Part 1. Overview Information

Key Dates

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

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

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

Conformance to all requirements (both in the How to Apply - Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the How to Apply - Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the How to Apply - 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.



Table of Contents
Part 1. Overview Information
Key Dates
Part 2. Full Text of Announcement
Section I. Notice of Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Purpose

The overall goal of this Notice of Funding Opportunity (NOFO) is to develop clinical research platforms that will enable proof-of-concept studies to demonstrate that combinations of interventions specifically tailored to target a participant’s unique, intact, rebound-competent HIV reservoir, and that also complement their distinct immunologic profile, have the potential to be curative for HIV. Knowledge gained from these initial proof-of-concept studies will help to inform the development and prioritization of more broad-based combination HIV curative strategies that will be effective for all people living with HIV.

Background

Millions of people living with HIV depend on daily antiretroviral therapy (ART) to maintain viral suppression. ART is able to control virus replication within a person and prevent HIV transmission to others, but it is not curative due to the virus’ ability to enter a latent state where it is impervious to immune-mediated clearance. Lifelong ART presents several challenges for people living with HIV at both the individual and societal levels. Therefore, HIV cure research remains a high priority of the National Institute of Allergy and Infectious Diseases (NIAID).

Thus far, five people have been reported to be cured of HIV infection via stem cell transplantation that was necessary to treat their concomitant blood cancers. These transplantations used donor cells that were naturally resistant to HIV infection due to mutations in the CCR5 HIV co-receptor gene. While these reports are encouraging, stem cell transplantation is not a safe or feasible cure strategy for people living with HIV without cancer.

Curative strategies for the broad population of people living with HIV are being developed and tested in animal models and the clinic with limited success. Examples include conserved element-based therapeutic vaccines, chimeric antigen receptor (CAR) T cells, immunomodulators like PD-1 inhibitors and IL15 superagonists, and latency reversing agents. However, these types of approaches fail to account for the unique proviral sequence diversity within each individual living with HIV or each individual’s immune genetic background, which could be hindering their overall success. Recent technological advances, such as single-cell omics, have made comprehensive evaluation of a participant’s HIV reservoir feasible. T cell epitope predictions based on HIV provirus sequences and human leukocyte antigen (HLA) haplotyping are also possible. Such information could potentially be leveraged to design a tailored combination of interventions that might be more successful in achieving HIV curative outcomes in future clinical trials.

Research Objectives and Scope

Applicants are encouraged to assemble highly collaborative, multidisciplinary teams with expertise in virology, immunology, single-cell analysis, bioinformatics, and clinical research to develop a practical clinical research platform for rapidly and efficiently profiling participants’ intact, rebound-competent HIV reservoirs and their immunologic profiles to provide relevant information needed to design a tailored combination of curative interventions for each participant. HIV curative approaches must specifically target each participant’s virologic and immunologic profile, with a goal of significant reduction or eradication of the rebound-competent HIV reservoir and/or the induction of durable post-treatment control of HIV viral rebound. Examples of participant profiling include in-depth characterization of the landscape of intact and defective proviruses, host major histocompatibility complex (MHC) alleles, CD4⁺/CD8⁺ T cell receptor repertoires, autologous neutralizing antibody (aNAb) specificities and titers, and proviral sensitivity to broadly neutralizing antibodies (bNAbs).

The scope for this NOFO includes basic and pre-clinical research as well as methods development and validation for optimal, rapid screening of potential participants in future clinical trials testing tailored HIV curative strategies. Combinatorial HIV curative strategies developed for this NOFO must include at least two tailored immunologic-based approaches. A tailored approach to specifically reactivate latent, replication-competent HIV should also be included. Tailored approaches should be validated by a comparison to non-tailored, more generally applicable approaches to demonstrate rigor, reproducibility, and significance of the results. Applicants are expected to utilize human blood and tissue samples from previously conducted or ongoing observational studies or clinical trials funded through other sources. Combinations of tailored interventions should be tested in vitro or ex vivo. In vivo pre-clinical studies in appropriate animal models are also within scope of this NOFO, but the focus of the research should be on developing a platform for studying HIV in humans. This NOFO will not support clinical trials but will support clinical research through observational studies and/or the analysis of blood and tissue samples from previously conducted or ongoing pre-clinical studies and clinical trials funded through other sources.

Examples of tailored immunologic approaches include, but are not limited to:

Selecting peptides exclusive to intact, rebound-competent proviruses that are predicted for presentation by a participant’s MHC Class I/II molecules and prioritized for resistance to immune escape for:

• inclusion in a T cell-targeted therapeutic vaccine modality
• designing engineered T cell receptors for development of an autologous or heterologous effector cell product
• expanding specific immune cells ex vivo for reinfusion

Sequencing a participant’s intact, rebound-competent proviral Envs for:

• tailoring appropriate combinations of bNAbs for passive delivery
• developing CAR T and/or CAR NK cell products
• engineering antibody-based therapeutics such as dual affinity retargeting antibodies (DARTs) or bi- and tri-specific killer cell engager antibodies (BiKEs and TriKEs)
• selecting aNAbs targeting immune escape-resistant epitopes and further optimizing/expanding aNAb-expressing B cells ex vivo for reinfusion

Examples of tailored approaches for reactivating latent, rebound-competent HIV include, but are not limited to:

• Determining antigen specificities of CD4⁺ T cells harboring intact, rebound-competent provirus to design strategies to specifically activate those infected cells
• Analyzing the intact, rebound-competent proviral promoter sequences and epigenetic landscape to tailor combinations of appropriate latency reversing agents
• Characterizing the phenotypes and gene expression profiles of CD4⁺ T cells harboring intact, rebound-competent proviruses to identify specific ways to target latency reversing agents to those cells
• Testing intact, rebound-competent provirus-infected T cell clones for viral reactivation with combinations of latency reversing agents

Applications focused on any of the following will be deemed non-responsive and will not be reviewed:

• Applications that propose clinical trials
• Applications that include viral or host gene editing approaches, such as CCR5 co-receptor editing or HIV LTR editing
• Applications that do not include at least two tailored immunologic-based approaches
• Applications focused primarily on SIV or SHIV
• Applications that do not include analysis of clinical samples from people living with HIV
• Applications that limit testing of interventions to HIV-infected cell lines

Program Structure

Research Program: The research program section should be organized into three highly collaborative and interdependent Research Foci, each with a distinct scientific theme or developmental goal, which together will synergize to accomplish the overall goals of the NOFO.

Clinical participant selection and sample acquisition: This section will discuss the scientific rationale for choosing particular human clinical samples for the development and testing of tailored interventions.

Regulatory considerations for future clinical trials: This section will discuss the practical and regulatory framework for the design, development, production, and selection of tailored interventions for use in future clinical trials to determine efficacy. It will outline addressable challenges in the design of future clinical trials testing tailored interventions to ensure regulatory compliance and approvals and enable rapid participant screening and the design or selection of relevant combinations of interventions to test.

Management and Operations: This section will provide the overall coordination for application activities such as administrative tasks, communication, strategic planning, adherence to timelines, resource allocation, tracking of publications and other metrics, and establishing efficient processes for activities across multiple institutions.

Executive Committee and Scientific Advisory Board: Each application will involve an Executive Committee (EC) and Scientific Advisory Board (SAB). The EC is an internal committee that will serve as the governing body of the research teams, assisting the PD/PI(s) in ongoing evaluations of research progress and milestones. The EC should put in place policies and procedures to support operations, including the reallocation of funds, development of needed working groups, engagement of new collaborators and/or technologies relevant to the evolving scientific projects, and establishment of guidelines for presentation and publication of the results of collaborative projects. The EC will consist of 3-5 voting members, chaired by the PD/PI(s), and should include 2-4 key personnel representing leadership of the Research Foci.

The SAB will be an independent, external advisory body that acts as a resource for the PD/PI(s) and the EC, but it will not be involved in the day-to-day activities of the research. The SAB should include at least 4 active members not affiliated with the applicant institution(s) or other institutions receiving funds from the award. The SAB will assist in review of research productivity, progress toward the proposed goals, adherence to timelines, and the continued relevance of the research approach. The SAB may recommend new scientific directions or re-prioritization of research as appropriate. The members of the SAB must be established within six months of the program start date. The SAB must meet with the PD(s)/PI(s), EC, and other key personnel at least once a year to review progress and provide recommendations regarding current and future research goals. Candidates for the SAB should not be named in the application or solicited prior to award.

Applicants are highly encouraged to contact the Scientific/Research Contacts to discuss their application and arrange a pre-application meeting prior to submission of their application.

Applicants are encouraged to leverage other resources and develop creative collaborations where possible to support the overall goals of the application. Institutional support is highly encouraged.

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

All organizations administering an eligible parent award may apply for a supplement under this NOFO.

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)

Local Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)

Federal Government

• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Organizations) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

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

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the How to Apply - Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information. 

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

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

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

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

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

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

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

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

Section IV. Application and Submission Information

1. Requesting an Application Package

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

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise. Conformance to the requirements in the How to Apply - Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

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:

Kristina S. Wickham, Ph.D.
Telephone: 301-761-5390
Email: kristina.wickham@nih.gov 

All page limitations described in the How to Apply – Application Guide and the Table of Page Limits must be followed.

The Research Strategy must consist of the following sub-sections with the indicated page limits:

Subsection A: Research Program Overview – one required – 12 pages

Subsection B: Management and Operations – one required – 6 pages

Subsection C: Research Foci – three required – 12 pages each

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

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

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

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

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

R&R Budget

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

The following should be included as part of the overall budget:

• Staff responsible for management and oversight of day-to-day operation, organization, communication, and coordination of collaborative activities, including webinars, teleconferences, Executive Committee (EC) and Scientific Advisory Board (SAB) meetings, and to track and record metrics of productivity, including research team membership, affiliations, and positions; publications; and meeting abstracts.
• Expenses for communication among investigators and for outreach to outside researchers.
• Travel and other expenses related to hosting an annual meeting for SAB evaluation and Strategic Planning activities (consisting of a kick-off meeting and a meeting near the end of Years 1 through 4). Travel expenses for SAB members should be included.

The budget justification should include a breakdown of the apportionment of funds for each of the proposed Research Foci and Management and Operations for the first year. The budgets for out-years should represent best estimates for the general research plan. Resource allocations are expected to change over time from what is initially proposed.

R&R Subaward Budget

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

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

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

Research Strategy: The Research Strategy must consist of a single attachment consisting of subsections A-C as designated below:

Subsection A: Research Program Overview

In a section titled, “Research Program Overview”, outline the overall scientific agenda, strategic plan, and a vision for interrelated and complementary research to achieve the overall Aims. Include a discussion of the scientific rationale for clinical participant selection and sample acquisition, as well as a summary of regulatory considerations for future clinical trials.

Within the scientific agenda, describe how the application will address various knowledge gaps relevant to current HIV cure strategies.  In addition, describe how academic partners will be integrated and how their specific expertise, resources and processes will facilitate translation of basic research findings into practical application.

For the strategic plan section, describe the comprehensive overview of implementation plans for the overall Aims and how they incorporate innovative, interdisciplinary approaches. Demonstrate clear strategies for effective collaboration and decision-making and how shifting scientific priorities, based on the emergence of new findings and/or the evolution of science in this area, will be accommodated with funding reallocation over the award period if necessary.  A discussion regarding potential bottlenecks and anticipated strategies to overcome major challenges should be included. Describe overarching milestones and timelines for the proposed research, alternative directions, and metrics for monitoring progress and performance toward scientific and therapeutic development goals.

For the clinical participant selection and sample acquisition section, outline the scientific rationale for the choice of particular human clinical samples selected for the development and testing of tailored interventions. Describe the availability of and access to desired clinical samples and the scientific rationale for choosing specific blood or tissue samples for screening and profiling participants and testing interventions. Discuss considerations of participant demographics that encompass the diversity of people living with HIV and clinical and reservoir characteristics that persuaded the selection of particular samples.

For the regulatory considerations for future clinical trials section, include a discussion of the regulatory approval requirements, including GMP, CLIA, and GCP compliance considerations, for testing proposed tailored interventions in future clinical trials. Discuss potential future challenges in the design of clinical trials to test tailored interventions, such as domestic or international regulatory compliance and the time/resources to properly screen and profile participants and generate appropriate GMP materials for testing.

Subsection B: Management and Operations

In a section titled “Management and Operations,” describe the oversight and coordination of the program, plans for meetings among key personnel and day-to-day activities. Describe the role of the PD/PI(s) in providing oversight for Management and Operations activities, and how they will engage the Executive Committee (EC) and Scientific Advisory Board (SAB) to obtain input on progress evaluation, strategic planning, and major decision-making. Describe the overall program leadership and management structure, communication frequency and procedures for information sharing, the coordination of activities, data management, and supervision of the program. Include a diagram to indicate the overall organizational and leadership structure. Describe specific plans and processes for establishing, tracking, reviewing, and managing milestones, and for tracking and reporting productivity, including metrics such as publications and presentations at meetings. Define clear lines of authority involving the PD/PI(s), EC, key personnel, and the SAB. Clearly explain strategies for coordination of the program, problem identification and resolution, prioritization of resources, and the establishment of a strong collaborative environment, as well as plans for fiscal accountability among multiple institutions and investigators. Describe the strategy for reallocating funds to accommodate changes in projects, including discontinuing unproductive or low-priority projects and initiation of new projects.

Describe plans to conduct regular teleconferences and meetings of the EC to discuss strategic planning and research progress and to conduct regular webinars and teleconferences to facilitate internal sharing of information and resources, discussions of current and future research directions, and to ensure interdisciplinary interactions and collaborations; these meetings will include NIH Program Staff.

Describe plans for coordination of resources, facilities, research and development activities and investigators across broad scientific areas and multiple institutions/organizations.

Executive Committee (EC): Applicants must identify three to five investigators who will constitute voting members of the EC for the program. Describe how the EC will regularly review research productivity and milestones and act to ensure that the goals of the program are achieved, including reallocating funds, modifying research priorities, discontinuing unproductive or unnecessary studies, and instituting changes in resources and personnel. Describe how the EC will work with the PD(s)/PI(s) to implement necessary changes, respond to SAB recommendations, and also facilitate sharing of data and scientific resources across the program. Describe EC voting procedures. If the EC contains an even number of members, explain a procedure for settling tied votes.

Scientific Advisory Board (SAB): Describe plans for convening the external SAB within the first six months of the program start date. Describe the number and type of persons serving on the SAB and the number of SAB members that will constitute a quorum. Importantly, candidates for the SAB should not be named in the application or solicited prior to award. Describe the potential structure of the annual SAB meeting and how SAB recommendations will be facilitated and communicated to the PD(s)/PI(s) and the EC.

Subsection C: Research Foci

In a section titled “Research Foci” clearly delineate three areas of Research Focus, written as integrated goals of a single research program that are organized around an overall synergistic combination of tailored HIV cure approaches that allows for flexibility in research directions as the program matures and as new findings, technologies, and opportunities arise.  Describe how the technologies and approaches proposed for profiling participant reservoirs and immune genetic backgrounds constitute a significant advancement beyond current methods with respect to precision, efficiency, or throughput and how the proposed tailored interventions represent a significant advancement beyond what is currently being tested.

For each Research Focus, describe the significance of the research, its relevance to the overall Aims and Scientific Agenda, and its synergy with other proposed research activities. Describe short-term objectives, with detailed plans for the first 1-2 years, followed by more general plans and alternate strategies for the remaining years. Provide measurable outcomes and go/no-go criteria where appropriate and outline a clear vision for future directions, with flexibility to redirect or replace research projects as the science evolves. Describe the research design, conceptual procedures, tools, technologies, and analyses to be used to accomplish the objectives. Include specific metrics for progress.

Describe plans to leverage other existing funded programs and resources where possible to secure services or common resources to support the needs of the program and any additional institutional support that adds value and synergy to the program structure, such as NIAID HIV/AIDS Clinical Trial Networks, Clinical and Translational Science Awards, Martin Delaney Collaboratories for HIV Cure Research, Centers for AIDS Research, Centers for HIV Structural Biology, Consortia for HIV/AIDS Vaccine Development, and Consortia for Innovative HIV/AIDS Vaccine and Cure Research.

Letters of Support: Applicants may include letters of support from organizations/individuals to articulate access to specific resources or expertise integral to the proposed project.

Resource Sharing Plan:

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

Other Plan(s):

Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

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

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

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

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

If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

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

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

See Part 2. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

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

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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

Information on the submission process and a definition of on-time submission are provided in the How to Apply – Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement Section 7.9.1 Selected Items of Cost.

Applications must be submitted electronically following the instructions described in the How to Apply - Application Guide. Paper applications will not be accepted.

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

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

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

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

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by National Institute of Allergy and Infectious Diseases (NIAID), NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

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

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.

Significance

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 to this NOFO:

To what extent is the overall Scientific Agenda compelling and inclusive of a clear rationale for the proposed tailored approaches and Research Foci? 

Investigator(s)

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 to this NOFO:

To what degree do the key investigators have sufficient expertise to successfully translate participant reservoir and immune system profiling to the design of tailored combinations of cure strategies?

Innovation

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?

Specific to this NOFO:

To what extent do the technologies and approaches proposed for profiling participant reservoirs and immune genetic backgrounds constitute a significant advancement beyond current methods with respect to precision, efficiency, or throughput? To what degree do the tailored interventions proposed represent a noteworthy advancement beyond what is currently being studied?

Approach

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? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

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

Specific to this NOFO:

To what extent is the Strategic Plan feasible and compelling as a way to implement the Scientific Agenda? How well do the overall program goals, expressed in the Scientific Agenda and Strategic Plan, address important technological and potential future regulatory challenges of tailoring HIV curative interventions to participants?

To what extent is there synergy among the Individual Research Foci toward the central objectives of the program? To what degree is the added value of supporting the proposed Research Foci, together, significantly greater than what could be achieved through support of each separately? To what degree are the plans under each of the Research Foci feasible to achieve in 5 years? How appropriate is the proposed approach for participant profiling and how feasible is it to apply towards the design of future clinical trials?

How appropriate are the plans and mechanisms for budgetary reallocation and shifting research priorities? How appropriate and feasible are the decision-making processes for incorporating new research activities in response to emerging opportunities and eliminating unproductive research projects to maintain innovation as the research evolves? To what degree are the proposed milestones, and metrics to monitor, quantify and evaluate progress and productivity appropriate and feasible?

To what extent are the curative strategies proposed specific and tailored to participants’ virologic and/or immunologic profiles?

How well are the members of the Executive Committee expected to be able to effectively manage changes in research priorities and resource allocation?

Environment

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?

Specific for this NOFO:

To what extent has the application described plans to leverage other existing funded resources and provided documentation that these resources will be available to the involved investigators? To what degree is there additional institutional support provided and are other funding sources leveraged to create added value and further synergy within the program structure?

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.

Protections for Human Subjects

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 will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the 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.

Inclusion of Women, Minorities, and 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 justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following three points: (1) a complete description of all proposed procedures including the species, strains, ages, sex, and total numbers of animals to be used; (2) justifications that the species is appropriate for the proposed research and why the research goals cannot be accomplished using an alternative non-animal model; and (3) interventions including analgesia, anesthesia, sedation, palliative care, and humane endpoints that will be used to limit any unavoidable discomfort, distress, pain and injury in the conduct of scientifically valuable research. Methods of euthanasia and justification for selected methods, if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals, is also required but is found in a separate section of the application. For additional information on review of the Vertebrate Animals Section, please refer to the Worksheet for Review of the Vertebrate Animals Section.

Biohazards

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.

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

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

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

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).

Resource Sharing Plans

Reviewers will comment on whether the Resource Sharing Plan(s) (i.e., Sharing Model Organisms) or the rationale for not sharing the resources, is reasonable.

Authentication of Key Biological and/or Chemical Resources:

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.

Budget and Period of Support

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 National Institute of Allergy and Infectious Diseases (NIAID), in accordance with NIH peer review policies and practices, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications will receive a written critique.

Applications may undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.

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

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Allergy and Infectious Diseases Council. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

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. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

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 recipient's business official.

Recipients must comply with any funding restrictions described in Section IV.6. 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 NOFO 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.

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

2. Administrative and National Policy Requirements

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, Recipients, and Activities, including of note, but not limited to:

• Federal-wide Standard Terms and Conditions for Research Grants
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

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

If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website. 

HHS recognizes that NIH research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this NOFO.

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 System for Award Management (SAM.gov) requirements. SAM.gov requires Federal agencies to review and consider information about an applicant in the designated integrity and performance system (currently SAM.gov) prior to making an award. An applicant can review and comment on any information in the responsibility/qualification records available in SAM.gov. NIH will consider any comments by the applicant, in addition to the information available in the responsibility/qualification records in SAM.gov, 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 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (HHS) grant administration regulations at 2 CFR Part 200, and other HHS, PHS, and NIH grant administration policies.

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

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

• Planning, directing, and executing the proposed research in accordance with the proposed timeline.
• Establishing the membership and responsibilities of the Executive Committee (EC) within three months of the award start date. Serving as a voting member of the EC.
• Establishing the Scientific Advisory Board (SAB) within six months of the award start date. Organizing, hosting, and attending an annual SAB meeting to review progress, plan, and design research activities, and establish priorities.
• Integrating and implementing the recommendations of the SAB into the activities of the program.
• Planning, organizing, hosting, and attending a kick-off meeting within the first three months of the award start date.
• Providing a summary outlining interaction among the group members and with the NIAID Program Official and NIAID Project Scientist(s) as part of the annual progress report.
• Organizing and hosting monthly teleconferences between the PD(s)/PI(s) and NIAID Program Staff to discuss research progress, administrative tasks, EC and/or SAB concerns, and changes in resource allocations or scientific direction.
• Recipients will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

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

• The role of NIAID will be to facilitate and not direct the activities. The NIAID PS will offer input on the deliberations and discussions of the recipients to contribute expertise, perspective, and assistance.
• Advising in the design of the research activities. 
• Reviewing and approving changes in research activities and resource allocation.
• Facilitating access to resources and information that otherwise might not be available to the recipient.
• Advising on the management and technical performance of the program. 
• Providing advice or assistance on specific scientific, technical, or management issues.
• Attending and participating in deliberations of the Scientific Advisory Board meeting.
• Attending and participating in the kick-off meeting.
• Attending and participating as a non-voting member of the Executive Committee meetings.
• Providing guidance to the recipients about (i) compliance with Federal regulations; (ii) oversight and monitoring of the collaborative research; (iii) feasibility of timely completion; and (iv) plans for interim monitoring and analysis.
• An agency Program Official or IC program director will serve as the NIAID Program Officer, responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

• None; all responsibilities are divided between recipients and NIH staff as described above.

Dispute Resolution:

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

3. Data Management and Sharing

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

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

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

The Federal Funding Accountability and Transparency Act of 2006 as amended (FFATA), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All recipients 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 2 CFR Part 200.113 and Appendix XII to 2 CFR Part 200, 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 (Responsibility/Qualification in SAM.gov, formerly 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 2 CFR Part 200 – 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.

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

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-480-7075

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

Leia Novak, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-761-7825
Email: Leia.novak@nih.gov  

Kristina S. Wickham, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-761-5390
Email: kristina.wickham@nih.gov 
 

Dustin Andrews
National Institute of Allergy and infectious Diseases (NIAID) 
Telephone: 301-761-7191 
Email: dustin.andrews@nih.gov 
 

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 2 CFR Part 200.