. It is therefore important to protect the coordinated patentability of the components developed so that a “package” of IP rights (as opposed to numerous individual patents) will be available. To this end the PMC will review all publications/ presentations of data developed during the course of the project for potential IP material.
Drafts of all publications and presentations of data will be submitted at least 20 days prior to submission for publication or presentation to the Committee for review. In the event the PMC determines a patent is necessary to protect any discoveries present, the publication/presentation that discloses such inventions will be withheld to allow for the filing of applicable patent applications. The Committee is not expected to have to meet in person on a regular schedule but should be able to conduct its business electronically on an “as needed” basis.
PMC permanent members:
Anthony James ex officio
Project Manager ex officio
Kevin Kennan - Assistant Director of Intellectual Property Administration at the Office of Technical Alliances, UC Irvine
Members ad hoc:
PCs from the IP originating lab(s)
IP personnel from the originating institution(s)
In the case of the unexpected unavailability of any member at a scheduled meeting they will be replaced by an appropriate (someone having the knowledge, responsibility and authority to act on the IP matter at hand) substitute who is endorsed by the rest of the committee.
Regulatory Compliance
We will maintain regulatory compliance in all areas that apply to project-related activities. We will monitor and adhere to intramural regulations and guidelines for research protocols and working conditions, as well as extramural regulations for shipping and receiving organisms and permits required to conduct research internationally. Institutional Review Boards, Institutional Animal Care and Use Committees, and Institutional Biosafety Committees oversee research protocol compliance regarding human subjects, use of vertebrate animals and the use of pathogens and recombinant DNA, respectively. Working conditions and worker safety are monitored by Environmental Health and Safety programs and certified through Biological Use Authorization. Records of current protocol approvals are maintained by the project manager. Copies of all assurances for Select Agents and Conflict of Interest Statements also are to be provided to the Project Manager. The project manager should be notified each time these protocols are reviewed and/or modified.
The movement of genetically engineered vectors into and within the USA is regulated by the United States Department of Agriculture/Animal and Plant Health Inspection Service (USDA/APHIS). A shipping permit from the Biotechnology Regulatory Services (BRS) (http://www.aphis.usda.gov/) is required for both inter-state transport as well as importation of genetically-modified (GM) vectors into the USA (APHIS form 2000 - http://www.aphis.usda.gov/brs/pdf/2000.pdf ). To help keep a record of regulatory compliance, each shipping application (APHIS form 2000) that is associated with the project should be completed with the assistance of and submitted by the Project Manager. This policy will assure that changes in the USDA application requirements result in an update of the template application. A two-way permit will cover the possibility that the receiver may want to send vectors back one day. It should be noted that the application procedure requires an inspection of the recipient’s insectary facilities by the USDA. The inspection will be the slowest step to the approval process. If the receiving party has been inspected previously and the sending party has not, it would be quicker to apply for a one-way permit.
Importation of exotic organisms into the USA is regulated by the Etiologic Agent Import Permit Program of the CDC (http://www.cdc.gov/od/eaipp). A permit to import a vector of human disease is required according to USPHS 42 CFR - Part 71 Foreign Quarantine.
Part 71.54 Etiologic agents, hosts, and vectors.
(a) A person may not import into the United States, nor distribute after importation, any etiologic agent or any arthropod or other animal host or vector of human disease, or any exotic living arthropod or other animal capable of being a host or vector of human disease unless accompanied by a permit issued by the Director.
(b) Any import coming within the provisions of this section will not be released from custody prior to receipt by the District Director of U.S. Customs Service of a permit issued by the Director (Centers for Disease Control and Prevention).
Applications filed with the CDC for permits to import mosquitoes have, at times, elicited responses indicating that importation permits for this species are unnecessary. Minimally, we ask that project members who anticipate importing mosquitoes from outside of the US keep these letters on file (with a copy provided to the Project Manager) and have a copy accompany any mosquito shipments into the country. Preferentially, we ask that you request that your application be considered regardless of the CDC’s interpretation of its necessity.
The California Department of Public Health (CDPH) also requires anyone wishing to import exotic vectors should first write to the Vector-Borne Disease Section (VBDS), 1616 Capitol Avenue MS 7307, P.O. Box 997413, Sacramento, CA 95899-7413 and provide information about the vector and any pathogens that the vector may carry. In addition, the letter shall include the sources of the vector, the reason for the importation, the time period you will have the vector, security and contingency provisions, plans for disposal of the vector upon completion of the time period, and any other pertinent information. VBDS will write a letter on behalf of the Director of the CDPH authorizing the importation. VBDS may request that a facility be inspected prior to authorization.
California Health and Safety code 116120.
(a) It shall be unlawful for any person to import into the state any exotic vector without written approval from the state department.
(b) The state department shall issue an applicant written authority to import into the state any exotic vector upon a determination by the state department that the public health and safety will not be endangered thereby.
(c) "Exotic vector" means a vector species that is not native to California and is not commonly found in the state.
(d) Any violation of this section is a misdemeanor.
Publicity
Public announcements about the UCIMI must be cleared by UC Irvine communications personnel.
1. Materials will be reviewed and approved by Tom Vasich, (949) 824-6455, tmvasich@uci.edu.
2. Correspondence or publicity efforts must indicate that they are being funded by the grantee institution (UC Irvine). Suggested language to describe affiliation with the project may include: “… supported by the University of California Irvine Malaria Initiative” or “…the University of California Irvine Malaria Initiative.”
3. Additional conditions apply to UCIMI work funded by the Bill and Melinda Gates Foundation (BMGF). Specifically:
PUBLICITY BY UCIMI: The BMGF’s prior written approval must be obtained before: (a) issuing a press release or other public announcement regarding the grant; and (b) any other public use of the Foundation’s name or logo. Requests for permission may be emailed to: grantee.comms@gatesfoundation.org two weeks in advance to provide the BMGF an opportunity to review and comment. Detailed guidelines are available at: www.gatesfoundation.org/grantseeker/documents/guidelines_communications_for_grantees.doc.
PUBLICITY BY OTHERS: The UCIMI, its subgrantees, subcontractors, contingent workers, agents, or affiliates may not state or otherwise imply to third parties that the BMGF directly funds or otherwise endorses their activities.
Publications
Manuscripts, research reports, or other publication resulting from work performed on this project must be reviewed by the Project Management Committee for the evaluation of potential IP property. Manuscripts intended to be published in peer reviewed journals should be submitted to the Project Manager upon submission of the manuscript to the journal. Other articles should be submitted to the Project Manager as soon as possible following the creation of a final draft. Submission of articles to the Project Management Committee should be accompanied by your opinion regarding the potential for IP within the submitted work. All manuscripts will be published as ‘open access’.
The following language for acknowledging support in manuscripts is suggested: “Funded by University of California Irvine Malaria Initiative.” This should included along with acknowledgements to other sources as needed.
Progress Reports
All researchers are responsible for communicating progress to the Project Manager. Semi-annual progress reports will be posted on the secure website for review. Annual progress reports will be posted before the annual meeting for review by all to prepare for the decision making process. In addition to written progress reports, data from each activity will be presented during the Annual Meetings.
References Cited [to be completed]
Griffin JT, Hollingsworth TD, Okell LC, Churcher TS, White M, Hinsley W, et al. Reducing Plasmodium falciparum malaria transmission in Africa: a model-based evaluation of intervention strategies. PLoS Med. 2010;7(8). PMCID: 2919425.
WHO. Guidance framework for testing of genetically modified mosquitoes. World Health Organization on behalf of the Special Programme for Research and Training in Tropical Diseases; 2014. ISBN 9789241507486. ,http://www.who.int/tdr/publications/year/2014/ Guidance_framework_mosquitoes.pdf.
WHO Working Group. Proceedings: Working Group on Strategic Plan to Bridge Laboratory and Field Research in Disease Vector Control. 14-16 July 2004, ICIPE, Nairobi, Kenya. UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training In Tropical Diseases. Frontis Press, Wageningen, The Netherlands, 2004.
World Malaria Report 2016. Geneva: World Health Organization; 2016. Licence: CC BY-NC-SA 3.0 IGO.