Opportunity Information: Apply for PAR 25 115
Towards a Better Understanding of the Neurological Effects of Infection-Associated Chronic Illnesses (R21 - Clinical Trial Optional) is an NIH grant opportunity (Funding Opportunity Number PAR-25-115) designed to spark early-stage, exploratory research on how infections can lead to lasting neurological and mental health-related problems. The core aim is to support studies that clarify what is happening in the brain, nervous system, and related biological pathways after an infectious event, with a strong emphasis on post-infectious or infection-triggered chronic illnesses. While the opportunity explicitly highlights post-acute sequelae of COVID-19 with neurological involvement (often referred to as Neuro-PASC), it also welcomes work on other conditions that may follow infections, such as post-treatment Lyme disease, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), postural orthostatic tachycardia syndrome (POTS), and broader post-viral fatigue syndromes.
A major theme of the NOFO is understanding neurological and/or mental health manifestations across these illnesses. Applicants can focus on a single condition, but the NIH signals particular interest in projects that look for shared mechanisms across multiple infection-associated chronic illnesses. In practical terms, this could mean identifying common biological signatures, overlapping neural circuit disruptions, shared immune or inflammatory pathways, similar autonomic nervous system dysfunction patterns, or convergent cognitive and psychiatric symptom profiles that appear across different post-infectious syndromes. The goal is not only to describe symptoms, but to move toward mechanistic explanations that can guide diagnostics and treatment development.
The scientific scope is intentionally broad as long as the work is grounded in a post-infectious etiology. The NOFO supports neurologically focused clinical research, including basic experimental studies in humans (BESH), which generally refers to carefully designed human studies that probe biological or physiological mechanisms without necessarily being a large-scale efficacy trial. It also supports mechanistic clinical trials, meaning trials that are structured to test scientifically compelling pathways and generate evidence about how an intervention affects underlying biology, not just whether symptoms improve. The emphasis on mechanistic work is meant to accelerate the pipeline toward effective treatments by identifying actionable targets and clarifying which biological processes are driving neurological and mental health outcomes after infection.
In addition to human-focused research, the NOFO encourages preclinical studies using animal models, cell culture systems, and/or human tissue models. This is important because many mechanistic questions (for example, about neuroinflammation, persistent immune activation, microvascular injury, autonomic regulation, viral or microbial remnants, blood-brain barrier changes, or immune-mediated neural dysfunction) may require controlled experimental systems to test hypotheses rigorously. Even with preclinical work, the application must clearly tie the project to a post-infectious cause or trigger, rather than studying neurological illness in a way that is disconnected from infection-associated origins.
Administratively, this is an NIH R21 mechanism, which typically supports exploratory, high-impact ideas that may be earlier in development and aimed at generating key proof-of-concept data. The NOFO is labeled "Clinical Trial Optional," meaning applicants may propose a clinical trial if it is appropriate for the scientific question, but they are not required to do so. The opportunity falls under NIH health-related funding categories (CFDA numbers 93.242 and 93.853) and uses the standard grant funding instrument.
Eligibility is expansive and includes many types of U.S. and non-U.S. organizations. Eligible applicants listed include state, county, and local governments; special district governments; independent school districts; public and private institutions of higher education; federally recognized Native American tribal governments; tribal organizations that are not federally recognized; public housing authorities and Indian housing authorities; nonprofit organizations with or without 501(c)(3) status (as long as they are not institutions of higher education); for-profit organizations (other than small businesses); and small businesses. The NOFO also explicitly notes additional eligible applicant categories such as Alaska Native and Native Hawaiian Serving Institutions, AANAPISI institutions, Hispanic-serving institutions, historically Black colleges and universities (HBCUs), tribally controlled colleges and universities (TCCUs), faith-based or community-based organizations, eligible federal agencies, U.S. territories or possessions, regional organizations, and foreign (non-U.S.) entities.
Key dates and identifiers included in the notice are the creation date of 2024-10-17 and an original closing date of 2025-11-16. The award ceiling and expected number of awards are not specified in the provided details, which often indicates applicants should consult the full NOFO text and NIH budget guidance for the R21 mechanism and institute-specific considerations.
Overall, this funding opportunity is aimed at pushing the field beyond symptom description toward biological and neurological explanations of why some people develop persistent cognitive, neurological, autonomic, and mental health problems after infections, and how those processes might be interrupted or treated. It encourages innovative, mechanism-driven proposals across clinical and preclinical domains, with a consistent requirement that the research be anchored in a post-infectious model of disease.Apply for PAR 25 115
- The National Institutes of Health in the health sector is offering a public funding opportunity titled "Towards a Better Understanding of the Neurological Effects of Infection-Associated Chronic Illnesses (R21 - Clinical Trial Optional)" and is now available to receive applicants.
- Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.242, 93.853.
- This funding opportunity was created on 2024-10-17.
- Applicants must submit their applications by 2025-11-16. (Agency may still review applications by suitable applicants for the remaining/unused allocated funding in 2026.)
- Eligible applicants include: State governments, County governments, City or township governments, Special district governments, Independent school districts, Public and State controlled institutions of higher education, Native American tribal governments (Federally recognized), Public housing authorities/Indian housing authorities, Native American tribal organizations (other than Federally recognized tribal governments), Nonprofits having a 501 (c) (3) status with the IRS, other than institutions of higher education, Nonprofits that do not have a 501 (c) (3) status with the IRS, other than institutions of higher education, Private institutions of higher education, For-profit organizations other than small businesses, Small businesses, Others.
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Frequently Asked Questions (FAQs)
What is the title of this NIH funding opportunity?
The opportunity is titled "Towards a Better Understanding of the Neurological Effects of Infection-Associated Chronic Illnesses (R21 - Clinical Trial Optional)".
What is the Funding Opportunity Number (FON)?
The Funding Opportunity Number is PAR-25-115.
What is the main purpose of this grant?
The purpose is to support early-stage, exploratory research that clarifies how infections can lead to lasting neurological and mental health-related problems. The emphasis is on identifying mechanisms in the brain, nervous system, and related biological pathways following an infectious event, especially in post-infectious or infection-triggered chronic illnesses.
Which post-infectious conditions are specifically highlighted?
The opportunity explicitly highlights post-acute sequelae of COVID-19 with neurological involvement (Neuro-PASC). It also welcomes research on other infection-associated chronic illnesses, including:
- Post-treatment Lyme disease
- Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
- Postural orthostatic tachycardia syndrome (POTS)
- Broader post-viral fatigue syndromes
Is the scope limited to Neuro-PASC (neurological Long COVID)?
No. While Neuro-PASC is highlighted, the NOFO welcomes research on other post-infectious or infection-triggered chronic illnesses, as long as the project is clearly grounded in a post-infectious etiology.
Does NIH prefer projects focused on a single condition or multiple conditions?
Applicants may focus on a single condition, but NIH signals particular interest in projects that look for shared mechanisms across multiple infection-associated chronic illnesses (for example, common biological signatures or convergent neurological and mental health manifestations).
What kinds of mechanisms or pathways does the NOFO encourage applicants to investigate?
Based on the description provided, the NOFO encourages work that moves beyond symptom description toward mechanistic explanations, including (as examples mentioned):
- Neuroinflammation
- Persistent immune activation
- Microvascular injury
- Autonomic regulation and autonomic nervous system dysfunction
- Viral or microbial remnants
- Blood-brain barrier changes
- Immune-mediated neural dysfunction
What types of neurological or mental health outcomes are in scope?
The NOFO emphasizes neurological and/or mental health manifestations across infection-associated chronic illnesses. This includes persistent cognitive, neurological, autonomic, and mental health-related problems that develop after infection, with the goal of linking these outcomes to underlying biology.
What research approaches are supported (clinical vs. preclinical)?
The scope is broad and includes both:
- Human-focused research, including neurologically focused clinical research and basic experimental studies in humans (BESH)
- Preclinical research, including animal models, cell culture systems, and/or human tissue models
In all cases, the project must be clearly tied to a post-infectious cause or trigger.
What are "basic experimental studies in humans (BESH)" in the context of this opportunity?
In the description provided, BESH refers to carefully designed human studies intended to probe biological or physiological mechanisms. These studies do not have to be large-scale efficacy trials; the focus is on understanding mechanisms.
Are clinical trials allowed under this NOFO?
Yes. The NOFO is labeled "Clinical Trial Optional", meaning a clinical trial may be proposed if it fits the scientific question, but a clinical trial is not required.
Does the NOFO encourage mechanistic clinical trials?
Yes. It supports mechanistic clinical trials designed to test scientifically compelling pathways and generate evidence about how an intervention affects underlying biology, not only whether symptoms improve.
Is symptom description alone sufficient for responsiveness to this opportunity?
The stated goal is to push the field beyond symptom description toward mechanistic explanations. Projects are expected to be mechanism-driven and aimed at clarifying biological and neurological processes following infection.
Can a project be purely preclinical (for example, animal models or cell culture)?
Preclinical studies are encouraged (animal models, cell culture systems, and/or human tissue models). However, the application must clearly connect the work to a post-infectious cause or trigger rather than studying neurological illness in a way that is disconnected from infection-associated origins.
What grant mechanism is being used?
This opportunity uses the NIH R21 mechanism, which is typically used for exploratory, early-stage, potentially high-impact ideas intended to generate key proof-of-concept data.
What is the NIH funding instrument type?
The opportunity uses the standard NIH grant funding instrument.
Are the award ceiling and expected number of awards provided?
No. In the provided details, the award ceiling and expected number of awards are not specified. This often means applicants should consult the full NOFO text and relevant NIH budget guidance for R21 awards and institute-specific considerations.
What are the CFDA numbers associated with this opportunity?
The opportunity is associated with CFDA numbers 93.242 and 93.853.
Who is eligible to apply?
Eligibility is described as expansive and includes many U.S. and non-U.S. organizations. Examples listed include:
- State, county, and local governments
- Special district governments
- Independent school districts
- Public and private institutions of higher education
- Federally recognized Native American tribal governments
- Tribal organizations that are not federally recognized
- Public housing authorities and Indian housing authorities
- Nonprofit organizations with or without 501(c)(3) status (as long as they are not institutions of higher education)
- For-profit organizations (other than small businesses)
- Small businesses
- Eligible federal agencies
- U.S. territories or possessions
- Regional organizations
- Foreign (non-U.S.) entities
Are minority-serving institutions and community-based organizations included in eligible applicants?
Yes. The NOFO explicitly notes additional eligible categories including:
- Alaska Native and Native Hawaiian Serving Institutions
- AANAPISI institutions
- Hispanic-serving institutions
- Historically Black colleges and universities (HBCUs)
- Tribally controlled colleges and universities (TCCUs)
- Faith-based or community-based organizations
Are foreign (non-U.S.) organizations eligible?
Yes. The listed eligibility includes foreign (non-U.S.) entities.
What is the creation date for this funding opportunity?
The creation date provided is 2024-10-17.
What is the original closing date?
The original closing date provided is 2025-11-16.
What is the overarching goal NIH is trying to achieve with this opportunity?
The overarching goal is to accelerate progress from observed post-infectious symptoms to actionable biological explanations, helping guide future diagnostics and treatment development for persistent neurological, cognitive, autonomic, and mental health problems that can follow infections.
Is there a consistent requirement across all proposed studies?
Yes. Across clinical and preclinical domains, the work must be anchored in a post-infectious model of disease, meaning the research question and approach should be clearly tied to infection-associated origins or triggers.
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Applicants also applied for:
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| TMD Collaborative for IMproving PAtient-Centered Translational Research (TMD IMPACT) (U54 Clinical Trial Optional) Apply for RFA DE 25 003 Funding Number: RFA DE 25 003 Agency: National Institutes of Health Category: Health Funding Amount: Case Dependent |
| NIDCD Early Career Research(ECR) Award (R21 Clinical Trial Optional) Apply for PAR 25 120 Funding Number: PAR 25 120 Agency: National Institutes of Health Category: Health Funding Amount: Case Dependent |
| Comprehensive Analysis, Surveillance, and Statistics Initiative for Diabetes in the Young (CASSIDY) Apply for RFA DP 25 043 Funding Number: RFA DP 25 043 Agency: Centers for Disease Control and Prevention - ERA Category: Health Funding Amount: $700,000 |
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| Innovation Grants to Nurture Initial Translational Efforts (IGNITE): Development and Validation of Model Systems to Facilitate Neurotherapeutic Discovery (R61/R33 Clinical Trial Not Allowed) Apply for PAR 25 060 Funding Number: PAR 25 060 Agency: National Institutes of Health Category: Health Funding Amount: $750,000 |
| Centers for Accelerating Phage (Bacteriophage) Therapy to Combat ESKAPE Pathogens (CAPT-CEP) (P01 Clinical Trial Not Allowed) Apply for RFA AI 24 069 Funding Number: RFA AI 24 069 Agency: National Institutes of Health Category: Health Funding Amount: $1,200,000 |
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