HHS-NIH-NIAID-BAA2023-1.pdf

Issuing Office: Office of Acquisitions, DEA, NIAID, NIH

5601 Fishers Lane, Room 3D38, MSC 9821, Bethesda, MD 20892-9821

Issuing Contracting Officer: Swee L. Teo

Email: teosl@niaid.nih.gov

Phone: (240) 669-5173

This solicitation contains opportunities to submit a proposal under the following distinct Research Areas, which are identified below:

RESEARCH

AREA

TITLE PAGE

NO.

PROPOSALS

DUE*

Development of Vaccine Candidates for

Biodefense and Emerging Infectious

Diseases

April 11, 2023

Development of Therapeutic Candidates for Biodefense, Antimicrobial Resistant

(AMR) Infections and Emerging

Infectious Diseases

The Antiviral Program for Pandemics

(APP): Development of Antivirals for

Specific RNA Viral Families of Pandemic Potential

March 13, 2023

Development of In Vitro Diagnostics for

Biodefense, Antimicrobial Resistant

Infections (AMR), and Emerging

* Proposals must be received before 3:00 PM Eastern Time on the date specified herein. Please see the

Proposal Submission Instructions (Section 4.3.2.1) for more information. For planning purposes, the

Government requests potential Offerors to submit a Notice of Intent. Please see Notice of Intent (Section

4.3.2.1.4) for more information.

Offers will be valid for 240 days unless a different period is specified by the Offeror on the Attachment entitled, "Proposal Summary and Data Record, NIH 2043.

NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES (NIAID)

2023 Division of Microbiology & Infectious Diseases (DMID)

Omnibus Broad Agency Announcement (BAA):

No. HHS-NIH-NIAID-BAA2023-1

Solicitation Issue Date: January 11, 2023

NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES (NIAID)

2023 DMID Omnibus Broad Agency Announcement

No. HHS-NIH-NIAID-BAA2023-1

TABLE OF CONTENTS

SECTION 1 – Broad Agency Announcement Information……………………………….………..………… p. 4

SECTION 2 – Contracting Officer Points of Contact……………………………….………..……………... p. 4

SECTION 3 – Research Areas and Technical Objectives……………………………….……..…..…………. p. 5

3.1 – Division of Microbiology and Infectious Diseases (DMID) Background………………….…… p. 5

3.2 – Funding and Award Information………………………………...………...………………..…… p. 6

3.3 – Research Areas

3.3.1 – Research Area 001: Development of Vaccine Candidates for Biodefense and Emerging

Infectious Diseases………………...…………………………………………………….…... p. 6

3.3.2 – Research Area 002: Development of Therapeutic Candidates for Biodefense, Antimicrobial

Resistant (AMR) Infections and Emerging Infectious Diseases………………………….…. p. 8

3.3.3 – Research Area 003: The Antiviral Program for Pandemics (APP): Development of Antivirals for Specific RNA Viral Families of Pandemic Potential…………………………………….. p. 12

3.3.4 – Research Area 004: Development of In Vitro Diagnostics for Biodefense, Antimicrobial

Resistant Infections and Emerging Infectious Diseases……………………………………… p. 15

3.4 – Research Areas 001, 002 and 003: Additional Technical Proposal Instructions ……….………... p. 19

3.5 – Research Areas 001, 002 and 003: Reporting Requirements and Deliverables ……........….……. p. 21

3.6 – Research Area 004: Additional Technical Proposal Instructions …………...………………….… p. 27

3.7 – Research Area 004: Reporting Requirements and Deliverables…………………………………. p. 30

SECTION 4 – Instructions, Conditions, and Notice to Offerors……………………………………………….. p. 32

4.1 – General Instructions to Offerors …………………………………………………………………... p. 32

4.2 – General Information……………………………………………………………………………… p. 35

4.3 – Instructions to Offerors…………………………………………………………………………… p. 37

4.3.1 – General Information…………………………...………………...………...……............ p. 37

4.3.2 – Technical Proposal Instructions …………………………………………….………..... p. 43

4.3.3 – Business Proposal Instructions……………………………………………………………. p. 74

SECTION 5 – Special Contract Requirements………………………………………………………………….. p. 89

SECTION 6 – Evaluation Factors for Award...………………………………………………………………… p. 116

SECTION 7 – Definitions…………………….………………………………………………………………… p. 124

SECTION 8 – Attachments…………………...………………………………………………………………… p. 125

SECTION 1. - BROAD AGENCY ANNOUNCEMENT INFORMATION

You are invited to submit a proposal in accordance with the requirements of this BROAD AGENCY

ANNOUNCEMENT (BAA). The BAA is governed by Federal Acquisition Regulation (FAR) 6.102 and further described in FAR 35.016 as well as the National Institutes of Health (NIH) Policy Manual, Manual Chapter

6035, Broad Agency Announcements. A BAA may be used as a solicitation mechanism for basic and applied research directed toward advancing the state-of-the-art or increasing knowledge or understanding and that part of development not related to the development of a specific system or hardware procurement. BAAs are general in nature, identifying areas of research interest, and shall only be used when meaningful proposals with varying technical/scientific approaches can be reasonably anticipated.

This BAA contains multiple distinct Research Areas. Offerors may submit a proposal in response to one, or more, of the Research Areas contained herein. Offers submitted in response to this BAA must present separate detailed technical and business proposals designed to meet the Technical Objectives described for each Research Area proposed. The Statement of Work (SOW), including the specific technical requirements and performance specifications, is developed and proposed by the Offeror, not the Government.

Proposals are NOT evaluated against each other since they are not submitted in accordance with a common

SOW issued by the Government. Instead, Research and Technical Objectives are provided in the BAA that describe individual Research Areas in which the Government is interested. Proposals received in response to the

BAA are evaluated in accordance with the Evaluation Factors for Award specified in Section 6. The

Government reserves the right to conduct discussions with all, some, one, or none of the proposals received in response to this BAA. If discussions are conducted, NIAID reserves the right to suggest modifying, adding or deleting milestones, decision points, research plans, processes, schedules, budgets or products. The Government also reserves the right to make awards without discussions. Additionally, the Government reserves the right to accept proposals in their entirety or to select only portions of proposals for award. Multiple awards are anticipated. The selection for award under this BAA will be based upon the evaluation factors, agency priorities, and the availability of funds.

SECTION 2. - CONTRACTING OFFICER POINT OF CONTACT

This BAA contains Research Areas issued by the Division of Microbiology and Infectious Diseases (DMID) within the NIAID. The Contracting Officer (CO) point of contact for questions is identified below:

Primary Point of Contact:

Swee L. Teo

Contracting Officer

Email: teosl@niaid.nih.gov

Phone: (240) 669-5173

Secondary Point of Contact:

Ebony Taylor

Contract Specialist

Email: ebony.taylor@nih.gov

Phone: (240) 292-0668 mailto:teosl@niaid.nih.gov mailto:ebony.taylor@nih.gov

SECTION 3. - RESEARCH AREAS AND TECHNICAL OBJECTIVES

3.1 - DIVISION OF MICROBIOLOGY AND INFECTIOUS DISEASES (DMID) BACKGROUND

Research supported by the National Institutes of Allergy and Infectious Diseases (NIAID), National

Institutes of Health (NIH), and the Department of Health and Human Services (DHHS), strives to understand, treat, and ultimately prevent the myriad infectious, immunologic, and allergic diseases that threaten millions of human lives. NIAID also has a key role in the development of new medical countermeasures (MCMs) against potential agents of bioterrorism, drug-resistant pathogens, and emerging and re-emerging infectious diseases. Through a variety of research grants and contracts, NIAID’s Division of Microbiology and Infectious Diseases (DMID) supports basic and applied research to develop and evaluate therapeutics, vaccines, and diagnostics targeting multiple pathogens, including

NIAID Emerging Infectious Diseases/Pathogens which encompass Category A, B, and C priority pathogens (https://www.niaid.nih.gov/research/emerging-infectious-diseases-pathogens).

NIAID/DMID intends to use this BAA to help address goals articulated in a number of strategic plans as well as pandemic preparedness. The National Biodefense Strategy released in 09/2018

(https://www.hsdl.org/?view&did=815921) articulates the need to enhance preparedness through MCMs, including vaccines, therapeutics, and diagnostics. The World Health Organization (WHO) has prioritized diseases with epidemic potential and for which there are no or insufficient MCMs

(https://www.who.int/blueprint/priority-diseases/en/), as well as pathogenic bacteria for which new antibiotics are urgently needed (https://www.who.int/news-room/detail/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed). Similarly, the Centers for Disease Control and

Prevention (CDC) has highlighted antibiotic resistant infections caused by urgent, serious, and concerning pathogens (https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf).

The coronavirus disease 2019 (COVID-19) pandemic has emphasized the need for a robust MCM development program, to include research resources and flexible platform technologies, aimed at preparedness against ribonucleic acid (RNA) viruses of pandemic potential. To this end, NIAID published a pandemic preparedness plan (https://www.niaid.nih.gov/research/pandemic-preparedness) that aims to develop countermeasures for prototype pathogens identified for each key RNA virus family that causes human disease and has high, pandemic potential. The viral families and prototype pathogens are outlined in a publication by NIAID leadership with input from the research community

(https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiac296/6649664. The NIAID pandemic preparedness plan contributes to the American Pandemic Preparedness Plan (APPP or AP3)

(https://www.whitehouse.gov/wp- content/uploads/2021/09/American-Pandemic-Preparedness-

Transforming-Our-Capabilities-Final-For- Web.pdf). The COVID-19 pandemic also highlighted the urgent need to develop safe and effective antivirals to combat severe acute respiratory syndrome coronavirus 2

(SARS-CoV-2), the pathogen that causes COVID-19, and the necessity to identify and develop sustainable platforms for targeted drug discovery and generate a robust pipeline of antivirals against viruses of pandemic potential. To address this gap, the Antiviral Program for Pandemics (APP)

(https://www.niaid.nih.gov/research/antivirals) was created to address the RNA virus families of pandemic potential. To protect people against Coccidioides infection, the NIAID Strategic Plan for Research to

Develop a Valley Fever Vaccine reflects the NIAID research priorities for developing a Valley fever vaccine (https://www.niaid.nih.gov/sites/default/files/niaid-strategic-plan-for-research-to-develop-a-valley-fever-vaccine9.9.22.pdf).

Through this BAA, NIAID aims to advance the research and development of promising candidate vaccines, therapeutics, and diagnostics for Biodefense, Emerging Infectious Diseases, and Pandemic Preparedness in each of four (4) Research Areas described in Section 3.3 below. NIAID BAA contracts advance products through early clinical trials, thereby reducing risk and becoming eligible for advanced clinical and manufacturing development funding.

https://www.niaid.nih.gov/research/emerging-infectious-diseases-pathogens https://www.hsdl.org/?view&did=815921 https://www.who.int/blueprint/priority-diseases/en/ https://www.who.int/news-room/detail/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed https://www.who.int/news-room/detail/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf https://www.niaid.nih.gov/research/pandemic-preparedness https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiac296/6649664 https://www.whitehouse.gov/wp-content/uploads/2021/09/American-Pandemic-Preparedness-Transforming-Our-Capabilities-Final-For-Web.pdf https://www.whitehouse.gov/wp-content/uploads/2021/09/American-Pandemic-Preparedness-Transforming-Our-Capabilities-Final-For-Web.pdf https://www.whitehouse.gov/wp-content/uploads/2021/09/American-Pandemic-Preparedness-Transforming-Our-Capabilities-Final-For-Web.pdf https://www.whitehouse.gov/wp-content/uploads/2021/09/American-Pandemic-Preparedness-Transforming-Our-Capabilities-Final-For-Web.pdf https://www.niaid.nih.gov/research/antivirals https://www.niaid.nih.gov/sites/default/files/niaid-strategic-plan-for-research-to-develop-a-valley-fever-vaccine9.9.22.pdf https://www.niaid.nih.gov/sites/default/files/niaid-strategic-plan-for-research-to-develop-a-valley-fever-vaccine9.9.22.pdf

3.2 – FUNDING AND AWARD INFORMATION

Contract funding for vaccine and therapeutic development will support candidate testing, manufacture, preclinical or nonclinical toxicology testing, and early clinical studies which may include Phase 1 or

Phase 2 clinical trials. Contract funding for diagnostics will support phases of in vitro diagnostic (IVD) product development from late-stage feasibility research through planning and design, development, up to and including design verification.

For all Research Areas, the total duration of a proposed contract should be consistent with the nature and complexity of the Offeror’s proposed research and may vary depending upon the scope of the project and the technical objectives. The total performance period comprised of combined Base Period and all Options proposed by an Offeror shall not exceed 5 years. If applicable, clinical trial activities are encouraged to start as soon as possible and be completed within the 5-year period.

The total budget estimated in the Fiscal Year 2024 (FY 24) is described below:

Research Areas 001, 002, and 004: For FY 24, the NIAID estimates up to $12.8 million for the award of

5-6 cost reimbursement type base contracts across all three Research Areas (001, 002 & 004). The estimated FY 24 funding is only for the non-severable Base period (direct and indirect costs combined). If options are proposed by an Offeror, they will be evaluated in accordance with Section 6 of the BAA. The number of awarded contracts will depend on the number of technically meritorious proposals, agency priorities, and availability of funds.

For Research Areas 001, 002, and 004, awards are anticipated to be made in or around May 2024. At the discretion of the Government, awards may be streamlined to meet agency needs.

Research Area 003: For FY 24, the NIAID estimates up to $3.5 million for the award of one (1) cost-reimbursement type base contract in Research Area 003 only. The estimated FY 24 funding is only for the non-severable Base period (direct and indirect costs combined). If options are proposed by an Offeror, they will be evaluated in accordance with Section 6 of the BAA. The number of awarded contracts will depend on the number of technically meritorious proposals, agency priorities, and availability of funds.

For Research Area 003, awards are anticipated to be made in or around November 2023. At the discretion of the Government, dates are subject to change.

3.3 - RESEARCH AREAS

3.3.1.1 - Technical Objectives

The goal of Research Area 001 is to protect human health and well-being by advancing specific vaccine candidates that utilize technology platforms that ideally elicit a rapid onset of immunity following a single dose, provide a durable response and are readily adaptable to multiple emerging pathogens. These vaccine technologies and platforms may include, but not limited to, any of the following: novel adjuvant vaccine formulations, delivery platforms that are scalable or produce mucosal immunity, nucleic acid-based platforms, 3.3.1- Research Area 001 - Development of Vaccine Candidates for

Biodefense and Emerging Infectious Diseases viral vectors, and nanoparticle/VLP approaches. This research area is restricted to the following pathogens:

• Pan-coronavirus vaccines that provide broad and ideally durable protective immunity, preference for candidates that incorporate novel immunogens

• SARS-CoV-2 variants of concern vaccine that elicits mucosal immunity and has demonstrated preclinical efficacy as shown by reduction of viral replication in the upper respiratory tract

• Alphaviruses (excludes Chikungunya)

• Filoviruses: Sudan, Marburg (excludes Zaire; adenovirus and recombinant vesicular stomatitis virus

(rVSV) vectored platforms)

• Flaviviruses (excludes Zika, Dengue)

• Orthopoxviruses: Especially next generation vaccines for smallpox (must also protect against monkeypox and excludes Modified Vaccinia Ankara (MVA)-based technologies) suitable for all ages and the immunocompromised

• Valley Fever (Coccidioidomycosis) o Optimal Valley fever vaccine candidates should align with specific criteria outlined in NIAID’s published strategy for Coccidioidomycosis (https://www.niaid.nih.gov/sites/default/files/niaid-strategic-plan-for-research-to-develop-a-valley-fever-vaccine9.9.22.pdf)

3.3.1.2. - Technical Approach

Research Area 001 focuses on the advancement of a promising lead vaccine candidate from pre-clinical testing through evaluation in a Phase 1 or Phase 2 clinical trial. A lead vaccine candidate is defined by the following criteria:

1. Antigen, adjuvant (if applicable), and delivery route have been selected and are clinically relevant.

Preliminary data with clinically relevant vaccine candidate has demonstrated proof-of-concept immunogenicity in relevant animal model(s)

2. Prefer, but do not require, evidence of proof-of-concept efficacy data in a relevant animal model

3. Platform has been defined and is appropriate to support Phase 1 and/or 2 clinical trials.

4. Prefer, but do not require, a defined manufacturing process

5. Prefer, but do not require, characterization of the lead candidate using well-characterized, quality-controlled assays including potency assay(s)

Proposals shall provide data on the lead vaccine candidate and experimental plans for the following:

1. Background on disease indication, gaps in corresponding medical countermeasure pipeline (if applicable)

2. Justification/rationale for antigen selection, immunogen design and/or platform selection including any seroepidemiology data

3. Characterization and optimization of the lead vaccine candidate

4. Non-clinical immunogenicity and efficacy studies (to include 2. and 3. from the paragraph above) and Investigational New Drug (IND)-enabling toxicology studies

5. Any clinical data available for the lead candidate and/or platform

6. A Clinical Development Plan and Technical Development Plan for the candidate product, including nonclinical, manufacturing, regulatory, and clinical activities to be undertaken

7. Description of current production processes including product characterization, assay development, formulation, and stability

8. Process development and manufacture of non-GMP and GMP lots of product, if applicable

9. Regulatory activities required to support proposed clinical trials

10. Development of all assays and reagents needed to support clinical trials

11. Clinical trial plan to be executed under the proposal https://www.niaid.nih.gov/sites/default/files/niaid-strategic-plan-for-research-to-develop-a-valley-fever-vaccine9.9.22.pdf https://www.niaid.nih.gov/sites/default/files/niaid-strategic-plan-for-research-to-develop-a-valley-fever-vaccine9.9.22.pdf

• Note: Upon completion of protocol development, DMID will determine if the offeror will hold the IND and conduct the clinical trial.

• Note: Phase 2 trial designs shall be no greater than 120 subjects.

12. A provision of human samples from all studies to be delivered to NIAID and, for subjects in clinical trials, obtaining future use consent form from volunteers for evaluation of their samples

Offerors may propose a vaccine against a single pathogen or multiple pathogens; NIAID reserves the right to negotiate vaccines for a single indication, multiple indications and/or combined indications, balancing the faster, straightforward development, and regulatory path of a single indication with flexibility and preparedness against multiple pathogens.

Adjuvant formulations and/or delivery platforms that reduce dosing requirements, lessen logistical requirements, bypass supply chain limitations, are readily scalable, and/or provide other benefits such as generation of potent mucosal immunity, are of specific interest. Cross-cutting technologies applicable to more than one vaccine component are also encouraged.

Organizations responding to this Research Area, collectively with the proposed subcontractors and consultants where applicable, must have documented expertise in vaccine development, including demonstrated knowledge of regulatory guidelines and submission processes for candidate products directed against emerging infectious diseases and/or biological threats identified in the Technical Objectives.

3.3.1.3 - Contracts awarded under this Research Area will NOT support the following activities; proposals containing any of these activities will be excluded from peer review and will not be considered further for award:

1. Basic research, selection of antigen or platform, and discovery of new candidates/products

2. Development of devices, diagnostics, or adjuvants in the absence of a companion vaccine antigen

3. Development of therapeutics

4. Vaccine candidates directed against pathogens that are not members of the viral families and/or genera listed in 3.3.1.1. above. Viruses, such as Zaire, Chikungunya, Zika, and Dengue are excluded

5. Vaccines against bacterial pathogens

6. Trained immunity: vaccine candidates that do not elicit an antigen-specific adaptive immune response and that are unlikely to elicit a memory immune response that persists beyond 28 days

7. Phase 3 clinical trials or activities that enable or support Phase 3 clinical trials

8. Research involving the use of Human Fetal Tissue

9. MVA-based platforms for smallpox/monkeypox as well as vaccine candidates for smallpox/monkeypox not suitable for use in the immunocompromised

3.3.2 - Research Area 002 - Development of Therapeutic Candidates for

Biodefense, Antimicrobial Resistant Infections, and Emerging Infectious

Diseases

3.3.2.1 - Technical Objectives

The objective of Research Area 002 is the development of new therapeutics for diseases caused by NIAID

Emerging Infectious Diseases/Pathogens including Category A, B and C priority pathogens (NIAID Emerging

Infectious Diseases/ Pathogens | NIH: National Institute of Allergy and Infectious Diseases) and certain bacterial and fungal pathogens identified in the 2019 CDC Antibiotic Resistance Threats Report (Antibiotic Resistance

Threats in the United States, 2019 (cdc.gov)).

https://www.niaid.nih.gov/research/emerging-infectious-diseases-pathogens https://www.niaid.nih.gov/research/emerging-infectious-diseases-pathogens https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf

Important notice to Offerors: For this research area, “therapeutic” activity refers to cure of disease, by elimination or substantial reduction of infective pathogens or toxins, by administration of a pharmaceutical agent after symptoms of disease are clinically observable.

A candidate therapeutic may be a lead series, a preclinical candidate, or a clinical candidate. It may be a small molecule (including natural products and peptides), a drug conjugate, or a biological product. Research Area 002 only supports development of therapeutic products.

Proposals are encouraged for non-traditional therapeutics and antitoxins, provided therapeutic activity in in vitro and in vivo models is demonstrated when used alone or in combination with a licensed drug in current clinical use. An antitoxin therapeutic lead series/lead/product candidate is a single product that is an agent intended for use in the cure of intoxication or an agent that has demonstrated activity against a specific toxin in an appropriate in vivo model of disease.

Proposals are encouraged for the development of broad-spectrum therapeutics with extended therapeutic activity against more than one pathogen in the list of NIAID Emerging Infectious Diseases/Pathogens including

Category A, B, and C priority pathogens and infectious pathogens listed in the 2019 CDC Antibiotic Resistance

Threats in the United States Report:

https://www.niaid.nih.gov/research/emerging-infectious-diseases-pathogens https://www.cdc.gov/drugresistance/biggest-threats.html.

Priorities are listed below; however, broad-spectrum therapeutics do not require activity against pathogens in the listed priorities. Limited spectrum therapeutic candidates that target high-priority pathogens for which no standard clinical treatment exists or for which drug resistance poses a significant public health concern are eligible if they target one of the specific pathogens listed below:

1. Antimicrobial Therapeutics

a. Active against the effects of one or more of the urgent or serious, and concerning drug-resistant bacterial threats or urgent fungal threats listed in the 2019 CDC Antibiotic Resistance Threats

Report (Antibiotic Resistance Threats in the United States, 2019 (cdc.gov));

b. Development of new therapies against severe infections and/or drug resistant strains of

Pseudomonas aeruginosa, Streptococcus pneumoniae, and Group B Streptococci.; OR

c. Development of new therapies against severe infections and/or drug resistant strains of fungal pathogens (C. auris, Coccidioides spp., Aspergillus fumigatus or Mucorales).

2. Antiviral Therapeutics

a. Drug candidates that block viruses via modulation of host responses or host targets

b. Pan-orthopox: must have activity against variola and monkeypox

c. Influenza

3. Antitoxin Therapeutics

a. Displayed activity against Ricin intoxication

b. Displayed activity against the effects of Staphylococcus enterotoxin B

c. Clostridium botulinum neurotoxin- Broad-spectrum activity against all known serotypes; non-biologics or biologics, if mAB cocktail (with no more than 5 mAB cocktail) against all the known serotypes of Clostridium botulinum neurotoxin (serotypes A, B, C, D, E, F, G)

3.3.2.2 - Technical Approach https://www.niaid.nih.gov/research/emerging-infectious-diseases-pathogens https://www.cdc.gov/drugresistance/biggest-threats.html

Research Area 002 will support lead optimization, pre-clinical (IND enabling) studies and clinical trials that include Phase 1 or Phase 2 studies or confirmatory trials of no greater than 120 subjects. For some pathogens or toxins, product efficacy determination under the Animal Rule is supported. The scope of support differs depending on the stage of the project being proposed, as outlined below:

Development Activities in-scope for Research Area 002:

Lead Optimization

• Optimizing a lead series by generation of new analogs with improved indicators of potency, safety, pharmacokinetics, and physiochemical properties compatible with the Target Product Profile (TPP)

• Conducting non-Good Laboratory Practices (non-GLP) in vivo toxicology aligned with the TPP

• Conducting in vivo efficacy determination in animal models of diseases consistent with the TPP

• Conducting experiments to identify pharmacokinetic/pharmacodynamic (PK/PD) relationships and define efficacious exposure targets for further pre-clinical and clinical studies

• Selecting a preclinical candidate and initiating IND-enabling studies

• Lead Optimization must be performed in the base period if proposed

Pre-Clinical (IND Enabling) Studies

• Demonstrating acceptable absorption, distribution, metabolism, and excretion (ADME) characteristics in non-GLP animal studies as necessary for IND filing

• Conducting GLP and non-GLP non-clinical studies for toxicology, pharmacology, and immunogenicity

(as appropriate)

• Continuing development of animal models for determining efficacy and defining PK/PD relationships for further preclinical and clinical studies

• Developing a scalable and reproducible manufacturing process amenable to GMP

• Manufacturing non-GMP and GMP-compliant drug substance and drug product

• Developing in-process assays and analytical methods for product characterization and release, including assessments of potency, purity, identity, strength, sterility, and quality as appropriate

• Preparing and submitting an IND to the U.S. Food and Drug Administration (FDA)

Phase 1 Studies

• Conducting Phase 1 clinical trial(s) to determine the safety and pharmacokinetics of the clinical test article in healthy volunteers

Phase 2 Studies

• Conducting Phase 2 clinical trials(s) to determine safety, pharmacokinetics, and efficacy of the clinical test article in patients. Phase 2 trial designs shall be no greater than 120 subjects

Proposals that do not include Lead Optimization are expected to complete evaluation in a Phase 1 or Phase 2 clinical trial within the 5-year proposed period of performance. Phase 1 and Phase 2 clinical trial completion is defined as completion of a Final Clinical Study Report following International Conference on Harmonization

(ICH) Guidelines on Structure and Content of Clinical Study Reports E3

(https://www.fda.gov/media/71271/download).

Proposals that include Lead Optimization are expected to provide clear plans and criteria for selecting a https://www.fda.gov/media/71271/download single clinical candidate therapeutic by the end of the base period of funding to enable completion of IND-enabling activities and submission of the IND within a 5-year period of performance.

3.3.2.3 –Additional Requirements

1. Stage-appropriate data must be provided. For proposals that include Lead Optimization, stage-appropriate data demonstrates achievement or near-achievement of preclinical candidate selection criteria by exemplars of the proposed lead series. For all other proposals, a single entity, the proposed preclinical candidate or product to be developed under the contract, must demonstrate achievement or potential to achieve all minimally acceptable criteria of the TPP.

2. In addition to proposal requirements in sections 3.4 and 4 of this solicitation, proposals submitted to this Research Area shall include the following:

• Complete chemical structure of the most advanced lead, preclinical candidate or, in the case of biologicals, a precise description of the candidate composition. The proposal is confidential and composition of matter pertaining to the proposal must be disclosed in the proposal.

• Complete chemical structures or compositions for all entities for which experimental data is provided.

• A Medicinal Chemistry Plan, to be executed in the base period, if Lead Optimization is proposed. Lead

Optimization may only be proposed in the base period of performance.

• In vitro potency against the pathogenic target or targets identified in the TPP. In vitro potency against surrogate pathogens is acceptable with reasonable justification.

• In vitro assessment of absorption, distribution, metabolism, excretion, and toxicity (ADMET).

• Therapeutic in vivo efficacy in an animal model of disease relevant to the indication identified in the

TPP using a dosing route and regimen consistent with the TPP.

• In vivo toxicology using a dosing route and regimen consistent with the TPP.

• In vivo pharmacokinetics (PK) in a relevant species with dosing route and regimen consistent with the

TPP.

3. Offerors responding to this Research Area, collectively with the proposed subcontractors and consultants where applicable, must have documented expertise in drug discovery and development, including demonstrated knowledge of regulatory guidelines, and submission processes for candidate products directed against emerging infectious diseases.

3.3.2.4 – Contracts awarded under this Research Area will NOT support the following activities;

proposals containing any of these activities will be excluded from peer review and will not be considered further for award:

1. Direct acting antivirals against viral families listed in Research Area 003.

2. Basic Research including target validation, high throughput screening, mechanism elucidation, lead series discovery, hit-to-lead optimization, and in vitro assay development.

3. Development of a product that is prophylactic, post-exposure prophylactic, or otherwise not therapeutic.

4. Development of a product from a known class that does not demonstrate, through data provided in the proposal, distinct and medically impactful differentiation from leading examples of the class.

5. Development of a product that is derived from, substantially similar to, or identical to an entity that has ever been part of a commercially available human consumable product in any jurisdiction worldwide.

Such products include, but are not limited to, homeopathic remedies, traditional medicines, supplements, foodstuffs, tinctures, extracts, and sham treatments (placebos).

6. Development of a product that is derived from, substantially similar to, or identical to an entity that has ever entered a Phase 3 clinical trial or has been approved for human or veterinary use in any jurisdiction worldwide. Such products include, but are not limited to, combinations not containing a novel agent, prodrugs, and alternate salt forms, crystal forms, formulations, dosing regimens, or clinical indications.

7. Development of a product that functions as a topical antiseptic.

8. Development of a product derived from serum.

9. Development of a device as the product or as a component of a product (such as a diagnostic or drug delivery device). Use of an existing device that does not require development is allowed.

10. Development of a product that is a probiotic or prebiotic or which exerts its therapeutic effect by modification of, or interaction with, non-pathogenic commensal organisms (such as the intestinal microbiome).

11. Research involving Human Fetal Tissue.

3.3.3.1 - Technical Objectives

The Antiviral Program for Pandemics (APP; https://www.niaid.nih.gov/research/antivirals) aims to develop safe and effective antivirals to combat SARS-CoV-2, the virus that causes COVID-19, as well as to build sustainable platforms for targeted drug discovery and development of a robust pipeline of antivirals against viruses with pandemic potential. APP will focus on antivirals that:

• Directly block viral targets and function; AND

• Are active against RNA viruses of pandemic potential (Coronaviridae, Bunyavirales, Filoviridae, Flaviviridae, Paramyxoviridae, Picornaviridae, or Togaviridae); AND

• Are new chemical entities which include small molecules and small biotherapeutics (e.g. nucleic acids or peptides) that are directly acting against viral targets and functions (not through the modulation of the host responses); AND

• Have safety profiles and suitable routes of administration (e.g. oral or intranasal) for broad use in the outpatient setting to treat early stages of infection by reducing viral burden.

Important notice to Offerors: For this research area, “therapeutic” activity refers to cure of disease, by elimination or substantial reduction of infective pathogens or toxins, by administration of a pharmaceutical agent after symptoms of disease are clinically observable.

A therapeutic candidate refers to an advanced lead series, optimized leads, or product candidate, that is a new chemical entity and either a small molecule or biotherapeutic.

Proposals are encouraged for the development of broad-spectrum therapeutics with extended therapeutic activity over more than one pathogen. Therapeutic candidates with a narrower spectrum of activity against priority viruses also are eligible.

Proposals are encouraged for the development of broad-spectrum small molecule or non-monoclonal antibody biotherapeutics, preferably for oral or intranasal dosing, with activity against one or more viruses of pandemic potential listed below. Limited spectrum therapeutic candidates that target pandemic pathogens for which limited standard clinical treatment exists or for which drug resistance poses a significant public health concern are eligible.

Therapeutics for viruses of pandemic potential: Display activity against infection caused by at least one of seven viral families with some examples below:

3.3.3 - Research Area 003 – Antiviral Program for Pandemics

(APP): Development of Antivirals for RNA Viral Families of

Pandemic Potential https://www.niaid.nih.gov/research/antivirals

• Coronaviridae (e.g. MERS, SARS-CoV-2)

• Bunyavirales (e.g. Lassa, Junin, Rift Valley Fever Virus, Andes, Sin Nombre, LaCrosse, California

Encephalitis, Crimean Congo Hemorrhagic Fever)

• Filoviruses (e.g. Ebola, Sudan, Marburg)

• Flaviviruses (e.g. Dengue, Zika, West Nile)

• Paramyxoviridae (e.g. Nipah, Hendra)

• Picornaviridae (e.g. EV-D68, EV-A71)

• Togaviridae (e.g. Chikungunya, EEE, VEE, WEE)

3.3.3.2 - Technical Approach

Research Area 003 will support lead optimization, pre-clinical (IND enabling) studies and Phase 1 clinical trial only. The scope of support differs depending on the stage of the project being proposed, as outlined below.

Development Activities in-scope for Research Area 003:

Lead Optimization

• Optimizing a lead series by generation of new analogs with improved indicators of potency, safety, pharmacokinetics, and physiochemical properties compatible with the TPP

• Conducting non-Good Laboratory Practices (non-GLP) in vivo toxicology aligned with the TPP

• Conducting in vivo efficacy determination in animal models of diseases consistent with the TPP

• Conducting experiments to identify pharmacokinetic/pharmacodynamic (PK/PD) relationships and define efficacious exposure targets for further pre-clinical and clinical studies

• Selecting a preclinical candidate and initiating IND-enabling studies

• Lead Optimization must be performed in the base period if proposed

Pre-Clinical (IND Enabling) Studies

• Demonstrating acceptable absorption, distribution, metabolism, and excretion (ADME) characteristics in non-GLP animal studies as necessary for IND filing

• Conducting GLP and non-GLP non-clinical studies for toxicology, pharmacology, and immunogenicity (as appropriate)

• Continuing development of animal models for determining efficacy and defining PK/PD relationships for further preclinical and clinical studies

• Developing a scalable and reproducible manufacturing process amenable to GMP

• Manufacturing non-GMP and GMP-compliant drug substance and drug product

• Developing in-process assays and analytical methods for product characterization and release, including assessments of potency, purity, identity, strength, sterility, and quality as appropriate

• Preparing and submitting an IND to the U.S. Food and Drug Administration (FDA)

Phase 1 Studies

• Conducting Phase 1 clinical trial(s) to determine the safety and pharmacokinetics of the clinical test article in healthy volunteers

Proposals that do not include Lead Optimization are expected to complete evaluation in a Phase 1 clinical trial within the 5-year proposed period of performance. Phase 1 clinical trial completion is defined as completion of a Final Clinical Study Report following International Conference on Harmonization (ICH) Guidelines on

Structure and Content of Clinical Study Reports E3 (https://www.fda.gov/media/71271/download).

Proposals that include Lead Optimization are expected to provide clear plans and criteria for selecting a single clinical candidate therapeutic by the end of the base period to enable completion of IND- enabling activities and submission of the IND within a 5-year period of performance.

3.3.3.3 –Additional Requirements

1. Stage-appropriate data must be provided. For proposals that include Lead Optimization, stage-appropriate data demonstrates achievement or near-achievement of preclinical candidate selection criteria by exemplars of the proposed lead series. For all other proposals, a single entity, the proposed preclinical candidate or product to be developed under the contract, must demonstrate achievement or potential to achieve all minimally acceptable criteria of the Target Product Profile (TPP).

2. In addition to proposal requirements in sections 3.4 and 4 of this solicitation, proposals submitted to this

Research Area shall include the following:

• Complete chemical structure of the most advanced lead, preclinical candidate or, in the case of biologicals, a precise description of the candidate composition. The proposal is confidential and composition of matter pertaining to the proposal must be disclosed in the proposal.

• Complete chemical structures or compositions for all entities for which experimental data is provided.

• A Medicinal Chemistry Plan, to be executed in the base period, if Lead Optimization is proposed.

Lead Optimization may only be proposed in the base period of performance.

• In vitro potency against the pathogenic target or targets identified in the TPP. In vitro potency against surrogate pathogens is acceptable with reasonable justification.

• In vitro assessment of absorption, distribution, metabolism, excretion, and toxicity (ADMET).

• Therapeutic in vivo efficacy in an animal model of disease relevant to the indication identified in the

TPP using a dosing route and regimen consistent with the TPP.

• In vivo toxicology using a dosing route and regimen consistent with the TPP.

• In vivo pharmacokinetics (PK) in a relevant species with dosing route and regimen consistent with the TPP.

3. Offerors responding to this Research Area, collectively with the proposed subcontractors and consultants where applicable, must have documented expertise in drug discovery and development, including demonstrated knowledge of regulatory guidelines, and submission processes for candidate products directed against emerging infectious diseases.

3.3.3.4– Contracts awarded under this Research Area will NOT support the following activities; proposals containing any of these activities will be excluded from peer review and will not be considered further for

1. Development of a product that does not meet all APP requirements as described in section 3.3.3.1.

2. Basic Research including target validation, high throughput screening, mechanism elucidation, lead series discovery, hit-to-lead optimization, and in vitro assay development.

3. Development of a product that is not demonstrated to have therapeutic efficacy with data provided in the proposal.

4. Development of a product that is prophylactic, post-exposure prophylactic, or otherwise not therapeutic.

5. Development of a product from a known class that does not demonstrate, through data provided in the proposal, distinct and medically impactful differentiation from leading examples of the class.

6. Development of a product that is derived from, substantially similar to, or identical to an entity that has ever been part of a commercially available human consumable product in any jurisdiction worldwide.

Such products include, but are not limited to, homeopathic remedies, traditional medicines, supplements, foodstuffs, tinctures, extracts, and sham treatments (placebos).

7. Development of a product that is derived from, substantially similar to, or identical to an entity that has ever entered a Phase 3 clinical trial or has been approved for human or veterinary use in any jurisdiction worldwide. Such products include, but are not limited to, combinations not containing a novel agent, prodrugs, and alternate salt forms, crystal forms, formulations, dosing regimens, or clinical indications.

8. Development of a product that functions as a topical antiseptic.

9. Development of a product derived from serum.

10. Development of a device as the product or as a component of a product (such as a diagnostic or drug delivery device). Use of an existing device that does not require development is allowed.

11. Development of a product that is a probiotic or prebiotic or which exerts its therapeutic effect by modification of, or interaction with, non-pathogenic commensal organisms (such as the intestinal microbiome).

12. Research involving Human Fetal Tissue.

13. Development of a product using monoclonal antibodies.

3.3.4.1 Technical Objective

NIAID is interested in supporting the development of promising diagnostics technologies in three areas for detection of signatures from biothreat pathogens and toxins, as well as pathogens causing emerging, reemerging, antimicrobial resistant infectious diseases, and for pandemic preparedness.

1. Next-Generation Nucleic Acid Sequencing on Portable Systems

The first objective of Research Area 004 is to improve the overall performance of nucleic acid sequencing solutions on portable commercial sequencing platforms for the targeted and agnostic detection and identification of microbial pathogens for biodefense, antimicrobial resistance, emerging infectious diseases, and pandemic preparedness.

Development activities that are IN SCOPE for this objective:

• Automated nucleic acid extraction and preparation method development

• Sequencing assay development to detect signatures from one or more required pathogens

• Metagenomic sequencing assay development for untargeted detection of required pathogens

• Internal and external controls standardization

• Integration of chemistry improvements on automated portable platforms

• Software development that accelerates data reduction and analysis processing to decrease overall time to result

• Reagent scale-up methods for process validation and pilot manufacturing

• Initial clinical testing to establish validation of performance

3.3.4 - Research Area 004 – Development of In Vitro Diagnostics for

Biodefense, Antimicrobial Resistant Infections, and Emerging

Areas of focus to improve performance could include, but are not limited to:

• Reduced turnaround time: Pathogen ID in 2-4 hours beginning with specimen processing

• Increased throughput on portable sequencing devices: > 10 patient samples processed per sequencing run

• Sensitivity: False negative rate of < 5% for infectious pathogen identification

• Specificity: False positive rate of < 5% for infectious pathogen identification

• Improved ease of use: Automated nucleic acid extraction and sample preparation, simplified transfer to portable sequencing system, data analyses operated, and interpreted with minimal training

Development activities should be consistent and compliant with presumed eventual submission to FDA for pre-Emergency Use Authorization (EUA) and/or 510(k) clearance.

2. Protein Detection

The second objective of Research Area 004 is to develop methods that improve protein analyte detection in one of two ways:

• First, technology improvements in high-complexity protein sequencing or mass spectrometry, especially in ways that bring protein-identification testing nearer to the patient.

• Second, near-patient, rapid, low-complexity, low-cost, and sensitive detection of proteins or other biomolecules, including methods that simplify or eliminate sample preparation, enhance target capture and detection, and increase signal output. Rapid diagnostic testing devices, so-called RDTs, are currently simple and cost-effective but suffer from lower clinical sensitivity than other methods of pathogen analyte detection. The objective here is to improve on clinical sensitivity and time-to-result, while maintaining simplicity and low cost.

Development areas that are IN SCOPE for this objective include but are not limited to:

• Mass spectrometry methods development for faster and more sensitive protein identification, especially near patient

• Sample preparation methods for first cycles of protein sequencing in model system

• Improved binding surfaces in lateral flow systems for capture and detection, e.g., graphene or other carbon- electrode surfaces

• Adoption of improved portable signal-detection devices to increase ease of use and for better analytical sensitivity

• Technology platforms for faster, easier development of capture moieties (such as nanobodies or aptamers) for target analytes

• Improved detection chemistries, including, as examples, amperometric or potentiometric, for faster, more- sensitive signal output

• Expanded types of clinical matrices, including oropharyngeal swabs, expired breath, and saliva

• Target antigens other than proteins will be considered IN SCOPE

Areas of focus in this objective to improve performance include but are not limited to:

• Short, accurate sequence identification from model toxin proteins in plasma or serum matrix

• Shorter lateral flow sample-to-result turnaround time, 2-5 min

• Greater analytical sensitivity in lateral flow devices, with analyte detection at < 10 pg/mL of clinical specimen

• Development time to produce new capture moieties (such as nanobodies or aptamers) reduced to days or weeks instead of months

• Simpler or no sample preparation

• Fewer or no external consumables for reagent or specimen manipulation

• Multiplex pathogen analyte detection in one run

3. Bacterial Identification and Phenotypic Antimicrobial Resistance Characterization

The third objective of Research Area 004 is to improve direct-from-blood or other biofluid detection and identification of microbial infection coupled with either genotypic antimicrobial resistance prediction or phenotypic antibiotic susceptibility testing (AST) characterization.

Development areas that are IN SCOPE for this objective include but are not limited to:

• Sample preparation methods, such as: improving ratio of pathogen-to-human nucleic acid ahead of molecular testing; improving barcoding chemistries; strategies for pooling clinical specimens for multi-sample sequencing

• Target amplification methods to improve analytical sensitivity

• Targeted and whole-genome sequencing methods to improve accuracy of bacterial identification

• Comprehensive genotypic antimicrobial resistance prediction

• Phenotypic AST characterization

Areas of focus to improve performance in this objective could include but are not limited to:

• Smaller volume of whole blood to detect bloodstream infection

• Greater clinical sensitivity to detect pathogen analyte direct from whole blood

• Shorter detection time to identify pathogen of infection without blood culture, < 4 hours

• Shorter reaction time for detection of…