Required Application Instructions

It is critical that applicants follow the 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 solicit applications from institutions proposing studies to break new ground in understanding of immune defense mechanisms and immune regulation at the mucosal surfaces. The purpose of this program is to discover and define novel basic immune mechanisms, cells, mediators, and pathways that provide a more complete understanding of mucosal immune defense mechanisms; to explore innovative hypotheses; and to address difficult unsolved questions in mucosal immunity. The ultimate goal is to develop the knowledge needed to facilitate future development of vaccines and immunotherapies to protect mucosal surfaces from infection and immune-mediated pathology. Studies may use relevant animal models or human tissues to achieve this goal. This program is not intended to support development and/or evaluation of mucosal vaccines or therapies, or research primarily focused on pathogens.

The mucosal immune system satisfies a range of diverse requirements from maintaining limited microbial burden in the lungs and upper reproductive tract to coexisting with up to 1014 bacteria in the large intestine. An imbalanced mucosal immune response to food, to the normal microbial flora, or even to pathogens can lead to chronic inflammation tissue injury, and chronic illnesses, so responses at the mucosa require tight controls. Recent studies have provided new clues about the strategies and cellular and molecular components used at different mucosal surfaces to detect and respond to pathogens without causing chronic inflammation, but much remains unknown.

In January 2008, the National Institute of Allergy and Infectious Diseases (NIAID) sponsored a workshop to discuss recent research advances in mucosal immune defense mechanisms. The workshop participants concluded that multiple gaps exist in the understanding of the basic immune mechanisms responsible for induction of broad systemic and mucosal immunity, priming, protection, and tolerance. These gaps hamper progress in developing therapeutic and vaccination strategies to provide mucosal and systemic protection from mucosal pathogens and inflammatory diseases. This led to RFA AI-10-008 "Immune Defense Mechanisms at the Mucosa Cooperative Study Group (U01)" which supported a cooperative program to address these research gaps. At the first Steering Committee meeting held in January 2012, the group adopted the name "Mucosal Immunology Studies Team (MIST)".

This FOA will support a cooperative study group, the Mucosal Immunology Studies Team (MIST), focused on research to define fundamental aspects of immunity at mucosal surfaces. This FOA intends to stimulate new basic and applied research that will contribute toward understanding broadly applicable host mechanisms of mucosal immunology.

Areas of interest and examples of research studies responsive to this FOA include, but are not limited to those listed below. Many of the following areas of investigation are not new, but advances in recent years suggest that these areas have matured to a level where directed research efforts can have an impact. These and other research areas may be addressed in this FOA in the context of defining new mechanisms relevant to immune responses at the mucosa. If infectious organisms/vaccines/adjuvants or mucosal diseases are used for the proposed studies, they must be as model agents/diseases to probe host mucosal immune responses to discover new information about mechanisms of immunity. Studies may use relevant animal models or human tissues to achieve this goal.

Mucosal Epithelium. Mucosal surfaces, lined by tightly joined epithelial cells, form a physical barrier between the body and the microbial flora, and also serve as a first line of immune defense against microbial invasion. Mucosal epithelial cells secrete a wide array of substances such as mucins, defensins, trefoil peptides, cathelecidins, lysozyme and nitric oxide, which non-specifically shield the mucosa from microbial damage. Epithelial innate immune receptors such as TLRs and NOD molecules recognize microbial motifs that trigger the production of cytokines and chemokines that activate and mobilize immune cells. Epithelial adhesion molecules participate in cell trafficking and localization of mucosal lymphocytes; polymeric Ig receptors and neonatal Fc receptors transport antimicrobial antibodies across the epithelium; and specialized follicle-associated epithelial cells play a role in antigen sampling. Although the myriad of active roles that mucosal epithelial cells play in host defense have begun to be recognized, many questions remain, including the importance of each role in maintaining homeostasis with the host flora versus protection against pathogen invasion. How epithelial cells interact with and respond to commensals and pathogens, and the resultant elaboration of factors involved in immune cell recruitment and function are examples of research areas that remain to be addressed.

Examples of potential research studies in this area include, but are not limited to:

• Relative contribution of specialized mucosal epithelial cells to mucosal surveillance, immunity, and tolerance.
• Factors that regulate epithelial barrier function, expression of innate immune receptors, chemokine and cytokine production, and antimicrobial peptide production.
• Epithelial factors influencing dendritic cell or T cell recruitment and differentiation.

Mucosal Immunoglobulin and Mucosal B Cell Responses. IgA isotype antibodies predominate at the mucosal surface and are considered a first line of defense against microbial invasion through the mucosa. Despite the abundance of IgA, and discoveries that have provided a framework for understanding induction of IgA-producing B cells and transport of IgA across the epithelial barrier, much remains unknown about the production and function of IgA. For example, mouse models of deficiencies in IgA or components of IgA transport or secretion provide conflicting evidence for the requirement of IgA for protective responses to mucosal pathogens. Recent evidence supports new roles for IgA in maintaining homeostasis with the normal flora and prevention of inflammation triggered by the normal flora and harmless antigens. Also, there is now evidence to suggest that IgA switch recombination may occur at non-traditional sites such as the lamina propria and that epithelial cell cytokines can influence this recombination. To facilitate mucosal vaccine development, more information is needed to understand where and how local IgA is produced, and to identify the precise role for IgA and other mucosal immunoglobulins in protection from infectious pathogens and maintaining a balance with commensal microbes.

Examples of research studies in this area include, but are not limited to:

• Mechanisms by which Peyer's patch derived B cells migrate to the large intestine.
• Role of T follicular helper cells in controlling IgA production.
• Epithelial, stromal, and dendritic cell mechanisms involved in elaboration of IgA-producing B cells.
• Effects of IgA efficiency on immune defense and homeostasis.

Mucosal Antigen Sampling, Processing, and Presentation. The mucosal immune system requires specialized mechanisms to access inhaled or ingested antigens which are separated from the submucosal immune tissues by a tight epithelial cell barrier. A specialized follicle-associated epithelium (FAE) contains gateway epithelial cells, the microfold or M cells, which overlay Peyer’s patches in the gut and the nasopharynx-associated lymphoid tissue (NALT) of the respiratory tract. M cells transport antigens to intraepithelial dendritic cells (DC) in the pockets below the M cells to initiate antigen specific immune responses. Lamina propria DCs that express tight junction proteins and directly sample the luminal compartment by extending dendrites between epithelial cells have been identified. More recent studies find that Goblet cell-associated passages and mucosal macrophages can take up and transport gut luminal antigens to mucosal DCs. In addition, the mucosal DC population has been found to comprise several subpopulations with distinct phenotypes and functions, and these populations vary depending on their precise location within the gut, airway, reproductive tract or other mucosal site. Different mucosal DC subsets have been shown to promote differentiation of B cells into IgA secreting cells, induction of regulatory T cells, or induction of Th17 cells. These new findings imply that mucosal DCs play a key role in orchestrating the balance of effector responses to mucosal pathogens and homeostasis with the microbial flora. The mechanisms, cells, and pathways governing processing, presentation and detection of mucosal antigens in promoting either a protective or tolerogenic host response are important areas for further study.

Examples of research studies in this area include, but are not limited to:

• Role of resident and recruited antigen presenting cells in the uptake, processing and presentation of antigen in settings of inflammation, infection, and homeostasis with the microflora.
• Factors regulating trafficking of antigen presenting cells and T cells to mucosal sites.
• Determination of the tissue site for presentation of antigens taken up in the lung, intestine, or urogenital tract, and influence of local conditions and mechanisms of uptake.

Mucosal Immunity and Inflammation. The mucosal immune system is challenged to respond to harmful organisms while regulating the resultant influx of immune cells to prevent tissue injury due to inflammation. In the gut, several lines of evidence support the idea that the commensal flora exert an anti-inflammatory influence on the mucosa. Alterations in the normal homeostasis with the microbial flora may lead to inappropriate responses in which commensal microbes serve as surrogate pathogens and thus stimulate a chronic inflammatory response. In the relatively sterile surfaces of the respiratory tract, failure to tightly control immune responses to pathogens can also lead to chronic inflammation and tissue destruction. To limit inflammatory responses, the airways, gut and other mucosal surfaces employ a range of complex physical, innate, and adaptive immune defenses. Alterations of any of these defenses could promote an uncontrolled inflammatory response that while limiting infection may lead to tissue injury. The complex mucosal systems to prevent responses to harmless antigens and limit inflammatory responses to pathogens are not well understood and are an important area for further study.

Examples of research studies in this area include, but are not limited to:

• Identification of antigens that drive inflammatory Th1/Th17 or regulatory T cells mucosal responses.
• Effects of respiratory tract remodeling after inflammation or infection on subsequent mucosal responses to inflammation or infection.
• Role of regulatory T cells in controlling immune responses to bacterial flora and harmless antigens
• Determine site of induction and factors that regulate development of mucosal effector and regulatory pathways.
• Role of innate lymphoid cells, MAIT cells, gamma delta T cells, etc. in mucosal protection, inflammation, and tolerance.
• Defining correlates of mucosal protection or tolerance and predictors of inflammatory outcome (e.g. cytokine profiles) in humans.

Cross-talk between the neural and immune response in mucosal immunity. Numerous connections between the nervous and mucosal immune system have been identified, suggesting an interplay among the mucosal immune system, the enteric nervous system, and the detection of microbes at the mucosal surfaces. Vagal nerve input plays a role in mucosal barrier function and mucosal inflammation through effects not only on intestinal motility, but also through neural release of mediators that direct T cells and macrophages. Receptors associated with the nervous system, such as the transient receptor potential (TRP) ion channel family member TRPV1, have been found on immune cells and appear to contribute to mucosal immune responses; likewise expression of innate immune receptors such as TLR2 and TLR4, typically associated with immune cells, by sensory cells at the mucosa appears to be critical for the enteric nervous system development. Tissues that are directly exposed to the external microbial flora such as mucosal surfaces of the digestive, lung, and urogenital tracts, are densely innervated by nervous system sensory receptors; and there is data to suggest that mucosal nerve fibers may directly modulate mucosal immune responses. The details of these interactions are unknown, and better knowledge of the connections between the nervous system and mucosal immunity is critical for understanding mucosal immune regulation, response to pathogens, and development of therapeutics for mucosal diseases.

Examples of research studies in this area include, but are not limited to:

• Role of enteric neuron and enteric glia secretion of inflammatory cytokines (e.g. IL-1, IL-6, IL-8) in mucosal immunity and mucosal inflammation.
• Mechanism by which TLR expression on enteric neurons influences mucosal immunity.
• Role of neurotrophins on immune cells in the lung.

The MIST program is intended to support studies that break new ground in the understanding of mucosal defense and mucosal immunoregulation. Proposed studies may include mucosal microbes/pathogens/vaccines/adjuvants/infections as probes to gain new insights into mucosal immune defense mechanisms.

Examples of research areas NOT supported by this FOA are listed below. Applications containing research in these areas will be considered non-responsive and will not be reviewed.

• Clinical trials; however, the use of samples obtained from human subjects in clinical trials funded through other mechanisms is allowed.
• HIV/AIDS/SIV.
• Studies that focus on skin or epidermis.
• Studies focused primarily on specific microbes, infections, vaccines, or adjuvants that do not use these agents as probes to gain new insights about mucosal immune mechanisms; studies focused on non-immune mechanisms of pathogenesis.
• Projects focused on autoimmune or inflammatory diseases (e.g. inflammatory bowel disease, celiac disease, cystic fibrosis, etc.), lung or intestinal transplantation, or asthma/allergy would be responsive only if these diseases are used as probes to gain new insights about mucosal immune mechanisms.
• Investigations that do not focus on the study of mucosal immune defense or immunoregulatory mechanisms, mucosal cells, mucosal molecules or mucosal pathways.

This FOA encourages New Investigators, and in particular Early Stage Investigators, to participate in this research program. Applicants without a prior track record of funding in mucosal immunity are welcome to apply as Program Directors/Principal Investigators (PDs/PIs) or as part of multidisciplinary teams that establish new collaborations or novel approaches.

Steering Committee. A Steering Committee will be established to direct the overall efforts of the MIST program. The steering committee will be composed at a minimum of PDs/PIs of each of the awards and a NIH Project Scientist serving as the representative of the NIH. The MIST Steering Committee will recommend procedures to solicit applications for support by the MIST Infrastructure and Opportunities Fund (see below), make recommendations to support specific applications through the MIST Infrastructure and Opportunities Fund (IOF), recommend budget allocations for each project to be supported through the IOF, and monitor the progress of funded projects. The Steering Committee will develop a "MIST Plan" that will articulate the goals of the MIST Program and is used as a reference for making recommendations regarding use of the IOF.

Infrastructure and Opportunities Fund. To capitalize on emerging opportunities, and sharing of resources and expertise consistent with the goals of MIST, an IOF of up to $500,000 direct costs per year for the entire program will be made available. One institution will be chosen by NIH after award from the successful applicants to manage the IOF for the entire MIST. This institution must agree to take responsibility for managing the IOF, including disbursement, administration, and reports. Management of the IOF will involve establishing an administrative structure, tracking funds and under the advice of the Steering Committee establishing procedures for reporting status to NIH and the Steering Committee. Examples of activities supported by the current IOF include development and management of a website for MIST activities; collaborative and pilot/feasibility projects among MIST members; translational projects; early stage investigator projects; and imaging and animal model development cores. IOF projects must be within the scope of this FOA and may be submitted by members of MIST or by outside investigators.

Applicants are encouraged to discuss any questions with the Scientific/Research Contact listed in below.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to 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) (formerly CCR) 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 and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. 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. 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 NOT-OD-11-101).

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement to do otherwise. 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.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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:

Andrea Wurster, PhD
National Institute of Allergy and Infectious Diseases (NIAID)
Scientific Review Program
5601 Fishers Lane
Room 3G33B, MSC 9823
Rockville, MD 20852-9823
Telephone: 240-669-5062
Fax: 301-480-2310
Email: wurstera@mail.nih.gov

All page limitations 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 an application to this FOA.

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

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

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

Other Attachments: The following attachment is required for this FOA, and must be included as a separate pdf attachment.

The filename IOF.pdf should be used and will be reflected in the final image bookmarking for easy access for reviewers.

Applicants should provide: A plan of how the IOF will operate to serve the MIST, including descriptions of: (1) an administrative structure that includes an experienced administrator; (2) methods of communication with the Steering Committee regarding the disbursement and tracking of IOF funds; and (3) methods for reporting on the status of IOF funds to NIAID. Also describe plans and procedures to ensure that all projects supported from the IOF will comply fully with all applicable Federal regulations, policies, and guidelines for research involving human subjects, including the evaluation of risks and protections in projects and appropriate ethical oversight.

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

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

The budget must include funds for travel to the Bethesda, Maryland area for 2 Steering Committee meetings within the first 12 months, and annually thereafter, for the PD/PI. For multi-PD/PI applications, the budget should include travel funds sufficient for all PD/PIs to attend the Steering Committee meetings.

Applications should include a section with a separate budget justification for the cost for the IOF. Applicants should assume 5 pilot/feasibility projects per year and an additional $4000 per year for website management. Within the Budget Justification applicants' should justify the salary and effort of the IOF administrator.

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

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

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

Specific Aims: List the broad, long range objectives and goals of the proposed project. Concisely and realistically describe the work to be completed.

Research Strategy: Within the research strategy, applicants must include the following:

A clear and detailed description of how the proposed hypothesis addresses novel approaches that will increase knowledge and advance understanding of mucosal immune defense mechanisms or addresses difficult unsolved questions in mucosal immunity.

If approaches including infectious organisms/vaccines/adjuvants or mucosal diseases are proposed, describe how these approaches model agents/diseases will advance research towards discovery of new information about mechanisms of mucosal immunity.

Describe in detail the rationale behind the choice of any proposed animal models or human tissues and how their use will advance the research strategy.

Letter of Support: Infrastructure and Opportunities Fund Management - All applicants should include a letter from the PD/PI(s) and the Institution's Signing Official agreeing to take fiscal responsibility for the management of the IOF, if chosen by NIAID to do so.

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: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

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.

Part I. Overview Information contains information about Key Dates. 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.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). 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. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

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.

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 Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues.

Important reminders:

All PD(s)/PI(s) 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. See Section III of this FOA for information on registration requirements.

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. 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 NOT-OD-13-030.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research 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 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? 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? Will the proposed studies increase knowledge and advance understanding of mucosal immune defense mechanisms or address difficult unsolved questions in mucosal immunity?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or 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?

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 project? 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?

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 children, 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?

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 six 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 six 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 children 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 five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. 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

For Renewals, the committee will consider the progress made in the last funding period.

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.

IOF Plan

Is provision of the proposed IOF management services to the program described in sufficient detail?

Is sufficient justification provided for the management methods proposed for the IOF?

Are the personnel charged with managing the IOF appropriate?

Are adequate plans and procedures proposed by the applicant in the IOF plan to assure compliance with relevant federal regulations and NIH policies for the protection of human research participants, including the evaluation of risks and protections in project proposals, appropriate ethical oversight of funded projects, and plans for monitoring data and safety in clinical research projects?

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 Wide Association Studies (GWAS) /Genomic Data Sharing Plan.

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.

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 grantee’s business official.

Awardees 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.

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, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

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 Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), 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 awardees 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 award 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 awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

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

• Acceptance and implementation of common guidelines approved by the MIST Steering Committee.
• Serving as a voting member of the Steering Committee (one PD/PI if multiple PD/PIs); and participating in MIST activities.
• Timely publication of major findings; submission of manuscripts to the NIAID Program Officer promptly upon acceptance for publication.
• Abiding by the MIST publication policy to be drafted with NIH assistance and adopted by the Steering Committee after award.
• Acknowledgement of NIAID support in publications and oral presentations of work performed under this agreement.
• Publication of findings linked to clinical trials (for example, mechanistic studies that utilize samples from a clinical trial) must adhere to the policies enacted by the governing body of the clinical trial and the sponsor of the trial.
• Awardees 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 HHS, PHS, and NIH policies.

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

• NIAID staff assistance will be provided by a Program Official from the Autoimmunity and Mucosal Immunology Branch, Division of Allergy, Immunology and Transplantation, NIAID, who will serve as the NIAID Project Scientist. The role of the NIAID Project Scientist will be to facilitate, and not to direct, the activities of MIST. The NIAID Project Scientist will serve as a voting member of the Steering Committee.
• The NIH Project Scientist will support MIST activities through technical assistance, advice and coordination of MIST activities. Support may be through selection of resources and identification of potential collaborations to further the goals of the Program; acting as a liaison to other mucosal immunity-related NIH programs; recruiting external advisors from the international mucosal immunity research community and soliciting their advice and attendance at MIST Steering Committee meetings; and participating in the preparation of publications for collaborative projects, as appropriate.
• An additional NIAID program official will be responsible for the normal scientific and programmatic stewardship of the award.
• NIAID program staff will select the PD/PI and Institution to manage and administer the IOF.

Areas of Joint Responsibility include:

Steering Committee

A Steering Committee will serve as the governing body of MIST. All MIST investigators will be required to accept and implement common guidelines and procedures approved by the Steering Committee.

• All U01 PD/PIs will serve as Steering Committee members. For multi-PD/PI awards, each PD/PI will serve on the steering committee, but each U01 will have only vote.
• NIH may appoint up to two external scientists or additional NIH staff to the Steering Committee as non-voting members. The Steering Committee may appoint additional non-voting members by majority vote.
• A chairperson will be selected from among the non-federal Steering Committee members.
• Subcommittees of the Steering Committee may be established as necessary.

The Steering Committee will:

• Serve as the main governing board of MIST;
• Develop a MIST Plan that outlines an overall agenda for MIST activities to produce maximum progress in the field of mucosal immunology, e.g. set goals, specify approaches, define milestones for MIST;
• Ensure that the activities of MIST are coordinated, productive, collaborative when appropriate, and directed toward the goals expressed in the MIST Plan;
• Identify scientific opportunities, emerging needs, and impediments;
• Provide guidance and recommendations to investigators regarding study implementation and conduct;
• Develop guidelines and policies for publication of collaborative project results;
• Compile reports of the MIST program accomplishments, as requested by the NIH Program Officer.
• Establish definitions and data collection standards for collaborative projects, as needed;
• Establish subcommittees as needed to provide recommendations on shared aspects of the cooperative research group, including but not limited to the activities listed above.
• Oversee the use of the IOF (see below) by developing initiatives to be supported by the IOF, determining review criteria and process for proposals for IOF use, and approving funding plans using IOF.

Additional details and responsibilities of the Steering Committee will be negotiated at the time of award or post-award.

In order to most efficiently utilize research resources and rapidly exchange scientific information to promote mucosal immunity research and NIH objectives, cooperation or opportunities to collaborate with other NIH funded programs may be initiated in future years if appropriate.

It is anticipated that decisions in all activities will be reached by consensus and that funding agency staff will be given the opportunity to offer and/or solicit ideas and opinions during this process. The manner of reaching consensus and the final decision-making authority will rest with the MIST Steering Committee.

An Infrastructure and Opportunities Fund (IOF) will be available to the Steering Committee:

• The MIST Steering Committee will oversee the MIST IOF. The IOF is provided to support MIST activities consistent with the goals of this program and the MIST Plan, e.g. support of innovative pilot and feasibility projects; support of MIST collaborative projects initiated after U01 award; and development of reagents and resources, including cooperative resources.
• Receipt of applications for and a review of progress of MIST IOF-funded projects shall occur at least yearly at a MIST Steering Committee Meeting.
• The Steering Committee will devise and implement means to make the immunology research community aware of MIST IOF initiatives and to ensure appropriate participation by researchers outside MIST.
• The Steering Committee’s responsibility to conduct and oversee these activities is intended to encourage those cooperative and collaborative efforts, among MIST members and the research community at large, that are best suited to achieve the goals of the program and to advance the understanding of immune defense mechanisms at the mucosa. The MIST Steering Committee will determine the goals, priorities, and evaluation criteria for the use of the MIST IOF.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. The three members will include: 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 awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16

When multiple years are involved, awardees 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 progress report, 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.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees 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 $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

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 registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Finding Help Online: http://grants.nih.gov/support/index.html
Email: commons@od.nih.gov

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-710-0267

Annette L. Rothermel, PhD
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3477
Email: arothermel@niaid.nih.gov

Andrea Wurster, PhD
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-5062
Email: wurstera@mail.nih.gov

Devon Bumbray-Quarles
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-2950
Email: dbumbray@niaid.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.