Towards a Better Understanding of the Neurological Effects of Infection-Associated Chronic Illnesses (R21 - Clinical Trial Optional) | PAR 25 115

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.

• 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.

Apply for PAR 25 115

[Watch] Creating a grant proposal using the step-by-step wizard inside the applicant portal: