Amendment_1.pdf

Amendment #1 to BAA-NIAID-DAIT-AI201800007 Large Scale T Cell Epitope Discovery

Amendment to Solicitation No.: BAA-NIAID-DAIT-AI201800007

Amendment No.: 1

Issue Date: May 9, 2018

Effective Date:

Proposal Due Date:

May 9, 2018

October 9, 2018 3:00 pm (Unchanged)

Issued By: Tom Bahrami, MBA Contracting Officer

NIH/NIAID

Office of Acquisitions 5601 Fishers Lane Room 3C20 MSC 9821 Rockville, MD 20852

Point of Contact: Brandon White, Contract Specialist whitebra@niaid.nih.gov

Name and Address of Offeror: To All Potential Offerors

The above numbered solicitation is amended as set forth below. The hour and date specified for receipt of proposals remains unchanged. Offerors must acknowledge receipt of this amendment. Failure to receive your acknowledgement of this amendment may result in the rejection of your offer.

The purpose of this Amendment (1) is to update the attachments in the solicitation document. Attachments 3 through 6 of the solicitation document are hereby replaced with the updated attachments provided with this Amendment (1).

Offerors are to follow the attachments set forth in this Amendment.

ATTACHMENT 3: BROAD AGENCY ANNOUNCEMENT DESCRIPTION

LARGE-SCALE T CELL IMMUNE EPITOPE DISCOVERY

BAA-NIAID-DAIT-NIH-AI-201800007

UBROAD AGENCY ANNOUNCEMENT INFORMATION

You are invited to submit a proposal in accordance with the requirements of this BROAD AGENCY ANNOUNCEMENT (BAA). The BAA is authorized by Federal Acquisition Regulation (FAR) 6.102 and further described in FAR 35.016 as well as the 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. BAA’s 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.

Offers submitted in response to this BAA must present detailed technical and business proposals designed to meet the Research and Technical Objectives described. The Statement of Work, 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 Statement of Work issued by the Government. Instead, Research and Technical Objectives are provided in the BAA that describe the research areas in which the Government is interested. Proposals received in response to the BAA are evaluated in accordance with Evaluation Factors for Award specified in Section M. NIAID will assess whether the work proposed should be redirected, removed, and/or whether schedule or budget adjustments should be made. As a result, during discussions with offerors, NIAID reserves the right to modify or delete proposed milestones, decision points, research plans, process, schedule, budget or product. The selection of proposals for award is based upon the evaluation factors, importance to the agency programs (programmatic balance), and fund availability.

NIAID estimates that the average annual total cost (direct and indirect costs combined) is 1 million dollars per award. However, it is anticipated that the total cost for the award(s) may vary depending upon the scope of the project and the technical objectives of the award(s). The length of time for which funding is requested should be consistent with the nature and complexity of the proposed research. The period of performance proposed by an offeror should not exceed five years.

ATTACHMENT 4: BACKGROUND and INTRODUCTION

Research supported and conducted by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), strives to understand, treat and ultimately prevent the myriad of infectious, immunologic, and allergic diseases that threaten millions of human lives. The NIAID Division of Allergy, Immunology, and Transplantation (DAIT) promotes and supports research to enhance the understanding of basic immunology, and the etiology, treatment and prevention of immunologic diseases. As a part of its continuing biodefense effort, NIAID announces recompetition of its Large-Scale T Cell Immune Epitope Discovery Program.

The primary goal of the program is to identify and validate immune epitopes that are important in the protection of humans from infectious or autoimmune diseases, or rejection of transplanted cells/organs/tissues; and/or contribute to immune-mediated pathogenesis triggered either by infection, autoimmune processes, the microbiome, or transplantation.

Protein-derived T cell epitopes can be identified by multiple approaches, including peptide mapping, screening of synthetic peptide libraries, generation and screening of recombinant DNA expression libraries, and the elution and chemical identification of naturally-occurring epitopes from Major Histocompatibility Complex (MHC) molecules using high-performance liquid chromatography coupled with mass spectrometry. Each of these methods can provide valuable information, with certain caveats. Peptide mapping and the screening of synthetic peptide libraries has been used to identify T cell epitopes with clinical relevance, but this method may not identify all naturally occurring ligands. Elution and sequencing methods have the advantage of providing direct information about peptide generation and MHC selection, although these methods can be technically challenging. Peptide elution methods also are useful in identifying MHC class I-binding T cell epitopes, but are generally less effective in defining MHC class II-binding T cell epitopes due to the decreased binding affinity and size variability of MHC class II-binding peptides.

Diverse types of T cell epitope prediction methods are available. One method uses information derived from identifying “peptide-binding motifs” for MHC alleles to develop binding algorithms.

Another method utilizes artificial neural networks, which provide an opportunity to analyze amino acid preferences at specific sites within a peptide sequence that are influenced by the properties of amino acids at other sites. Some artificial neural network approaches also incorporate antigen processing events into the peptide prediction process, but few also consider T cell receptor binding dynamics. Some predictions of peptide binding utilize MHC structure analysis where the three-dimensional crystal structure of an MHC molecule is used to model peptide homology and fit.

Pathogen-derived non-peptidic ligands, such as lipid, carbohydrate, glycolipid, and other compounds can stimulate potent immunogenic responses from T cells. Methods directed at determining non-peptide T cell ligands, such as thin layer and high-performance liquid chromatography, mass spectrometry, and nuclear magnetic resonance, have been used to identify these molecules. However, methods to predict the sequences or structures of non-peptidic epitopes have not yet been described.

In 2003 and 2004, NIAID developed and competed the Large-Scale Antibody and T Cell Epitope Discovery Program (RFP-NIH-NIAID-DAIT-03-043, and 04-039, respectively), and DAIT funded fourteen contracts in 2004. Twelve contracts were experiment-based, with eleven focusing on T cell epitope discovery and one on B cell epitope discovery. The remaining two contracts supported the development of T cell epitope prediction algorithms.

In 2008 and 2013, NIAID competed separate immune epitope discovery programs: the Large- Scale T Cell Epitope Discovery Program (BAA-NIAID-DAIT-NIHAI2008-032) (BAA-NIAID-DAIT-

NIHAI-2013-167, and the B Cell Epitope Discovery and Mechanisms of Antibody Protection Program (BAA-NIAID-DAIT-NIHAI2008-031) (BAA-NIAID-DAIT-NIHAI-2013-164). In 2014, four contracts were awarded under the Large-Scale T Cell Epitope Discovery Program and five contracts were awarded under the B Cell Epitope Discovery and Mechanisms of Antibody Protection Program. The current T cell epitope discovery contractors have provided valuable immune epitope information to the research community, including identification and validation of human T cell recognition of 2,300 T cell epitopes, and identification of epitopes derived from experimentally developed vaccines that correlate with protective natural immunity to pathogen infection. All immune epitope information is being submitted to the NIAID-supported Immune Epitope Database and Analysis Resource (28T UIEDBU28T) for public distribution.

The 2014 contract awards were made to the following institutions:

HHSN272201400045C La Jolla Institute for Allergy and Immunology, La Jolla, CA HHSN272201400046C University of Massachusetts Medical School, Worcester, MA HHSN272201400048C The Scripps Research Institute, La Jolla, CA HHSN272201400049C University of Washington, Seattle, WA

The current solicitation focuses on the identification and validation of immunodominant and subdominant T cell epitopes, which bind MHC class I, MHC class II, or non-classical MHC/HLA molecules (e.g., HLA-E, HLA-F, HLA-G, H-2M, H-2Q, H-2T, CD1, MR1). A companion solicitation for B cell epitopes is also available - B Cell Epitope Discovery and Mechanisms of Antibody Protection, BAA-NIAID-DAIT-NIHAI201800001.

National security, public health emergency, and general health care needs underscore the urgency for developing protective immune-based therapies and vaccines, as well as diagnostics against infectious agents. For example, naturally emerging and re-emerging infectious pathogens, such as: Mycobacterium tuberculosis; Zika; Chikungunya; Plasmodium spp.; and influenza viruses; continue to pose major health threats to the global population. The discovery and validation of novel T cell epitopes will facilitate the design and development of vaccines and lead to improved immune-based therapeutics and diagnostic tools. These resources are important for the prevention, treatment, and detection of such infections, and can provide critical information needed to select MHC-peptide or other MHC-ligand complexes that induce T cell activation for the generation and maintenance of protective immunity. In addition, this Large-Scale T Cell Immune Epitope Discovery Program serves as a key component of NIAID’s mission to elucidate basic mechanisms of immune protection.

The microbiome can influence the course and progression of immunity through the bioavailability of nutrients and metabolites and by effects on immune system development and function, including on mucosal T cells. Although T cell recognition of commensal microbiota is a subject of increasing study, there are few examples of defined epitopes, which limits both qualitative analyses; for example, the basis of cross-reaction with self-antigens, and quantitation using tetramers.

Understanding the contribution of alternatively processed peptide products, cryptic peptides, hybrid peptides, and neoantigens to overall immune response is of great consequence. The functional role of these epitopes in the immune pathology of autoimmune disease and contribution to constructive host response to pathogen-infection, vaccination, or immune-mediated disease remains to be investigated.

Although T cell responses to self-epitopes are commonly seen in human autoimmune disease, the immunologic significance of any given response is often uncertain. Refined definition of autoimmune T cell epitopes is complicated not only by the rarity of autoreactive T cells, but also by the role of post-translational modifications (such as splicing of hybrid peptides and conversion of arginine residues to citrulline) required for the generation of some epitopes. The http://www.iedb.org/ recent emergence of these post-translationally modified T cell epitopes as significant components of the self-epitope universe highlights a general lack of knowledge regarding the scope and critical features of the set of T cell epitopes relevant to human autoimmune diseases.

Animal models of autoimmune diseases provide strong evidence that autoreactive T cells are likely to play pathogenic roles and often suggest self-antigens or epitopes that may be important in human disease, but direct links between human T cell responses to individual self-epitopes and immunopathogenic mechanisms are generally lacking. Overall, currently defined T cell self-epitopes are inadequate as biomarkers of autoimmune disease risk and progression.

Thus, a critical need still exists for definition of human T cell epitopes in autoimmune diseases and the subsequent application of this knowledge to improved definition of autoimmune states and understanding of how autoimmune diseases begin and progress.

T cell recognition of alloantigens in transplantation rejection, tolerance, and graft versus host disease occurs through multiple pathways, including direct recognition of the donor MHC (HLA in humans) alloantigen on the surface of donor cells by recipient CD4 and CD8 T cells; and indirect recognition of linear peptides from the donor HLA, or other donor proteins that differ from the recipient, that are internalized and presented by the recipient’s HLA molecules on recipient cells. Evidence supports that donor HLA molecules that differ from the recipients are the predominant alloantigen. The relative roles of alloreactive CD4 or CD8 T cells and the recognition pathways vary and are influenced by the specific HLA molecules of the donor and recipient. The indirect CD4 T cell response dominates in chronic rejection of transplanted organs and plays a key role in the development of donor specific antibodies. Therefore, the recipient CD4 T cell alloresponse to donor HLA peptides presented by recipient HLA Class II is the primary focus of transplantation studies under this BAA. An additional complexity in the alloimmune T cell response is the sheer number of unique alloreactive TCRs. While new TCR sequencing-based approaches for studying alloresponses are very powerful, identification and validation of alloreactive T cell epitopes under this BAA will offer a unique opportunity to facilitate research and generate tools to address the mechanisms of transplant rejection and tolerance.

ATTACHMENT 5: RESEARCH AND TECHNICAL OBJECTIVES

RESEARCH and TECHNICAL OBJECTIVES

The primary purpose of this solicitation is to support highly interactive, multi-disciplinary teams, whose research efforts are focused on large-scale discovery of T cell immune epitopes associated with infectious or autoimmune diseases, and rejection of, or tolerance to, transplanted cells/organs/tissues. The discovery of epitopes associated with T cell responses to commensals and how they may be altered by the inflammatory state will also be supported by this solicitation.

Validation of these epitopes and defining their role in immune protection or immune-mediated pathogenesis in humans is required. Investigators may include development/refinement of T cell epitope prediction tools as part of their research plan. It is anticipated that the multi-disciplinary teams will minimally include immunologists with the appropriate expertise in epitope identification and validation, and either microbiologists and/or virologists with expertise in the target pathogen(s), clinicians with expertise in the target autoimmune diseases, or clinicians with expertise in transplantation, as appropriate. This program will not support studies related to HIV/AIDS, or allergen epitopes, including those which are infection-related.

The focus of each proposal must be in one of the following three areas, although Offerors may submit multiple proposals to one or more areas:

1. Infectious disease/vaccine responses

2. Autoimmune disease: this research area also could include the identification of pathogen-specific epitopes that are implicated in induction of autoimmune disease.

3. Transplantation of cells, tissues, or organs

For the purpose of this BAA, large-scale epitope discovery is defined as methods that will allow for extensive identification and validation of a broad range of novel T cell epitopes:

• from one or more pathogens; or

• associated with one or more human autoimmune diseases; or

• from alloantigens in transplantation rejection, tolerance, and/or graft versus host disease.

The contract will support mechanistic clinical trials where the primary objective is to obtain human samples for detailed analysis of immune function in response to pathogens, vaccines, or autoimmune diseases. Clinical trials for transplantation studies will not be supported by this solicitation. This contract will also support clinical research in all three research areas (infectious diseases/vaccines; autoimmune diseases; transplantation) in which human samples are collected after standard of care interventions, and studies in which the human samples are obtained from independently-funded clinical trials. This program will not support the design and conduct of clinical trials where the primary objective is to test the safety or efficacy of an investigational vaccine, adjuvant or other product for licensure. For additional guidance on the NIH definition of clinical trial refer to: https://grants.nih.gov/policy/clinical-trials/definition.htm. Animal models may be included with a justification describing how the animal studies will facilitate identifying human T cell epitopes.

Offerors shall propose a milestone driven research program that must include each of the following three components:

A. Epitope Identification.

1. For studies proposing T cell epitope discovery for infectious pathogens, vaccines, commensals, or autoimmunity: Research conducted under this solicitation https://grants.nih.gov/policy/clinical-trials/definition.htm shall include one or more types of T cell epitope discovery. Examples include, but are not limited to: discovery of CD8+ T cell epitopes presented by MHC class I molecules;

discovery of CD4+ T cell epitopes presented by MHC class II molecules; discovery of peptide or non-peptide epitopes/ligands presented by non-classical MHC molecules; and unique epitopes derived from cryptic (non-coding) translation products, or hybrid-peptide epitopes.

2. For transplantation studies: The focus shall be on CD4 T cell epitopes of donor HLA peptides presented by recipient MHC class II molecules. Transplantation studies may also include CD8 T cell epitopes of donor HLA peptides presented by recipient MHC class I molecules and/or CD4 or CD8 T cell direct recognition of donor HLA molecules. Note:

for transplantation studies HLA typing must be high resolution molecular typing.

3. For all studies: State-of-the-art technologies shall be used, such as, but not limited to:

computer-based epitope prediction algorithms, genome-wide scanning, proteomics, mass spectrometry, and/or expression or peptide/ligand library screens. Human samples may be obtained from infected individuals; patients administered vaccines against infectious diseases; human subjects diagnosed with the autoimmune disease under study, or transplant recipients and/or donors for transplantation studies; and/or samples from new, ongoing, or completed clinical trials. Appropriate animal models may be used to facilitate identifying human epitopes with a clear justification for the animal models chosen.

B. Epitope Validation. In vitro validation studies are required, using primary human T cells that demonstrate immunogenicity/antigenicity or diagnostic potential of all newly defined T cell epitopes shown to bind to classical or non-classical MHC molecules. In addition, validation studies are encouraged, but not required, to examine/correlate the role of these epitopes in immune protection or immune-mediated pathogenesis or tolerance through analysis of human samples or in animal models that provide data relevant to human responses.

C. Epitope Submission. All epitope information generated under the contract shall be submitted to the Immune Epitope Database and Analysis Resource (IEDB) to facilitate access and use of these data by the broader research community.

In addition to the required activities described above, this solicitation will also support, but does not require, the development/refinement of robust computational models/algorithms for predicting peptide or glycolipid epitopes that bind to MHC class II molecules, non-classical MHC molecules, or under-represented MHC class I molecules. New or improved methods may include, but are not limited to: advanced algorithms and computational models for predicting epitopes and/or host immune responses to particular T cell epitopes;

and developing algorithms, computational models, and artificial neural network programs based on specific biological, biochemical, or physical features of epitopes (such as their genomic sequence, amino acid sequence, in vivo processing and presentation events, antigen or epitope structure and/or dynamics of the peptide/MHC/TCR complex). All computer software (computational tools, mathematical models, and predictive algorithms) generated under the contract shall be submitted to the IEDB to facilitate access and use of these tools by the broader research community.

This solicitation will not support the following activities:

a. Clinical trials in the following areas:

i. Infectious disease/vaccine or autoimmunity studies: design and conduct of clinical trials are excluded when the primary objective of the trial is to test the safety or efficacy of an investigational vaccine, adjuvant or other product for licensure.

ii. Design and/or conduct of any type of transplantation clinical trial; however, human samples may be obtained from ongoing or completed transplantation clinical trials.

Epidemiological studies that contribute to validation of relevant candidate epitopes are permitted.

b. Xenotransplantation studies.

c. Patient care. While analysis of patient samples is strongly encouraged and costs associated with collection of those samples is permitted (including reasonable compensation for subject participation), contract funds shall not be used for expenses related to patient medical care.

d. Development/refinement of computational models or algorithms for T cell epitope prediction in the absence of laboratory studies of T cell epitope discovery and validation.

e. T cell epitope discovery or algorithm development in the absence of validation studies.

f. Studies focused on vaccine and/or product development.

g. Validation of previously identified T cell epitopes.

h. Discovery and validation of MHC class I pox virus T cell epitopes.

i. Development of MHC class I epitope prediction algorithms for the following well characterized MHC class I molecules: H-2 Db, H-2 Dd, H-2 Kd, H-2 Ld, HLA A*0101, HLA

A*0201, HLA A*0202, HLA A*0203, HLA A*0206, HLA A*0301, HLA A*1101, HLA A*2601,

HLA A*2901, HLA A*3101, HLA A*3301, HLA B*0702, HLA B*0801, HLA B*1501, HLA

B*2705, HLA B*5401, HLA B*5801.

j. Identification, mapping, and validation of HIV/AIDS epitopes, including related viruses (SIV, MAIDS, etc.) or allergen epitopes.

k. Discovery and validation of B cell epitopes.

ATTACHMENT 6: ADDITIONAL TECHNICAL PROPOSAL INSTRUCTIONS

FORMAT FOR TECHNICAL PROPOSAL, and TABLE OF CONTENTS

It is strongly recommended that offerors use the following template as the format for the Technical Proposal. All information presented in the Technical Proposal should be presented in the order specified below.

These Additional Technical Proposal Instructions reflect the requirements of the BAA and provide specific instructions and formatting for the Technical Proposal. While Section L. of the BAA provides a generic set of Technical Proposal Instructions applicable to all NIH R&D solicitations, these Additional Technical Proposal Instructions are tailored to the specific requirements of the BAA. The information requested in these instructions should be used along with Section L of the BAA to format and prepare the Technical Proposal, and should be used as a Table of Contents for your Technical Proposal. Offerors should follow the instructions in Section L of the BAA, and include the information requested here.

Offerors are advised to give careful consideration to the Broad Agency Announcement Description, Background and Introduction, Research and Technical Objectives, all reference materials and attachments, the Technical Evaluation Criteria in Section M, and the BAA as a whole in the development of their Technical Proposals.

Offerors proposing subcontracts and/or consultants to perform portions of the proposed Statement of Work should clearly identify the specific tasks for which they plan to utilize subcontractors and/or consultants, as well as the method and level of integration/coordination between the prime Contractor and all proposed subcontractors and/or consultants, and the expected advantages of such an approach.

Offerors must refer to the BAA Attachment entitled “Packaging and Delivery of the Proposal,” which details strict guidelines, including page limitations, formatting and layout of proposals, and prohibits the offerors use of links to internet web site addresses (URLs) to direct readers to alternate sources of information.

TECHNICAL PROPOSAL – TABLE OF CONTENTS

SECTION 1:

1) PROPOSAL TITLE PAGE. Include BAA title and number, name of organization, DUNS number, and identify if the proposal is an original or a copy. Offerors that include data in their proposals that they do not want disclosed to the public for any purpose, or used by the Government except for evaluation purposes, shall also include the legend regarding Restriction on Disclosure and Use of Data prescribed by FAR 52.215-1 (e)]

2) TABLE OF CONTENTS

SECTION 2: TECHNICAL PROPOSAL OVERVIEW (suggested 3-page maximum)

Provide a brief description of the proposed project, including:

1) 3-5 sentence summary describing the concept the offeror is proposing.

https://www.acquisition.gov/sites/default/files/current/far/html/52_215.html

2) A summary describing the scope of the activities proposed, including a list of all the pathogens to be used in the proposed studies.

3) A brief description of the activities proposed by the offeror and all proposed subcontractors, including identifying all proposed subcontractors and a list of key personnel for the offeror and the proposed subcontractors with degrees, titles and role in the project.

4) By area of expertise, provide the total number of staff, the number available to be assigned to the contract for the offeror and all proposed subcontractors, and total number of additional staff to be hired and trained.

5) A brief description of the facilities and other resources to be made available by the proposed prime contractor (offeror) and any proposed subcontractors.

SECTION 3: STATEMENT OF WORK FORMAT (suggested maximum of 10 pages)

Offeror(s) are required to provide a Statement of Work in their proposal. The Statement of Work shall be developed by each offeror based on the information in the Attachment entitled “Research and Technical Objectives,” and shall consist of two parts: (1) Scope, and (2) Technical Requirements. Provided below is an outline of the Statement of Work format that should be used by all offeror(s) in the preparation of their Technical Proposals. The headers and subheaders may be adjusted to match the requirements as proposed in each offeror’s individual technical proposal.

Contracts awarded as a result of this BAA will include the Statement of Work proposed by the offeror, as negotiated and accepted by the Government. Offeror(s) will be required to perform the activities and provide the resources appropriate to the scope of their specific negotiated Statement of Work.

The opening paragraph under the Technical Requirements section of the Statement of Work shall be followed by a description of all activities that the Contractor shall perform after the award of the contract. The Technical Requirements shall include all activities required to effectively implement the project and shall include a description of all items to be delivered to the Government during performance of the contract, such as progress reports, financial reports, end products, and other deliverables, along with a timetable for their delivery.

[NOTE TO OFFEROR: Each offeror shall provide detailed specifications of the requirement utilizing the following sample outline of tasks and subtasks. Any tasks or subtasks that are not applicable to your proposed effort should be deleted. Any tasks or subtasks specific to your proposed effort not addressed below shall be added.]

[See Statement of Work outline on next page]

SAMPLE STATEMENT OF WORK

1. SCOPE

Instruction to offerors: Provide a brief description (one to two paragraphs) of the overall project and objectives in broad terms that indicates the size and magnitude of the proposed effort.

2. TECHNICAL REQUIREMENTS

[NOTE TO OFFEROR: The Technical Requirements shall begin with the following introductory paragraph.]

Independently, and not as an agent of the Government, the Contractor shall furnish all necessary services, qualified professional, technical, and administrative personnel, material, equipment and facilities, not otherwise provided by the Government under the terms of this contract, as needed to perform the tasks set forth below. Specifically, the Contractor shall:

A. SCIENTIFIC AND TECHNICAL APPROACH

1. EPITOPE IDENTIFICATION

2. EPITOPE VALIDATION

3. EPITOPE SUBMISSION

4. EPITOPE PREDICTION TOOLS (if applicable)

B. SCIENTIFIC AND TECHNICAL PERSONNEL

C. PROJECT MANAGEMENT

D. FACILITIES, EQUIPMENT AND OTHER RESOURCES

E. OTHER CONSIDERATIONS

F. POST-AWARD ACTIVITIES

SECTION 4: TECHNICAL DISCUSSIONS

In addition to the guidance in section l of the BAA, this section of your technical proposal should include documentation to demonstrate how you will accomplish the work detailed in your proposed Statement of Work. It is recommended that your proposal be organized in accordance with the order of your Statement of Work and the technical evaluation criteria provided in Section M.

Additionally, please ensure that your Technical Proposal addresses the following:

Organizational Experience:

In addition to the information requested under Section L, Part c. Business Proposal Instructions, paragraph 12, Qualifications of the Offeror, all offerors are requested to include in their technical proposals a description of at least two examples of similar projects performed by your organization that are of comparable size and scope and/or related to the effort proposed in response to this BAA. The projects may be either completed or ongoing.

SCIENTIFIC AND TECHNICAL APPROACH (suggested maximum of 30 pages)

In this section of the Technical Proposal, Offerors shall provide a detailed description of the rationale, approach, technologies, and potential pitfalls and alternatives (as needed) that will be pursued to identify and validate the identified epitopes, as outlined below. For studies involving animal models, Offerors should provide a justification in this section for the use or development of the proposed animal models. This justification should also describe how the use of animal models will result in identifying human T cell epitopes related to pathogens causing infectious diseases; rejection of, or tolerance to, transplanted cells/organs/tissues; or epitopes associated with T cell responses to autoimmune disease. Clearly identify all proposed pathogens to be included in all proposed studies.

The focus of each proposal must be in one of the following three areas, although multiple proposals may be submitted by the same Offeror:

1. Infectious disease/vaccine responses

2. Autoimmune disease: this research area also could include the identification of pathogen-specific epitopes that are implicated in induction of autoimmune disease.

3. Transplantation of cells, tissues or organs

Note: This solicitation will support mechanistic clinical trials where the primary objective is to obtain human samples for detailed analysis of immune function in response to pathogens, vaccines, or autoimmune diseases. Clinical trials for transplantation studies will not be supported by this solicitation. This solicitation will also support clinical research in all three research areas (infectious diseases/ vaccines; autoimmune disease; transplantation) in which human samples are collected after standard of care interventions, and studies in which the human samples are obtained from independently-funded clinical trials. This program will not provide funds to support the design and conduct of clinical trials where the primary objective is to test the safety or efficacy of an investigational vaccine, adjuvant or other product for licensure. For additional guidance on the NIH definition of clinical trial refer to:

https://grants.nih.gov/policy/clinical-trials/definition.htm. Animal models may be included with a justification describing how the animal studies will facilitate identifying human T cell epitopes.

Offerors shall propose a milestone driven research program that must include each of the following three components: (1) epitope identification, (2) epitope validation, and (3) epitope submission. Epitope prediction tools may also be proposed, if applicable. Include the following:

1. EPITOPE IDENTIFICATION

Provide a detailed description of:

a. The existing or novel methods, technologies, and other procedures proposed to identify T cell epitopes that bind MHC class I, MHC class II, or non-classical MHC molecules. The use of human T cells is required for identification of human T cell epitopes. Clearly state the source of human subject materials being used. For infectious diseases, human samples may be obtained from infected individuals; human subjects immunized with licensed vaccines, where the vaccine is administered according to the product label instructions; or collected in new, ongoing, or completed clinical trial. For autoimmune diseases, human samples may be obtained from appropriately diagnosed individuals.

Existing identification methods may include, but are not limited to:

• Screening of synthetic peptide libraries

• Elution and sequencing of peptide epitopes from MHC and non-classical MHC molecules

• Binding studies of peptides and other ligands to MHC and non-classical MHC molecules https://grants.nih.gov/policy/clinical-trials/definition.htm

• Evaluation of antigen or pathogen mutants with respect to their ability to bind to MHC or non-classical MHC molecules or to stimulate T cell responses

• Algorithms or mathematical models to predict epitopes from genome or protein sequences, and/or lipid or carbohydrate structures. Offerors may apply existing computational methods, propose to improve existing computational approaches, or develop novel computational methods/algorithms. However, the use or development of such methods must be accompanied by experimentation to confirm the biological significance of the predicted epitopes.

b. The rationale for the proposed experimental system(s) chosen for epitope identification, including the pathogens, epitope identification methods, human populations, and animal models (if any) employed for the proposed studies.

2. EPITOPE VALIDATION

a. The methods proposed to validate the antigenicity or diagnostic potential of all newly defined human T cell epitopes shown to bind to MHC molecules and elicit an immunogenic human T cell response using in vitro (required) and in vivo (optional) methods, including, but not limited to:

• ELISA

• ELISpot

• Intracellular cytokine assays

• T cell proliferation assays

• Cytotoxic T cell assays (e.g., chromium release, measurement of perforin production, other methods of measuring cytotoxic activity)

• MHC class I or class II tetramer staining

• In vivo challenge and protection studies (animal models only)

b. Clearly state the source of human subject materials being used.

c. For studies involving animal models, provide a justification for the use or development of the proposed animal models. This justification should also describe how the use of these animal models will result in the validation of human T cell epitopes.

3. EPITOPE SUBMISSION

a. The plans and procedures for internal management and sharing of immunological and related data among the contractor and subcontractor(s) supported under the contract.

b. The plans and procedures to submit detailed epitope information to the IEDB within six (6) months following completion of validation studies. A description of the required epitope submission information is included in the “Reporting Requirements” section of this BAA. The types of data fields contained within the IEDB are listed at: https://help.iedb.org/hc/en-us/articles/114094146751-Field-by-field-Guide-for-DST-Beta-. The IEDB homepage is www.iedb.org.

4. EPITOPE PREDICTION TOOLS (if applicable) https://help.iedb.org/hc/en-us/articles/114094146751-Field-by-field-Guide-for-DST-Beta-https://help.iedb.org/hc/en-us/articles/114094146751-Field-by-field-Guide-for-DST-Beta-

a. The plans and procedures for development or refinement of epitope prediction algorithms or computational methods, including how the tools will be validated/evaluated, procedures for development of documentation and a tutorial on use of the computational tool or algorithm.

b. The plans and procedures for submission of computational models or epitope prediction tools and their accompanying documentation/tutorial to the IEDB within six (6) months of evaluation of the tool’s/model’s efficacy. The plans should also include alternative methods for supplying public access to the novel computational models or prediction tools if the IEDB decides not to host the tool.

SECTION 5: SCIENTIFIC AND TECHNICAL PERSONNEL

1) Principal Investigator (PI): Provide relevant documentation to describe:

• CV (5 pages maximum)

• Qualifications, education and relevant training

• Previous experience with projects of comparable size and complexity (limited to the past 5 years)

• References to relevant publications

• Availability for the proposed project (level of effort to commit to the project)

• Address the previous experience of the PI to: assess progress in accordance with established tasks and timelines; recommend modifications to research programs based on current information and/or new and improved approaches and technologies; ability to keep projects on time and on budget; and ability to assess performance, identify performance problems, and design and implement remedial actions when necessary.

2) Project Manager (if applicable): Describe the qualifications of the Project Manager for monitoring and tracking day-to-day progress, project activities, fiscal status and timelines of complex research programs; management of subcontracts and consulting; coordinating and managing communication; reporting on project status and progress; effectively communicating with the project team and the Government; and assuring compliance with regulatory requirements.

3) Other Key Scientific and Technical Personnel: For all proposed key scientific and technical personnel provide relevant documentation to describe:

• CV (3 pages maximum)

• Qualifications, education and relevant training

• Previous experience with projects of comparable size and complexity (limited to the past 5 years)

• References to relevant publications

• Availability for the proposed project (level of effort to commit to the project)

SECTION 6: PROJECT MANAGEMENT

1) Provide a Project Management Plan for the overall organization that addresses the planning, initiation, implementation, conduct, monitoring and completion of tasks identified in the proposed Statement of Work. If consultants and/or subcontractors are proposed, include a plan to manage, coordinate, and oversee the work performed by consultants and/or subcontractor(s).

2) Provide a Staffing Plan that describes roles, responsibilities, and level of effort for all scientific and technical personnel, including all proposed subcontractors and consultants. Provide an administrative and technical framework indicating clear lines of authority and responsibility for all proposed personnel, and clearly indicate those individuals who are Key Personnel. Include a chart of the proposed organizational/management structure for the project.

3) Describe the project management systems that will be used to track activities and to keep multiple activities on time and budget. The plan must include a description of the quality control methods that will be used to ensure the effective and efficient initiation, implementation, management, and oversight of contract requirements.

4) Provide a milestone-based timeline for completion of major tasks for the project. Milestones and timelines must be provided for each component of the research program. Milestones must reflect key criteria of success in each proposed research area and tangible outcomes of each stage of the research program. Stages of the research program may be undertaken.

5) Outline how the PI (or Project Manager) will communicate with the Contracting Officer’s Representative (COR) and Contracting Officer and how the PI (or Project Manager) will communicate, monitor, and manage the project both internally and externally (at subcontractor facilities).

6) Provide a plan for soliciting, evaluating, negotiating, awarding, and managing subcontracts in accordance with FAR Clause 52.244-2 (if applicable).

SECTION 7: FACILITIES, EQUIPMENT, AND OTHER RESOURCES

The Technical Proposal should document availability and adequacy of facilities, equipment, space and other resources necessary to carry out the proposed Statement of Work, including:

1) Location and features of facilities including a floor plan and a list of equipment and resources dedicated to the project for the prime contractor and any proposed subcontractors (lease or ownership information should be provided).

2) Identification and description of ALL support resources (including Information

Technology systems, Vertebrate Animal description and IACUC approvals (as described in section L of the BAA), biocontainment protocols and facilities, and authorization to work with select agents, (if applicable) which will be required to effectively complete the technical requirements of the contract.

3) Copies of materials submitted for Institutional Biosafety Committee Review and documentation of approval of experiments by IRB and IACUC committees to the COR with each annual report.

SECTION 8: OTHER CONSIDERATIONS

Other than those detailed in the Government Furnished Property clause or otherwise publicly available, the offeror shall not propose government furnished resources, to include government employees, facilities, intellectual property or biological materials. If you propose government furnished resources your proposal will not be considered further for award.

This section of the Technical Proposal should document other resources not covered in 1 through 4 above necessary to carry out the proposed Statement of Work.

SECTION 9: POST-AWARD ACTIVITIES

1. Contract Initiation and Annual Program Progress Meetings:

a. Contract Initiation Meeting. The two-day contract initiation meeting will be organized by the NIAID and will take place within three (3) months of contract award, at a site chosen by the COR.

Contractors will be notified of the date of the meeting within 14 calendar days of the contract award and are required to attend. The Principal Investigator and up to three (3) additional personnel from each awarded contract must attend this meeting. The IEDB contractors, contractors from the other T cell immune epitope discovery contracts, contractors from the B cell epitope discovery and mechanisms of antibody protection contracts, and additional NIH extramural staff may also attend this meeting.

b. Annual Program Progress Meetings. The contractor shall attend the two-day annual program meetings, organized and scheduled by NIAID staff with contractor input. The Principal Investigator and up to three (3) additional personnel from each awarded contract shall attend this meeting. The IEDB contractors, contractors from the other T cell immune epitope discovery contracts, contractors from the B cell epitope discovery and mechanisms of antibody protection contracts, and additional NIH extramural staff may also attend this meeting. An Immune Epitope Discovery Working Group (IEDWG), composed of external scientists, will also attend the annual program progress meetings.

2. Teleconferences:

The Contractor shall plan and conduct quarterly teleconference meetings with the COR, and other designated NIAID staff, during the first year of the contract period of performance, to discuss technical progress and financial invoices. A teleconference schedule for subsequent years will be established by the COR. One week prior to the teleconference, the Contractor shall submit an agenda to the COR. Within one week after each teleconference, the Contractor shall provide a meeting summary of the teleconference to the COR. The timing of the bi-monthly teleconference meetings may be altered or adjusted by the COR as needed to address progress on the contract.

3. Additional Contract Meetings/Teleconferences:

The PI, Project Manager, key investigators, and key subcontractor personnel shall attend additional meetings or teleconferences at the request of the COR. Such ad hoc meetings will be requested, as necessary, to discuss contract specific issues and to review recommended changes or deviations from milestones and timelines in the Statement of Work.

4. Immune Epitope Discovery Working Group (IEDWG):

NIAID will convene an IEDWG, composed of external scientists. The main purpose of the IEDWG is to advise the COR on the operations and scientific progress of all the contracts awarded under this BAA and make recommendations regarding future directions. The composition of the IEDWG shall be proposed by the contractor and shall be subject to approval by the COR prior to distribution of invitations by the COR to the proposed IEDWG members. Within fourteen (14) calendar days of contract award, the Principal Investigator of the contract will provide the COR a list of six (6) recommended leading scientists knowledgeable in the multiple research areas related to the contract. The list of recommended individuals should not be provided in the proposal and should not be contacted by the Offerors. The total number of IEDWG members shall not exceed seven (7).

Post award, NIAID staff will determine if individual IEDWGs or a single IEDWG for both the Large-scale T Cell Immune Epitope Discovery and the B Cell Epitope Discovery and Mechanisms of Antibody Protection Programs will be established.

CORRECT SP