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

The National Institutes of Health (NIH), through a collaboration of its participating components—the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Mental Health (NIMH), and the Office of the Director (OD)—has released funding opportunity PAR-25-115. This Notice of Funding Opportunity (NOFO) invites R21 exploratory/developmental research grant applications focused on understanding the neurological and mental health-related manifestations of infection-associated chronic illnesses. Examples of such illnesses include Post-Acute Sequelae of COVID-19 (PASC or Long COVID), post-treatment Lyme Disease, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), postural orthostatic tachycardia syndrome (POTS), and other related post-infectious syndromes. The purpose of this funding opportunity is to support innovative basic, translational, and mechanistic clinical research projects that will clarify the underlying neuropathophysiological mechanisms driving these illnesses. Research may focus on a single condition or compare multiple related syndromes. Emphasis is placed on studies that address pathways contributing to long-term neurological sequelae, including but not limited to immune dysregulation, neuroinflammation, microvascular dysfunction, autoimmunity, mitochondrial derangements, and gut-brain or lung-brain axis interactions. Mechanistic clinical trials and preclinical studies involving cell cultures, animal models, or human tissue are encouraged, provided they are framed within a post-infectious etiology. The grant allows for projects up to two years in length, with direct costs not exceeding $275,000 across both years and no more than $200,000 in any single year. Applications proposing clinical trials are permitted but not required. All projects must include a Data Management and Sharing Plan and adhere to NIH's rigor and transparency standards, including justifications for sample size, methodology, and experimental controls. For applicable studies, engagement with diverse populations—particularly underserved groups—is strongly encouraged, as is stakeholder engagement with individuals affected by the studied conditions and their caregivers. Eligibility extends to a broad range of domestic and international applicants, including higher education institutions, nonprofits, for-profit entities, tribal and local governments, and foreign organizations. Applicant institutions must complete various federal registrations (SAM, eRA Commons, Grants.gov) before submission. PDs/PIs must also be registered with eRA Commons. Applications must conform to all NIH formatting and submission requirements, including those outlined in the Research (R) Instructions and the specific NOFO. Applications are accepted on NIH's standard R21 due dates: February 16, June 16, and October 16 of 2025. Letters of intent are encouraged 30 days prior to the respective due date. The earliest submission date is January 16, 2025, and the expiration date for this NOFO is November 17, 2025. Funding decisions will follow peer and council reviews and consider scientific merit, alignment with NIH priorities, and availability of funds. This opportunity is considered recurring, with future cycles anticipated. Primary contacts include Dr. William Daley (NINDS, william.daley@nih.gov, 301-496-1431), Dr. Leonardo Tonelli and Dr. Douglas Meinecke (NIMH), and Dr. Vicki Shanmugam (OD/OADR). Applicants are strongly encouraged to consult with NIH staff to ensure the alignment of proposed studies with programmatic goals.