MILESTONE

Update 2019

Gantt Chart (downloadable version by request)

UCI Malaria Initiative

Decision point

PI: James

Milestone

Project Start date

4/1/17

4/1/18

4/1/19

4/1/20

4/1/21

Milestone or Decision Point

Group

Year 1

Year 2

Year 3

Year 4

Year 5

Specific Aim

Activity

6/30/17

9/1/2017

12/1/2017

3/1/2018

6/1/2018

9/1/2018

12/1/2018

3/1/2019

6/1/2019

9/1/2019

12/1/2019

3/1/2020

6/1/2020

9/1/2020

12/1/2020

3/1/2021

6/1/2021

9/1/2021

12/1/2021

3/1/2022

Objective 1: Project Administration

1. Recruit Project Personnel

1. Write Job Description/announcements

1.1.1

UCI

1.1.1a

2. Advertise positions

1.1.2

UCI

1.1.2a

3. Interview Candidates

1.1.3

UCI

1.1.3a

4. Fill positions

1.1.4

UCI

1.1.4a

2. Develop comprehensive Project Plan

1. Develop draft project plan

1.2.1

UCI

1.2.1a

1.2.1b

1.2.1c

1.2.1d

3. Develop decision-making protocol

1. Develop decision making protocol

1.3.1

UCI

1.3.1a

1.3.1a

4. Develop communications strategy

1. Reactive plan

1.4.1

All

1.4.1a

1.4.1b

1.4.1b

1.4.1c

1.4.1d

2. Proactive plan

All

1.4.2a

1.4.2b

1.4.1b

1.4.1c

1.4.1d

5. Develop central web portal

1. Develop central website

1.5.1

UCI

1.5.1a

1.5.1b

2. Update website (ongoing process)

1.5.2

UCI

1.5.2a

1.5.2b

1.5.2c

1.5.2d

1.5.2e

1.5.2f

1.5.2g

1.5.2h

1.5.2i

6. Develop regulatory plan

1. Implement procedures for tracking research-related regulatory requirements (IBC, IACUC, CDC, USDA, others)

1.6.1

All

1.6.1a

1.6.1b

1.6.1c

1.6.1d

1.6.1e

1.6.1f

1.6.1g

1.6.1h

2.Review and develop knowledge base for regulatory requirements for potential field sites (see 4.2.4)

1.6.2

UCI, UCD

1.6.2a

1.6.2b

1.6.2c

1.6.2d

1.6.2e

1.6.2f

1.6.2g

1.6.2h

3. Work with field team to obtain necessary permits and regulatory approvals for sample collection and site establishment. (see 4.2.4)

1.6.3

UCI, UCD

1.6.3a

1.6.3b

1.6.3c

1.6.3d

1.6.3e

1.6.3f

1.6.3g

1.6.3h

1.6.3i

4. Hire Community Engagement consultant, begin permitting and regulatory analysis. Hire regulatory Consultant

1.6.4a-b

1.6.4a

1.6.4b

7. Annual meeting of project participants

1. Host annual meeting

1.7.1

UCI

1.7.1a

1/31/2019

1.7.1b

1.7.1c

1.7.1d

1.7.1f

Objective 2: Develop and test Anopheles gambiae strains carrying autonomous gene-drive systems linked to anti-pathogen effector genes.

1. Recruit Project Personnel

1. Write Job Description/announcements

2.1.1

UCI, UCSD

2.1.1a

2. Advertise positions

2.1.2

UCI, UCSD

2.1.2a

3. Interview Candidates

2.1.3

UCI, UCSD

2.1.3a

4. Fill positions

2.1.4

UCI, UCSD

2.1.4a

2. Develop CRISPR/Cas9 gene-drive systems for Anopheles gambiae

1. Identify and clone appropriate promoter sequences (for example, β2-tubulin, U6, vitellogenin, carboxypeptidase, G12) for expressing CRISPR/Cas9 gene-drive system components

2.2.1

UCI, UCSD

2.2.1a

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

2.2.2

UCI, UCSD

2.2.2a

3. Design and synthesize gene-drive constructs, and verify sequence

2.2.3

UCI, UCSD

2.2.3b

2.2.3c

3. Engineer additional anti-parasite effector genes

1. Develop additional single-chain (scFv) immunological reagents to inactivate P. falciparum (Pfs47 with Barrillas-Mury, NIH; Pfs230 with Narum, NIH; Ashley Birkett, PATH)

2.3.1

UCI, UCSD

2.3.1a

2.3.1b

2.3.1c

Moved to Specific Aim 7

3. Make An. gambiae transgenic lines to test additional effector genes using transposon-mediated transgenesis

2.3.2

UCI, UCSD

2.3.3a

2.3.3b

2.3.3c

Moved to Specific Aim 7

4. Perform challenge assays with P. falciparum to determine efficacy of novel effector constructs

2.3.3

UCI, UCSD

2.3.4a

2.3.4b

2.3.4c

Moved to Specific Aim 7

4. Generate transgenic mosquitoes carrying gene-drive elements and the parasite- resistance genes.

1. Engineer effector cassettes with multiple molecules targeting different stages of the parasites.

2.4.1

UCI, UCSD

2.4.1a

2.4.1b

2.4.1c

2.4.1d

2.4.1e

2.4.1f

2.4.1g

2.4.1h

2.4.1i

2. Perform ‘swap’ experiments to integrate effector molecules into the AgNosCd-1 gene-drive line.

2.4.2

2.4.2a

2.4.2b

5. Develop and maintain detailed laboratory standard operating procedures, experimental records, budgets, and provide reports to appropriate components of the administrative core

1. Aim establishes and maintains the laboratory documents to validate strain development and other standard operating procedures.

2.5.1

UCI, UCSD, UCD

2.5.1a

2.5.1b

2.5.1c

2.5.1d

2.5.1e

2.5.1f

2.5.1g

2.5.1h

2.5.1i

6. Test the gene-drive performance characteristics of the AgNOSCd-1 strain with no included effector molecules.

1. Conduct small cage trials with first gene-drive line (nanos, cardinal). Drive features of the AgNOSCd-1 strain tested in small cage trials.

2.6.1

UCI, UCSD

2.6.1a

2.6.1

2.6.1a

2. Develop method for accurately measuring NHEJ rate

2.6.2

UCI

2.6.2a

2.6.2

3. Assay in vitro the effects of gRNA single nucleotide polymorphisms on Cas9-gRNA nuclease activity.

2.6.3

UCB, UCI, UCSD

2.6.3a

4. Assay in vivo the effects of gRNA single nucleotide polymorphisms on Cas9-gRNA nuclease activity (Field sample dependent)

2.6.4

All

2.6.4a

2.6.4b

5. Determine life-table parameters of the AgNosCd-1 strain using fitness components

2.6.5

UCB, UCI, UCSD

2.6.5a

6. Refine life-table parameter estimates of AgNosCd-1 strain using cage trial data

2.6.6

UCB, UCI, UCSD

2.6.6a

2.6.6b

2.6.6c

2.6.6d

2.6.6e

7. Use fitted model of gene drive system and its effects on An. gambiae life-table parameters to predict behavior of system in the environment.

2.6.7

UCB, UCI, UCSD

2.6.7a

2.6.7b

2.6.7c

2.6.7d

2.6.7e

2.6.7f

2.6.7g

2.6.7h

2.6.7i

2.6.7j

2.6.7k

2.6.7l

2.6.7m

7. Test the gene-drive performance characteristics of the AgNOSCd-1 strain with included effector molecules.

1. Conduct small cage trials with first gene-drive line (nanos, cardinal).

2.7.1

2.7.1a

2.7.1b

2.7.1c

2. Refine life-table parameter estimates of AgNosCde-1 strain using cage trial data

2.7.2

2.7.2a

2.7.2b

2.7.2c

3. Use fitted model of gene drive system and its effects on An. gambiae life-table parameters to predict behavior of system in the environment

2.7.3

2.7.3a

8.Test the effector performance characteristics of the strains

1. Conduct parasite challenge assays on transgenic An. gambiae lines

2.8.1

2.8.1a

2.8.1b

2.8.1c

2.8.1d

2.8.1e

9. Mathematical modeling to support target product profile recommendation

1. Develop an epidemiological module for the MGDrivE modeling framework

2.9.1

2.9.1

2. Mathematical modeling to support target product profile recommendation

2.9.2

2.9.2

10. Make recommendation for release strain

1. Recommend a specific TPP for release

2.10.1

2.9.1a

2 Initiate TPP specific Risk Assessment

2.10.2

2.9.2a

11. Develop target product profile for recommended strains

1.Work with FNIH and other non-UCI MI projects to develop consensus on TPP parameters and develop values for ‘ideal’ and ‘minimally acceptable’.

2.11.1

2.11.1a

2. Adopt consensus TPP parameters for ‘ideal’ and ‘minimally acceptable’ and assure AgNosCd-1 fits profile.

2.11.2

2.11.2a

3. Report TPP and test results to WHO Vector Control Advisory Group (VCAG)

2.11.3

2.11.3a

12. Perform risk assessment for recommended strain

1. Work with field site to identify regulatory structure of the proposed field site

2.12.1

All

2.12.1a

2.12.1b

2. Identify credible independent entity to conduct site-relevant risk assessment.

2.12.2

All

2.12.2a

2.12.2b

3. Conduct site-relevant risk assessment of product

2.12.3

All

2.12.3b

Objective 3: Evaluate field site(s) for population alteration trials

1. Recruit Project Personnel

1. Write Job Description/announcements

3.1.1

UCD, UCB, UCLA

3.1.1a

2. Advertise positions

3.1.2

UCD

3.1.2a

3. Interview Candidates

3.1.3

UCD

3.1.3a

4. Fill positions.

3.1.4

UCD

3.1.4a

2. Evaluation of Potential Field Sites for Selection of Four Candidate Sites

1. Literature survey for the evaluation of 13 potential GEM field trial sites

3.2.1

UCD

3.2.1a

2. Analysis of remotely sensing data for 13 potential field sites.

3.2.2

UCD, UCLA

3.2.2a

3. Select, based on set criteria, four candidate sites.

3.2.3

UCD, UCB, UCLA

3.2.3a

3. Evaluation of Candidate Field Sites for Selecting Final Field Trial Site

1. Prepare site visits to four candidate field sites and nearest mainland.

3.3.1

UCD

3.3.2a

3.3.2b

3.3.2c

3.3.2d

2. Visit villages on each candidate site and nearest mainland to collect Anopheles specimens.

3.3.2

UCD

3.3.4a

3.3.4b

3.3.4c

3. Analysis of genotype data to assess entomological parameters

3.3.3

UCD

3.3.5a

3.3.5b

3.3.5c

4. Analysis of insecticide resistance

3.3.4

UCD

3.3.6a

3.3.6b

3.3.6c

5. Analysis of genome data to assess degree of genetic isolation of sites

3.3.5

UCB

3.3.7a

3.3.7b

3.3.7c

6. Model evaluation of candidate field sites

3.3.6

UCD

3.4.1a

3.4.1b

3.4.1c

4. Assess “Colonizability” of An. gambiae from Candidate Field Sites

1. Establish mosquito rearing protocols & insectary at UC Davis (UCI has these? Clarify and forward)

3.4.1

UCD

3.4.1a

3.4.1b

3.4.1c

2. Assess ease of colonization for An. gambiae for each site

3.4.2

UCD

3.4.2a

3.4.2b

3.4.2c

5. Select Field Trial Site

1. Prepare a written evaluation of each of the four candidate sites.

3.5.1

All

3.5.1a

2. Make final decision on the project field site

3.5.2

All

3.5.2a

6. Model evaluation of candidate field site

1. Mosquito Collection and Research Activities at Field Site Union of Comoros

3.6.1

UCI UCD

3.6.1a

2. Determine feasibility of establishing An. coluzzii colony and An. gambiae colony in Grande Comore.

3.6.2

UCI UCD

3.6.2a

3.Conduct preliminary WHO insecticide resistance assays

3.6.3

UCI UCD

3.6.3

7. Research and Training Activities at UC Davis and UC Irvine

1. DNA extraction, sequencing and analysis of site collected mosquitoes.

3.7.1

UCI UCD

3.7.1a

2. Provide training at UCI MI for field site collaborators

3.7.2

UCI UCD

3.7.2a

3. Develop plan for field station at field site (more specific)

3.7.3

UCI UCD

3.7.3a

4. Provide training at UCI MI in construct and microinjection.

3.7.4

UCI

3.7.4a

8. Develop and implement timeline/plan for continued research with field site collaborators

1. Conduct follow up workshop for site collaborators and stakeholders

3.8.1

UCI UCD

3.8.1a

2. Create and implement strategy for next phase of research at field site(s) with collaborators

3.8.2

UCI UCD

3.8.2a

9. Develop Field Station at Field Site

1. Upgrade or install insectary facilities at Grand Comore

3.9.1

UCI UCD

3.9.1a

2. Upgrade or install laboratory facilities at Grande Comore.

3.9.2

UCI UCD

3.9.2a

3. Evaluate and rent housing for onsite UCI MI staff

3.9.3

UCI UCD

3.9.3a

4. Rent of purchase suitable housing for UCI MI staff

3.9.4

UCI UCD

3.9.4a

5. Acquire necessary furnishings for field station and hire security.

3.9.5

UCI UCD

3.9.5a

10. Hire Field Site Personnel

1. Recruit, Hire and Train post-doctoral biologist(s) to direct field work at each field site.

3.10.1

UCI UCD

3.10.1a

2. Recruit, Hire and Train administrative personnel to assist with administrative duties at field site.

3.10.2

UCI UCD

3.10.2a

3. Recruit, Hire and Train National/local to site biologist(s) who will work as field station staff.

3.10.3

UCI UCD

3.10.3a

11. Conduct Second Season of Mosquito Sampling at Field Site

1. Conduct mark release recapture studies

3.11.1

UCD

3.11.1a

2. Sample aquatic organisms co-inhabiting larval mosquito breeding sites

3.11.2

UCD

3.11.2a

12. Marked Release of TPP

1. 1st release of TPP at selected site

3.12.1

All

3.12.1

13. Post release evaluations

1. Recaputue and sequence

3.13.1

3.13.1

2. Parasites disect and assess for the number of pasasites

3.13.2

3.13.2

3. Community Assessment - evaluate the stakeholders and community about the project.

3.13.3

3.13.3

Objective 4: Community Engagement

1. Build Relationships and Establish Collaborations

1. Conduct workshops at potential fields sites

4.1.1

UCI

4.1.1a

2. Conduct stakeholder assessment of all sites

4.1.2

UCI

4.1.2a

3. Draft regulatory frameworks for candidate sites

4.1.3

UCI

4.1.3a

4. Documentation and data collection of all communication and engagement

4.1.4

UCI

4.1.4a

2. Site and Community Assessment

1. Develop and implement community assessment

4.2.1

UCI

4.2.1a

2. Develop and implement educational tools

4.2.2

UCI

4.2.2a

3. Develop process for responding to community (Communication Plan) questions and concerns

4.2.3

UCI

4.2.3a

4. Regulatory Planning with field site collaborators with regulatory consultant (see 1.6.4)

4.2.4

UCI

4.2.4a

5. Refine Communication Plan

4.2.5

UCI

4.2.4a

3. Education and Capacity Building

1.Recruit and train onsite CE personnel

4.3.1

UCI

4.3.1

2. Develop and implement training plan

4.3.2

UCI

4.3.2a

4.3.2b

4.3.2c

4.3.2d

4.3.2e

3. Begin delivery of public education

4.3.3

UCI

Facilitate communication for regulatory and contractual processes (see 1.4.6)

4.3.4

UCI

4.3.4

4. Evaluation and Communication Development

1. Assessment/Evaluation of Public Education and Tools (revise if necessary at this time)

4.4.1

UCI

4.4.1a

4.4.1b

4.4.1c

2. Report on community and stakeholder support

4.4.2

UCI

4.4.2a

4.4.2b

4. Evaluation of Stakeholder Groups

4.4.3

UCI

4.4.3a

4.4.3b

4.4.3c

5. Communication Management

1. Refinement of Communication Plan

4.5.1

UCI

4.5.1a