Therapeutics for Eliminating Hepatitis B Virus cccDNA (R21/R33 Clinical Trial Not Allowed) | RFA AI 22 068

Opportunity Information: Apply for RFA AI 22 068

The National Institutes of Health (NIH) announced a discretionary grant opportunity titled "Therapeutics for Eliminating Hepatitis B Virus cccDNA (R21/R33 Clinical Trial Not Allowed)" under Funding Opportunity Number RFA-AI-22-068 (CFDA 93.855). This program focuses on early-stage to mid-stage therapeutic discovery work aimed at one of the central challenges in curing chronic hepatitis B: the persistence of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) inside infected liver cells. Because cccDNA functions as a stable nuclear template that can continue producing viral components even when circulating virus is suppressed, it is widely viewed as a major barrier to a true cure. The purpose of the announcement is to solicit applications that identify and develop new antiviral strategies that either eliminate cccDNA from infected cells or durably suppress its activity, thereby reducing or preventing viral rebound.

The award mechanism is the R21/R33 phased innovation structure, which is commonly used when a project needs an exploratory, high-impact first phase followed by a more advanced development phase, with clear milestones separating the two stages. In practical terms, the R21 phase typically supports high-risk, proof-of-concept work such as identifying promising compounds, modalities, or approaches and demonstrating initial activity against cccDNA in relevant experimental systems. The R33 phase is intended for projects that successfully meet the R21 milestones and are ready to move into more robust optimization and development activities, such as strengthening efficacy data, refining mechanisms of action, improving delivery or potency, and generating the kind of preclinical package needed to justify subsequent translational efforts. Importantly, this specific opportunity states "Clinical Trial Not Allowed," meaning the work must remain non-clinical; applicants can conduct preclinical and laboratory research, but they should not propose prospective human studies designed to evaluate safety or efficacy in people under the NIH definition of a clinical trial.

The scientific emphasis is explicitly on discovering new antivirals that impact HBV cccDNA in infected cells. That can include approaches designed to remove cccDNA entirely, damage it so it is no longer functional, prevent its formation or replenishment, or lock it into a durable inactive state that prevents viral gene expression. While the summary text is brief, the intent clearly centers on therapeutics that address the cccDNA reservoir, rather than incremental improvements to strategies that only suppress viral replication without affecting cccDNA persistence. Competitive projects would typically be expected to articulate why their approach is likely to reduce the cccDNA burden or silence cccDNA-driven transcription in biologically meaningful models, and to define measurable, go/no-go milestones consistent with the phased R21/R33 structure.

Eligibility is broad and includes many types of U.S. organizations and governmental entities, reflecting NIH's standard inclusive approach for biomedical research funding. Eligible applicants include state, county, city or township, and special district governments; independent school districts; public and state-controlled and private institutions of higher education; and Native American tribal governments (federally recognized) as well as other Native American tribal organizations. The opportunity is also open to nonprofits with or without 501(c)(3) status (other than institutions of higher education), public housing authorities/Indian housing authorities, for-profit organizations (other than small businesses), and small businesses, as well as other entities that meet NIH eligibility requirements. The announcement additionally highlights a range of "other eligible applicants" such as Alaska Native and Native Hawaiian Serving Institutions, Asian American Native American Pacific Islander Serving Institutions (AANAPISI), Hispanic-serving Institutions, Historically Black Colleges and Universities (HBCUs), Tribally Controlled Colleges and Universities (TCCUs), faith-based or community-based organizations, eligible federal agencies, regional organizations, U.S. territories or possessions, and non-domestic (non-U.S.) entities/foreign organizations. Taken together, this means the program is designed to attract a wide pool of applicants, including institutions serving underrepresented communities and international groups with strong HBV research capabilities.

Administratively, the opportunity was created on October 3, 2022, and listed an original closing date of February 14, 2023. The funding instrument type is a grant, and the activity category is health. The posted summary does not specify an award ceiling or the expected number of awards, which typically means applicants would need to consult the full announcement text for budget caps, project period limits, and any institute-specific expectations. Overall, the opportunity is best understood as a targeted NIH call for innovative, milestone-driven preclinical therapeutic discovery aimed at the elimination or durable suppression of HBV cccDNA, with the longer-term goal of enabling curative strategies for chronic hepatitis B without proposing human clinical trials under this FOA.

• The National Institutes of Health in the health sector is offering a public funding opportunity titled "Therapeutics for Eliminating Hepatitis B Virus cccDNA (R21/R33 Clinical Trial Not Allowed)" and is now available to receive applicants.
• Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.855.
• This funding opportunity was created on 2022-10-03.
• Applicants must submit their applications by 2023-02-14. (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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