Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization. 

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the NOFO) 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.

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

1. Use the NIH ASSIST system to prepare, submit and track your application online.
2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.
3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Purpose

The purpose of this notice of funding opportunity (NOFO) is to support the establishment or continuation of longitudinal infant cohorts to determine and compare how initial and repeated natural influenza infections and/or influenza vaccinations shape infant and childhood immunity to future influenza exposures. Research supported under this program will define and characterize immunity acquired upon initial exposure to influenza antigens from natural infections and/or vaccinations and examine how these exposures influence immune responses to subsequent influenza infections and/or vaccines. The goal of this research is to provide key information to facilitate design of durable, broadly protective influenza vaccines.

Background

Seasonal influenza outbreaks occur annually and cause significant worldwide morbidity and mortality, particularly in vulnerable populations such as infants, young children, and the elderly. An even greater threat to the general population is the ever-present and unpredictable emergence of a novel viral strain for which humans may have limited to no pre-existing immunity. Because influenza viruses exhibit frequent antigenic change, influenza vaccines are developed against the strains predicted to circulate in the upcoming influenza season and novel strains that have the potential to widely infect humans. Therefore, annual vaccination remains the cornerstone for the control of influenza. Seasonal influenza vaccines typically contain two strains of influenza A (H1N1 and H3N2) virus and one or more influenza B viruses formulated as trivalent or quadrivalent vaccines, respectively. Currently available influenza vaccines provide suboptimal protection against seasonal influenza and provide limited protection against newly emerging strains. Numerous factors can significantly reduce vaccine effectiveness to circulating strains and contribute to waning immunity. A major advancement in influenza control would be the development of a vaccine that confers broad, robust, and durable protection against many or most seasonal strains of influenza, as well as novel strains that could cause significant morbidity and mortality in humans.

Humans encounter numerous influenza strains and may receive numerous vaccinations throughout their lifetime. Immune responses to these exposures are determined by the genetics of the infecting viruses and intrinsic factors, including host genetics, exposure and vaccination history, age, the presence or absence of chronic illnesses, and immune status. Additionally, one's initial infection with an influenza virus impacts immunity, including antibody responses, to subsequent infections with new strains. This concept of "original antigenic sin" was proposed in 1960 by Thomas Francis, Jr. to describe the impact of pre-existing immunological memory from an initial influenza encounter upon exposure to a different influenza virus. Recent epidemiologic evidence suggests that exposure during early childhood elicits a lifelong immunologic "imprint" that impacts the response to subsequent novel strains, including providing protection against novel hemagglutinin (HA) subtypes from the same phylogenetic group as the original infecting virus. Immunological "imprinting" has important implications for public health because it may also negatively influence responses to subsequent influenza infections and vaccinations. A better understanding of “imprinting” could allow it potentially to be harnessed for future vaccine design that provides infants with a broader immune landscape and protection from subsequent infections.

Understanding how infants' immune responses are altered or expanded by their encounter with subsequent influenza infections and/or vaccinations will be critical to define the breadth of immunological coverage that can be achieved with an effective universal influenza vaccine. Detailed immunological studies of clinical samples from infants will provide new insights into the mechanisms by which immunity is acquired following initial exposure to influenza via infection or vaccination and help define which influenza antigen/epitope-associated responses result in more broad-based immunity. This initiative is intended to support the establishment or continuation of focused, multi-disciplinary, prospective studies of longitudinal infant cohorts and immunological research studies to address critical knowledge gaps.

Research Objectives and Scope

Despite early exposure to natural influenza infections or vaccinations, influenza infections continue to occur throughout life. Numerous studies have shown that one's initial exposure to influenza impacts immunity to subsequent exposures with different influenza strains. However, the impact of initial influenza infections and/or vaccinations on immunity to subsequent influenza exposures is not well understood. This initiative responds to the need for increased investments in clinical and basic research in well-characterized infant cohorts by exploring the impact of birth year, initial and subsequent vaccinations, and natural infections on influenza immunity. Recent innovations in the study of human immunology coupled with other advanced technologies can be leveraged to determine the critical immune components required for generation, maintenance, and evolution of broadly protective immunity against influenza in humans. Specifically, this research initiative will support the establishment or continuation of infant cohorts coupled with immunological analyses to determine how initial natural influenza exposure and/or primary influenza vaccination shape infant and childhood immune responses to subsequent influenza infections and/or vaccines. The findings from this research will help to advance the design of a universal influenza vaccine.

This initiative will support a synergistic and cross-disciplinary effort to generate, coordinate, and integrate data from human clinical samples to address critical questions in influenza immune "imprinting" research. The study findings will be made available to the public as rapidly as possible. The clinical data and biological samples collected from the cohort(s) are expected to be available for sharing and use by the scientific community to continue research in this important field, as appropriate and consistent with achieving the goals of the program.

This NOFO requires applicants to establish or continue prospective cohort(s) of infants that will be followed prior to and after:

• receiving their initial influenza vaccination (i.e., clinician routinely recommended vaccine); and/or
• having an initial documented clinical diagnosis of influenza infection (i.e., clinician confirmed, molecularly diagnosed, and subtyped confirmed) prior to receiving their initial influenza vaccination.

Infant enrollment ideally should occur between birth and prior to initial influenza exposure. These cohorts are expected to be followed for at least three influenza seasons, with desired capabilities to follow for longer periods, to understand the impact of initial and subsequent influenza infections and/or vaccinations on the breadth and quality of influenza-specific humoral and T cell-mediated immune responses, as well as innate immune responses triggered by influenza vaccines or natural infections.

This program supports inclusion of domestic prospective cohorts and appropriate international cohorts, especially from countries where infection or vaccination rates complement those seen in the U.S. Inclusion of relevant international cohorts facilitates recruitment and retention of additional participants, allowing for experimental and statistical validation of research results and strengthening clinical applications.

Inclusion of pregnant women and post-partum mothers in the prospective cohorts is strongly encouraged. Pregnant women should be followed at least through the last trimester of pregnancy and post-partum mothers followed through infant weaning. Each mother's influenza exposure history (i.e., vaccine and natural infection) and circulating influenza-specific antibody responses should be captured during pregnancy, immediately post-partum, and through weaning in order to examine the effects of maternal influenza exposure and circulating maternal anti-influenza antibodies on infant immune responses to influenza vaccines or natural infection.

Areas of research must address both topics listed below (identified as 1 and 2):

1. Determination of the effect of repeated exposures to infections and/or vaccinations on the maintenance and evolution of influenza-specific humoral and T cell-mediated immunity in infants/young children.

Within this topic, examples of areas of research include:

• Changes in antibody titer, specificity and function, including changes in post-translational modifications;
• Impact on B cell subset generation and maintenance, including plasmablasts, long-lived plasma cells and memory B cells;
• Impact on the differentiation, specificity, function and maintenance of effector and memory T cell populations;
• Impact on the differentiation, specificity, and function of innate cell populations (e.g., trained immunity).
   

2. Comparison of immune mechanisms/components elicited by influenza vaccination versus natural infection.

Within this topic, examples of areas of research include:

• Understanding the cross-talk between components of innate and adaptive immunity elicited by influenza vaccination versus natural infection that impacts acquired influenza immunity;
• Comparison of B cell and T cell responses elicited by influenza vaccination versus natural infection;
• Comparison of the quality and functionality of antibodies induced by natural infections or vaccination, including hemagglutination inhibition assay (HAI), neutralizing antibody responses, neuraminidase antibody responses, as well as antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), antibody-dependent complement deposition (ADCD), and stalk-binding assays;
• Impact of other respiratory virus infections or routine childhood vaccinations on anti-influenza immunity;
• Impact of maternal anti-influenza immune status on offspring’s immune response to initial influenza vaccine or infection (in neonatal period prior to weaning).

The approach taken to establish, maintain, and characterize the cohort, including determination of the type of experimental and clinical data and biological samples to collect, should provide the greatest degree of innovation possible to advance our understanding of rational universal influenza vaccine design for this vulnerable population.

Program Infrastructure and Support

Administration and Leadership Team
The Administration and Leadership Team, led by the Program Director(s)/Principal Investigator(s) [PD(s)/PI(s)], will be responsible for organizing, coordinating, and providing oversight for the implementation and execution of activities that facilitate progress and completion of the research project. This team will serve as the administrative oversight, coordination, and communications hub for the entire study. The Administration and Leadership Team will also work with the Data Stewardship and Analysis Team to develop efficient and statistically powered study designs and provide support for the preliminary and final data analyses for the research.

Data Stewardship and Analysis Team
The Data Stewardship and Analysis Team will be responsible for the range of activities related to data including: collection, management, analyses, quality assurance and standards, and development of statistically powered study designs for the study. The Data Stewardship and Analysis Team will also implement processes and procedures for receipt, storage, retrieval, and inventory of biological specimens, harmonization of specimens to clinical and experimental data (including metadata), tracking and monitoring of biological specimen use, storage, and/or distribution, and executing data sharing agreements among recipients of these awards, and for sharing of data/meta-data with the broader research community including public repositories recommended by NIAID program staff. Team members will work with key personnel to develop efficient study designs and statistical calculations and provide support for the preliminary and final data analyses for the study.

Clinical Research Support Team
The Clinical Research Support Team will be responsible for leading and coordinating the activities associated with human subjects’ research across the study, including for example, multi-site coordination, pre-study community outreach, tracking and monitoring enrollment, recruitment, maintenance, and status of regulatory documents with data collection and reporting, and compliance with human subjects’ research data and quality procedures. This team will serve as the process and procedure hub for the interaction among the clinical sites and other functional work areas.

External Advisory Committee (EAC)
An External Advisory Committee will be established post-award by NIAID to review progress and to provide recommendations to investigators as part of the annual programmatic meeting. The EAC membership will consist of scientific experts in the fields of infant and child health, immunology, and influenza virology. Following establishment, the EAC will meet annually to review the progress of the recipient projects and make recommendations to the PDs/PIs regarding direction of the research program on an ongoing basis and in consultation with NIAID staff. Note that  new applicants should not contact, recruit, or name potential EAC members until application review activities are completed. For a renewal application, applicants should provide the names of current and former members but should not recruit or name new members until application review activities are completed.

Annual Programmatic Meetings
In the first year of the award, a kick-off meeting will be held to articulate and establish the major roles and functions of the program. Beginning in year 02 of the award and annually thereafter, a program meeting will be held to facilitate collaborations, provide progress reporting, seek new research directions and ideas, and update NIAID. These meetings will be attended by the PD(s)/PI(s), key personnel, EAC members, the NIAID Project Scientist, other NIAID personnel, and other relevant interest holders.

Opportunity Fund
In consultation with NIAID, each recipient will develop and manage an Opportunity Fund that is intended to support research in new or emerging research, promote sharing of resources and expertise, and other collaborative activities consistent with the research objectives of the award. The recipient will be responsible for developing the specific processes necessary for solicitation, review, selection, and implementation of small pilot projects awarded through the Opportunity Fund. These small projects may include for example, collaborative pilot/feasibility projects among recipients, early-stage investigator or trainee research projects, or other activities that further the collaborative objectives and goals among the recipients.

Applications proposing any of the following topic areas will be considered nonresponsive and will not be reviewed:

• Applications that are not focused on the effect of repeated exposures to natural infections or vaccinations on the maintenance and evolution of influenza-specific humoral and T cell-mediated immunity in infants and children.
• Clinical trials; however, clinical research and research using samples from human subjects are allowed.
• Studies on HIV, SIV or AIDS.
• Studies using animals or animal models.
• Genome-wide association studies (GWAS).
• Behavioral research.

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions - Includes all types

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

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)

Local 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).

Federal Governments

• 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 Organizations)

Foreign Organizations/International Collaborations

Non-domestic (non-U.S.) Entities (Foreign Organizations) 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.

NIH will no longer issue awards (i.e., new, renewal, or non-competing continuation) to domestic or foreign entities that involve foreign subawards/subcontracts. All NIH-funded research involving foreign subawards/subcontracts must be submitted in response to a NOFO that is specifically designated for funded international collaborations. This new requirement was effective, May 1, 2025.

Applications involving foreign subawards/subcontracts submitted in response to this NOFO will be deemed noncompliant and will not be considered for funding. This policy applies to all monetary international collaborations resulting in foreign subawards/subcontracts, however, it does not preclude unfunded international collaborations or foreign components, funding for foreign consultants, or procurement of unique equipment or supplies from foreign vendors.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the How to Apply- 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. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information.

• System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registrations; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov – Applicants must have an active 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 their organization to develop an application for 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 How to Apply-Application Guide.

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility

Number of Applications

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

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

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

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise (in this NOFO, in a policy notice, or other notice from NIH Guide for Grants and Contracts). 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.

Page Limitations

All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed, with the following exceptions or additional requirements:

For this specific NOFO, the Research Strategy section is limited to 30 pages.

The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO.

SF424(R&R) Cover

All instructions in the How to Apply - Application Guide must be followed.

SF424(R&R) Project/Performance Site Locations

All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Other Project Information

All instructions in the How to Apply- Application Guide must be followed, with the following additional instructions:

Facilities and Other Resources:

• In separate section titled "Information Technology Access," briefly describe the features of the institutional environment that are relevant to the implementation of the proposed unified collaborations across teams and functions. If applicable, describe available information technology (IT) resources associated with the enrollment and field sites with respect to access to computers, source and status of reliable, secure internet connections, and other communications.
• In a separate section titled "Biological Sample Storage and Access," briefly describe the facilities available to securely store, manage, and retrieve biological specimens for use by the PD(s)/PI(s) and key personnel.

SF424(R&R) Senior/Key Person Profile

All instructions in the How to Apply- Application Guide must be followed, with the following additional instructions:

• Within the Biosketch under Personal Statement, describe how all Key Personnel demonstrate strong administrative, technical, and management expertise in areas critical to the success of the application, including experience working productively in team collaborative environments. Demonstrate how specific expertise supports the multi-disciplinary approach to guarantee a successful, integrated effort towards the goals of the research project.

R&R or Modular Budget

All instructions in the How to Apply- Application Guide must be followed, with the following additional instructions:

• In Year 01, include funds in the budget for the PD(s)/PI(s), collaborators, site-specific personnel, and other key personnel to travel to and participate in a kickoff meeting to be held shortly after the award over one full day in the Bethesda, MD area. Beginning in Year 02, include funds in the budget for the PD(s)/PI(s), collaborators, site-specific personnel, and other key personnel to travel to and participate in an annual program meeting to be held over two full days in the Bethesda, MD area. Do not include costs associated with organizing and holding the kickoff or annual program meetings.
• Include costs associated with biological specimen collection, processing, shipping, and storage as well as costs for depositing reagents, research data/associated metadata, and tools to NIAID-supported repositories (see listing of repositories here: https://www.niaid.nih.gov/research/resources).
• Opportunity Fund: Beginning in Year 02, applicants are expected to budget at least $100,000 each year in direct costs to support 1 – 2 activities or projects per year through this fund.

R&R Subaward Budget

All instructions in the How to Apply - Application Guide must be followed.

PHS 398 Cover Page Supplement

All instructions in the How to Apply - Application Guide must be followed.

PHS 398 Research Plan

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

Specific Aims: List in priority order, the broad, long-range objectives and goals of the proposed research, and indicate how these goals will be accomplished based on the proposed studies. Concisely describe the hypothesis or hypotheses to be tested. Indicate how the outcomes from the proposed hypotheses coalesce to support the overall goals and objectives of the research.

Research Strategy:

• Describe how the structure of prospective cohorts and immunologic analyses will determine how initial and repeated natural influenza infections and/or influenza vaccinations impact infant and childhood immunity to future influenza exposures.
• Describe the methods that will be used to detect subclinical influenza infections in all cohorts and if applicable, differentiate circulating maternal influenza-specific antibodies from infant-generated antibodies.
• Describe the immunologic analyses that will be conducted to quantitate and characterize humoral and cell-mediated immune responses generated by initial and subsequent influenza vaccinations or natural influenza infections. Describe strategies for oversight and implementation of standardized approaches in the identification and clinical characterization of human subjects, including the clinical meta-data that will be captured.

In separate sections within the Research Strategy, using the suggested titles below, include the following:

Administrative Plan:

• Describe the administrative and organizational structure of the research study and the unique features of the organizational structure that will promote success of the long-range goals and objectives. Describe how functional work teams will provide relevant input and support for the cohort establishment to address the research hypotheses.
• Describe the overall management plan, including the organizational structure of the Administrative Leadership Team, governance, staffing plan, lines of authority, the process for tracking and monitoring progress, the fiscal management plan, and other administrative procedures to ensure progress in meeting the goals and objectives of the research.
• Describe how communications will be planned, implemented, and provided to collaborators, teams, or sites.
• Without repeating information from individual biosketches, describe the team's experience with designing and implementing infant cohorts, and past accomplishments specifically related to cohorts.
• Describe plans to achieve synergy and interaction among key investigators to ensure efficient cooperation, communication and coordination across the multiple sites and team structure.

Data Stewardship and Analysis Plan:

Without duplicating information included in the Data Management and Sharing Plan (DMSP), describe the following:

• The role of the Data Stewardship and Analysis Team in oversight, implementation, and management of the data stewardship and analysis plan.
• The overall plan and approach for biostatistical support systems; for example: 1) preliminary data analyses, 2) estimates of power and sample size, 3) research study design and protocol development. Describe plans to estimate and acquire adequate sample size to achieve the needs of the research program. Describe the plan to support the data analytics and design features unique to the research study.
• Internal data acquisition strategies to achieve harmonization of systems and procedures for data management, data quality, data analyses, and dissemination within the funded project(s) for data and data-related materials generated by the research.
• The extent to which dedicated systems or procedures will be utilized to harmonize the acquisition, curation, management, inventory, and storage of data and samples. Describe the training for the data and sample collection, in terms of the use of electronic data capture systems, that will be provided to all staff including those at enrollment sites.
• Quality control procedures for the data and biological specimens and how to identify and resolve issues with quality control that serves to maintain the integrity of data and specimens.
• Site-specific Information Technology (IT) resources for data/metadata and facilities for biological sample storage to support the activities of the study.

Clinical Management Plan:

Without duplicating information included in the PHS Human Subjects and Clinical Trials Information Section or Research Strategy, describe the following:

• The role of the Clinical Research Support Team in oversight, implementation, and management of the clinical management plan.   
• Plans for clinical research site selection including feasibility, capacity, and capabilities, and study development, conduct, and oversight.
• Strategies for oversight and implementation of standardized approaches in the recruitment and clinical characterization of adequate numbers of relevant human subject populations. Describe the process to ensure the prompt screening, enrollment, retention, and completion of studies. Describe novel approaches and solutions to study enrollment.
• Plans for comprehensively training clinical research site staff to ensure timely execution or completion of the research and compliance with all necessary regulations, policies, or laws.
• The process for training the staff at each enrollment/collection location to ensure high quality capture of all data types (e.g. clinical visit data, biological specimen collection, etc.), uniform data collection, and compliance with any standardized procedures.

Opportunity Fund:

Describe the following:

• The strategic approach to the Opportunity Fund and how it will support the research objectives of the award, including management of the processes and procedures for solicitation, review, selection, prioritization, development, and implementation of activities related to the use of the Opportunity Fund.

Project Benchmarks and Timelines:

Describe the following:

• Specific quantifiable benchmarks by annum, including annual projections for the overall research study and for tracking progress from individual sites, collaborators, and teams.
• How benchmarks will be developed specifically for the outcome(s) for each activity. Benchmarks should be quantifiable, scientifically justified, and feasible. Benchmarks should include the completion of major research study activities, including, for example, protocol development, case report forms, scheduled clinical visits, obtaining clearances, study completion, and analysis of final data. Benchmark criteria should not simply be a restatement of the specific aims.
• The associated timelines and identified outcomes for the research study, using a Gantt chart or equivalent tool, accounting for start-up activities (if applicable), engagement of multiple enrollment sites, the accurate identification and subsequent enrollment of participants, and all planned assessment and measurements on subjects (including collection of biological samples). Within this section, consider the use of existing resources that would facilitate the progress of the project in terms of enrollment or data collection, for example, practice-based research networks, electronic medical records, administrative database, or patient registries.

Letters of Support: Provide all appropriate letters of support, including any letters necessary to demonstrate the support of consortium/site participants.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply - Application Guide.

 Other Plan(s): 

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.
• All investigators funded under this NOFO are expected to share their data publicly through the ImmPort database or other public portals approved by NIAID. Therefore, the Data Management and Sharing Plan should include a summary of how the applicant will manage data submission and interactions with ImmPort. Influenza sequence and related data are expected to be deposited into GenBank.  

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply - Application Guide.

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply- 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 How to Apply - Application Guide must be followed.

Section 2 - Study Population Characteristics

2.2 Eligibility Criteria
Describe the planned selection process, accounting for infants before and after initial influenza vaccination and infants before and after initial documented clinical diagnosis of influenza, and how the plan accounts for the inherent complexities of the inclusion and exclusion process.

2.3 Age Limits
Describe the approach to enrolling age-appropriate infants for at least three influenza season cycles and how it will promote success of the overall program.

2.4 Inclusion of Women and Minorities
As applicable, discuss the complexities surrounding the enrollment of children, pregnant women, and fetuses to achieve varied representation.

2.5 Recruitment and Retention Plan
Describe how subjects for enrollment will be identified to enable implementation of the inclusion and exclusion criteria, and detail the verification process (e.g., medical record, clinical diagnostic tests) for conditions requiring verification (i.e., vaccination, influenza assay) through at least three influenza season cycles.

2.7 Study Timeline
If applicable, address the timeline for the planned enrollment process with respect to the required conditions of the subject pool.

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
Describe the  power analyses with respect to exposure, vaccination, and age-matched control subjects; and describe how the cohort will achieve adequate sample/subject size to support the successful completion of the goals and objectives of the proposed research project.

3.1.2 Adequacy of Protection Against Risks

3.1.2.a. Informed Consent and Assent
Describe the unique consent and assent procedures to ensure protections for the diverse sample of human subjects (e.g., pregnant women/fetus, neonates, young infants, children) necessary to achieve success of the overall program.

Delayed Onset Study

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

PHS Assignment Request Form

All instructions in the How to Apply- Application Guide must be followed.

Foreign Organizations

Foreign (non-U.S.) organizations must follow policies described in the NIH Grants Policy Statement, and procedures for foreign organizations described throughout the How to Apply- Application Guide.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 2. 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

4. Submission Dates and Times

Part I. 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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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 How to Apply-Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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 Section 7.9.1 Selected Items of Cost.

Applications must be submitted electronically following the instructions described in the How to Apply 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 How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form. 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 NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply 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. 

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113 and NIH Grants Policy Statement Section 4.1.35.

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at grantdisclosures@oig.hhs.gov.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy

Section V. Application Review Information

1. Criteria

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

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following scored review criteria and additional review criteria (as applicable for the project proposed). An application does not need to be strong in all categories to be judged likely to have a major scientific impact.

Reviewers will consider Factors 1, 2 and 3 in the determination of scientific merit, and in providing an overall impact score. In addition, Factors 1 and 2 will each receive a separate factor score. 

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

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.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the Center for Scientific Review, in accordance with NIH peer review policies and practices, 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 will receive a written critique.

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.

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

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 NOFO. 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.

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 Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov. NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

3. Anticipated Announcement and Award Dates

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 Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient’s business official.

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

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk.  For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process.

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

2. Administrative and National Policy Requirements

The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities.

All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.

By applying for or accepting federal funds from HHS, recipients certify compliance with all federal antidiscrimination laws and these requirements and that complying with those laws is a material condition of receiving federal funding streams. Recipients are responsible for ensuring subrecipients, contractors, and partners also comply.

Applicants and recipients are strongly encouraged to refer to the NIH Director’s Statement of Priorities, entitled “Advancing NIH’s Mission Through a Unified Strategy.” 

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations. Pursuant to 2 CFR 200.340, by accepting an NIH award, the recipient agrees that continued funding for the award is contingent upon the availability of appropriated funds, recipient satisfactory performance, compliance with the Terms and Conditions of the award, and may also otherwise be terminated, to the extent authorized by law, if the agency determines that the award no longer effectuates the program goals or agency priorities, in line with 2 CFR 200.340(a)(4).

Pursuant to the Cybersecurity Act of 2015, Div. N, § 405, Pub. Law 114-113, 6 USC § 1533(d), the HHS Secretary has established a common set of voluntary, consensus-based, and industry-led guidelines, best practices, methodologies, procedures, and processes.

Successful recipients under this NOFO agree that:

When recipients, subrecipients, or third-party entities have:

1. ongoing and consistent access to HHS owned or operated information or operational technology systems; and 
2. receive, maintain, transmit, store, access, exchange, process, or utilize personal identifiable information (PII) or personal health information (PHI) obtained from the awarding HHS agency for the purposes of executing the award.

Recipients shall develop plans and procedures, modeled after the NIST Cybersecurity framework, to protect HHS systems and data. Please refer to NIH Post-Award Monitoring and Reporting for additional information. 

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 (HHS) grant administration regulations at 2 CFR Part 200, and other HHS, PHS, and NIH grant administration policies.

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

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

• Planning, directing, and executing the proposed research study through oversight, management, and coordination of the participating sites, personnel, and outcomes.
• Serving as the administration oversight for the proposed research.
• Publishing research results in peer-reviewed journals, presenting research outcomes at professional meetings, and providing research updates at annual program meetings.
• Recipients will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current 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:

• Monitoring scientific progress of the research, including recommending modifications to experimental approaches (which will require prior approval). The NIAID project scientist will support and coordinate this process but will not direct it.
• Advising recipient on the development and modification of benchmark plans (which will require prior approval).
• Advising on project or program modifications to ensure projects are compliant with NIH, HHS, and other relevant policies.
• Advising on the selection of and facilitating access to NIAID-supported resources and services.
• Assisting with prioritization of resources and implementation of data and resource sharing plans.
• Providing advice on scientific, operational, or administrative activities to facilitate progress and implementation of collaboration(s) related to the overall goals and objectives of the program.
• Establishing an External Advisory Committee (EAC) and attending EAC meetings.
• Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

• Reviewing the entirety of program benchmarks annually and updating them based on recommendations from the EAC.
• Prioritizing the selection of projects for support by the Opportunity Fund to meet the program goals of the U01 and reporting outcomes to NIAID and the EAC.
• Coordinating the scientific objectives and progress at the annual meetings to facilitate the achievement of program goals.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between recipients and NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened: a designee of the recipient, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and HHS regulation 45 CFR Part 16.

Consistent with the 2023 NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement Section 8.4.1 Reporting. To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting.

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 Section 8.6 Closeout. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

Section VII. Agency Contacts

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

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

Grants.gov Support Center - Questions regarding Grants.gov registration and services (e.g., Workspace, subscriptions).

imprintingNOFO@mail.nih.gov

Center for Scientific Review (CSR)
Email: NOFOReviewContact@csr.nih.gov

NIAIDFinancial-GrantsContact@mail.nih.gov

Section VIII. Other Information

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 2 CFR Part 200.