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.Apply for RFA AI 22 068
- 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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Frequently Asked Questions (FAQs)
What is the title of this NIH grant opportunity?
The opportunity is titled "Therapeutics for Eliminating Hepatitis B Virus cccDNA (R21/R33 Clinical Trial Not Allowed)."
What is the Funding Opportunity Number (FOA number)?
The Funding Opportunity Number is RFA-AI-22-068.
What CFDA number is associated with this opportunity?
The listing references CFDA 93.855.
What kind of funding mechanism does this opportunity use?
This FOA uses the R21/R33 phased innovation award mechanism. It is structured as an exploratory first phase (R21) followed by a development phase (R33) if R21 milestones are met.
What is the main scientific focus of the program?
The program focuses on discovering and developing therapeutic strategies intended to eliminate hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) from infected liver cells or to durably suppress cccDNA activity.
Why is HBV cccDNA a major target in chronic hepatitis B cure research?
cccDNA acts as a stable nuclear template in infected liver cells and can continue producing viral components even when circulating virus is suppressed. Because it persists, it is widely viewed as a major barrier to achieving a true cure and preventing viral rebound.
What types of approaches are responsive to this FOA?
Approaches described as responsive include strategies that (1) eliminate cccDNA, (2) damage cccDNA so it is no longer functional, (3) prevent formation or replenishment of cccDNA, or (4) lock cccDNA into a durable inactive state that prevents viral gene expression.
Is this opportunity intended for incremental improvements to existing HBV suppression strategies?
Based on the stated intent, the emphasis is on therapeutics that address the cccDNA reservoir rather than approaches that only suppress viral replication without affecting cccDNA persistence.
What work is typically supported in the R21 phase?
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.
What work is typically supported in the R33 phase?
The R33 phase is intended for projects that meet R21 milestones and are ready for more advanced optimization and development, such as strengthening efficacy data, refining mechanisms of action, improving delivery or potency, and generating a preclinical package that can justify subsequent translational efforts.
Are clinical trials allowed under this FOA?
No. The FOA states "Clinical Trial Not Allowed," meaning applicants should not propose prospective human studies designed to evaluate safety or efficacy in people under the NIH definition of a clinical trial.
What kinds of studies are allowed if clinical trials are not allowed?
The FOA allows non-clinical work such as laboratory research and preclinical studies, as long as the application does not propose prospective human studies that meet the NIH definition of a clinical trial.
What does "milestone-driven" mean in the context of an R21/R33?
The phased R21/R33 structure is described as having clear milestones separating the two stages, with go/no-go decision points used to determine whether a project transitions from the R21 phase into the R33 phase.
What should a competitive application be able to explain based on the FOA summary?
Competitive projects would typically be expected to explain why the proposed approach is likely to reduce cccDNA burden or silence cccDNA-driven transcription in biologically meaningful models, and to define measurable go/no-go milestones consistent with the R21/R33 phased structure.
What is the funding instrument type and activity category?
The funding instrument type is a grant, and the activity category is health.
When was this opportunity created?
The opportunity was created on October 3, 2022.
What was the original closing date listed for this opportunity?
The original closing date listed was February 14, 2023.
Does the summary provide an award ceiling or expected number of awards?
No. The posted summary does not specify an award ceiling or the expected number of awards.
Who is eligible to apply?
Eligibility is broad and includes many U.S. organizations and governmental entities, as well as other eligible applicants noted in the summary, including non-U.S. (foreign) organizations.
Are state and local government entities eligible?
Yes. Eligible applicants include state governments, county governments, city or township governments, and special district governments.
Are public and private colleges and universities eligible?
Yes. Eligible applicants include public and state-controlled institutions of higher education and private institutions of higher education.
Are independent school districts eligible to apply?
Yes. Independent school districts are listed among eligible applicants.
Are Native American tribal governments or tribal organizations eligible?
Yes. Federally recognized Native American tribal governments and other Native American tribal organizations are listed as eligible applicants.
Are nonprofits eligible, including those without 501(c)(3) status?
Yes. Nonprofits with or without 501(c)(3) status (other than institutions of higher education) are listed as eligible.
Are for-profit organizations eligible?
Yes. For-profit organizations (other than small businesses) are listed as eligible, and small businesses are also listed separately as eligible.
Are public housing authorities eligible?
Yes. Public housing authorities and Indian housing authorities are listed as eligible applicants.
Are institutions serving specific communities highlighted as eligible?
Yes. The summary highlights eligibility for 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), and Tribally Controlled Colleges and Universities (TCCUs).
Are faith-based or community-based organizations included as eligible applicants?
Yes. Faith-based or community-based organizations are included among the "other eligible applicants" listed in the summary.
Are federal agencies eligible to apply?
Yes. Eligible federal agencies are listed among the other eligible applicants.
Are U.S. territories or possessions eligible to apply?
Yes. U.S. territories or possessions are included among the other eligible applicants.
Are non-U.S. entities and foreign organizations eligible to apply?
Yes. The summary explicitly includes non-domestic (non-U.S.) entities/foreign organizations among eligible applicants.
What is the overall purpose of this funding opportunity?
The purpose is to solicit applications that identify and develop new antiviral strategies that eliminate HBV cccDNA from infected cells or durably suppress cccDNA activity to reduce or prevent viral rebound, supporting progress toward curative strategies for chronic hepatitis B.
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