Part 1. Overview Information

Key Dates

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

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

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

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

Applications that do not comply with these instructions may be delayed or not accepted for review.

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

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



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

Background

It has long been known that, in a subset of individuals acutely infected with certain pathogens, chronic sequelae can continue to persist (or develop de novo) long after the acute symptoms have resolved. Commonly referred to as infection-associated chronic illnesses, these conditions are often characterized by a failure to recover following an initial infection even though the original pathogen is no longer detectable using common analytic methods. Several prevalent chronic illnesses - including but not limited to ME/CFS, POTS/dysautonomia, post-treatment Lyme Disease (PTLD), fibromyalgia, mast cell activation syndrome (MCAS), and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infection (PANDAS), among others - have long been suspected to have an infectious trigger in a certain subset of individuals. Importantly, such conditions tend to involve a core group of symptoms, many of which are neurological and/or mental health-related (for example, extreme levels of fatigue, post-exertional malaise, neurocognitive impairment/brain fog, mood and anxiety disorders, orthostatic intolerance, unrefreshing sleep, headaches, and myalgia/arthralgia, among other symptoms). 

While many infectious agents have been linked to the occurrence of infection-associated chronic illnesses, the COVID-19 pandemic has resulted in widespread interest in these phenomena. Recent epidemiological studies indicate that nearly one in five people infected with SARS-CoV-2 (the virus responsible for COVID-19) continue to experience a spectrum of symptoms beyond the acute phase, a condition now referred to as “Post-Acute Sequelae of COVID-19” (PASC) or “Long COVID”. Strikingly, there is a good deal of overlap between the neurological and mental health-related symptoms of PASC (Neuro-PASC) and other suspected infection-associated chronic illnesses such as ME/CFS and POTS, suggesting that these conditions might share an underlying pathophysiology. To date, ongoing work in the field has identified multiple mechanisms of interest that may be therapeutically targetable, including an ongoing exacerbated inflammatory response, microvascular and/or thromboembolic dysfunction, pathogen-induced autoimmunity, bioenergetic failure with metabolic and mitochondrial derangements, gut dysbiosis, and the reactivation of latent pathogens. A deeper understanding of how such mechanisms drive the neuropathophysiology of infection-associated chronic illnesses would greatly enhance ongoing efforts for therapeutic development. 

Research Areas of Interest

National Institute of Neurological Disorders and Stroke (NINDS)

The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease for all people. This NOFO invites R01 applications that propose to investigate the neuropathophysiological mechanisms of infection-associated chronic illnesses across the lifespan. Clinical research focused on scientifically compelling pathways that drive the neurological sequelae of infection-associated chronic illnesses (including basic experimental studies involving humans (BESH) and/or mechanistic clinical trials) is within the scope of this initiative. Preclinical studies utilizing animal, cell culture, and/or human tissue models are also encouraged. All applications must propose mechanistic studies in the context of an infection. 

When appropriate, this NOFO strongly encourages applications that include a plan for stakeholder engagement. Stakeholder engagement involves people with lived experience (individuals with the disease), families and caregivers, their representatives, health care professionals, and the clinical research team working in active partnership at various levels across the continuum of clinical research. Continued respectful, equitable, and bidirectional knowledge transfer during stakeholder engagement can improve participant retention, adherence, and ability to participate in the study protocol. Engagement can help build trust in communities that may be fearful of participating in clinical research because of stigmas and medical mistrust. 

NINDS and NIMH are committed to reducing the disproportionate burden of neurological disease borne by underserved groups of society, including racial and ethnic minority, rural, and socioeconomically disadvantaged populations. Persons from racial and ethnic minority groups and people living in rural areas are disproportionately affected by infection-associated chronic illnesses, including experiencing increased risk for infection, hospitalization, and death. Additionally, socioeconomically disadvantaged populations are more likely to be at risk for poorer health outcomes. Women also remain disproportionately affected by infection-associated chronic illnesses, and the reasons for this remain understudied. Therefore, ensuring appropriate inclusion of populations that experience health disparities is strongly encouraged, when applicable. 

Applicants are encouraged to leverage existing research resources for their studies, including but not limited to clinical biospecimen samples from the NINDS Human Biospecimen and Data Repository (BioSEND;  https://biosend.org/) or cell lines from the NINDS Human Cell and Data Repository (NHCDR; https://stemcells.nindsgenetics.org/). Applications proposing to collect biospecimens from prospectively enrolled study participants are strongly advised to consult the BioSEND website for information about sample banking and budgeting (request a quote for biospecimen banking costs https://biosend.org/request_a_quote.html). Applicants are also encouraged to leverage the NINDS Human Cell and Data Repository (NHCDR) for banking of peripheral blood mononuclear cells (PBMC) and/or fibroblasts and induced pluripotent stem cell (iPSC) line derivation, when applicable (contact NHCDR for more information). Information about available ME/CFS biospecimens (www.searchMECFS.org ) and related clinical data (www.mapMECFS.org ) are also available and may be of use.

NINDS strongly encourages applicants to consult with NINDS Program staff to ensure the suitability of their application for this NOFO.

Research activities of interest to NINDS for this NOFO include (but are not limited to) the following (please note that all of these activities, in addition to others that may not be explicitly mentioned, would be of equal interest to NINDS and that the ordering of the below bullet points is not meant to imply a hierarchy of interest):

• Mechanisms of brain microvascular dysfunction, coagulopathy and vasculopathy that could contribute to the pathogenesis of infection-associated chronic illnesses.
• Mechanistic research in the context of infection-associated chronic illnesses focused on the potential role of brain waste clearance via the glymphatics and perivascular spaces.
• Studies of chronic neuroinflammation in the context of infection-associated chronic illnesses and how this relates to specific mechanisms of neurodegeneration and synaptic dysfunction.
• How pathological cellular events in the white matter, such as aberrant glial activation, demyelination, and/or impaired neurogenesis and neurotrophic support, are induced and or exacerbated in infection-associated chronic illnesses.
• Research focused on CNS or PNS-specific autoimmunity and/or autoantibodies that may result in damage to the nervous system.
• Identification of persistent pathogen reservoirs and/or the effect of latent viral reactivation on chronic immune dysfunction in the context of neurological manifestations of infection-associated chronic illnesses.
• Mechanisms of infection-associated hypothalamic-pituitary-adrenal (HPA) axis dysfunction as it relates to chronic immune dysregulation (e.g., T cell exhaustion), neuroinflammation, and the neural circuitry of sickness behaviors.
• Mechanisms of peripheral to CNS crosstalk, such as via the gut-brain or lung-brain axes, that contribute to neurological sequelae in the context of infection-associated chronic illnesses.
• Studies focused on potential mechanisms of mitochondrial dysfunction and/or other metabolic derangements that contribute to nervous system dysfunction.
• Research to elucidate the underlying mechanisms of autonomic nervous system dysregulation that contributes to postural orthostatic tachycardia, neurally-mediated hypotension, and heart rate variability in some individuals.
• Research on genetic risk or protective factors that may modulate neurological symptoms in infection-associated chronic illnesses.
• Research focused on sex-dependent mechanisms and factors with the potential to enhance a mechanistic understanding of neurological health disparities in women affected by infection-associated chronic illnesses.
• Projects designed to identify overlapping mechanisms of Neuro-PASC and other infection-associated chronic conditions with similar neurologic symptoms, such as ME/CFS, post-viral fatigue syndromes, post-treatment Lyme Disease, Epstein-Barr Virus infection, or other related disorders.
• Studies to better understand the impact of infection-associated chronic illnesses on pre-existing neurological conditions, as well as their potential for enhancing the risk of future neurological disease development, including Alzheimer's Disease and Alzheimer's Disease Related Dementias (AD/ADRD).
• Development and validation of animal and cell culture models that better represent these conditions.

National Institute of Mental Health (NIMH)

The National Institute of Mental Health (NIMH) accepts research to transform the understanding and treatment of mental illness through basic and clinical research, paving the way for prevention, recovery, and cure. For this initiative, the NIMH is interested in supporting mental health research questions related to infection-associated chronic illnesses. NIMH research areas of interest include 1) exploring mechanisms and pathophysiology of conditions derived from infections contributing to new and worsening mental illness outcomes, 2) identifying modifiable targets uniquely or robustly implicated in conditions derived from infections and relevant to new and worsening mental illness, and 3) conducting mechanistic clinical trials probing the biological or behavioral processes of those targets that may be pursued in future mental health therapeutic development. Basic and translational research are relevant but note that for this NOFO, NIMH only allows mechanistic clinical trials (see NOT-MH-23-375: Consolidated Notice on NIMH Clinical Trial Policies).

For the purposes of this NOFO, the NIMH has interest in:

• Research establishing experimental systems to model post-infection conditions contributing to mental illness specifically and/or mental health related outcomes after resolution of infections and in the absence of detectable pathogens.
• Studies of the post-infection mechanisms affecting brain endothelial cells, brain lymphatics and glial cells responsible for triggering cognitive and emotional deficits, including the impact of stress, hormonal influences as well as sex effects in experimental systems relevant to mental illness.
• Studies to understand the impact of post infectious processes on the neuro-immune milieu and the resulting disruption of neuronal circuits, function, or behavior relevant to mental health.
• Studies to identify mechanisms by which people with mental illness are at increased risk of infection and death.
• Mechanistic clinical trials (see NOT-MH-23-375) to probe the relevance of therapeutic targets uniquely or robustly implicated specific to post-infections and mental illness.
• Studies elucidating the pathogenesis of the mental illness characteristic of post-infectious processes such as PANDAS.
• Studies to characterize the impact of infections on mental illness, clinical management, and treatments.

The following are examples of studies considered of low priority to NIMH in response to this NOFO:

• Studies in which the infectious process is not yet resolved, and the presence of the pathogen is still detectable by conventional methods.
• Studies focusing on mental health relevant functions in the presence of significant neurological dysfunction, sickness and/or sickness behavior/malaise and/or immunological deficits as the primary clinical manifestation or phenotype.
• Clinical trials to develop therapeutic interventions, to test the safety and/or tolerability of an intervention, to demonstrate pharmacodynamic or neurodynamic effects to establish dosing or to demonstrate the efficacy or effectiveness of an intervention.

NIMH strongly encourages applicants to consult with NIMH Program Officials when developing plans for an application. This early contact will provide an opportunity to clarify NIMH policies and guidelines and identify whether the proposed project is consistent with NIMH mission and program priorities. This is particularly important if there is doubt as to whether the submission is determined to be an NIH-defined clinical trial, and if found to be a clinical trial, whether it is a mechanistic clinical trial as defined by NIMH. Studies proposing to model post infection processes contributing to mental illness specifically and/or mental health related outcomes should align with the guidance provided in NOT-MH-19-053: Notice of NIMH’s Considerations Regarding the Use of Animal Neurobehavioral Approaches in Basic and Preclinical Studies.

Office of Autoimmune Disease Research (OD/OADR)

OADR is part of the Office of Research on Women’s Health (ORWH) in the Office of the Director, NIH, and works with the 27 NIH Institutes and Centers to advance rigorous autoimmune disease research. OADR co-funds autoimmune disease applications and research projects that have received an award from one of the participating NIH Institutes and Centers (ICs) listed in the announcement. Applications seeking OADR co-funding should ensure that the proposed work is aligned with areas of OADR portfolio interest and additionally should align with at least one goal and objective outlined in the Trans-NIH Strategic Plan for Women’s Health Research.

Applications Not Responsive to this NOFO:

Applications proposing the following will be considered non-responsive to this NOFO and will not be reviewed:

• Broad observational, epidemiological, and neuroimaging studies without a significant mechanistic component (i.e., projects where the primary intent is to correlate patient-reported symptoms and/or neuropsychological testing with neuroimaging and/or other neurophysiological phenotypes without the interrogation of underlying mechanisms).
• Applications that propose clinical trials to develop therapeutic interventions, to test the safety and/or tolerability of an intervention, to demonstrate pharmacodynamic or neurodynamic effects to establish dosing, or to demonstrate the efficacy of an intervention. Applicants interested in evaluating treatments for clinical efficacy should apply through one of the NINDS clinical trial NOFOs listed at the NINDS Funding-Opportunities website. 
• Research that targets post-intensive care syndrome following an infection in which it is hard to distinguish what is due to critical illness versus chronic illness. 
• Research on infection-associated chronic illnesses that is unrelated to changes in neurological and/or mental health.
• Research focused solely on the acute phase of an infection with no implications for chronic illness.

Non-responsive studies will be administratively withdrawn prior to review.

Additional Considerations

Investigators are urged to follow the NIH guidance for rigor and transparency in grant applications (https://grants.nih.gov/policy/reproducibility/guidance.htm) and additional research practices described at https://www.ninds.nih.gov/Funding/grant_policy to ensure that robust experiments are designed, potential experimenter biases are minimized, results and analyses are transparently reported, and results are interpreted carefully. These recommended research practices include, where applicable: rationale for the chosen model(s) and primary/secondary endpoints, clear descriptions of tools and parameters, blinding, randomization, ensuring adequate sample size, pre-specified inclusion/exclusion criteria, handling of missing data and outliers, appropriate controls, preplanned analyses, appropriate quantitative techniques, clear indication of exploratory vs. confirmatory components of the study, consideration of limitations, and plans for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications.

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

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

• 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).

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

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

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

Applicant Organizations

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

• 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 and Notice of NIH's Interest in Diversity, NOT-OD-20-031.

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 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:

William Daley, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Phone: 301-496-1431
E-mail: [email protected]

Page Limitations

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

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

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

Other Attachments:

SF424(R&R) Senior/Key Person Profile

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

R&R or Modular Budget

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

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Research Strategy:

Significance: In addition to the topics covered in the SF424 (R&R) Application Guide, applicants must also clearly discuss how the project will advance a mechanistic understanding of the neurologic and/or mental health-related manifestations of infection-associated chronic illnesses. This discussion must include specific information describing how the proposed study will contribute to the prevention and/or treatment of these conditions. 

Approach: In addition to the topics outlined in the SF424 (R&R) Application Guide, describe in detail the approach that will test the proposed neuropathogenesis in the context of an infection-associated chronic illness or illnesses (if comparing multiple conditions). Outline how data will be obtained, analyzed, and interpreted with sufficient rigor to quantitatively assess project outcomes. Where appropriate, provide a strong and rigorous rationale for design of neurologically-focused or mental health-focused mechanistic clinical trials and describe how the design of the project considers potential sex and gender differences that may affect the questions asked and the analysis performed. Without duplicating details of the PHS Human Subjects and Clinical Trials Information Form, describe how the planned enrollment will appropriately represent the sex/gender, race, ethnicity and age of the population of individuals in the U.S. affected by the neurological/mental health manifestations of infection-associated chronic illnesses. Describe the use of the NIH Common Data Elements and, as applicable, other NIH resources to standardize the collection of clinical data. When appropriate, include a plan for stakeholder engagement.

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

Other Plan(s): 

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

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

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

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

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-definedclinical 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.

PHS Assignment Request Form

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

Foreign Organizations

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

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

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

4. Submission Dates and Times

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

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

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

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

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

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at [email protected].

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.

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). An application does not need to be strong in all categories to be judged likely to have a major scientific impact.

Review Criteria

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

Factor 1: Importance of the Research

Significance

• Evaluate the importance of the proposed research in the context of current scientific challenges and opportunities, either for advancing knowledge within the field, or more broadly. Assess whether the application addresses an important gap in knowledge in the field, would solve a critical problem, or create a valuable conceptual or technical advance.
• Evaluate the rationale for undertaking the study, the rigor of the scientific background for the work (e.g. prior literature and/or preliminary data) and whether the scientific background justifies the proposed study.

Innovation

• Evaluate the extent to which innovation influences the importance of undertaking the proposed research. Note that while technical or conceptual innovation can influence the importance of the proposed research, a project that is not applying novel concepts or approaches may be of critical importance for the field.
• Evaluate whether the proposed work applies novel concepts, methods or technologies, or uses existing concepts, methods, technologies in novel ways, to enhance the overall impact of the project.

Specific to this NOFO:

• Evaluate the extent to which the project further advance a mechanistic understanding of the neurologic and/or mental health-related sequelae of infection-associated chronic illnesses. 
• Assess the appropriateness of the proposed model and/or human participant population for addressing the mechanistic impact of infection-associated chronic illnesses on the nervous system.
• Evaluate how well the study identifies or explores scientifically compelling pathways that can ultimately accelerate translation to preventative measures and/or effective treatments for the neurological consequences of infection-associated chronic illnesses.

Factor 2. Rigor and Feasibility

Approach

• Evaluate the scientific quality of the proposed work. Evaluate the likelihood that compelling, reproducible findings will result (rigor) and assess whether the proposed studies can be done well and within the timeframes proposed (feasibility).

Rigor:

• Evaluate the potential to produce unbiased, reproducible, robust data.
• Evaluate the rigor of experimental design and whether appropriate controls are in place.
• Evaluate whether the sample size is sufficient and well-justified.
• Assess the quality of the plans for analysis, interpretation, and reporting of results.
• Evaluate whether the investigators presented adequate plans to address relevant biological variables, such as sex or age, in the design, analysis, and reporting.
• For applications involving human subjects or vertebrate animals, also evaluate:
  • the rigor of the intervention or study manipulation (if applicable to the study design).
  • whether outcome variables are justified.
  • whether the results will be generalizable or, in the case of a rare disease/special group, relevant to the particular subgroup.
  • whether the sample is appropriate and sufficiently diverse to address the proposed question(s).
• For applications involving human subjects, including clinical trials, assess the adequacy of inclusion plans as appropriate for the scientific goals of the research. Considerations of appropriateness may include disease/condition/behavior incidence, prevalence, or population burden, population representation, and/or current state of the science.

Feasibility:

• Evaluate whether the proposed approach is sound and achievable, including plans to address problems or new challenges that emerge in the work. For proposed studies in which feasibility may be less certain, evaluate whether the uncertainty is balanced by the potential for major advances.
• For applications involving human subjects, including clinical trials, evaluate the adequacy and feasibility of the plan to recruit and retain an appropriately diverse population of participants. Additionally, evaluate the likelihood of successfully achieving the proposed enrollment based on age, racial, ethnic, and sex/gender categories.
• For clinical trial applications, evaluate whether the study timeline and milestones are feasible.

Factor 3. Expertise and Resources

Investigator(s)

• Evaluate whether the investigator(s) have demonstrated background, training, and expertise, as appropriate for their career stage, to conduct the proposed work. For Multiple Principal Investigator (MPI) applications, assess the quality of the leadership plan to facilitate coordination and collaboration.

Environment

• Evaluate whether the institutional resources are appropriate to ensure the successful execution of the proposed work.

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

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, 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, 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.

Vertebrate Animals

When the proposed research includes Vertebrate Animals, evaluate the involvement of live vertebrate animals 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. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animals Section.

Biohazards

When the proposed research includes Biohazards, evaluate whether specific materials or procedures that will be used are significantly hazardous to research personnel and/or the environment, and whether adequate protection is proposed.

Resubmissions

As applicable, evaluate the full application as now presented.

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.

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

Evaluate 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 the Center for Scientific Review, in accordance with NIH peer review policies and practices, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

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

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

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

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

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

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

3. Anticipated Announcement and Award Dates

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

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

Section VI. Award Administration Information

1. Award Notices

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

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

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

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

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

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that all 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.

Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

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

2. Administrative and National Policy Requirements

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

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

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

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations.  NIH may terminate awards under certain circumstances.  See 2 CFR Part 200.340 Termination and NIH Grants Policy Statement Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support. 

Not Applicable

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

4. Reporting

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

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement Section 8.6 Closeout. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

Section VII. Agency Contacts

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

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

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: [email protected] (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: [email protected]

William Daley, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Phone: 301-496-1431
E-mail: [email protected]

Leonardo Tonelli, Ph.D.
National Institute of Mental Health (NIMH) for Basic Studies
Telephone: 301-443-5288
Email: [email protected]

Douglas Meinecke, Ph.D.
National Institute of Mental Health (NIMH) for Clinical Studies
Telephone: 301-443-6767
Email: [email protected]

  Vicki Shanmugam, MBBS, MRCP, FACR, CCD
  Director, Office of Autoimmune Disease Research | Office of Research on Women’s Health

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email: [email protected]

Rita Sisco
National Institute of Mental Health (NIMH)
Telephone: 301-443-2805
Email: [email protected]

Heather Weiss
National Institute of Mental Health (NIMH)
Telephone: 301-443-4415
Email: [email protected]

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.