Discover Therapeutics to Eliminate HBV cccDNA From Infected Cells

Funding News Edition: November 02, 2022
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Help NIAID advance research to identify new antivirals that can eliminate hepatitis B virus (HBV) and covalently closed circular DNA (cccDNA) from infected cells through the funding opportunity announcement (FOA) Therapeutics for Eliminating Hepatitis B Virus cccDNA (R21/R33, Clinical Trial Not Allowed).

Phased Innovation Awards

Due to the high-risk, high-impact nature of the research, this FOA will use the R21/R33 Exploratory/Developmental Phased Award activity code. NIAID will provide support for up to 2 years (R21 phase) for milestone-driven research to identify novel anti-HBV drugs whose activity will be based on (a) elimination or significant reduction and (b) transcriptional suppression of HBV cccDNA facilitated by the development of sensitive and reliable assays to measure and quantitate HBV cccDNA.

Selected applicants deemed successful in the R21 phase may receive additional support for up to 3 years (R33 phase) to demonstrate durability and benefit as well as initiate preclinical studies, as described in further detail below. Applicants should be aware that the R21 phase requires applicant-defined milestones, which NIAID will peer review and approve prior to award.

Before the end of the R21 phase, awardees will submit the R33 transition package, which includes a detailed progress report describing how the initial milestones were met and a description of how the completed work justifies continuation with the originally proposed R33 studies. NIH program staff will evaluate these materials and determine which grants will be selected for continued funding. Those grants selected for funding will then transition to an R33 award without the need to submit a new application. R33 funding decisions will be based on the original R21/R33 peer review. For more information, refer to the Phased Award SOP.

Scientific Aims

The purpose of this FOA is to solicit applications that use novel cell-based assays to identify drugs that can eliminate HBV cccDNA in cells chronically infected with HBV, and to further develop them for therapeutic use, either alone or in combination with other approaches, to effect a functional cure of chronic HBV.

  • For Phase I (R21), proposed studies must
    • Develop assays for reliable, sensitive, quantitative detection of HBV cccDNA.
    • Discover drugs to inhibit HBV proteins, nucleic acids, or cellular factors and mechanisms of chronic infection using HBV cccDNA assays.
    • Evaluate their effects on HBV cccDNA in appropriate experimental models. Investigators must identify candidates to bring forward into the R33 phase for preclinical development.
  • For Phase II (R33), proposed studies must
    • Demonstrate durability of anti-HBV activity; demonstrate significant benefit in combination with approved drugs or drugs in development.
    • Initiate preclinical studies of new drug compounds shown to reduce HBV cccDNA.

Note that the preclinical development phase is not expected to be completed by the end of the award period.

NIAID will not review applications that do not propose all the research activities listed above for phase I (R21) and phase 2 (R33), and include a milestones section for phase I (R21).

Award Budget Information

Application budgets are limited to $275,000 in direct costs over the 2-year project period for the R21 phase, with a maximum of $200,000 in direct costs allowed in any single year. The R33 award phase is limited to $300,000 in direct costs per year.

Submission Information

Applications are due by February 14, 2023, at 5 p.m. local time of the applicant organization. The maximum period of funding for the entire R21/R33 award is 5 years.

Direct any questions to Dr. Rajen Koshy, NIAID’s scientific/research contact, at or 240-627-3294. Direct review related questions to NIAID’s peer review contact Dr. Zhuqing “Charlie” Li at 240-669-5068 or

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