It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

The purpose of this Funding Opportunity Announcement (FOA) is to support the formation of Cooperative Research Centers (CRCs) to pursue vaccine development through multidisciplinary investigations into the host immune response to Clostridioides difficile infection (CDI). To this end, it will be critical to advance knowledge of immunity against CDI by leveraging clinical samples, identifying new protective antigens, and employing novel vaccine and adjuvant platforms. Information stemming from this research initiative will serve as a guide to develop the next generation of C. difficile vaccines to be tested in appropriately devised model systems.

CDI is the most common healthcare-associated infection in the U.S. and is listed as an Urgent Threat in the CDC’s 2019 Antibiotic Resistance Threat report. Recent estimates indicate that CDI rates have declined, although there are still approximately 223,900 infections and 12,800 deaths annually. CDI is a toxin-mediated disease, and the clinical manifestations range from asymptomatic colonization to severe fulminant CDI, which can progress to toxic megacolon, sepsis, and death. Antibiotic exposure is a primary risk factor for acquiring CDI; other factors include age (>65 yrs.) and prior hospitalization. Recent epidemiological data show a positive trend towards reduced hospital-associated infections, likely a reflection of improving antibiotic stewardship; however, this gain is seemingly offset by a rise in community acquired CDI.

The pathogenesis and clinical manifestations of CDI are mediated primarily through the activity of two large protein exotoxins, toxin A (TcdA) and toxin B (TcdB). C. difficile binary toxin (CDT) is a third toxin that is expressed by up to 30% of C. difficile strains and appears to contribute to disease pathogenesis. Nearly all clinically significant C. difficile strains express TcdB; some strains do not express TcdA; and epidemic BI/NAP1/027 strains can produce all three toxins. Regardless of the toxinotype, the host immune response to CDI is primarily directed towards TcdA and TcdB, and antibodies against these two toxins, particularly TcdB, have been shown to be an important predictor of disease outcome. Whilst many individuals have some detectable antitoxin antibodies, toxin-specific antibody levels tend to wane with advanced age, and low levels of antitoxin antibodies are associated with increased risk for recurrent CDI (rCDI). Conversely, elevated levels of circulating IgG antibodies against TcdA and TcdB are associated with asymptomatic colonization and protection from rCDI. Systemic antitoxin IgG has been studied extensively, but there has been less research on the role of local secretory IgA, and aspects of cellular immunity, including B-cell memory, are even less well defined.

Repeat infections with C. difficile are common and demonstrate that natural infection may not stimulate a protective immune response. The lack of protection following primary CDI could be due to insufficient antibody production, infection with an antigenically distinct strain or toxinotype, or other host related factors, such as waning immunity. Recent studies investigating TcdB identified critical sequence variations that contribute to differences in toxicity and may also influence the production of TcdB neutralizing antibodies. The two TcdB variants (TcdB1 and TcdB2) are associated with distinct C. difficile lineages, and adaptive immune responses to one lineage may not result in protective immunity against other lineages. The induction of a strong toxin-neutralizing antibody response likely plays a key role in protection from disease, whereas immunity to cell surface antigens and other polysaccharides are likely important for promoting pathogen clearance. Germination of C. difficile spores and colonization are critical steps in C. difficile pathogenesis, and adaptive immune responses that impact colonization have the potential to reduce transmission in healthcare facilities and community.

Research focused on C. difficile has increased substantially over the past two decades, leading to the availability of more therapeutics targeted to treat primary and rCDI. For example, fidaxomicin is a narrow-spectrum antibiotic approved in 2012 for the treatment of primary CDI and, more recently in 2016, the FDA approved bezlotoxumab, a monoclonal antibody against TcdB shown to reduce the rate of rCDI by up to 40%. Restoration of the gut microbiome using fecal microbiota transplantation or more defined consortia, appears highly effective against rCDI, but a more complete safety profile for this product class needs to be established in future prospective studies. Despite the promise of these new and innovative treatments, the disease burden still is not fully addressed, and licensed vaccines are needed for the primary prevention of CDI and as potential therapy for rCDI. Research on adaptive host immunity to CDI has been comparatively limited, and efforts to support research on the mechanistic aspects of protective immunity and vaccine development are warranted.

CDI vaccine development began several decades ago based on early data showing that prior exposure to C. difficile induces neutralizing antitoxin antibodies that can protect against disease. There are now several clinical stage CDI vaccines under development that use traditional vaccine technology (e.g., toxoids), and all have several common features, including a protein or subunit-based approach focused on generating systemic IgG anti-toxin immunity, with or without a traditional adjuvant. However, there are several lines of evidence suggesting that a highly efficacious CDI vaccine may be more elusive than originally thought. The unexpected termination of a large Phase 3 CDI vaccine trial due to futility in establishing efficacy was recently reported. The vaccine was safe and immunogenic, but it did not show efficacy in reducing the incidence of CDI. Additionally, there are tens of thousands of cases of rCDI reported each year. The basis for rCDI is multifactorial, and new cutting-edge research has highlighted a critical role for the gut microbiota, not only in providing resistance to C. difficile colonization, but also in generating a robust host immune response.

In 2018, NIAID hosted a programmatic workshop (Vaccines against Clostridium difficile infection: A Roadmap for the Future) that focused on C. difficile vaccine development. Experts in the field identified high-priority knowledge gaps, discussed high-quality benchmarks for CDI vaccine development, and considered the public health impact of introducing a licensed CDI vaccine. Bottlenecks and gaps identified during this workshop include the role of systemic vs. local (mucosal) immunity, the impact of the gut microbiome on host immunity, and the number and diversity of antigens needed to cover prevalent toxinotypes. The need to identify correlates of protection, to gain new insights in toxin antigenic variation, and to explore new vaccine targets that have the potential to impact bacterial colonization were identified as high priorities. Technical issues in CDI diagnostics, along with the difficulties of targeting an aging population with co-morbidities and waning immunity, were also identified as obstacles.

An ideal CDI vaccine should be suitable for use in the target population, prevent deleterious gastrointestinal colonization, provide broad and robust protection from primary infection, and possess therapeutic potential to prevent rCDI. Original studies conducted over the past several decades provided key insights about the role of systemic anti-toxin immunity and the association with protection from disease. However, to achieve the goals of this program, investigative teams will need to advance the current knowledge base with clinical research in high-risk populations, de novo explorations of novel protective immunogens, innovative vaccine delivery platforms, and new or existing adjuvants capable of stimulating localized immunity. Existing or established animal models have been used to provide key proof of concept data for CDI vaccines, but the development of new model systems is warranted, including those that more accurately reflect the target population (>65 yrs.), which often has co-morbidities, repeated exposure to antibiotics, and, presumably, some prior immunological memory to C. difficile.

The purpose of this initiative is to support vaccine development through multidisciplinary investigations into the host immune response to CDI. Principal Investigators within each Cooperative Research Center (CRC) should have prior experience that demonstrates their ability to integrate multiple data streams to guide the development of next generation CDI vaccines. Access to clinical data and samples collected in prior clinical trials with high-risk populations, as well as prospective sample collection, and/or pre-clinical animal models will be important to study immune responses in human subjects and to investigate correlates of protection. Potential areas of research for this program include, but are not limited to, the following:

• Advance the knowledge of immunological protection against CDI:
  • Evaluate the breadth, diversity, and neutralizing capacity of antibodies (antitoxin) from high-risk and other relevant at-risk patient populations.
  • Leverage clinical samples to investigate correlates of protection and aspects of immunological memory that influence protective immunity.
  • Investigate the impact of the host microbiota on vaccine-induced immunity.
  • Investigate key knowledge gaps, such as the role of mucosal or local immunity and the potential to reduce colonization.
  • Investigate the role of cellular immunity in protection against CDI.
• Conduct new research on microbial pathogenesis considered important for broadly protective host immunity:
  • Explore the impact of antigenic variation on host protective immunity to C. difficile.
  • Investigate aspects of C. difficile pathogenesis and life cycle (spore vs. vegetative) that could lead to the discovery of novel protective antigens.
• Application of pre-clinical models, vaccine platforms, and novel adjuvants:
  • Construct prototypic pre-clinical candidate vaccines designed to test new and existing vaccine targets that have the potential to impact colonization with C. difficile.
  • Study pre-clinical vaccine candidates in animal models that parallel the pathophysiology of the disease.
  • Leverage new microphysiological systems (e.g., organoids) that include key components of the host immune system for vaccine testing.
  • Use novel vaccine platforms (e.g., mRNA) and adjuvant technology focused on stimulating mucosal immunity in the gut.
• Develop new animal models to conduct pertinent translational studies to evaluate immunogenicity and correlates of protection.
  • Pre-clinical models that parallel the pathophysiology of human disease (e.g., >65 y, humanized microbiota)

Collaborative Multidisciplinary Teams

Multidisciplinary and highly synergistic teams are required to accomplish the goals set out in this FOA. Teams that bridge disparate scientific disciplines allow a holistic integration of the science and new data that emerge from the Research Projects and Cores within each center. Examples of appropriate expertise include, but are not limited to, the microbiome, immunology, microbial pathogenesis, infectious disease, as well as vaccine and adjuvant platform technologies.

Program Components

Each Cooperative Research Center (CRC) will consist of an Administrative Core, Scientific Cores, and at least two Research Projects organized around a central theme or set of hypotheses. The components of an application include:

Administrative Core

The Administrative Core will be responsible for conducting program oversight and coordination, monitoring overall progress, and supervising the entire range of the program's research and administrative responsibilities.

Scientific Cores

Scientific Core(s) will provide shared support activities to at least two Research Projects. Examples of support activities include but are not limited to the following: antigen discovery, microbiology, animal models, immunological assays, vaccine and adjuvant platform development, clinical core to provide clinical samples to other cores and projects.

Research Projects

Each Program should propose at least two Research Projects organized around a common theme or hypotheses. One or more Research Projects should investigate aspects of host immunity that lead to new insights and activities focused on next generation vaccine development for CDI.

Annual Programmatic Meeting

Annual Programmatic Meetings will be held to facilitate communication and collaboration across the awarded CRCs.

Note: At the end of the five-year program, each CRC is expected to have validated critical insights regarding protective immunity to CDI through the identification of a potential vaccine candidate that can be further advanced in a preclinical program.

Applications that do not include the following will be considered non-responsive and will not be reviewed:

• One or more Research Projects that investigate aspects of host adaptive immunity to CDI.
• Milestones and timelines for the Overall program component

See Section VIII. Other Information for award authorities and regulations.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons.If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time per 2.3.7.4 Submission of Resubmission Application.". This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

The application forms package specific to this opportunity must be accessed through ASSIST or an institutional system-to-system solution. A button to apply using ASSIST is available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Maryam Feili-Hariri, Ph.D.

Telephone: 240-669-5026

Email: haririmf@niaid.nih.gov

Available Component Types	Research Strategy/Program Plan Page Limits
Overall	12 pages
Admin Core	6 pages
Core (use for Scientific Core[s])	12 pages
Project (use for Research Projects)	12 pages

Additional page limits described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide, and should be used for preparing a multi-component application.

The application should consist of the following components:

• Overall: required, 1
• Administrative Core: required, 1
• Scientific Core(s): required, minimum of 1, no maximum
• Research Projects: required, minimum of 2, no maximum

When preparing your application, use Component Type Overall .

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

Complete entire form.

Note: Human Embryonic Stem Cell lines from other components should be repeated in cell line table in Overall component.

Follow standard instructions.

Enter primary site only.

A summary of Project/Performance Sites in the Overall section of the assembled application image in eRA Commons compiled from data collected in the other components will be generated upon submission.

Include only the Project Director/Principal Investigator (PD/PI) and any multi-PDs/PIs (if applicable to this FOA) for the entire application. Document the PD(s)/PI(s) leadership and scientific ability to develop an integrated and focused research center, without duplicating information in the biosketches.

A summary of Senior/Key Persons followed by their Biographical Sketches in the Overall section of the assembled application image in eRA Commons will be generated upon submission.

The only budget information included in the Overall component is the Estimated Project Funding section of the SF424 (R&R) Cover.

A budget summary in the Overall section of the assembled application image in eRA Commons compiled from detailed budget data collected in the other components will be generated upon submission.

Specific Aims: List in priority order, the broad, long-range objectives and goals of the proposed CRC. Concisely describe the hypothesis or hypotheses to be tested. Outline a clear plan for how multidisciplinary investigations into the host immune response to CDI will translate into novel strategies and approaches for CDI vaccine development.

Research Strategy: Summarize the overarching theme of the proposed program. A multi-component, multidisciplinary application should be viewed as a confederation of interrelated Cores and Research Projects, each capable of standing on its own merit and complementary to one another. This section should provide the conceptual rationale of the program and lay out a broad strategy for accomplishing the stated goals. When describing the program, each Core and Research Project should be cited briefly as to its place in the overall scheme. Provide details of the program goals and organizational structure of components, describing how these will increase knowledge of an important area relevant to host immunity, the design of vaccines and defining a protective immune response against C. difficile. Summarize the special resources that make this application strong or unique. A visual representation of the interactions amongst the components and complementary scientific endeavors can delineate the collaborative and synergistic potential of the proposed program. Describe how the individual projects are independent, yet complementary and how they add value to each other and to the overall, stated, objectives of the Center. Discuss the cohesiveness of the program, and how the multidisciplinary interactions, coordination, and synergy of the Research Projects and Scientific Cores are significantly integrated, and how they relate to a single, common theme. Discuss how the scientific gains and synergy achieved by combining the research projects and cores into a multi-project CRC are superior to the gains achievable if each project were pursued independently.

Milestones and timelines: In a section clearly labeled, "Milestones and Timelines", provide proposed timelines and milestones for the overall program, sufficient to identify a potential vaccine candidate that can be further advanced in a preclinical program at the end of the award.

Letters of Support: If clinical samples or other resources will be provided by others, include a letter of support stating which resources will be provided and for what purpose.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Overall)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, there must be at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record within the application. The study record(s) must be included in the component(s) where the work is being done, unless the same study spans multiple components. To avoid the creation of duplicate study records, a single study record with sufficient information for all involved components must be included in the Overall component when the same study spans multiple components.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Complete one Study Record for each study if it spans multiple components. For each study that spans components, describe the components involved with the study. The Study Record must include sufficient information for all components that are involved in the particular study.

Section 2.9 Inclusion Enrollment Report(s)

Should the study span more than one component, include the IER with the Study Record in the Overall Component and insert a comment in the comment field of the IER to indicate what other components it is associated with.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

When preparing your application, use Component Type Core.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

Enter Human Embryonic Stem Cells in each relevant component.

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• For institutions/organizations proposing a single PD/PI, the PD/PI must serve as the Administrative Core Director. For institutions/organizations proposing multiple PD(s)/PI(s), the Contact PD/PI must serve as the Administrative Core Director.
• Provide details regarding the experience of the Administrative Core Director to illustrate his/her qualifications to manage the overall program, without duplicating information in the biosketches.

Budget forms appropriate for the specific component will be included in the application package.

Meetings: Beginning in Year 02, include funds in the budget for costs associated with attending and participating in an annual program meeting (1 meeting per budget year) or reverse site visit to be held in the Bethesda, MD area. Include costs for attendance by the PD(s)/PI(s) and key personnel. Do not include costs associated with organizing and holding the annual program meetings.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

Specific Aims: List in priority order, the broad, long-range objectives and goals of the proposed Administrative Core.

Research Strategy: Describe plans and procedures for establishing and managing an

Administrative Core that provides the organizational capacity to ensure the following:

• Coordinating, supervising, identifying and resolving problems, and managing all research program activities, which includes sponsoring activities to advance the research program’s integration.
• Providing a supportive structure sufficient to ensure the accomplishment of all research program goals, administrative support, fiscal and project management, implementation and oversight of subcontracts.
• Assisting Core and Research Project Leaders with administrative aspects of their projects, such as gathering of annual progress reports and facilitating other communications with awardees and their mentors.
• Promoting collaboration and coordination among Core and Research Project Leaders.
• Fostering outreach activities to promote collaborations with the pertinent scientific communities.
• Communicating with other awarded research programs regarding collaboration and coordination of activities and projects.
• Communicating and interacting with the NIAID Project Scientist, Program Officer, or other staff.

Management Plan: Include a Management Plan that describes the organization of the proposed program and its management structure. This plan should be sufficient to identify a potential vaccine candidate that can be further advanced in a preclinical program at the end of the award. The Management Plan should include:

• The organization of the Center and its management structure such that it forms a cohesive, integrated and efficient Center that provides scientific and administrative oversight of all Center Research Projects and Cores.
• An overview of how all the Research Projects will be coordinated, integrated, and managed to answer the scientific questions and hypotheses proposed within the application and within the scope of this FOA.
• A discussion of how the Administrative Core Lead will a) provide programmatic direction, coordination, and administrative management of the Center; and b) create within the Administrative Core an infrastructure that promotes cross-discipline interactions among the Research Projects and Scientific Cores.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Appendix:

Only limited items are allowed in the Appendix.Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.

When preparing your application, use Component Type Core.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

Enter Human Embryonic Stem Cells in each relevant component.

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

ASSIST will default to Project Lead . If you would like to use a different category, then replace Project Lead below with a different Category (e.g., Core Lead).

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

Specific Aims: List in priority order, the broad, long-range objectives and goals of the proposed Core.

Research Strategy: Describe how the proposed Core activities will contribute to program synergy and meeting the research program's goals and objectives. Explain the rationale for selecting the general methods and approaches to accomplish the Core activities.

Indicate the relevance and synergistic contributions of the Core to the primary theme of the proposed program and provide justification for the Core to support at least two Research Projects effectively. Applications must provide a clear description of the facilities, techniques, and skills that the Core will provide to the Research Projects. Cores should not be duplicative of other services or facilities available to the program investigators. Examples of services that might be provided by a Core include, but are not limited to, immunological evaluation, sequencing and bioinformatics support, antigen discovery, vaccine and adjuvant resources, microbiology and/or services related to the microbiome, organoids, animal models, or a clinical service that will provide clinical samples.

Milestones and Timelines: In a clearly labeled section titled "Milestones and Timelines", provide annual timelines and milestones for the proposed core services. Include specific criteria by which milestone achievement will be assessed and a timeline for the anticipated attainment of each milestone.

Letters of Support: Provide letters of support from collaborators and institutions that are applicable to the Scientific Core, including a Memorandum of Understanding (MOU) or Materials Transfer Agreement (MTA) that documents availability and/or access to human materials for each source (i.e., sample availability corresponding to the outlined timelines), as applicable.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Include an attachment that indicates that the details of the study are included in the Overall component within this attachment.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the SF424 (R&R) Application Guide must be followed.

When preparing your application, use Component Type Project.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

Enter Human Embryonic Stem Cells in each relevant component.

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

Specific Aims: List, in priority order, the broad long-term goals and specific objectives of the proposed Research Project. Concisely describe the hypothesis or hypotheses to be tested.

Research Strategy: Describe how the proposed project will contribute to meeting the program’s overall goals and explain the rationale for selecting the methods to accomplish the Specific Aims. State the biological significance of the research and indicate the project's relevance to the primary theme of the application. Describe how the proposed vaccine technology represents a novel or paradigm shifting approach or methodology towards mucosal immunity. In addition, state the Research Project’s relationship to the research program s goals and how they relate to and synergize with other Cores or Research Projects in the application. Outline novel strategies to develop broadly protective neutralizing antibodies and improve upon existing anti-toxin approaches. Describe how the goals and components are organized in a way that will increase knowledge of an important area relevant to host immunity and the design of vaccines against Clostridioides difficile.

Milestones and timelines: In a clearly labeled section titled "Milestones and Timelines", provide timelines and milestones for the proposed project.

Letters of Support: Provide letters of support from collaborators that are applicable to the Research Project, including a Memorandum of Understanding (MOU) or Materials Transfer Agreement (MTA) that documents availability and/or access to human materials for each source (i.e., sample availability corresponding to the outlined timeline), as applicable.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Appendix: Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Include an attachment that indicates that the details of the study are included in the Overall component within this attachment.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the SF424 (R&R) Application Guide must be followed.

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov.

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies) using ASSIST or other electronic submission systems. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

For information on how your application will be automatically assembled for review and funding consideration after submission go to: http://grants.nih.gov/grants/ElectronicReceipt/files/Electronic_Multi-project_Application_Image_Assembly.pdf.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) and component Project Leads must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management (SAM). Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the Center to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the Center proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a Center that by its nature is not innovative may be essential to advance a field.

Does the Center address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the Center are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Specific to this FOA: Does the proposed overall research strategic plan address important areas and will it advance knowledge towards defining a protective immune response against CDI? Is the Center as a whole scientifically compelling? Are the goals and components organized in a way that will increase knowledge of an important area relevant to host immunity and the design of vaccines against Clostridioides difficile?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the Center? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI , do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Specific to this FOA: Does the Center Director have the leadership and scientific ability to develop an integrated and focused research center?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the Center? Have investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the Center involves human subjects and/or NIH-defined clinical research, are the plans to address:

1) the protection of human subjects from research risks, and

2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Specific to this FOA: Are there coordination and synergy of the individual research projects with the scientific core(s) (if applicable) that advance the achievements of the central objectives of the Center? Are the individual projects independent, yet complementary and do they add value to each other and to the overall, stated, objectives of the Center? Are the proposed timelines and milestones for the overall Center adequate to identify a potential vaccine candidate that can be further advanced in a preclinical program at the end of the award?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Specific to this FOA: Do the proposed projects outline strategies likely to develop broadly protective neutralizing antibodies and improve upon existing anti-toxin approaches?

Is/are the Project Lead(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-Project Lead(s), do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Specific to this FOA: Does the proposed vaccine technology represent a novel or paradigm shifting approach or methodology towards mucosal immunity?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address:

1) the protection of human subjects from research risks, and

2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the Core activities to meet the needs of individual Research Projects or other Cores, and to contribute to Center goals and objectives, in consideration of the following points (as applicable for the Core proposed).

Reviewers will consider each of the review criteria below, as appropriate for the individual core, in the determination of merit and will give an overall impact score for each Core but will not give separate scores for each criterion.

Are the plans and procedures outlined for the Administrative Core adequate to support the accomplishment of the program's goals? Is the Management Plan appropriate to facilitate the identification of a vaccine candidate that can be further advanced in a preclinical program by the end of the award period? Are the plans for coordination among Core and Research Project leaders, problem identification and resolution, and the establishment of a strong collaborative environment for the program appropriate?

Will the Core contribute to program synergy and meeting the program's goals and objectives?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Not Applicable

Not Applicable

Not Applicable

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genomic Data Sharing Plan .

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by the National Institute of Allergy and Infectious Diseases in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Allergy and Infectious Diseases Council. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the recipient’s business official.

Recipients must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities, including of note, but not limited to:

• Federalwide Research Terms and Conditions
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment

Acknowledgment of Federal Funding

If a recipient is successful and receives a Notice of Award, in accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.

HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA.

• Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. HHS provides guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at https://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.
• Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html.
• HHS funded health and education programs must be administered in an environment free of sexual harassment. Please see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html; https://www2.ed.gov/about/offices/list/ocr/docs/shguide.html; and https://www.eeoc.gov/eeoc/publications/upload/fs-sex.pdf. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.
• Recipients of FFA must also administer their programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws. Collectively, these laws prohibit exclusion, adverse treatment, coercion, or other discrimination against persons or entities on the basis of their consciences, religious beliefs, or moral convictions. Please see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 and 2 CFR Part 200.206 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75 and 2 CFR Part 200, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

• Retaining primary responsibility for the planning, directing, and executing the proposed scientific activities;
• Keeping the NIAID Program Official apprised of any potential impediments to execution of the goals of any one Research Project or Core;
• Recipients will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

• The Project Scientist will facilitate collaborations and to leverage the resources available to the research program.
• The Project Scientist will monitor the progress of the research program, help coordinate research approaches, and contribute to the shaping of research projects or approaches as warranted. The Project Scientist will support and facilitate this process but will not direct it.
• The Project Scientist will coordinate access to other NIAID resources, as well as assist the research efforts by facilitating access to fiscal and intellectual resources provided by industry, private foundations, NIH intramural scientists and other federal government agencies as appropriate.
• The Project Scientist will assist in the determination of the site for the Annual Programmatic Meeting; and
• Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

• The NIAID Project Scientist and the PD(s)/PI(s) will hold regularly scheduled calls to coordinate to facilitate the achievement of program goals.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement. NIH FOAs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR 200.301.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All recipients of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over the threshold. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and 2 CFR Part 200.113 and Appendix XII to 45 CFR Part 75 and 2 CFR Part 200, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 and 2 CFR Part 200 Award Term and Condition for Recipient Integrity and Performance Matters.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: https://grants.nih.gov/support/index.html (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-637-3015

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

Ryan Ranallo, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3351
Email: Ryan.ranallo@nih.gov

Maryam Feili-Hariri, Ph.D.
National Institute of Allergy and Infectious Diseases
Telephone: 240-669-5026
Email: haririmf@niaid.nih.gov

Karinne Chevalier-Davis
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3407
Email: karinne.chevalierdavis@nih.gov

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75 and 2 CFR Part 200.