Impact of Initial Influenza Exposure on Immunity in Infants (U01 Clinical Trial Not Allowed)

Impact of Initial Influenza Exposure on Immunity in Infants (U01 Clinical Trial Not Allowed) is sponsored by National Institutes of Health (NIH). Funds research to understand how initial influenza exposures influence immunity in infants and children, aiming to inform universal vaccine design.

Expired RFA-AI-18-010: Impact of Initial Influenza Exposure on Immunity in Infants (U01 Clinical Trial Not Allowed) This notice has expired. Check the NIH Guide for active opportunities and notices. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) of Participating Organizations National Institute of Allergy and Infectious Diseases ( NIAID ) Funding Opportunity Title Impact of Initial Influenza Exposure on Immunity in Infants (U01 Clinical Trial Not Allowed) U01 Research Project Cooperative Agreements Funding Opportunity Announcement (FOA) Number Companion Funding Opportunity Additional Information on Eligibility .

Catalog of Federal Domestic Assistance (CFDA) Number(s) Funding Opportunity Purpose The purpose of this Funding Opportunity Announcement (FOA) is to establish, follow, and characterize longitudinal cohorts of infants to determine how initial and repeated natural influenza infections and/or influenza vaccinations shape infant and childhood immunity to future influenza exposures.

The ultimate goal of this research is to provide key information to facilitate design of durable, broadly protective influenza Open Date (Earliest Submission Date) Letter of Intent Due Date(s) July 2, 2018, by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on this date.

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. AIDS Application Due Date(s) It is critical that applicants follow the Research (R) Instructions (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 I. Funding Opportunity Description Section II. Award Information Section III.

Eligibility Information Section IV. Application and Submission Section V. Application Review Information Section VI.

Award Administration Information Section VII. Agency Contacts Section VIII. Other Information Full Text of Announcement Section I.

Funding Opportunity Description The purpose of this Funding Opportunity Announcement (FOA) is to establish, follow, and characterize longitudinal cohorts of infants to determine 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 ultimate goal of this research is to provide key information to facilitate design of durable, broadly protective influenza vaccines.

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 pandemic strain.

Influenza viruses exhibit frequent antigenic change and influenza vaccines are developed against the strains predicted to circulate in the upcoming influenza season and those with significant pandemic potential. 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 most or all seasonal strains of influenza, as well as novel strains that could cause the next pandemic.

Humans encounter numerous influenza strains and receive numerous vaccinations throughout their lifetime. Immune response 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 ability to respond to subsequent novel strains, but that also can provide 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 negatively influence responses to subsequent influenza infections and vaccinations. Recent technological advances now allow for the collection of smaller blood volumes, increased cell recovery, and the need for fewer cells for detailed immunological analyses.

With these improvements, it is now possible to conduct detailed immunological studies from clinical samples from infants. Such studies would 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.

Additionally, 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.

This initiative is intended to support focused multi-disciplinary prospective longitudinal infant cohort establishment and immunological research studies to address critical knowledge gaps. Research Objectives and Scope Despite early exposure to natural influenza infection or repeat vaccinations, influenza infections continue to occur throughout life.

Numerous studies have shown that one's initial influenza infection impacts immunity to subsequent infections 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, vaccination, 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, the research initiative will support cohort establishment and analyses of infant cohorts 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 This initiative will support an integrated, synergistic, cross-disciplinary effort to generate, coordinate, and integrate data from clinical research 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 FOA requires applicants to establish 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 should occur minimally between birth and prior to initial influenza exposure.

These cohorts are expected to be enrolled over multiple influenza seasons and will 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.

Inclusion of domestic and international prospective cohorts Inclusion of pregnant women and post-partum mothers in the prospective cohorts is encouraged. The pregnant women should be followed at least through the last trimester of pregnancy and post-partum mothers following 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 should address the following topics: 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, including; in antibody titer, specificity and function, including changes in post-translational modifications B cell subset generation and maintenance, including plasmablasts, long-lived plasma cells and memory B cells; and the differentiation, specificity, function and maintenance of effector and memory T cell populations Comparison of immune mechanisms/components elicited by influenza vaccination versus natural infection, including: the cross-talk between components of innate and adaptive immunity elicited by influenza vaccination versus natural infection that impacts acquired influenza of B cell and T cell responses elicited by influenza vaccination versus natural 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) and stalk-binding assays.

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

Given the importance of this prospective cohort generation, all data generated by the funded program is expected to be deposited in the ImmPort database or other portal(s) approved by NIAID and biological samples should be made available to the scientific community.

Influenza sequence and related data are expected to be deposited in the NIAID-supported Influenza Research Program Infrastructure and Support The members of 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 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.

Management and Analysis Team The members of the Data Management and Analysis Team will be responsible for implementing procedures for the collection, oversight and inventory of data and biological samples, including, for example, harmonization, quality control, and uniformity of data collection processes, troubleshooting data system problems and developing solutions.

Team members will also 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. This team will serve as the hub for expertise with sharing data with ImmPort or other portal(s), approved by NIAID, and for study design planning and data analyses.

The members of the Clinical Support Team will be responsible for coordinating the functions at individual enrollment sites to facilitate multiple study procedures related to recruitment, enrollment, data and biological sample collection.

This team will serve as the process and procedure hub for the interaction among the clinical sites and other functional work An External Advisory Committee will be established to review progress and to provide recommendations to investigators as part of the annual programmatic meeting.

The EAC will also make recommendations regarding the continuation or re-direction of the research program on an ongoing basis and in consultation with NIAID staff. Note that applicants should not name or contact potential EAC members in their application.

The EAC will be established after A kick-off meeting and annual program meetings will be held to articulate and establish the major roles and functions of the program and to facilitate collaborations, provide progress reporting, seek new research directions and ideas, and update NIAID on issues of need.

These meetings will be attended by the PD(s)/PI(s), Key personnel, NIAID staff, and the EAC Note that applications proposing any of the following topic nonresponsive and will not be reviewed : Applications that are not focused on understanding how initial and repeated natural influenza infections and/or influenza vaccinations shape infant and childhood immunity to future influenza exposures. Any Phase clinical trials.

HIV, SIV or AIDS studies. Genome-wide association studies (GWAS). VIII.

Other Information for award authorities and regulations. Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities.

See Section VI. 2 for additional information about the substantial involvement for Application Types Allowed Glossary and the SF424 (R&R) Application Guide provide details on Not Allowed: Only accepting applications that do not help determining whether you are doing a clinical trial? Funds Available and Anticipated Number of Awards NIAID intends to commit $5.

0 million in FY 2019 to Recommended budgets for direct costs of up to $3. 1 million per year may be requested. The scope of the proposed project should determine the project period.

The maximum period is 7 years. 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 Nonprofits Other Than Institutions of Higher Education Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Nonprofits without 501(c)(3) IRS Status (Other than Institutions For-Profit Organizations (Other than Small Businesses) City or Township Governments Special District Governments Indian/Native American Tribal Governments (Federally Recognized) Indian/Native American Tribal Governments (Other than Federally Eligible Agencies of the Federal Government U.S. Territory or Possession 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 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 Foreign components, as defined in the NIH Grants Policy Statement , are allowed. 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 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 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. 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 must have an active DUNS number and SAM registration in order to complete the 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.

Eligible Individuals (Program Director/Principal 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 This FOA does not require cost sharing as defined in the NIH Grants Policy Statement . 3.

Additional Information on Eligibility 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 A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission 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 ). Section IV. Application and Submission Information 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. 2. Content and Form of Application Submission It is critical that applicants follow the Research (R) Instructions (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 For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant 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 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: All page limitations described in the SF424 Application Page Limits must be followed, with the following exception: For this specific FOA, the Research Strategy is limited to Instructions for Application Submission The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an All instructions in the SF424 (R&R) Application Guide SF424(R&R) Project/Performance Site Locations All instructions in the SF424 (R&R) Application Guide SF424(R&R) Other Project Information All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions: and Other Resources : In separate section titled "Information Technology Access," include a brief description of the features of the institutional environment that are relevant to the effective implementation of the proposed unified collaborations across Teams and functions.

Describe available 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," describe the facilities available to 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 SF424 (R&R) Application Guide must be followed.

with the following additional instructions: Within the Biosketch under Personal Statement, describe the leadership approach and experience of the PD(s)/PI(s) with respect to developing and executing multi-disciplinary research program(s) of a similar Within the Biosketch under Personal Statement, all Key Personnel should 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.

All instructions in the SF424 (R&R) 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 and up to five members of the EAC to travel and attend a kickoff meeting to be held shortly after the award over 1 full day in the Bethesda, MD area.

Beginning in Year 02, include funds in the budget for 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 submission of data into the ImmPort database or other publicly accessible portal(s) approved by NIAID.

Also include costs associated with biological sample collection, processing, If applicable, include costs associated with clinical protocol development, informed consent form development, development of a manual of procedures for the clinical protocol, development of case report forms, training of clinical personnel prior to protocol initiation (e.g., cGCP and protocol-specific training), clinical study monitoring, and capturing and reporting adverse events related to any procedure, and handling protocol All instructions in the SF424 (R&R) Application Guide PHS 398 Cover Page Supplement All instructions in the SF424 (R&R) Application Guide All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions: 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 longitudinal cohorts and immunological studies.

Concisely describe the hypothesis or hypotheses to be tested.

Indicate how the work proposed dovetails to address the overall goals and objectives of the Describe how establishment and immunologic analyses of prospective cohorts will determine how initial and repeated natural influenza infections and/or influenza vaccinations impact infant and childhood immunity to future 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 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 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, and describe how the staff at each enrollment/collection site will be trained and comply with the quality standards for data and sample collection and compliance with the standardized procedures.

In a separate section labeled, "Administrative Management Plan," describe the administrative and organizational structure of the research study and the unique features of the organizational structure that serve to facilitate accomplishment of the long-range goals and objectives. Describe how functional work Teams will provide relevant input and support for the Cohort establishment for addressing the research hypotheses.

Describe the overall management plan, including how resources will be managed, organized and prioritized, and how subcontracts and consultants, if applicable, will be selected/funded and monitored. Describe how communications will be planned, implemented and provided to collaborators, teams or sites.

Describe an overall plan for nominating, vetting, and inviting membership on the EAC and for including the EAC recommendations in the overall research direction and progress towards milestones of the award. The EAC will be developed in collaboration with NIAID. Note that applicants should not name or contact potential EAC members in their application.

Without repeating information from individual biosketches, describe the team's experience with designing and implementing infant cohorts, and past accomplishments, specifically related to cohorts. In addition, describe plans to achieve synergy and interaction among key investigators to ensure efficient cooperation, communication and coordination across the multiple sites and Team structure.

In a separate section labeled, "Data Management Plan," describe internal and external data acquisition strategies to achieve harmonization of systems and procedures for data management, data quality, data analyses, and dissemination for all of the data and data-related materials generated by the research study.

Describe how uniformity of procedures and high-quality content from all study sites and the research study, in terms of the data collection, management and storage functions. Within the plan, indicate 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 how training for the data and sample collection, in terms of the use of electronic data capture systems, will be provided to all staff including those at enrollment sites. Describe how these data taken together will address the overall goals and objectives of the research study.

In a separate section labeled, "Statistical Analysis Plan," describe the overall plan for biostatistical support systems and personnel to perform the following functions in support of the research project, 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 achieve adequate sample size to achieve the needs of the research program. Describe how unique and innovative approaches to statistical analysis of prospective observational cohort data will achieve the aims of the research study. Describe the plan to support the data analytics and design features unique to the research study.

In a labeled section called, Project Milestones, describe specific quantifiable milestones by annum, and include annual projections for the overall research study and for tracking progress from individual sites, collaborators, and Teams. Milestones must specify the outcome(s) for each activity.

Milestones should be quantifiable and scientifically justified, and 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. Milestone criteria should not simply be a restatement of the specific aims.

Using a Gantt chart or equivalent tool, describe the associated timelines and identified outcomes for the research study. 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.

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

Within that plan, applicants should describe plans for transfer and uploading of all types of data from the program into the ImmPort database or other publicly accessible portal(s) approved by NIAID. Applicants are also expected to provide a timeline for the planned acceptance, quality check, transfer and upload of data of all types.

All investigators funded under this FOA will be expected to share their data through ImmPort or other portal(s) approved by NIAID, as well as any collected biological samples. Therefore, the Resource Sharing plan should include a summary of how the applicant will manage data submission and interactions with the chosen portal(s), as well as sharing of biological samples with the scientific community.

of Support : Provide all appropriate letters of support, including any letters necessary to demonstrate the support of consortium/site Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide, with the following modifications: As the first attachment, for clinical research protocol(s), attach "Clinical Research Protocol."

This attachment should contain the complete clinical research protocol. As the second attachment, attach the informed consent forms for the proposed research project, "Informed Consent Forms."

Include the following items in the consent form or draft informed consent form(s): (1) all data and biological sample types that will be collected as part of the proposed study; (2) that no charges to the subject for participation in the proposed study are incurred; and (3) agreement to share the subject's de-identified data obtained from the proposed study.

Any incentives provided to subjects to participate in the proposed study should be clearly described and justified. As the third attachment, attach the informed assent forms for the proposed study, "Assent Forms."

PHS Human Subjects and Clinical Trials Information 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 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 2 - Study Population Describe in detail the inclusion and exclusion criteria for subject selection with respect to the required conditions: infants before initial influenza vaccination, infants after initial influenza vaccination, infants before initial documented clinical diagnosis of influenza (i.e. clinician confirmed, molecularly diagnosed, and subtyped confirmed