It is critical that applicants follow the Research (R) 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 FOA is to support individual projects that determine the functional interactions of immune cells present at the maternal-fetal interface, including mechanisms of responses to vaccination, infection, and/or ionizing radiation that protect or impact the fetus and that may influence fetal immune system development. Applications are sought that (1) identify and define immune mechanisms during normal pregnancy, and/or (2) identify and elucidate mechanisms of immune responses triggered by infections vaccinations, and/or ionizing radiation during pregnancy. Projects may include interactions between immune and non-immune cells that support a healthy pregnancy, and/or studies to determine the effects of commensal microorganisms, maternal infectious disease, vaccines, or ionizing radiation on pregnancy outcomes or the developing fetal immune system. In order to determine the impact of the factors studied prenatally on fetal immune system development, studies of early postnatal immune system development and function (i.e., up to 6 months of age in humans, and a relevant/appropriate postnatal age in proposed animal models) may be included in the proposed projects. This initiative will support hypothesis-driven and descriptive studies, given the current state of knowledge regarding interactions of immune cells between the placenta and the uterus. If descriptive studies are included, they are expected to lay a foundation leading to the discovery of novel phenomena or major advances in the future. Innovative studies that break new ground or extend discoveries toward new directions are encouraged.

Pregnancy involves complex interactions between fetal trophoblasts and maternal decidual immune cells that allow the embryo, and later the fetus, to develop in the uterus. Uterine natural killer (NK) cells, immature dendritic cells (DCs), T cells, and macrophages contribute to modulation of the uterine environment to sustain a successful pregnancy. The uterine mucosa undergoes a specialized tissue reaction, decidualization, that supports the development and function of the placenta. During the decidualization process, endometrial fibroblasts differentiate, accompanied by changes in morphology and gene expression, to form the structure that encases the fetus and the placenta. The placenta actively produces various immunomodulatory factors to prevent rejection of the fetus by the innate and adaptive immune system of the mother. Microbiota have been detected in the placenta and their role in immune-metabolic functions during pregnancy are largely unknown. Most studies to date have focused on endocrinological, physiological, and developmental approaches to understand interactions at the maternal-fetal interface. However, a variety of immune cell populations are present at the human maternal-fetal interface, primarily Natural Killer (NK) cells (~70% of immune cells), macrophages (~20%), and T cells (~10-20%), with DCs, B cells and NKT cells being less frequent. Gaining better insight into the roles and interactions of these immune cells may provide alternative approaches to address and prevent adverse outcomes during pregnancy.

While NK cells have been known to regulate vascular remodeling during pregnancy, the mechanism by which this is accomplished is not known. Although uterine NK cells comprise the largest proportion of leukocytes during the first trimester of pregnancy, their numbers decline after the placenta is formed. In addition, placental NK cells appear to be distinct from those seen in the periphery. Functional capabilities of placental NK cells include the promotion of placental vascular growth, decidualization, trophoblast invasion, and immune regulation. Uterine NK cells, upon co-stimulation with HLA-G on extravillous trophoblasts, have recently been shown to be responsible for optimizing maternal nourishment of the fetus and for secreting growth-promoting factors that are critical for the development of blood vessels, bone, cartilage, neurite, and cardiac tissue in the fetus. However, mechanisms regulating placental and uterine NK cell activation and regulation remain to be elucidated.

Macrophages constitute the second most abundant immune cell population at the maternal-fetal interface. However, studies of human and mouse decidual macrophages are limited. For example, investigators have yet to examine whether their antigen processing and presentation capabilities are involved in regulation of responses within this interface. Immune cells such as DCs, T cells, and B cells are present to a lesser number, and their role(s) and function(s) during gestation remain to be elucidated. Interactions between mast cells that are present in the uterus and cervix and the other cells at the maternal-fetal interface mediate implantation and preserve quiescence until parturition. Mechanisms by which these processes are accomplished also need further study.

Advanced gestational age and the process of parturition trigger changes in inflammatory signals within the decidua. For example, the production and release of a variety of biologically active inflammatory mediators that include prostaglandins, cytokines, growth factors, chemokines, and reactive oxygen species at the maternal-fetal interface lead to uterine contractions and cervical changes, commonly referred to as labor. The role of and mechanisms by which effector immune cells potentiate inflammatory conditions during late gestation and labor require additional understanding.

Dysregulation of critical metabolic processes or encounters with pathogens may lead to local or systemic immune activation that results in adverse outcomes, such as preeclampsia, preterm birth or loss of fetal viability. Immune system interactions during pregnancy directly affect women and their offspring from post-partum and beyond. Infectious agents including, but not limited to, cytomegalovirus (CMV), herpes simplex virus-2 (HSV-2), human papilloma virus (HPV), influenza, rubella, respiratory syncytial virus (RSV) and Zika virus may have devastating effects on fetal development by mechanisms such as excessive immune activation or direct infection of the fetus. Further studies are needed to elucidate mechanisms by which innate and adaptive immune cells interact during infections in pregnant women. The adverse impact of emerging infections during pregnancy underscores the importance of understanding interactions between the mother's immune system and infectious agents because implications extend not only to the mother, but the health of the embryo, fetus, and neonate.

Ionizing radiation can result in congenital defects, growth retardation, immune dysfunction, or microencephaly and neonatal mortality, depending on the absorbed radiation dose and the gestational age at time of exposure (i.e., pre-implantation, organogenesis, or fetal stage). Studies are needed to establish appropriate animal models of in-utero exposures to elucidate health outcome in the surviving offspring, as well as to test the efficacy of FDA-approved medical countermeasures against radiation lethality.

This FOA invites applications to define immune mechanisms at the maternal-fetal interface that mediate a healthy pregnancy as well as during encounters with infectious agents, vaccinations, and/or ionizing radiation. Applicants are strongly encouraged to use human tissues and cells (e.g., cord blood, placenta post-partum), which may include samples obtained from human subjects given licensed vaccines or from independently funded completed or ongoing clinical trials. Recognizing that tissues and cells may not be easily obtained from women at different periods during pregnancy, applicants may use relevant animal models to elucidate immune mechanisms during natural infection or via challenge studies. Applicants are expected to provide a rationale and justification for the animal models used, the age(s) selected, and time-frame chosen for evaluation. Studies of early postnatal immune system development and function (i.e., up to 6 months of age in humans, and a relevant/appropriate postnatal age in proposed animal models) may be included in the proposed projects. All data generated by the funded program is expected to be deposited in the NIAID-supported ImmPort database or another public database designated by NIAID.

Areas of research interest to NIAID include, but are not limited to:

• Mechanisms that determine the phenotype and density of leukocytes that populate the interface between the placenta and uterus during various stages of pregnancy.
• Induction and recruitment pathways of decidual regulatory T cell activation, expansion, and effector function.
• Epigenetic regulation of maternal immune function during pregnancy, and the impact of this regulation on the developing fetal immune system.
• Role of maternal cytokines during infection at the placental interface and their impact on the development of fetal immune organs.
• Influence of maternal immunization or infection on the developing fetal immune system.
• Molecular mechanisms that regulate cytotoxicity of immune cells and promote maternal-fetal tolerance, while preserving the ability of these immune cells to respond to infections and/or vaccines.
• Regulation of inflammatory and anti-inflammatory mechanisms during the various stages of pregnancy.
• Inflammatory mechanisms and immune cell interactions during labor and parturition.
• Studies of postnatal immune system development and function in infants 6 months of age or younger to correlate the impact of the factors studied prenatally on fetal immune system development.
• Mechanisms by which infections are controlled at the placental-maternal immune system interface.
• Role(s) of inflammatory mediators during infection and impact on fetal outcome (e.g. preterm birth, spontaneous abortion, intrauterine growth restriction, brain injury).
• Mechanisms by which macrophages prevent inflammation during pregnancy.
• Mechanisms of apoptotic cell clearance and maintenance of homeostasis at the maternal-fetal interface.
• Microbiome and leukocyte interactions at the interface between the placenta and uterus
• Effects of infection and inflammation on regulatory T cell function, effector T cell activity, and extravillous trophoblast migration.
• Role(s) of cytotoxic decidual NK and virus-specific CD8+ T cells during placental infections.
• Mechanisms by which activated T cells with pathogen-specificity infiltrate the maternal-fetal interface.
• Identification of unique (non-maternal) immune responses in the fetus/infant that could serve as biomarkers of congenital infection (e.g., Zika virus, Cytomegalovirus).
• Role(s) of maternal and fetal/infant immune responses in the type and severity of symptoms of congenital infection.
• Determination of differences in maternal/fetal immune responses to primary infection vs. re-infection or reactivation, and correlation of these differences with the outcomes of infection.
• Elucidation of the effects of ionizing radiation during preimplantation, organogenesis or fetal stages on outcomes, including the developing fetal immune system. Emphasis is given to the use or development of appropriate animal models of exposures to elucidate health outcomes in the surviving offspring, and to test the effects and efficacy of FDA-approved medical countermeasures against radiation lethality on fetal development.

Areas of interest to NICHD: NICHD will support HIV/AIDS - related projects in the research areas defined by NIAID above, with emphasis on specific areas such as:

• Effects of HIV infection on the developing pre-birth immune system.
• Effects of HIV infection on placental development and changes after anti-retroviral treatment.

The FOA will support clinical trials where the primary objective is to obtain human samples for mechanistic studies of immune function. Such mechanistic trials include: administering licensed vaccines as standard of care in accordance with FDA guidance. The inclusion of human samples obtained from independently funded clinical trials also is permitted.

To assist in the overall evaluation of the research program, all awardees will participate in a kickoff meeting and subsequent annual meetings arranged by the NIAID and NICHD program officers, to be held in the Bethesda, MD area. The purpose of these annual meetings is to discuss individual program progress and foster collaborations among the funded investigators. All investigators are expected to attend these annual meetings, together with additional scientific staff from their research groups, when appropriate; and are expected to give oral presentations on current and planned projects/activities. The program progress meetings are open to investigators supported under this FOA and to NIH extramural staff.

Note that applications proposing any of the following topic areas will be considered nonresponsive and will not be reviewed:

• Clinical trials in which the primary objective is to test the safety or efficacy of an investigational vaccine, adjuvant or other product.
• Cancer studies, including those recruiting pregnant women undergoing cancer chemotherapy.
• Behavioral research or epidemiological studies.
• Studies in fetuses with known genetic abnormalities, including developmental defects.
• Studies in infants undergoing transplantation procedures; infants with autoimmune diseases or receiving immunosuppressive therapy.

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:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o 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).

Buttons to access the online ASSIST system or to download application forms are 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 Research (R) Instructions in the SF424 (R&R) Application Guide, 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:

Nancy Vazquez-Maldonado, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-5044
Email: nvazquez@niaid.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.

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:

In all project budget years, include funds for the PD(s)/PI(s) and key personnel to travel and attend annual programmatic meetings to be held over 1.5 days in the Bethesda, MD area.

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: Describe the central scientific theme of the proposed research program.

Research Strategy:

• Summarize the overall research plan for the application and explain how the proposed research program supports mechanistic, descriptive, and/or hypothesis-testing studies to understand immune responses and function at the maternal/fetal interface.
• Describe the potential gain in fundamental knowledge of immune interactions and functions at the maternal-fetal interface.
• Describe the novelty or innovation of the research in terms of how the outcome will lead to new and potentially transformative discoveries in the role and mechanisms of immune cells during pregnancy.
• For descriptive studies, describe how the descriptive studies lay a foundation that may lead to the discovery of novel phenomena or major advances in the future. Demonstrate how the descriptive studies suggest and explore creative, original, or potentially transformative concepts in understanding immune interactions, function, and mechanisms at the maternal-fetal interface.
• Provide a plan for management and quality control of data for the proposed study, including the statistical design (including power calculations) and analysis plan for the animal studies.
• Demonstrate the feasibility of the proposed approach.
• For applications proposing the use of animal models, include a justification for the use of the proposed animal model with respect to their relevance to human pregnancy.

Letters of Support: Provide any institutional letters of support, memoranda of understanding (MOU) and letters of collaboration specific to the proposed research. For projects obtaining samples from independently funded clinical trials, include an MOU from the clinical trial director agreeing to provide samples according to a timeline established by the applicant. The MOU for the use of biological human samples should confirm agreement among the various parties that outlines their expectations of the agreement in the following areas: (1) ownership, analysis, access, and release of data from the proposed studies; (2) access to the data from the parent clinical trial (how/when) that is needed to analyze the data generated by the proposed studies, including procedures for prevention of unblinding of the parent trial; (3) documentation of quality assurance procedures for both the parent clinical trial and the proposed studies, and documentation of data and safety monitoring procedures for the parent clinical trial, especially for efficacy trials; (4) intellectual property management; and (5) publication of the proposed study results.

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.
• Applicants funded under this FOA will be expected to share their data to ImmPort or other public portals designated by NIAID. Therefore, the Resource Sharing plan should include a summary of how the applicant will manage data submission and interactions with the chosen portal(s).

Appendix:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide, with the following additional instructions:

• As an attachment, for completed or draft consent forms for the use of biological human samples from ongoing or completed clinical research, attach "Informed Consent to Use Samples." This attachment must contain copies of the completed or draft informed consent forms for the use of samples from ongoing or previous clinical research. Within the forms, the following items should be addressed: (1) additional blood or tissue that will be collected as part of the proposed study; (2) the right of the subjects to refuse to participate in the proposed study and still participate in the parent clinical research; (3) that no charges to the subject for participation in the proposed study are incurred; and (4) agreement to share the subject's de-identified data obtained from the proposed study as well as the parent trial. Any incentives provided to subjects to participate in the proposed study, if in addition to those under the parent clinical research, should be clearly described and justified; (5) indication that the samples can be used for third party analyses and proposed immune studies.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials (and when applicable, clinical trials research experience) 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 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:

Section 3 - Protection and Monitoring Plans

3.1 Protection of Human Subjects

3.1.1 Risks to Human Subjects

3.1.1.a Human Subjects Involvement, Characteristics, and Design

Additional Instructions

For studies involving the use of identifiable human biospecimens collected from independently funded clinical research, applicants should include both historical and current study information that is clearly distinguishable within the same study record when providing the information requested.

3.1.1.b Study Procedures, Materials and Potential Risks

Additional Instructions

For applications proposing to use samples from ongoing or completed clinical research, provide a timeline for the request, transportation and arrival of the biological samples, and the timeline associated with the preparation and use of the biological samples.

Delayed Onset Study

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

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.

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). 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.

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. For assistance with application submission, contact the Application Submission Contacts in Section VII.

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 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. 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.

In addition, for applications involving clinical trials:

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

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 there a strong scientific premise for the project? 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: For descriptive studies: Do the studies lay a foundation that may lead to the discovery of novel phenomena or major advances in the future?

In addition, for applications involving clinical trials

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Are the PD(s)/PI(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-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

In addition, for applications involving clinical trials

With regard to the proposed leadership for the project, do the PD(s)/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating 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?

In addition, for applications involving clinical trials

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the 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 children, justified in terms of the scientific goals and research strategy proposed?

Specific to this FOA: If applicable, is the proposed animal model appropriate and relevant to human pregnancy and the studies' scientific goals and research strategy?" If applicable, how well does the proposed animal model correspond to the same or similar developmental stage in human fetuses or infants? Do the proposed studies utilize novel and potentially transformative concepts for the understanding of immune interactions, functions, and mechanisms at the maternal-fetal interface? If applicable, do the consent forms provide sufficient detail to clarify the process of subject participation?

In addition, for applications involving clinical trials

Does the application adequately address the following, if applicable

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period 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?

In addition, for applications involving clinical trials

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

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.

Study Timeline

Specific to applications proposing clinical trials

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

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 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 (GDS).

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 NIAID, 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 on the basis of established PHS referral guidelines 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 appropriate national Advisory Council or Board. 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 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.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain "applicable clinical trials" on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration of all trials whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that the application as well as all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols. Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

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.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person's race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. 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. HHS provides general 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/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. 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. 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. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. 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 http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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 "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

Not Applicable

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 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.

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.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, 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 Award Term and Conditions 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 registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

Mercy PrabhuDas, Ph.D., M.B.A.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3534
Email: mprabhudas@niaid.nih.gov

Melody Mills, Ph.D.
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3318
Email: millsm@niaid.nih.gov

Denise Anne Russo, Ph.D.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6871
Email: DRusso1@mail.nih.gov

Nancy Vazquez-Maldonado, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-5044
Email: nvazquez@niaid.nih.gov

Donna Sullivan
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-2979
Email: dsullivan@niaid.nih.gov

Bryan Clark, MBA
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6975
Email: clarkb1@mail.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 .