HR001118S0017.pdf

Broad Agency Announcement PREventing EMerging Pathogenic Threats (PREEMPT)

BIOLOGICAL TECHNOLOGIES OFFICE

HR001118S0017

January 19, 2018

HR001118S0017, PREEMPT

TABLE OF CONTENTS

PART I: OVERVIEW INFORMATION

PART II: FULL TEXT OF ANNOUNCEMENT

1. Funding Opportunity Description

1.1. Program Overview

1.2. Program Metrics

1.3. Ethical, Legal, and Societal Implications (ELSI)

1.4. Protection of Sensitive Information

2. Award Information

2.1. General award information

2.2. Fundamental Research

3. Eligibility Information

3.1. Eligible Applicants

3.2. Organizational Conflicts of Interest

3.3. Cost Sharing/Matching

4. Application and Submission Information

4.1. Address to Request Application Package

4.2. Content and Form of Application Submission

4.3. Funding Restrictions

4.4. Other Submission Requirements

5. Application Review Information

5.1. Evaluation Criteria

5.2. Review of Proposals

6. Award Administration Information

6.1. Selection Notices

6.2. Administrative and Policy Requirements

6.3. Reporting

6.4. Electronic Systems

7. Agency Contacts

8. Other Information

9. Appendix 1 – Volume II checklist

PART I: OVERVIEW INFORMATION

Federal Agency Name – Defense Advanced Research Projects Agency (DARPA), Biological Technologies Office

Funding Opportunity Title – PREventing EMerging Pathogenic Threats Announcement Type – Initial Funding Opportunity Number – HR001118S0017 Catalog of Federal Domestic Assistance Numbers (CFDA) – 12.910 Research and Technology Development Dates o Posting Date – January 19, 2018 o Proposal Abstract Due Date and Time – February 13, 2018 4:00 ET o Proposal Due Date and Time – March 27, 2018 4:00 ET o BAA Closing Date – March 27, 2018 o Proposers’ Day – January 30, 2018 https://www.fbo.gov/spg/ODA/DARPA/CMO/DARPA-SN-18-18/listing.html

Concise description of the funding opportunity – DARPA is soliciting innovative proposals to develop novel and scalable approaches to preempt viral spillover and transmission from animals or vectors into humans.

Anticipated individual awards - Multiple awards are anticipated.

Types of instruments that may be awarded - Procurement contract, cooperative agreement or other transaction.

Any cost sharing requirements - Cost sharing may be required under applicable statutory regulations for other transactions for prototype projects awarded under the authority of 10 U.S.C. § 2371b.

Agency contact o Points of Contact

James Gimlett, Ph.D. Program Manager Biological Technologies Office

The BAA Coordinator for this effort may be reached at:

PREEMPT@darpa.mil

DARPA/BTO

ATTN: HR001118S0017

675 North Randolph Street https://www.fbo.gov/spg/ODA/DARPA/CMO/DARPA-SN-18-18/listing.html mailto:PREEMPT@darpa.mil

PART II: FULL TEXT OF ANNOUNCEMENT

1. Funding Opportunity Description

This publication constitutes a Broad Agency Announcement (BAA) as contemplated in Federal Acquisition Regulation (FAR) 6.102(d)(2) and 35.016 and 2 CFR § 200.203. Any resultant award negotiations will follow all pertinent law and regulation, and any negotiations and/or awards for procurement contracts will use procedures under FAR 15.4, Contract Pricing, as specified in the BAA.

DARPA is soliciting innovative proposals for research to develop new tools and models to quantify the likelihood of a virus to jump from an animal host into humans, and to develop and validate new scalable technologies to target potential human-capable viral pathogens in wild reservoirs and/or mosquito vectors to prevent transmission to humans.

1.1. PROGRAM OVERVIEW

Introduction During U.S. international operations, military forces are deployed to remote locations around the globe, often in areas where endemic and emerging diseases are prevalent1. Most of these emerging and re-emerging diseases originate in animal reservoirs and then jump into humans.

Numerous trends, including the increased interactions between human, animal and insect populations due to increased population densities, globalization, densification of livestock production, and rising human encroachment into animal habitats, have increased the risks of new viral outbreaks in those regions where Department of Defense (DoD) personnel are typically deployed. Often, DoD personnel are among the first responders in outbreak situations. Emerging infectious diseases, for which few medical countermeasures are available, represent a major threat to the warfighter and national security and could have devastating impacts on U.S. public health.

Despite biosurveillance efforts around the globe, new viral outbreaks continue to outpace preparedness efforts and show no signs of abating. During the first three quarters of 2017 outbreaks of avian influenza A (H7N9), Chikungunya, MERS coronavirus, Ebola, Seoul virus, Hepatitis E, Hepatitis A, Yellow Fever, Lassa, and Zika viruses were recorded2. While current biosurveillance strategies focus on detection of known pathogens within the human population following an infectious outbreak event, there is a dearth of research and surveillance on sentinel or reservoir animals3. Animal-specific viruses that have the potential to infect humans (namely “human-capable” pathogens), but have not yet spilled over into human populations, are rarely considered. As a result, infectious agents are detected only after an outbreak—that is, after an animal pathogen has adapted to become capable of infecting humans. Consequently, the outbreak response is largely reactive and not initiated until after an epidemic has already begun. The PREEMPT program represents a radical departure from current practice, aiming to target viral

1 Halliday Jo E.B. et al. (2017). Driving improvements in emerging disease surveillance through locally relevant capacity strengthening. Science.

2 World Health Organization (2017). http://www.who.int/csr/don/archive/year/2017/en/.

3 Metcalf, J.E. and Lessler, J. (2017). Opportunities and challenges in modeling emerging infectious diseases.

Science.

http://www.who.int/csr/don/archive/year/2017/en/ biothreats within the animal reservoirs where they originate and preempt their entry into human populations before an outbreak occurs.

Recently, the scientific community has advanced its understanding of host-pathogen genetics and mechanisms of adaptation across hosts4,5, developed analytic tools to predict animal hosts of new and potential human-transmissible viruses, and learned how to identify “hot spot” geographic regions where an animal-to-human virus jump is imminent6,7. This understanding is empowered by new high-throughput data generation capabilities and sophisticated analytic and computational tools. Together, this new understanding and capability hold great promise for the development of advanced integrated models that can assess and likely provide guidance for action that prevents human virus emergence before the virus gains entry to the human population. The PREEMPT program aims to develop new tools and models to quantify the likelihood of a virus quasispecies (QS) to jump from an animal host into humans. In parallel, PREEMPT seeks to develop and validate new scalable technologies that prevent transmission of viral pathogens in wild reservoirs and/or mosquito vectors to humans or to bridge animals that serve as intermediary hosts prior to virus jump into humans.

Research Objectives PREEMPT research objectives are structured along two Technical Areas (TAs). Both Technical Areas must be performed in parallel by vertically integrated, interdisciplinary teams. Proposers must present a plan to address both Technical Areas and meet key milestone decision points that occur at the end of year 2.

1) TA1: Develop and validate integrated, multiscale models that quantify the likelihood a human-capable virus will emerge from an animal reservoir residing in a “hot spot” geographic region.

2) TA2: Develop scalable approaches that target and suppress the animal virus in its reservoir(s) and/or vector(s), to reduce the likelihood of virus transmission into humans.

Technical Area 1 (TA1)

4 Lloyd-Smith, J.O. (2010). Identifying genetic markers of adaptation for surveillance of viral host jumps. Nature Reviews Microbiology.

5 Plowright, R.K. et al. (2017). Pathways to zoonotic spillover. Nature Reviews Microbiology.

6 Olival, K.J. et al. (2017). Host and viral traits predict zoonotic spillover from mammals. Nature.

7 Han, B.A. et al. (2016). Undiscovered Bat Hosts of Filoviruses. PLoS Negl Trop Dis.

https://www.ncbi.nlm.nih.gov/pubmed/28555073

Studies within TA1 must produce and validate models that: (a) quantify the likelihood of a virus to jump into a new animal species and/or humans, (b) identify opportunities for proactive intervention, and (c) determine likely efficacy, scalability, and sustainability of prevention strategies.

Proposers are expected to leverage high-throughput virus screening methods, metagenomics, ecological surveillance, and advanced modeling tools to generate risk models for species jump that will enable near real-time data analysis and identification of potential risks and risk factors.

This far-forward biosurveillance system should also identify opportunities for preemptive intervention, assessing likely efficacy, scalability, safety, and sustainability of preemptive strategies to target viral threats in animal reservoirs and/or vectors before they enter the human population.

TA1 Components Proposers should address, at minimum, the following aspects:

1) Selection of zoonotic or vector-borne viral pathogen(s) (multiple viruses within the same family may be addressed if they share a common animal reservoir and/or vector)

2) Field data collection

3) Multi-species field samples studied in a controlled laboratory setting

4) Data analysis, integration, and model development

5) Real-time data sharing and analysis

6) Model outputs

7) Experimental validation of model predictions in a controlled, environment-simulated laboratory setting

1. Selection of zoonotic or vector-borne viral pathogen

This BAA only will consider proposals focused on zoonotic and/or vector-borne viruses.

Microorganisms other than viruses are not responsive to this announcement. A rationale for the viruses selected is required. Virus selection may be based on, but is not limited to, the following factors: high frequency of re-emergence (e.g. avian influenza virus), patterns of virus host range or host breadth (predicted zoonotic potential), potential for rapid spread due to vector-mediated transmissibility, severity of disease pathology, and likelihood of pandemic threat.

2. Field data collection

Proposers must identify and justify suitable geographic “hotspots” within which they will collect field data. Proposers must consider all of the following criteria when selecting geographic hot spots for field data collection:

1) Previous evidence of geographic distribution of zoonotic reservoirs and/or vectors for known or unknown human viruses; these maps may be based on epidemiological, phylogenetic, ecological, biogeographic, socio-economic data, or other;

2) Evidence of past species jump events in or near the selected geographic location;

3) Demonstrated capabilities and infrastructure to perform research in the selected geographic region and/or collaboration with an established DoD or Department of Health and Human Services (DHHS) partner (e.g., a Naval Medical Research Unit site, Armed Forces Research Institute of Medical Sciences, or Centers for Disease Control), such that the performer can coordinate far-forward surveillance activities and access local lab and analytics capabilities;

4) Appropriate levels of in-country government approval, cooperation, infrastructure and logistical support where samples will be collected and analyzed; and

5) Rationale for reservoirs/species to be sampled.

Where applicable, proposers must consider seasonal distribution (e.g., wet-dry seasons for mosquito), temporal ecological factors (e.g., time of fruiting for fruit bats), and temporal behavioral traits (e.g., sexual maturation) of zoonotic species for field sampling. Potential geographic areas may include, but are not limited to, endemic regions; those undergoing ecological shifts (thus increasing risk for spillover due to changes in animal-human interactions);

those harboring host species with high zoonotic potential that are in proximity to human populations and “bridge” animal hosts (e.g., human-bat-swine ecosystems); and prior sites of spillover events or outbreaks. The selection of geographic areas of common military deployment that also meet the above criteria is strongly encouraged. Proposers should describe feasible approaches to increase the probability of detecting viruses within animal reservoirs and/or vectors—residing in selected geographic areas—that have the potential to become human-capable. Proposers should describe sample collection methods in detail, being sure to include longitudinal sampling frequency. Development of novel and rapid sampling approaches for the real-time continuous screening of emerging or re-emerging pathogens at the human-animal interface is encouraged. Proposers are encouraged to identify field samples that were collected during past outbreak events, or field data already generated, that could be accessed for retrospective analyses. In such cases, proposers should describe how and where the data were collected, and establish quality control methods for data evaluation and use. Although human use research will not be funded by PREEMPT, the use of human samples or data from prior outbreaks obtained through other programs may be included in the research plan as long as samples are appropriately de-identified (see, for example, https://humansubjects.nih.gov/human-specimens-cell-lines-data).

3. Multi-species laboratory testing of field samples

Proposers should discuss protocols to determine and quantify the virus population QS diversity from the vector or reservoir at the time of sample collection (t=0) in a manner that minimizes QS alterations, which commonly result from cell line passaging. Proposers should assess the need for longitudinal collection of samples to understand viral QS temporal dynamics (temporal changes in sequence and fitness landscapes) in field virus populations. The initial viral QS isolated from a field sample (t=0) will be hereon annotated as “QS0”. Proposers must describe in vitro and/or in vivo experiments to assess jump potential of the QS0 population to a relevant new host. Experimental approaches to monitor viral species jump may include, but are not limited to:

changes in viral population QS during cell line passaging between relevant species; infection of appropriate animal models; infection of natural animal hosts; and controlled, multi-species laboratory ecosystems.

https://humansubjects.nih.gov/human-specimens-cell-lines-data https://humansubjects.nih.gov/human-specimens-cell-lines-data

Lab testing should determine the key parameters influencing the probability of a viral QS0 to jump and adapt to a new host species. Potential parameters across different host animals or vectors may include, but are not limited to:

1) QS diversity profiles

2) Rates of virus infection and amplification

3) Virus incubation period

4) Viremia and viral shedding

5) Transmission bottlenecks

6) Animal host evolutionary and immune pressures

The data generated should enable the development of genotype-to-phenotype maps and the determination of mutation(s) associated with virus jump to a new host.

4. Data analysis, integration, and model development

Proposers should identify the relevant data needed for developing integrated models of risk assessment. Proposers should discuss the development of probabilistic models of virus jump using advanced computational methods and tools, including both model-driven and data-driven approaches. Models should integrate multi-scale and cross-host species data, including but not limited to, field and experimental data (e.g., QS dynamics), ecological data (e.g., demographic, socio-economic, epidemiological, biogeographical, and other metadata), and other relevant data available, especially that generated from past spillover events. Models should consider all factors associated with pathogen emergence and transmission, particularly multi-host immunological landscapes. Models should also capture viral evolutionary trajectories, fitness landscapes in zoonotic and/or vector species, and quantify the transmission dynamics underlying species jump.

5. Real-time data sharing and analysis

The PREEMPT program is expected to generate significant amounts of data, primarily from next generation sequencing (NGS) of viral populations and analysis of host molecular signatures.

Proposers should identify methods for near-real-time data sharing and analysis.

6. Model outputs

Proposers should explain how they will develop probabilistic models and machine learning techniques that integrate multi-scale and cross-species data (e.g., molecular signatures, demographic, ecological, socio-economic, epidemiological, weather, climate, and other metadata) to quantify a pathogen’s likelihood to cross species barriers and infect humans.

Models should capture viral evolutionary trajectories and mutations that govern species jump.

Models should quantify transmission dynamics, accounting for the diversity of viral QS. Models should identify key parameters of the pathogen, host species, vector dynamics, and ecological interactions contributing to species jump, and should inform a preemption strategy by identifying optimal pressure points (e.g., jump-enabling mutations, stochastic transmission bottlenecks, and viral amplification requirements) that can be targeted to reduce the likelihood of species jump.

For proposals addressing vector-borne viruses, proposers should describe methods to quantify the likelihood of virus adaptation to a new vector and propose experimental methods to validate these predictions. Proposers should discuss metrics for grading model accuracy, sensitivity, and specificity. Models should be able to receive dynamic biosurveillance inputs and accommodate virus QS changes.

7. Experimental validation of model predictions

Proposers must describe in detail a plan to establish relevant in vivo, multi-species experimental approaches to validate model outputs. Experimental testing may closely resemble or recapitulate real-life settings (e.g., climate, phylogenetically adjacent host species, and vector “biting” patterns) to enable the quantification of the probability of spillover and/or transmission events in a controlled manner. Approaches that closely recapitulate real-life ecosystems and natural hosts are strongly encouraged. To improve model accuracy, sensitivity, and specificity, performers must iterate both theoretical and empirical experiments.

TA1 Key Outputs The key outputs for TA1 must include the following:

1) Integrated models that quantify likelihood of virus jump and can be easily adapted to receive dynamic surveillance and virus data input.

2) Stochastic models quantifying bottlenecks (e.g., transmission, cell entry, and infection rates) and mutational fitness maps (e.g., enabler mutations and their frequency).

3) Identification and assessment of potential preemptive intervention targets to preempt virus jump from the reservoir and/or vector.

Technical Area 2 (TA2) Studies within this technical area aim to develop deployable and scalable methods to preempt viral jump across species.

TA2 Components Technical Area 2 aims to develop deployable and scalable methods to preempt viral jump to other species. Proposers must address, at minimum, all of the following aspects:

1) Proof-of-concept preemption approaches;

2) Scalable delivery methods;

3) Analysis of long-term sustainability; and

4) Experimental validation.

1. Proof-of-concept preemption approaches

Proposers should describe how the output of TA1 in silico models will guide preventive method design, and how quantitative information of virus-host species barriers and transmission bottlenecks will be used to develop strategies to preempt emergence of human-capable viruses.

Models should guide the selection of: host species to be treated (e.g., wild animals, “bridge” animals, vectors, and livestock); potential molecular targets (e.g., key mutation(s) enabling receptor binding in a new host); targets associated with transmission cycle dynamics (e.g., reduction of viral load within the reservoir and/or vector that would preclude transmission); and other relevant factors identified by the models. Proposers should describe the preemptive methods that address different model outputs. Examples of preemptive approaches include but are not limited to:

1) Specific disruption of jump-capable genes from virus QS in reservoirs and/or vectors using small interfering RNAs or CRISPR/Cas-based targeted deletions.

2) Suppression of virus jump to a new host through antibody-mediated virus neutralization.

3) Suppressed reservoir and/or vector viremia using virus defective interfering particles

(DIPs) to outcompete virus replication.

4) Suppressed transmission among animal reservoirs through induced immunity (e.g., vaccinate the animal).

5) Alternative methods informed by experimental and theoretical models. The development of novel preemptive approaches are strongly encouraged.

2. Scalable delivery methods

Proposers must describe scalable approaches to deliver the preemptive therapeutic to achieve animal and/or vector population-level control of the targeted virus, including strategies for reaching less accessible animal reservoirs (e.g., rodents or non-human primates). Approaches that enable host-to-host therapeutic distribution (i.e., do not require individual treatment) that are self-limiting, only activate when the viral pathogen target is present, and/or have a controllable “on/off-switch” are encouraged. Potential scalable methods of inoculation may include, but are not limited to:

1) Self-disseminating treatments or preventives (e.g., transmissible recombinant vaccines, therapeutic interfering particles, or self-spreading antiviral therapies).

2) Bait vaccination or treatment of wild or domestic animals.

3) Spray-based methods.

Approaches that utilize genetic modifications of vectors (e.g., engineered mitochondrial DNA) are acceptable. The proposed method of inoculation must be justified. The proposer must describe strategies for closely controlling preemptive delivery and spread.

3. Analysis of long-term safety and efficacy

Proposers must establish initial methods to assess the long-term safety and efficacy of preemptive approaches (e.g., determine the mechanism by which species specificity of a vaccine is maintained, and assess evolutionary stability and ecological safety).

4. Experimental validation

Proposers must describe approaches to validate preemptive methods of choice in controlled experimental models. Multi-species experimental platforms that closely recapitulate real-life ecosystems and use natural hosts are strongly encouraged.

TA2 Key Outputs The key outputs of TA2 must include the validation of new “block-before-jump” preemption technologies for one of the following:

1) Validate suppression of virus jump from wild animal reservoir to humans and/or an intermediate animal carrier (e.g., domestic livestock).

2) Validate suppression of virus jump or transmission from wild reservoir to vector, vector to a different vector species, and/or from vector to human.

Period of Performance DARPA anticipates that the PREEMPT program will provide up to three and a half years of funding for research and development to be performed over Phase I (base) and II (option) periods of 24 and 18 months, respectively.

Timeline PREEMPT spans a 42-month effort with a 24-month Phase I (base) and an 18-month Phase II (option). In general, Phase I should provide early validation of zoonosis risk models, and Phase II should establish efficacy and scalability of zoonosis prevention approaches.

Phase I (Base period) Phase I efforts aim to develop experimental and mathematical models to quantify the likelihood a virus will jump from one host species to another, identify potential targets for spillover preemption, and develop scalable methods of preemption. During Phase I, performer teams will:

1) Identify the genetic adaptations that enable species jump.

2) Develop mathematical models to quantify the likelihood of species jump based on:

a. Molecular data (e.g., viral QS data from deep sequencing) and

b. Ecological data (e.g., immune state of the host population before pathogen emergence, species relatedness, etc.).

3) Identify bottlenecks for intervention (e.g.. transmission, cell entry, viral amplification, infection rate, and other mechanisms associated with viral cross-species compatibility).

4) Develop initial scalable platforms that target viruses in reservoirs and/or vectors to prevent viral jump into other animals or humans.

By the end of year 1 (Phase I) performers will be expected to have:

1) Identified signatures of fitness and spillover potential of a pathogen between two species.

2) Quantified the genetic and transmission factors requirements of viral QS to jump to a new host (e.g., develop genotype-to-phenotype maps, identify specific mutations, etc.) using far-forward biosurveillance data from selected high-risk regions.

By the end of year 2 (Phase I) performers will be expected to have:

1) Initially demonstrated that models can quantify the probability of human-capable virus pathogens to jump from one species to another species.

2) Demonstrated proof of concept methods for targeting human-capable virus pathogens in the reservoirs and/or vectors to reduce the probability of virus jump.

3) Provided initial strategies to scale up preemption methods.

Phase II (Option period) Phase II efforts aim to develop probabilistic models for intra- and inter-species viral amplification and transmission dynamics, integrated models for risk assessment, and experimental validation of new approaches to preempt species jump. During Phase II, performer teams will extend Phase I modeling efforts to:

1) Quantify intra- and inter-species viral amplification dynamics and transmission.

2) Develop integrated models that quantify the probability of a virus QS to jump to bridge animal species or to humans.

3) Experimentally validate scalable methods for their ability to preempt zoonotic spillover.

By the end of year 3.5 (Phase II) performers will be expected to:

1) Demonstrate accuracy of risk assessment and preemption models in a relevant multi-species experimental setting.

2) Demonstrate the ability to suppress viral jump to a new species in controlled experimental settings.

It is recognized that appropriate milestones and metrics may depend upon the type of virus, the reservoir, the mechanisms of species jump, and the proposed preemption methods. Proposers must offer quantitative milestones and metrics (see Tables 1 and 2 below for notional metrics) for their proposed proof-of-principle use case. Proposers must demonstrate relevant research experience in the required technical areas. Proposals involving multiple teams and/or experimental approaches should be structured as unified efforts that address the program Technical Areas in parallel, in an integrated manner.

1.2. PROGRAM METRICS

In order for the Government to evaluate the effectiveness of a proposed solution in achieving the stated program objectives, proposers should note that the Government hereby promulgates the following program metrics that may serve as a guideline for assessing program progress, risk and impact. Although the following program metrics are provided, proposers should note that the Government has identified these goals with the intention of bounding the scope of effort while affording the maximum flexibility, creativity, and innovation in proposing solutions to the stated problem. Proposers should offer more appropriate and specific metrics for their particular use case and technical approach, including intermediate metrics (i.e. every 6 months, or sooner) to help further evaluate progress. Final metrics are to be negotiated at the time of contracting.

Table 1: Notional Milestones, Deliverables, and Program Metrics for TA1

Phase Milestones and Deliverables Program Metric Collected field surveillance data:

Virus QS molecular data (e.g. from deep sequencing) and metadata from longitudinal samples (e.g.

obtained from selected high-risk areas (e.g. bat cave) and/or from prior outbreak event

Host species immune molecular data

Quantitative measures of:

Longitudinal viral population QS (QSt=0, QSt=6 months, QSt=12 months,..) diversity in selected high-risk areas (e.g. frequency of mutations, evolutionary trajectories) (6 months)

Viral QS diversity in samples obtained from animal, vector, and/or human from prior outbreak event (e.g. frequency of species-specific mutations) (9 months)

Immune molecular signatures from host reservoir or intermediate reservoir species (12 months)

Multi-species lab test data:

Virus QS genotype-phenotype maps for at least 2 relevant host species

Quantitative measures of:

Cell entry and adaptation across species in vitro and/or in vivo (e.g. QS diversity during passage across species) (18 months)

I

Initial mathematical models that assess risk of virus jump

Model capability to describe/predict:

Virus QS evolutionary trajectories between 2 relevant species (9 months) Key molecular factors that could be targeted to prevent virus jump in vitro and/or in vivo (e.g. signatures of fitness of a pathogen between two relevant host species) (18 months)

Molecular targets for preemption (24 months)

Established testbeds for validation of model predictions

Testbeds mimic natural environment as quantified by performer-defined parameters (24 months)

Multi-species lab test data Quantify virus QS transmission factors between two species in vivo

Quantitative measures of:

Virus amplification and transmission dynamics (e.g. rate of infection vs.

viremia, amplification rates, and incubation time) (30 months)

II

Advanced mathematical models that assess risk of virus jump Integration of molecular data and virus amplification/transmission dynamics Integration of host immune evolutionary pressures and virus QS dynamics

Models predict:

Intra- and inter-species transmission dynamics (36 months) Probability of spillover (risk assessment)

(42 months) Top 2 targets to reduce probability of transmission between two species to

Phase Milestones and Deliverables Program Metric inform TA2 (42 months)

Further validation of model prediction in established testbeds

Validated model prediction accuracy in multispecies environment (42 months)

Table 2: Notional Milestones, Deliverables, and Program Metrics for TA2 Phase Milestones and Deliverables Program Metric

I Proof-of-concept demonstration of preemptive approach that reduces either the probability of virus jump or the frequency of virus QS variants at high risk for species jump

Quantitative validation of preemptive approach as established by performer (24 months) Examples:

Frequency of high-risk mutation within virus QS in reservoir reduced >3X

Virus incubation period in vector extended >3X

Virus amplification rate in reservoir or vector reduced >3X

Viremia in host or vector reduced >5X Demonstrated efficacy of preemption method

Reduced probability of transmission between two species by >5X in vivo for top 2 targets (36 months)

II

Demonstrated scalability of preemption method

Quantitative scalability as established by performer (42 months)

Data Sharing Proposers must ensure all technical data items (including experimental findings, processed data, methods of processing, research reports, and publications) and software (source code and executables) generated from PREEMPT program funding are made available to DARPA.

Regularly submitted reports (e.g., monthly or quarterly) should contain all relevant project data, including (but not limited to) raw and analyzed data and any necessary annotations and interpretation. Data and/or samples collected from de-identified human volunteers/patients from previous outbreak events must include associated anonymized metadata (e.g., signs/symptoms, diagnostic test results, interventions, clinical observations, and outcomes). All raw data and metadata should be recorded according to approved experimental standards.

To gain enhanced scientific value from open collaboration in fundamental research, DARPA may seek permission to share some or all program-generated data with the broader research community as open data (including the possibility of accessing, reusing, and redistributing under appropriate licensing terms) to the extent permitted by applicable laws and regulations (e.g., privacy, security, and export control).

DARPA anticipates that a large amount of data will be generated under this program by each performer and that the analyses and validation will be strengthened by compiling and integrating information across all performers. Performers are strongly encouraged to establish the appropriate agreements to enable collaboration and data sharing. DARPA encourages sharing of pre-existing data, including those generated through funding by other sources, although this is not a requirement of the program.

As feasible, DARPA intends to share data within the PREEMPT performer community to promote program goals. To facilitate sharing and exchange of data items, performers will be required to enter an Associate Contractor Agreement (ACA); an ACA clause will be included in the contract or agreement awarded.

PREEMPT Transition Plan Proposers must include a PREEMPT Technology Transition Plan. Proposers must indicate the types of partners (e.g., government, private industry, non-profit) they plan to pursue and submit a timeline with incremental milestones toward successful engagement. Proposers should begin transition activities during the early stages of the program (Phase I). Awardees must include DARPA in the development of transition relationships. If the transition plan includes a start-up company, a business development strategy must be included as well. The extent by which the proposed intellectual property (IP) rights will impede the Government’s ability to transition the technology will be considered in the proposal evaluation.

1.3. ETHICAL, LEGAL, AND SOCIETAL IMPLICATIONS (ELSI)

DARPA is committed to ensuring that efforts funded under this BAA adhere to ethical and legal regulations currently in place for federally and DoD-funded research. Program developments will be discussed with a panel of expert external advisors with expertise in bioethical and biosafety issues that may emerge as a consequence of advances in biomedical science and technology. Proposers to this BAA should address potential ethical, legal, and societal implications of the proposed technology.

1.4. PROTECTION OF SENSITIVE INFORMATION

PREEMPT is a 6.1 fundamental research program aimed at enhanced biosurveillance and novel approaches to preempt viral pathogens in animal reservoirs from jumping into human populations. DARPA follows current DoD policy for contracted fundamental research. DARPA recognizes, however, that PREEMPT program components aimed at understanding and quantifying mechanisms for viral zoonotic spillover could potentially generate sensitive information that could be misused. Since this is a fundamental research program, the risk of misuse currently cannot be reasonably evaluated. However, proposers are notified that during proposal evaluation and/or program performance, when such a risk reasonably can be evaluated, DARPA may determine that risk of misuse creates exceptional circumstances, compelling reasons, and/or national security reasons under current DoD policy for contracted fundamental research. DARPA therefore expects that proposers to this program understand and will comply with various government guidance regarding potential gain-of-function research of concern (GOFROC)8 and dual use research of concern (DURC)9,10,11,12,13. See https://www.phe.gov/s3/dualuse/Pages/default.aspx for further information.

8 Gain-of-Function Research (GOFROC) refers to studies with the potential to generate pathogens with pandemic potential exhibiting high transmissibility and high virulence.

https://www.phe.gov/s3/dualuse/Pages/default.aspx

DARPA requires that proposals include a Risk Mitigation Plan that will be incorporated into any resulting agreements or contracts and includes the following information:

1) An assessment of potential risks to public health, agriculture, plants, animals, the environment, and national security.

2) Proposed guidelines that the proposer will follow to ensure maximal biosafety and biosecurity during the course of the research.

3) A communication plan that addresses content, timing, and the extent of distribution of potentially sensitive dual-use information. The plan must also address how input from DARPA, other government, and community stakeholders will be taken into account in decisions regarding communication and publication of potentially sensitive dual-use information.

2. Award Information

2.1. GENERAL AWARD INFORMATION

Multiple awards are possible. The amount of resources made available under this BAA will depend on the quality of the proposals received and the availability of funds.

The Government reserves the right to select for negotiation all, some, one, or none of the proposals received in response to this solicitation and to make awards without discussions with proposers. The Government also reserves the right to conduct discussions if it is later determined to be necessary. If warranted, portions of resulting awards may be segregated into pre-priced options. Additionally, DARPA reserves the right to accept proposals in their entirety or to select only portions of proposals for award. In the event that DARPA desires to award only portions of a proposal, negotiations may be opened with that proposer. The Government reserves the right to fund proposals in phases with options for continued work, as applicable.

The Government reserves the right to fund a Phase II option based on funding availability, an

9 Dual Use Research of Concern (DURC) refers to life sciences research that can be reasonably anticipated to provide knowledge, information, products or technology that could be directly misapplied to pose a significant threat with broad potential consequences to public health and safety, agricultural crops and other plants, animals, the environment, materiel, or national security.

10 Proposed framework for the oversight of dual use life sciences research: strategies for minimizing the potential misuse of research information, National Science Advisory Board for Biosecurity (NSABB). June 2007.

11 Recommendations for the evaluation and oversight of proposed gain-of-function research by the National Science Advisory Board for Biosecurity (NSABB). May 2016.

12 Tools for the Identification, Assessment, Management, and Responsible Communication of Dual Use Research of Concern: A Companion Guide to the United States Government Polices for Oversight of Life Sciences Dual Use Research of Concern. NIH. September 2014.

13 United States Government Policy for Oversight of Life Sciences Dual Use Research of Concern. DURC Policy.

March 2012.

assessment of Phase I research results, and a determination that awarding the option is in the best interests of the Government. The Government reserves the right to request any additional, necessary documentation once it makes the award instrument determination. Such additional information may include but is not limited to Representations and Certifications (see Section VI.B.2., “Representations and Certifications”). The Government reserves the right to remove proposers from award consideration should the parties fail to reach agreement on award terms, conditions, and/or cost/price within a reasonable time, and the proposer fails to timely provide requested additional information. Proposals identified for negotiation may result in a procurement contract, grant, cooperative agreement, or other transaction, depending upon the nature of the work proposed, the required degree of interaction between parties, whether or not the research is classified as Fundamental Research, and other factors.

Proposers looking for innovative, commercial-like contractual arrangements are encouraged to consider requesting Other Transactions. To understand the flexibility and options associated with Other Transactions, consult http://www.darpa.mil/work-with-us/contract-management#OtherTransactions.

In all cases, the Government contracting officer shall have sole discretion to select award instrument type, regardless of instrument type proposed, and to negotiate all instrument terms and conditions with selectees. DARPA will apply publication or other restrictions, as necessary, if it determines that the research resulting from the proposed effort will present a high likelihood of disclosing performance characteristics of military systems or manufacturing technologies that are unique and critical to defense. Any award resulting from such a determination will include a requirement for DARPA permission before publishing any information or results on the program. For more information on publication restrictions, see the section below on Fundamental Research.

2.2. FUNDAMENTAL RESEARCH

It is DoD policy that the publication of products of fundamental research will remain unrestricted to the maximum extent possible. National Security Decision Directive (NSDD) 189 defines fundamental research as follows:

‘Fundamental research’ means basic and applied research in science and engineering, the results of which ordinarily are published and shared broadly within the scientific community, as distinguished from proprietary research and from industrial development, design, production, and product utilization, the results of which ordinarily are restricted for proprietary or national security reasons.

As of the date of publication of this BAA, the Government expects that program goals as described herein may be met by proposers intending to perform fundamental research and proposers not intending to perform fundamental research or the proposed research may present a high likelihood of disclosing performance characteristics of military systems or manufacturing technologies that are unique and critical to defense. Based on the nature of the performer and the nature of the work, the Government anticipates that some awards will include restrictions on the resultant research that will require the awardee to seek DARPA permission before publishing any information or results relative to the program.

http://www.darpa.mil/work-with-us/contract-management#OtherTransactions

Proposers should indicate in their proposal whether they believe the scope of the research included in their proposal is fundamental or not. While proposers should clearly explain the intended results of their research, the Government shall have sole discretion to select award instrument type and to negotiate all instrument terms and conditions with selectees. Appropriate clauses will be included in resultant awards for non-fundamental research to prescribe publication requirements and other restrictions, as appropriate. This clause can be found at http://www.darpa.mil/work-with-us/additional-baa.

For certain research projects, it may be possible that although the research being performed by the awardee is restricted research, a subawardee may be conducting fundamental research. In those cases, it is the awardee’s responsibility to explain in their proposal why its subawardee’s effort is fundamental research

3. Eligibility Information

3.1. ELIGIBLE APPLICANTS

All responsible sources capable of satisfying the Government’s needs may submit a proposal that shall be considered by DARPA.

3.1.1. Federally Funded Research and Development Centers (FFRDCs) and Government Entities

FFRDCs FFRDCs are subject to applicable direct competition limitations and cannot propose to this BAA in any capacity unless they meet the following conditions: (1) FFRDCs must clearly demonstrate that the proposed work is not otherwise available from the private sector. (2) FFRDCs must provide a letter on official letterhead from their sponsoring organization citing the specific authority establishing their eligibility to propose to Government solicitations and compete with industry, and their compliance with the associated FFRDC sponsor agreement’s terms and conditions. This information is required for FFRDCs proposing to be awardees or subawardees.

Government Entities Government Entities (e.g., Government/National laboratories, military educational institutions, etc.) are subject to applicable direct competition limitations. Government entities must clearly demonstrate that the work is not otherwise available from the private sector and provide written documentation citing the specific statutory authority and contractual authority, if relevant, establishing their ability to propose to Government solicitations.

Authority and Eligibility At the present time, DARPA does not consider 15 U.S.C. § 3710a to be sufficient legal authority to show eligibility. While 10 U.S.C.§ 2539b may be the appropriate statutory starting point for some entities, specific supporting regulatory guidance, together with evidence of agency approval, will still be required to fully establish eligibility. DARPA will consider FFRDC and http://www.darpa.mil/work-with-us/additional-baa

Government entity eligibility submissions on a case-by-case basis; however, the burden to prove eligibility for all team members rests solely with the proposer.

3.1.2. Non-U.S. Organizations

Non-U.S. organizations and/or individuals may participate to the extent that such participants comply with any necessary nondisclosure agreements, security regulations, export control laws, and other governing statutes applicable under the circumstances.

3.2. ORGANIZATIONAL CONFLICTS OF INTEREST

FAR 9.5 Requirements In accordance with FAR 9.5, proposers are required to identify and disclose all facts relevant to potential OCIs involving the proposer’s organization and any proposed team member (subawardee, consultant). Under this Section, the proposer is responsible for providing this disclosure with each proposal submitted to the BAA. The disclosure must include the proposer’s, and as applicable, proposed team member’s OCI mitigation plan. The OCI mitigation plan must include a description of the actions the proposer has taken, or intends to take, to prevent the existence of conflicting roles that might bias the proposer’s judgment and to prevent the proposer from having unfair competitive advantage. The OCI mitigation plan will specifically discuss the disclosed OCI in the context of each of the OCI limitations outlined in FAR 9.505-1 through FAR 9.505-4.

Agency Supplemental OCI Policy In addition, DARPA has a supplemental OCI policy that prohibits contractors/performers from concurrently providing Scientific Engineering Technical Assistance (SETA), Advisory and Assistance Services (A&AS) or similar support services and being a technical performer.

Therefore, as part of the FAR 9.5 disclosure requirement above, a proposer must affirm whether the proposer or any proposed team member (subawardee, consultant) is providing SETA, A&AS, or similar support to any DARPA office(s) under: (a) a current award or subaward; or (b) a past award or subaward that ended within one calendar year prior to the proposal’s submission date.

If SETA, A&AS, or similar support is being or was provided to any DARPA office(s), the proposal must include:

The name of the DARPA office receiving the support;

The prime contract number;

Identification of proposed team member (subawardee, consultant) providing the support; and An OCI mitigation plan in accordance with FAR 9.5.

Government Procedures In accordance with FAR 9.503, 9.504 and 9.506, the Government will evaluate OCI mitigation plans to avoid, neutralize or mitigate potential OCI issues before award and to determine whether it is in the Government’s interest to grant a waiver. The Government will only evaluate OCI mitigation plans for proposals that are determined selectable under the BAA evaluation criteria and funding availability.

The Government may require proposers to provide additional information to assist the Government in evaluating the proposer’s OCI mitigation plan.

If the Government determines that a proposer failed to fully disclose an OCI; or failed to provide the affirmation of DARPA support as described above; or failed to reasonably provide additional information requested by the Government to assist in evaluating the proposer’s OCI mitigation plan, the Government may reject the proposal and withdraw it from consideration for award.

3.3. COST SHARING/MATCHING

Cost sharing is not required; however, it will be carefully considered where there is an applicable statutory condition relating to the selected funding instrument. Cost sharing is encouraged where there is a reasonable probability of a potential commercial application related to the proposed research and development effort.

For more information on potential cost sharing requirements for Other Transactions for Prototype, see http://www.darpa.mil/work-with-us/contract-management#OtherTransactions

4. Application and Submission Information

4.1. ADDRESS TO REQUEST APPLICATION PACKAGE

This announcement, any attachments, and any references to external websites herein constitute the total solicitation. If proposers cannot access the referenced material posted in the announcement found at http://www.darpa.mil, contact the administrative contact listed herein.

4.2. CONTENT AND FORM OF APPLICATION SUBMISSION

All submissions, including abstracts and proposals must be written in English with type not smaller than 12 point font. Smaller font may be used for figures, tables, and charts. Copies of all documents submitted must be clearly labeled with the DARPA BAA number, proposer organization, and proposal title/proposal short title.

4.2.1. Proposal Abstract Format

Proposers are strongly encouraged to submit an abstract in…