Part 1. Overview Information

Participating Organization(s)
National Institutes of Health (NIH)

Components of Participating Organizations

National Institute of Allergy and Infectious Diseases (NIAID)

Funding Opportunity Title
Fc-Dependent Mechanisms of Antibody-Mediated Killing (U01 Clinical Trial Not Allowed)
Activity Code
U01 Research Project – Cooperative Agreements
Announcement Type
New
Related Notices
None
Funding Opportunity Announcement (FOA) Number
RFA-AI-18-042
Companion Funding Opportunity
PA-19-020, R21 Exploratory/Developmental Grant
Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.855  

Funding Opportunity Purpose

This Funding Opportunity Announcement (FOA) invites applications from institutions and organizations to conduct research focused on elucidating mechanisms of Fc-dependent, antibody-mediated killing of infected or aberrant cells, or antibody-mediated therapeutic ablation of cells implicated in immune pathologies, including autoimmune and allergic diseases. Studies supported by this FOA are expected to define variables that affect efficiencies of antibody-dependent cellular cytotoxicity (ADCC) and/or antibody-dependent cell-mediated phagocytosis (ADCP), both in vitro and in vivo. U01 awardees will be expected to attend annual Program Progress/Steering Committee meetings and present progress to fellow awardees and to NIAID program staff. The goal of the meetings is to facilitate collaborations between funded investigators and to accelerate development of mechanistic models that incorporate the collective findings of this program. Advances in our understanding of these Fc-dependent killing mechanisms will inform more efficient design and optimization of ablative antibody therapeutics and may also inform design of vaccines that preferentially elicit ADCC- or ADCP-efficient antibody responses.

This FOA uses the U01 grant mechanism, while the companion FOA, PA-19-020, uses the R21 mechanism. Short-term high risk/high reward projects with limited or no preliminary data or utilizing existing data may be most appropriate for the R21 mechanism.      

Key Dates

Posted Date
October 5, 2018
Open Date (Earliest Submission Date)
January 02, 2019
Letter of Intent Due Date(s)

January 2, 2019

Application Due Date(s)
February 1, 2019 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)
Not Applicable
Scientific Merit Review
June 2019
Advisory Council Review
October 2019
Earliest Start Date
December 2019
Expiration Date
February 02, 2019
Due Dates for E.O. 12372
Not Applicable
Required Application Instructions
It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide,except where instructed to do otherwise (in this FOA or in a Notice from 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.

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.
  4. Table of Contents

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose
 

The purpose of this Funding Opportunity Announcement (FOA) is to support research that addresses knowledge gaps in the mechanisms of Fc-dependent, antibody-mediated killing of infected or aberrant cells, or antibody-mediated therapeutic ablation of cells implicated in immune pathologies, including autoimmune and allergic diseases. Targets of therapeutic Fc-dependent, antibody-mediated killing include: pathogen-infected cells, malignant cells, and host cells implicated in immune pathologies (e.g., autoimmune and allergic disease). Studies supported under this program will be focused on either or both of two killing mechanisms: antibody dependent cellular cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP). There is growing recognition of ADCC and ADCP in humoral control of infection, a research area within the mission of NIAID. Progress in this area will enable more efficient design and optimization of ablative antibody therapeutics and may also inform the design of vaccines that elicit ADCC or ADCP-competent antibody responses. 
 

Background
 

Therapeutic monoclonal antibodies have shown much promise for the treatment of infectious and immune-mediated diseases and cancer. Antibodies contain two general types of domains; a bivalent F(ab')2 domain that is highly variable and responsible for the ability of antibodies to recognize an extraordinarily large universe of antigens, and a constant (Fc) region associated with functional activities. The subclass or isotype of the Fc region influences functional capabilities of the antibody. Among these functions are killing of pathogens or infected host cells through complement-mediated killing or killing of cells through binding of Fc domains to Fc receptor (FcR)-bearing effector cells.
 

There is growing recognition of the importance of two Fc/FcR-dependent mechanisms of antibody-mediated protection in the destruction of infected host cells. These mechanisms are dependent upon recruitment of effector cells bearing FcRs that, upon interaction with the Fc domains of antibodies bound to infected cells, are activated to deploy cytotoxic programs to destroy their targets.

 

The first mechanism is antibody-dependent cellular cytotoxicity (ADCC). Multiple effector cell types are competent to kill target cells via ADCC, at least under in vitro assay conditions. These cell types include: NK cells, neutrophils, macrophages, monocytes and eosinophils. These FcR-bearing effectors kill their targets through release of cytotoxic molecules following engagement of their FcRs by antibodies bound to the target cell surface.

 

The second mechanism is antibody-dependent cell-mediated phagocytosis (ADCP).  Multiple FcR-bearing effector cell types have demonstrated proficiency in ADCP, including neutrophils, macrophages, monocytes, and dendritic cells. In these cases, Fc/FcR interactions between target bound antibodies and FcR-bearing effector cells promote engulfment and destruction of target cells by effector cells.

 

For therapeutic applications, monoclonal antibody development is commonly focused on cytotoxic destruction of infected, malignant, or pathogenic host cells. On infected cells, the target antigen may be a pathogen-derived epitope displayed on the cell surface. For malignant cells, it may be a tumor-associated antigen. In the case of autoimmune or allergic disease, the antibody therapeutic may be used for selective ablation of cell types responsible for immune pathology.

 

The importance of antibody isotype and glycosylation status on ADCC and ADCP efficiencies is widely recognized, and these two parameters are active areas of research. However, it is still difficult to predict ADCC or ADCP killing efficiencies based on antibody isotype and Fc glycosylation patterns alone, making it challenging to reliably design antibodies that mediate Fc-dependent killing in vivo . For example, antibodies that recognize identical or overlapping epitopes on a target cell antigen may have dramatically different abilities to mediate ADCC or ADCP, even when they are engineered to have identical Fc regions and glycosylation patterns. In addition, the relative contribution of each killing mechanism to in vivo efficacy is difficult to evaluate and may vary even within an individual, depending on anatomical location and the microenvironment of target cells. A key microenvironmental variable is the availability and type of effector cells required for Fc/FcR-mediated killing. Preliminary evaluation of antibody therapeutics continues to rely on empirical testing of each antibody for cytotoxic activities under in vitro assay conditions. Even when ADCC-competent antibodies are identified and optimized for highly efficient in vitro killing, the results often fail to translate to in vivo efficacy. 

 

Elevation of NK cell numbers during infection has led to speculation that they may serve as primary effector cells for ADCC. However, NK cells have additional antibody-independent roles in innate control of infection and their increased frequencies may be independent of potential roles as effector cells for ADCC-mediated killing in vivo. Importantly, closer consideration must be given to the role of other cell types present at sites of infection as potential effectors of antibody-mediated killing. For example, alveolar macrophages may play critical roles in the control of respiratory infection through ADCC, ADCP, or both killing mechanisms. In fact, cancer studies suggest that while NK cells are the most commonly used effector cells for in vitro ADCC assays, monocytes and macrophages are often identified to be the main effectors of antibody-mediated killing of cancer cells in vivo.
 

Research Objectives and Scope

 

The goal of this initiative is to expand our mechanistic understanding of two pathways of Fc-dependent, antibody-mediated killing: ADCC and ADCP. These are highly complex processes that are understudied and for which preliminary data may be severely limited.


This FOA was developed to support high priority research for mechanistic understanding of ADCC and ADCP, translation of mechanistic observations made using in vitro systems for evaluation of in vivo efficacy, and to address complications associated with interpretation of in vivo results. In June 2017, NIAID assembled a group of external scientists representing academic, biotechnology and pharmaceutical sectors to identify research gaps that should be addressed to accelerate our understanding of the mechanisms of ADCC and ADCP, both in vitro and in vivo . Consensus recommendations for addressing research gaps were incorporated into the list of high priority research areas below.  

 

This initiative will support research that increases our fundamental understanding of ADCC and ADCP. Examples of relevant model systems for functional, mechanistic evaluation of ADCC- and/or ADCP-mediated killing include: cytotoxic killing of infected human cells ( in vitro), in vivo infection models (animal models only), and ex vivo studies using human tissues; the use of model antigens expressed on the target cell surface (which may include tumor antigens); and cytotoxic killing of cells implicated in human immune-mediated disease, (e.g., studies using experimental or licensed human monoclonal antibodies for ablation of cell types associated with autoimmune disease or allergy.) 
 

Under this FOA, high priority research areas include, but are not limited to:
 

  • Hypothesis-driven, mechanistic studies that increase our understanding of the molecular mechanisms of cytotoxic killing by ADCC and/or ADCP. Studies must include evaluation of human monoclonal antibodies. While animal models may be used for in vivo validation, applications should include justification for the proposed animal models, with discussion of their translational relevance to our understanding of ADCC and/or ADCP in humans.

  • Descriptive studies to evaluate the contributions of the availability, anatomical distribution and phenotypic characteristics of appropriate effector cell types in human tissues to in vivo killing mechanisms and overall efficacy of therapeutic antibodies.   It is expected that knowledge gained through these studies will improve our ability to predict Fc-dependent, cytotoxic functions of antibodies, and will inform design, development and optimization of ablative monoclonal antibody therapeutics for treatment of infectious diseases, autoimmune disease, allergy, and cancer. Results may also inform the design of therapeutic vaccines that preferentially elicit antibodies with Fc-mediated killing functions.

Research topics that fulfill program objectives include, but are not limited to:
 

  • Availability, frequencies, and phenotypes of physiologically relevant human effector cell types at tissue sites, coupled with evaluation of relevant killing mechanisms at sites chosen.

  • FcR expression patterns on individual human effector cell types, including:

  • Variations in FcR expression patterns among cells of a particular effector cell type, as a function of maturation stage, activation status, and anatomical environment.

  • Variations in post-translational modification of FcRs, both within categories of effector cells or among different effector cell types.

  • Target antigens and how the nature of epitopes bound by human antibodies affect cytotoxic killing.

  • Valency or density of human antibodies bound to epitopes on the target cell.

  • Signaling or other biochemical pathways involved in ADCC or ADCP killing.

  • Optimal epitope characteristics, which may include: physical distance between the targeted antibody epitope and the target cell membrane; epitope orientation; epitope accessibility, etc.

  • Conformational requirements/changes associated with binding of human antibodies to target cells, as required for efficient mediation of ADCC and/or ADCP cytotoxicity.

  • Antibody paratope (or (Fab')2, or idiotype)-associated factors: Antibodies with closely related variable regions may mediate widely variable efficiencies of ADCC or ADCP. Killing efficiencies do not necessarily correlate with affinities of antibody for target antigens, even when specific for the same epitope and bearing identically Fc domains engineered for optimized ADCC or ADCP function.  

  • Studies to perform comparative, mechanistic evaluation of ADCC and/or ADCP using existing antibody collections obtained during design or development of therapeutic monoclonal antibodies are acceptable, with strong justification for the value of the antibody collection(s) for proposed hypothesis-driven, mechanistic research.

Applications including t he following types of studies will be considered non-responsive and will not be reviewed:
 

  • Clinical trials (the NIH definition of clinical trials is available at http://grants.nih.gov/grants/policy/hs/glossary.htm). 

  • Studies on non-human monoclonal antibodies

  • Studies involving antibodies that recognize AIDS, HIV, or SIV epitopes, as studies on killing of HIV-infected cells by HIV-specific antibodies are funded through other solicited research programs.

  • Studies exclusively examining antibodies to tumor-associated antigens, unless studies also include other model antigen systems and/or are designed such that results will be more broadly applicable to understanding of ADCC or ADCP-mediated killing in infectious or autoimmune diseases.

  • Studies for which the primary objective is the design or development of therapeutic monoclonal antibodies

  • Studies solely focused on evaluation of antibody isotype

  • Studies solely focused on antibody glycosylation, as such studies on the roles of glycosylation of cytotoxic killing are already supported through active investigator-initiated grants and other solicited research programs.

Steering Committee :  A Steering Committee (SC) will be formed with the PDs/PIs and NIAID Program Officer to coordinate and facilitate research activities for the overall program; facilitate compliance with the data- and other resource-sharing policies; and promote optimal research flexibility, synergy, and efficiency . Annual Program Progress meetings will be held to discuss the progress of individual research programs. PD(s)/PI(s) are expected to participate in Program Progress meetings by presenting the aims, status and highlights of their project, attend annual face-to-face SC meetings to be held immediately following adjournment of Program Progress meetings, and participate in SC-related activities and teleconference meetings. NIH staff may appoint other subject matter experts as non-voting members of the Steering Committee to provide additional expertise and perspective.

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

Section II. Award Information

Funding Instrument
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 this FOA.
Application Types Allowed
New

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.

Clinical Trial?
Not Allowed: Only accepting applications that do not propose clinical trials

Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards

NIAID intends to commit $2.0M in FY 2020 to fund 3-5 awards.

Award Budget
Application budgets are capped at $300,000 (direct costs) per budget period.
Award Project Period
The scope of the proposed project should determine the project period. The maximum period is 5 years.     
NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

  • State Governments
  • County Governments
  • City or Township Governments
  • Special District Governments
  • Indian/Native American Tribal Governments (Federally Recognized)
  • Indian/Native American Tribal Governments (Other than Federally Recognized)
  • Eligible Agencies of the Federal Government
  • U.S. Territory or Possession
Other
  • Independent School Districts
  • Public Housing Authorities/Indian Housing Authorities
  • Native American Tribal Organizations (other than Federally recognized tribal governments)
  • Faith-based or Community-based Organizations
  • Regional Organizations
  • Non-domestic (non-U.S.) Entities (Foreign Institutions)
Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed. 
Required Registrations

Applicant organizations

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

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

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

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

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

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

2. Cost Sharing

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 not accept:

  • A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
  • A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
  • An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101)

Section IV. Application and Submission Information

1. Requesting an Application Package

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 instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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

 

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

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

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

The letter of intent should be sent to:

Zhuqing "Charlie" Li, Ph.D. 
Telephone: 240-669-5068
Fax: 301-480-2408
Email: liz@niaid.nih.gov 

Page Limitations
All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed
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 application to this FOA.
SF424(R&R) Cover
All instructions in the SF424 (R&R) Application Guide must be followed.
SF424(R&R) Project/Performance Site Locations
All instructions in the SF424 (R&R) Application Guide must be followed.
SF424(R&R) Other Project Information
All instructions in the SF424 (R&R) Application Guide must be followed.
SF424(R&R) Senior/Key Person Profile
All instructions in the SF424 (R&R) Application Guide must be followed with the following additional instructions:

If the research histories of the PD(s)/PI(s) and collaborators do not include publications specifically focused on mechanisms of ADCC or ADCP-mediated killing, applicants should document relevant expertise for the proposed Specific Aims. Relevant experience may include (but is not limited to): experience in evaluation of aspects of antibody structure/function, antibody engineering, or in the study of effector cell types relevant to Fc-dependent, antibody-mediated killing.

 

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

R&R Subaward Budget
All instructions in the SF424 (R&R) Application Guide must be followed.
PHS 398 Cover Page Supplement
All instructions in the SF424 (R&R) Application Guide must be followed.
PHS 398 Research Plan
All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Research Strategy:

Applicants should provide a rationale for how the proposed work will contribute to advancing our understanding of the fundamental molecular and cellular mechanisms of ADCC- and/or ADCP-based killing.

 

Because our understanding of ADCC and ADCP is very limited, both descriptive research and hypothesis-driven, mechanistic research are acceptable under this FOA and preliminary data that specifically address mechanisms of Fc-dependent, antibody-mediated killing are not required.  However, applicants should provide strong rationale for how proposed studies will fill knowledge gaps relevant to Fc-dependent, antibody mediated killing and provide preliminary data, where possible, to demonstrate feasibility of the proposed approaches.

 

If included in the research strategy, applicants should provide thorough justifications for selection of in vivo animal models and ex vivo human tissues, with explanations for how results are translationally relevant to in vivo Fc-mediated killing in humans. 


Applications should include Gantt charts with proposed milestones and anticipated timelines. 

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

The following modifications also apply:

  • All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
     
  • All investigators funded under this FOA will be expected to share their data publicly through  ImmPort ( www.immport.org ), the Immune Epitope Database ( www.iedb.org ) or other public portals approved by NIH.  Complete antibody heavy and light chain sequences associated with proposed studies should be deposited into the Protein Data Bank ( www.wwpdb.org ) Therefore, the Data Sharing plan should include a summary of how the applicant will manage data submission and interactions with ImmPort, IEDB and PDB.
Appendix:
Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
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 Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

PHS Assignment Request Form
All instructions in the SF424 (R&R) Application Guide must be followed.
 

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

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

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

4. Submission Dates and Times

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

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

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

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

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.

7. Other Submission Requirements and Information

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

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

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

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

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

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.
Post Submission Materials
Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

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.

Overall Impact
Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).
Scored Review Criteria
Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

 

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

Specific for this FOA:

As appropriate for the specific aims of the application (mechanistic and descriptive studies):
 

How well will the proposed mechanistic or descriptive studies address knowledge gaps in Fc-dependent, antibody-mediated killing that will lead to a better understanding of the fundamental molecular and cellular mechanisms of ADCC- and/or ADCP-based killing?

For in vivo animal/ ex vivo human studies: How well will findings from animal models or ex vivo human tissues inform the ability to predict in vivo mechanisms of ADCC or ADCP-mediated killing?

 

 

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

Specific for this FOA:

If the PD(s)/PI(s), collaborators, and other researchers have no records of publication specifically focused on mechanisms of Fc-dependent, antibody-mediated killing, do they have demonstrated expertise in areas relevant to the proposed Specific Aims?

 

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

 

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

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

 

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

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

 

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

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

 Individuals Across the Lifespan

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

 

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

 

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

 

Not Applicable.

 

Not Applicable

 

Not Applicable

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

 

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

 

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

 

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

 

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

 

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by NIAID, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.
As part of the scientific peer review, all applications:
  • May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
  • Will receive a written critique.
Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.
Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Allergy and Infectious Diseases Council. The following will be considered in making funding decisions:
  • Scientific and technical merit of the proposed project as determined by scientific peer review.
  • Availability of funds.
  • Relevance of the proposed project to program priorities.

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 VI. Award Administration Information

1. Award Notices

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

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

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

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

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General  and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency.  HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

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

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.
 

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

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

  • Serve as a voting member on the Steering Committee (SC); accept and implement the policies and procedures developed by majority vote of the Steering Committee.
  • Work closely with NIAID staff in the scientific, technical, and administrative management of this program.
  • Collaborate, share reagents, assays, animal models, human samples, and experimental results with other investigators funded under this FOA
  • The PD/PI are expected to share all data generated under this FOA publicly through public portals designated by NIAID. Data submission and release plans will be negotiated prior to award.  The PD/PI will establish procedures within the project to ensure that all members of the program support and conform to the data-sharing and other resource-sharing plans. The final versions of NIAID-approved sharing plans will become a condition of the award. Note that funding beyond the first year may be subject to downward negotiation depending on the progress made in meeting negotiated data- and other resource-sharing plans.

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

  • Provide input into the design of research activities and advise in project management and technical performance.
  • Coordinate NIAID staff assistance with regard to:
  • Oversight and monitoring of collaborative research
  • Feasibility of timely progress towards completion of planned activities
  • Plans for incorporation of new technologies or other resources
  • Evaluation of the adequacy of data-sharing and other resource-sharing plans. NIAID program staff may require modifications of sharing plans with the applicant and will ensure that all funded investigators conform to data-sharing and other resource-sharing policies
  • Facilitate collaborations with and access to other NIAID-supported research resources and services.
  • Access confidential data generated under this Cooperative Agreement for use in the preparation of internal reports on the activities of the awardees.

Additionally, an agency program official or IC program director, which may be the same as the project scientist, 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:

 

Steering Committee: The Steering Committee of the Fc-Dependent Mechanisms of Antibody-Mediated Killing program will coordinate and facilitate research activities for the overall program; facilitate compliance with the data- and other resource-sharing policies; and promote optimal research flexibility, synergy, and efficiency.  The Steering Committee will include the PD/PI from each awarded U01 as a voting member and the NIH Program Officers as non-voting members.
 

Dispute Resolution:
 

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

3. Reporting

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.
A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000.  See the NIH Grants Policy Statement for additional information on this reporting requirement.

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

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.
Application Submission Contacts
eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten on-time submission, and post-submission issues)

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

General Grants Information (Questions regarding application processes and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

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

Scientific/Research Contact(s)

Stacy E. Ferguson, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3504
Email: fergusonst@mail.nih.gov 

Peer Review Contact(s)

Zhuqing "Charlie" Li, Ph.D.

National Institute of Allergy and Infectious Diseases (NIAID)

Telephone: 240-669-5068

Email: liz@niaid.nih.gov

Financial/Grants Management Contact(s)
Kevin R. Heath II
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-761-7690
Email: kevin.heath@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.
Authority and Regulations
Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.


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