The NIH Hepatitis B Cure 

Strategic Plan Working Group 

July 2022 

STRATEGIC PLAN 

FOR NIH 

RESEARCH TO 

CURE HEPATITIS B 

2022 UPDATE 
TABLE OF CONTENTS 

1 

Executive Summary..................................................................................................................... 2 

Introduction................................................................................................................................. 4 

Strategic Priority 1: Understanding Hepatitis B Biology ............................................................. 6 

Strategic Priority 2: Developing Tools and Resources .............................................................. 10 

Strategic Priority 3: Creating Strategies to Cure and Prevent Hepatitis B................................ 14 

Conclusion ................................................................................................................................. 18 

Appendix 1. NIH Hepatitis B Cure Strategic Plan Working Group Members............................ 20 

Appendix 2. Analysis of Public Comments to Request for Information (RFI) ........................... 22 

Appendix 3. NIH-Supported Research Resources ..................................................................... 24 

Appendix 4. Abbreviations ........................................................................................................ 27 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Executive Summary 

According to the World Health Organization (WHO), approximately 296 million people 

worldwide are chronically infected with hepatitis B virus (HBV) with 1.5 million infections each 

year despite the availability of highly effective vaccines for prevention. HBV is transmitted 

through sex, contact with infected blood or bodily fluids, or from an infected mother to her 

baby. Infection can range from acute disease that resolves within a few weeks or months to a 

longer-term chronic infection that may last six months or longer. The vast majority of those 

individuals who become infected are unaware that they are infected; the WHO estimates this 

number to be almost 90% worldwide. In the United States, approximately 1.6 million people are 

living with chronic HBV and in about 20-30% of adults, chronic infection results in lifethreatening complications such as cirrhosis (scarring of the liver), liver failure or liver cancer. 

Chronic hepatitis B infection can be treated with medications, including oral antiviral agents. 

Treatment can slow the progression of cirrhosis, reduce incidence of liver cancer and improve 

long term survival. However, there is no intervention that cures HBV infection. An ideal cure 

would not only eliminate HBV infection and also reduce or eliminate these life-threatening 

complications. 

In 2019, the National Institutes of Health (NIH) released the Strategic Plan for Trans-NIH 

Research to Cure Hepatitis B, which detailed NIH efforts to advance innovative hepatitis B 

research and improve strategies for vaccination, screening, and follow-up to care. The plan also 

established a feasible and clinically relevant definition for a hepatitis B cure and included 

prevention strategies that would contribute to eliminating transmission of HBV. 

Recently, the COVID-19 pandemic 

has impacted all facets of biomedical 

research, including research on 

hepatitis B. Since early 2020, 

hepatitis B researchers have faced 

the challenge of conducting research 

with limited access and availability of 

resources. However, many of the 

lessons learned and technologies 

developed during the COVID-19 

pandemic may be leveraged to 

advance hepatitis B research. 

Box 1. Strategic Plan for NIH Research to Cure 

Hepatitis B 2022 Update 

Vision: To end the hepatitis B epidemic 

Mission: To develop a hepatitis B cure and 

improved strategies for vaccination, screening, 

and follow-up to care 

Cure definition: Sustained loss of hepatitis B virus 

surface antigen (HBsAg), preferably with 

antibodies against HBsAg, and undetectable HBV 

DNA in serum after completion of a finite course 

of treatment. 

The Strategic Plan for NIH Research to Cure Hepatitis B 2022 Update reaffirms NIH’s 

commitment to the vision and mission outlined in the 2019 strategic plan to end the hepatitis B 

epidemic by developing a cure and improving vaccination, screening, and follow-up to care (Box 

1). The 2022 Update incorporates recent advancements and includes updates in three priority 

areas vital to developing a cure: 

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• Strategic Priority 1: Understanding Hepatitis B Biology—viral and host factors 

underlying HBV pathogenesis, immunity, reactivation, and transmission; impact of 

epidemiological factors, including coinfections with other hepatitis viruses, human 

immunodeficiency virus (HIV) and other microorganisms 

• Strategic Priority 2: Developing Tools and Resources—biomarkers, cell culture and 

animal models, data science tools, diagnostics 

• Strategic Priority 3: Creating Strategies to Cure and Prevent Hepatitis B—expanded 

clinical research capacity; strategies to block replication of HBV and eliminate HBVinfected cells; strategies to promote screening, vaccination, and follow-up to care; and 

guidelines for implementing a future cure regimen 

NIH anticipates that this plan will serve as a foundation for future research investments that 

provide the comprehensive research base needed to develop a cure and prevention strategies 

for hepatitis B infection. Implementing such strategies will depend on a concerted international 

effort by numerous public health stakeholders to end the hepatitis B epidemic. 

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Introduction 

Although a highly effective preventive vaccine for hepatitis B has been available for more than 

40 years, approximately 1.5 million people worldwide get infected with hepatitis B virus each 

year, and approximately 900,000 die from either fulminant hepatitis (acute liver failure) or 

complications due to chronic HBV 

Box 2. Chronic HBV Infection infection. Chronic infection with HBV is 

People with chronic HBV infection 

• 296 million people worldwide 

• 1.6 million people in the United States 

Transmission 

• Perinatal transmission 

• Contact with blood 

• Sexual activity 

• Needle sharing 

Outcomes 

• Inactive HBV carrier state 

• Chronic hepatitis 

• Cirrhosis (scarring of liver) 

• End stage liver disease 

• Liver cancer (hepatocellular carcinoma) 

• Premature death in 25% of people with 

chronic hepatitis B 

the result of a dynamic interaction 

between the virus and the host. The 

clinical spectrum of chronic HBV infection 

is broad, ranging from an inactive carrier 

state to chronic hepatitis and long-term 

complications such as cirrhosis (scarring of 

the liver), liver failure, and hepatocellular 

carcinoma (HCC), with 25% of people with 

chronic hepatitis B dying prematurely (Box 

2). Worldwide, rates of HCC are also 

increasing, mostly due to chronic HBV 

infection. 

Hepatitis B is a blood-borne disease. HBV 

can be transmitted through sexual 

contact, needle sharing, or other routes of 

exposure to infected blood or body fluids. 

In addition, the virus can remain 

infectious on surfaces for at least seven 

days. In areas with high levels of infection, HBV infection is most often transmitted perinatally 

during birth or in early childhood by exposure to infected blood or other body fluids. Among 

infants infected during the first year of life, 80%–90% will develop chronic infection, while the 

rate decreases to 30%–50% for children infected between the ages of 1 and 5 years. In contrast 

to children, about 95% of adults with acute HBV infection recover completely and do not 

become chronically infected (Figure 1). 

Increasing the vaccination rate among infants and children is a critical element in controlling 

the HBV epidemic. Since 1991, the CDC Advisory Committee on Immunization Practices (ACIP) 

Guidelines has recommended universal hepatitis B vaccination of neonates within 24 hours of 

birth, followed by 2 additional doses during infancy. However, in the United States, full 

vaccination coverage within 7 months is estimated to be 63%, well below the target of 90%. 

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Current treatment regimens help control HBV 

infection, but treatment is required for many 

years or for life. In addition, high treatment 

costs, the need to continuously monitor the 

disease, and adherence to the regimen are 

significant burdens. Many people with chronic 

HBV infection are not aware of their status. This 

leads to a risk of transmission and to 

reactivation of the liver disease, often following 

immunosuppression or medical treatment for 

conditions such as cancer or autoimmune 

disease. Additionally, the risk of developing 

cirrhosis and liver cancer is elevated among 

patients treated for HBV infection compared 

with uninfected individuals. The CDC ACIP 

recently recommended universal hepatitis B 

vaccination for adults ages 19 through 59 years. 

In 2017, the U.S. Food and Drug Administration 

(FDA) approved the 2-dose Heplisav-B vaccine, 

yet only an estimated 25% of adults in the 

Unites States are currently vaccinated for 

hepatitis B. In 2021, CDC ACIP guidelines 

recommended the vaccination of all children and adults up to age 60. That same year, the FDA 

approved a 3-dose vaccine, PreHevbrio, which has higher response rates in adults. Current HBV 

vaccines are now nearly 100% effective after three doses in most populations. 

In 2020 and 2021, the COVID-19 pandemic impacted all aspects of hepatitis B research and 

patient care. In the United States, racial and ethnic minority populations were 

disproportionately impacted by the pandemic, with higher rates of infection, hospitalization, 

and mortality due to COVID-19. These outcomes caused an unprecedented focus on health 

disparities in these populations, and underscore the important role that social determinants of 

health play in contributing to health outcomes. To mitigate the continuing spread of the 

pandemic, large clinical trials were initiated to test SARS-CoV-2 vaccine candidates. These trials 

purposefully recruited diverse populations to ensure that vaccine efficacy could be evaluated 

broadly. Awareness of health disparities and the importance of inclusive clinical research is 

shifting focus onto research questions relevant to all people living with hepatitis B and creating 

better approaches to answer these questions. 

Figure 1: Age at time of HBV infection correlates with risk of 

developing chronic hepatitis B. Among infants 0−1 year old 

at time of HBV infection, 80-90% typically develop chronic 

hepatitis B. This rate drops to 30–50% in children 1–5 years

old at time of infection, and 5% for individuals infected as 

adults. 

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The NIH Hepatitis B Cure Working Group, led by the National Institute of Allergy and Infectious 

Diseases (NIAID), was established to coordinate and facilitate research across the NIH towards a 

hepatitis B cure. The working group developed the Strategic Plan for Trans-NIH Research to 

Cure Hepatitis B in 2019 and reconvened to update the plan in 2022. This group consists of 

scientific and policy experts from NIAID, the National Institute of Diabetes and Digestive and 

Kidney Diseases (NIDDK), National Cancer Institute (NCI), National Institute on Minority Health 

and Health Disparities (NIMHD), and NIH Office of the Director (OD). Members from National 

Institute on Alcohol Abuse and Alcoholism (NIAAA) and National Institute on Drug Abuse (NIDA) 

also joined in 2022 (Appendix 1). To seek broad public input, NIH issued a Request for 

Information (RFI) and received several responses 

from academia, advocacy organizations, industry, 

government, clinical trial networks, and not-forprofit organizations, as summarized in Appendix 

2. 

The Strategic Plan for NIH Research to Cure 

Hepatitis B 2022 Update is focused on three 

interdependent and complementary priority areas 

(Figure 2). Improving our understanding of the 

biology of HBV and developing new tools and 

resources for HBV research are fundamental to 

creating strategies to cure and prevent hepatitis 

B. Furthermore, to effectively address the global 

public health challenges posed by HBV infection, a 

curative treatment will need to go hand in hand 

with better approaches for prevention, screening, 

and follow-up to care. 

Figure 2: Strategic Plan for NIH Research to Cure Hepatitis 

B is built on three priority areas that are vital to

developing a cure: 1. Understanding hepatitis B biology,

2. Developing tools and resources to advance HBV 

research, and 3. Creating strategies to cure and prevent 

hepatitis B. 

Strategic Priority 1: Understanding Hepatitis B Biology 

Developing a cure for HBV will require continued advances in understanding the complex 

molecular and immune mechanisms underlying infection and disease. Clinical manifestations of 

chronic hepatitis B can vary greatly and can transition between different phases (immunetolerant, immune-active, and inactive). These phases are differentiated using markers of viral 

replication (hepatitis B e antigen [HBeAg], hepatitis B surface antigen [HBsAg], and HBV DNA), 

and markers of liver disease such as alanine aminotransferase (ALT) levels. Studies that 

elucidate the viral lifecycle and host responses to infection can identify potential targets for 

intervention in HBV infection and disease. Successful cure therapies will likely require two 

strategies: one that directly inhibits viral activity and a second that prevents viral spread to 

uninfected cells. 

The HBV life cycle is unique in that during replication, genomic DNA is converted to a molecular 

template DNA, called covalently closed circular DNA (cccDNA), that is used to amplify all viral 

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RNAs. Silencing HBV cccDNA is considered essential for a cure. Developing assays to quantify 

cccDNA and assess its transcriptional activity is also a critical component in curing HBV. 

Continuing to advance our understanding of the function of various viral proteins and host 

factors is necessary for improving the assays, models, and other resources needed to move 

toward a cure. 

The clinical outcomes of HBV infection are affected 

by many factors, including age, sex, gender, race, Box 3. Strategic Priority 1 — 

ethnic or geographical origin, host and viral Understanding Hepatitis B Biology 

genotype, immunosuppression, comorbidities 1.1 Identify viral factors that control 

(especially other forms of liver disease), and infection and disease 

coinfection with hepatitis D virus (HDV), hepatitis C 1.2 Understand immune responses and 

virus (HCV), HIV, or other microorganisms. Thus, other host factors of HBV infection 

large and diverse clinical studies are needed to 1.3 Characterize clinical pathology and 

provide insights into the complexity and diversity of factors that affect disease 

host-pathogen interactions. Results from these progression and control in various 

investigations will inform the breadth of assays and subpopulations and age groups 

studies needed to develop and evaluate diagnostic 

tools and curative therapies for use in various care settings and populations. 

Objective 1.1 Identify viral factors that control infection and disease 

The mechanisms involved in HBV replication are obvious therapeutic targets. Indeed, current 

treatments include nucleoside and nuecleotide analogues, which block viral replication, and 

interferon, which both boosts the host immune response and prevents viral replication. 

However, discontinuing treatment usually leads to a rebound of viral replication. Investigations 

into understanding each step of the HBV lifecycle and the role of various viral factors in the 

progression of disease are necessary to develop new classes of antivirals and new treatment 

strategies to cure chronic hepatitis B. The general function of many essential viral proteins 

(including HBx, HBsAg, HBcAg, and HBeAg) are known, but their multiple interactions in HBV 

replication, immune suppression, and pathogenesis remain to be elucidated. The biogenesis, 

homeostasis, decay, and transcriptional regulation of cccDNA, are all potential targets for 

therapeutic intervention. 

Continued investigations into the mechanisms of the HBx protein in viral replication, its 

regulatory function in the transcription of cccDNA, and its role in HBV pathogenesis may also 

lead to the development of antiviral agents that target HBx and block cccDNA transcription. 

Defining these mechanisms at the molecular level across the different HBV and host genotypes 

will lay the foundation for targeting cccDNA, either directly or indirectly, to cure patients 

chronically infected with HBV. 

Studies of HBV DNA integrated within host chromosomes, which is known to cause host genetic 

perturbations, may elucidate the multistep process of HCC development. New technology7 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

intensive studies using genome-wide association studies (GWAS), RNA sequencing, and singlecell sequencing may advance important mechanistic insights underpinning this process and 

identify targets essential to halt its progression. 

Objective 1.2 Understand immune responses and other host factors of HBV 

infection 

HBV infection resolves in 95% of adults, indicating that the 

immune response can clear the infection and prevent it 

from becoming chronic. Furthermore, up to 10% of 

patients with chronic HBV spontaneously become 

functionally cured, exhibiting a sustained loss of HBsAg 

and antibodies against HBsAg. Continued research to 

understand the nature of such effective host immune 

responses are crucial for harnessing them therapeutically. 

To accomplish this, the roles of both the adaptive and the 

innate immune responses to HBV infection need to be 

better characterized. Extensive analyses of systemic and 

tissue specific (liver) T-cell and B-cell responses, T-cell 

exhaustion in HBV persistence, and T-cell recovery, as well 

as mechanisms by which HBV proteins impact antiviral 

innate and adaptive immunity, are still needed to better understand immune control of the 

virus. These studies should consider the impact of coinfections with either HCV, HDV, or HIV on 

HBV-specific immunity, as well as various stages of liver disease. 

Figure 3: Hepatitis B core antigen (HBcAg, red) 

in the cytoplasm of human liver cancer cells

(HepG2) transfected with HBV. Cell nuclei are 

labelled in blue. Credit: NIAID 

Objective 1.3 Characterize clinical pathology and factors that affect disease 

progression and control in various subpopulations and age groups 

Age at the time of infection is the most significant factor in a person’s risk of developing chronic 

HBV infection, with children at highest risk of chronic infection. A cure that is effective in 

children will have the most impact and requires the identification of age-related differences in 

the immune response to HBV. 

Some of the variety in clinical outcomes is related to genetics. For instance, GWAS in people 

with chronic hepatitis C have linked single-nucleotide polymorphisms with spontaneous and 

treatment-induced clearance of hepatitis C virus infection. This association also appears to be 

dependent on race, HCV genotype, and viral load. Several GWAS have suggested linkages 

between gene variants and HBV persistence and HBV-related HCC. Further research is needed 

to identify relevant genes and elucidate mechanisms of HBV disease progression, response to 

therapy, and vaccine responsiveness. 

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HBV genotype is another factor affecting disease progression. Patients with cirrhosis are usually 

considered at higher risk of developing HCC, but certain HBV genotypes, such as African A1 and 

Alaskan F1b, are strongly associated with HCC with or without underlying cirrhosis. Additional 

studies are needed to examine the role of HBV genotype in disease progression, including the 

development of cirrhosis and HCC, and in the response to therapy. 

In addition to genetics, many factors influence the clinical outcome and effectiveness of a cure. 

Coinfection with HCV or HIV leads to more severe liver disease and higher mortality. 

Furthermore, treating HCV infection in patients coinfected with HBV can potentially cause HBV 

to flare and the reverse may also be true. HDV is an incomplete, unique RNA virus that requires 

HBV to provide HBsAg for virion assembly, release, and transmission. HDV coinfection 

significantly exacerbates both acute and chronic liver disease. Several social, behavioral, and 

dietary factors also must be considered, particularly as they relate to important comorbidities 

and coinfections. Alcohol misuse and other dietary factors can compound HBV-induced liver 

disease in the presence of comorbidities such as cirrhosis and fatty liver disease. Other 

behaviors, such as needle sharing, can lead to coinfection with either HIV, HDV, or HCV. 

Furthermore, substance use disorders may have effects on the outcome of viral infections. 

Additional research is necessary to study the mechanisms whereby substance use affects viral 

pathogenesis, antiviral immunity and disease progression of HBV mono-infection or coinfection 

with HIV, HDV, or HCV. 

Clinical pathology studies need to focus on persons in and from HBV-endemic countries, to 

examine biological, environmental, social, or cultural factors that might affect the immune 

response to the virus and disease progression in these groups. Environmental exposures to 

mold-derived aflatoxin, smoking, or the parasitic disease schistosomiasis may affect the 

progression of hepatitis B-induced liver disease. Factors that protect certain populations may 

also be identified, such as the contribution of diet or microbiome to the enhancement of 

natural immunity 

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Strategic Priority 2: Developing Tools and Resources 

Achieving the research objectives outlined in Strategic Priority 1 to advance understanding of 

hepatitis B biology requires standardized 

tools and resources including reagents, 

laboratory methods, animal models, and 

assays. This effort also includes the 

application of novel technology such as 

comprehensive systems biology analyses of 

patient data, laser capture microdissection, 

digital droplet polymerase chain reaction 

(PCR), and deep sequencing. Use of 

biorepositories and online platforms allow 

investigators to share resources, tools, 

data, and samples for basic research, 

product testing, and clinical evaluation. The 

development of new data science tools can 

accelerate research, illuminating new 

potential mechanisms of disease and 

possible drug effects, or interactions. Improved cell culture systems, including human organoid 

cultures, to support fundamental research and product development, and new animal models 

that better reflect human HBV infection and related diseases, are also necessary. Finally, 

biomarkers for various stages of disease, and improved and validated diagnostic, monitoring, 

and assessment tools will advance fundamental and clinical HBV research. 

Box 4. Strategic Priority 2 — Developing 

Tools and Resources 

2.1 Share and standardize data, reagents, 

procedures, and assays 

2.2 Improvecell culture and cell-free 

systems to support fundamental 

research and product development 

2.3 Improve and create new animal models 

that reflect the progression of human 

liver disease 

2.4 Establish biomarkers for disease 

progression and response to therapy 

2.5 Develop diagnostics and tools for 

monitoring disease and evaluating 

therapeutics 

Objective 2.1 Share and standardize data, reagents, procedures, and assays 

HBV research is conducted globally in an array of academic, government, and industry settings. 

Harmonizing procedures for producing and purifying infectious HBV nucleic acid species and 

proteins to be used in preclinical research will enable researchers to integrate scientific findings 

on drug candidates and vaccines from diverse locations. Such efforts include establishing 

standard recombinant plasmids for inducible and constitutive bacterial and eukaryotic 

expression of HBV proteins and developing hybridomas for monoclonal antibodies to HBV 

proteins. Standardizing protocols for immunoassays, such as methods that quantify cytokinesecreting cells, intracellular cytokine staining, and T-lymphocyte proliferation and cytotoxicity 

assays, are important. Together, these steps will facilitate the exchange of standardized 

samples and data between investigators and expand the hepatitis B knowledge base. 

Artificial intelligence and data science have emerged as increasingly powerful tools to address 

questions in HBV research. Applying these tools to large clinical data sets can identify factors 

linked to infection and disease progression, revealing important biological mechanisms to be 

explored and suggesting possible avenues for a cure. Such analyses depend on validated, 

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standardized biological and clinical data sets, including standardized measures of social 

determinants of health. Improving data science tools and the availability of hepatitis B 

biological and clinical data will accelerate the development of a hepatitis B cure. Augmented 

reality (AR) technology is an example of a method for researchers to communicate and learn 

about structural and functional features of biomolecules and viruses. NIAID added a module 

about HBV to its public virtual reality application PathogensAR to educate researchers, 

clinicians, and the public about HBV. 

NIH will leverage existing clinical/epidemiological cohorts, (Appendix 3) such as the Hepatitis B 

Research Network (HBRN) and its repository, and global networks, such as the International 

Epidemiological Databases to Evaluate AIDS (IeDEA), the HIV/AIDS Clinical Trials Networks and 

the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) to advance 

hepatitis B cure research and continue to support the development of new standardized 

reagents, protocols, and assays. NIH is facilitating the sharing of key resources through 

biorepositories such as BEI, a repository supported by NIAID. The new NIH Policy on Data 

Management and Sharing, effective January 2023, aims to increase openness and facilitate 

sharing. The NIH Office of Data Science Strategy is developing data science educational 

opportunities for biomedical researchers as well as data science tools and databases, such as 

the Generalist Repository Ecosystem, to facilitate access to standardized data. 

Objective 2.2 Improve cell culture and cell-free systems to support fundamental 

research and product development 

Although cell culture systems for HBV are improving, continued investigations on improved 

systems are critical to support research toward a hepatitis B cure. Current studies primarily rely 

on transfection of human hepatoma cell lines, such as HepG2 2.2.1, with expression plasmids 

containing HBV genomic DNA. The recent identification of the sodium taurocholate cotransporting polypeptide (NTCP) receptor has enabled infection of a variety of cultured cells 

engineered to express NTCP, such as HepG2-NTCP and Huh7-NTCP. However, these cells are 

not easily infected, possibly reflecting the need for other, unidentified, receptor components. 

Virus secretion and spread within these cultures also remain low. New cell culture or co-culture 

models that are easily infected and support cell-to-cell spread of the virus are needed to 

elucidate the mechanisms of infection, viral persistence, and clearance—whether spontaneous, 

drug-mediated, or immune-mediated. Such models also will be necessary to screen antiviral 

drugs and evaluate combination therapy approaches that target multiple steps in the 

replication cycle (e.g., inhibitors of viral entry, translation, and assembly). 

Advanced resources such as cell lines derived from human embryonic stem cells collected 

within existing guidelines or induced pluripotent stem cells will aid the development of robust, 

specific, and reliable cccDNA reporter cell culture systems that would be particularly useful for 

developing antiviral therapies. The development of organoids that may physiologically reflect 

normal liver biology will also be useful for advancing fundamental knowledge of HBV biology 

and host-pathogen interactions, and for developing and screening potential new therapies. 

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may lead to new strategies to prevent or

treat and possibly cure chronic hepatitis B.

Platform technologies that are easily adapted to various diseases or conditions have shown 

promise for other diseases, such as mRNA-based vaccines for COVID-19. The combination of 

these emerging technologies and new possible targets 

New validated, cell-free test systems for highthroughput screening of potential antiviral agents will be necessary to spur progress in 

developing hepatitis B cure therapies. Potential agents include oligopeptide libraries of factors 

likely to produce promising cure strategies, such as known T-helper and cytotoxic T-cell 

epitopes. Automated screening of biomolecules can also be used to examine virus-specific 

targets affecting transcription, translation, viral packaging, export, and infection. 

Objective 2.3 Improve and create new animal models that reflect the progression 

of human liver disease to evaluate hepatitis B virology, liver pathogenesis, and 

novel cure strategies 

Developing animal models that recapitulate human disease is crucial for both basic and 

preclinical studies. Preclinical studies require a clear understanding of which aspects of the 

disease each model accurately reflects. A model to study perinatal or vertical transmission, a 

major cause of chronic HBV infection, would be valuable. 

In vivo studies on HBV currently rely on tupaia, woodchuck, duck, and mouse models. The 

tupaia, commonly known as a tree shrew, is the only non-primate that can be infected with 

HBV, however viral replication in these animals is low and transient. This model was used to 

identify NTCP as a receptor for HBV. The woodchuck model is often used for preclinical studies 

but it is a surrogate model that relies on infection with the woodchuck hepatitis virus (WHV), 

which is similar to HBV. Infection of mice with HBV is complicated and necessitates either an 

alternate delivery method, such as microinjection or the use of an HBV-carrying vector; 

modification of the mice by transgenic expression of the virus; or transplantation of human 

liver cells into immunodeficient mice to enable long-term replication and establishment of 

cccDNA. 

The limitations of these small animal models underscore the need for developing a viable 

nonhuman primate model and an immunocompetent mouse model to address complex 

questions in HBV research. Fortunately, several new models of chronic HBV infection are being 

developed. Notably, the transgenic expression of the HBV entry receptor NTCP in mice and 

rhesus macaques enables HBV infection and replication in immunocompetent animals, 

although it does not yet lead to viral persistence or cause disease. Preliminary results suggest 

that alternate models, such as spider monkeys, can develop long-term HBV infection. NIH will 

support studies to determine how well the dynamics of host-pathogen interactions, viral 

pathology, and responses to vaccines and therapeutics seen in animal models are replicated in 

humans. These new or improved models are essential to test potential cure strategies. 

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Objective 2.4 Establish biomarkers for disease progression and response to 

therapy 

There is a need for biomarkers to detect early HBV infection, stages of liver injury (including 

HCC), viral replication, and response to therapy. Potential biomarkers include pre-genomic RNA 

(pgRNA) and quantitative HBsAg. HBV cccDNA, a key indicator of HBV replication, is restricted 

to the nucleus of infected hepatocytes and is difficult to measure. Surrogate serum markers of 

cccDNA and HBV replication within liver cells are needed. Recent reports suggest that the 

hepatitis B core-related antigen (HBcrAg) is a reliable indicator of cccDNA transcription and may 

also be useful in distinguishing the different phases of chronic hepatitis B. Similarly, serum HBV 

RNA has also been shown to be a potential biomarker for chronic hepatitis B infection and 

treatment response. Further studies are needed to explore the usefulness and validation of 

these biomarkers in guiding clinical management and predicting the outcome of antiviral 

therapy. 

Using state-of-the art technologies, including data science tools, to systematically collect and 

analyze clinical, immunologic, and virologic data from people with chronic HBV will be vital to 

understanding complex host-pathogen interactions and their relationship to clinical outcomes. 

Analysis of these data can in turn help identify and validate biomarkers that reflect disease 

progression and predict the response to treatment in various populations. Such biomarkers will 

form the basis of improved assays not only to further fundamental knowledge of HBV and 

identify vulnerabilities that can be exploited for a cure, but also to evaluate the efficacy of 

potential cure approaches. These biomarkers will need to be validated in different racial and 

ethnic populations to ensure their broad applicability. 

Objective 2.5 Develop diagnostics and tools for monitoring disease and evaluating 

therapeutics 

Diagnostics and monitoring tools for clinical research, which build on biomarkers identified as 

part of Objective 2.4, need to be developed in parallel with candidate therapies. The last few 

years have seen the application of machine learning to develop new approaches to diagnose 

people with hepatitis B and to identify those at high risk of disease progression. Developing, 

standardizing, and validating affordable point-of-care diagnostics suitable for use in resourcelimited settings and in low- and middle-income countries where chronic HBV infection is 

prevalent is a priority. 

NIH supports the development of improved assessments of treatment efficacy, such as 

minimally invasive approaches to measure disease progression. This could involve enhancing 

clinical techniques that build on existing biopsy methods to obtain liver tissue for examination 

and advancing noninvasive in vivo imaging methods such as transient elastography, a 

specialized form of ultrasound. NIH also will support the development of improved methods to 

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assess liver synthetic function and hemodynamics (portal hypertension). Expanding assessment 

approaches will be key to developing and evaluating promising HBV countermeasures. 

In addition, improved diagnostics will be needed to enable early detection and treatment of 

HCC in the context of HBV infection. Existing antiviral drugs reduce but do not eliminate the risk 

of developing HCC. As some risk of developing HCC remains even after HBV infection has been 

eliminated, periodic post-treatment monitoring of individuals is important. Such monitoring is 

especially important for people with cirrhosis and those who were infected with HBV genotypes 

known to be associated with HCC in the absence of cirrhosis. 

Strategic Priority 3: Creating Strategies to Cure and Prevent 

Hepatitis B 

Developing strategies to cure chronic HBV infection will include interventions to reduce related 

morbidity and mortality and will build on insights gained from the biology of HBV and 

protective immune mechanisms in acute infection, as outlined above. The model systems, 

assays, biomarkers, and other resources developed as outlined in Strategic Priorities 1 and 2, 

are critical for testing potential new therapies and advancing the most promising approaches 

into clinical studies. Increased clinical research capacity and collaborations between academic 

and industry partners are required to learn more about the disease in humans and to test cure 

and prevention strategies. 

In addition to curing hepatitis B, improving prevention strategies is essential to ending the 

hepatitis B epidemic. Implementation of the new guidelines to vaccinate all children and adults 

would make significant progress toward eliminating transmission of HBV. Developing culturally 

appropriate, multi-level prevention strategies that reach diverse and high-risk populations, and 

those with limited English proficiency, would also accelerate the elimination of HBV 

transmission by addressing barriers at the individual, community, and structural levels. 

Objective 3.1 Create cure strategies that suppress viral replication and/or 

stimulate the immune response 

As outlined in Strategic Priority 1, multiple approaches are required for blocking viral entry into 

uninfected hepatocytes, preventing viral replication, and silencing or eradicating cccDNA. 

Individual drugs, and drug combinations to target each of the viral proteins are in various 

stages of development, and some are currently being evaluated in clinical trials. NIH is 

stimulating research to develop these approaches, including advancing small molecule drugs 

that target essential HBV proteins and strategies that degrade or suppress transcription of 

cccDNA. Current approaches to degrade cccDNA (e.g., by CRISPR/Cas9) are challenging in terms 

of translation to the clinic. 

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NIH is promoting the development and testing of new and existing approaches to facilitate an 

effective host immune response to the virus, as in individuals who naturally resolve an acute or 

chronic HBV infection. Immunotherapies aimed at curing HBV could eliminate infected cells, 

prevent virus spread from persistently 

infected cells, and block mechanisms used 

by the virus to 

evade the host immune response. These 

agents may include those that modulate 

adaptive immunity, such as immune 

checkpoint inhibitors (e.g., anti-PD1/PD

L1 antibodies) and chimeric 

antigen receptor (CAR) T cells, which 

already are being used to treat a wide 

range of cancers, as well as agents that 

modulate innate immunity. 

Box 5. Strategic Priority 3 — Creating Strategies 

to Cure and Prevent Hepatitis B 

3.1 Create cure strategies that suppress viral 

replication and/or stimulate the immune 

response 

3.2 Expand clinical research capacity 

3.3 Evaluate curative approaches in diverse 

populations 

3.4 Develop effective strategies to screen and 

vaccinate diverse populations and ensure 

follow-up to care and adherence to 

treatment 

-

Combination therapies that suppress viral replication and stimulate the immune response to 

prevent viral spread are likely to be the most effective approaches to cure hepatitis B. New 

therapies will need to be explored as potential combinations and developed together. As 

potential therapeutics are being developed, such as HBx protein, capsid inhibitors, siRNAs, 

nucleic acid polymers/ S-antigen transport-inhibiting oligonucleotide polymers (NAPs/STOPs), 

antisense oligonucleotides (ASOs), and entry inhibitors, additional effort is needed to 

systematically design and test combinations of these candidates in new and improved animal 

models before evaluating them in humans. 

Objective 3.2 Expand clinical research capacity 

Testing putative cure regimens, new diagnostics, and improved prevention strategies will 

require expanded clinical research capacity, with a particular emphasis on involving populations 

at high risk of HBV, including at-risk and minority populations and children. Building clinical 

research capacity includes multiple infrastructure resource components, from identifying 

clinical research sites and recruiting relevant diverse populations, to training staff and 

deploying new tools at clinical sites. The COVID-19 pandemic enabled the large-scale 

application of innovative strategies, such as telehealth visits for clinical research, expanded 

involvement of community leaders, and enrollment of at-risk minority populations. Applying 

these approaches to hepatitis B clinical research could lead to the development of more 

relevant and easier-to-use interventions to cure and prevent hepatitis B. NIH will build on its 

existing investments in clinical research infrastructure and resources (Appendix 3) in the United 

States and in locations where HBV is endemic. In addition, leveraging NIH resources in settings 

where both HBV and HIV are endemic will facilitate the development of an HBV cure as well as 

treatment approaches for people coinfected with HIV. 

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To accomplish this ambitious research agenda, it will be critical to recruit and train investigators 

in the field of HBV research for both clinical and basic research. An analysis of the NIAID 

hepatitis B portfolio revealed that few researchers focus exclusively on HBV. However, many 

investigators do include HBV in studies of HIV, liver cancer, or other aspects of liver function. 

Encouraging multidisciplinary collaborations helps draw on expertise from diverse disciplines, 

including virology, immunology, systems biology, data science, genetics, and epidemiology. 

Pursuing the research opportunities described in this plan should enable an increased focus on 

HBV research, improve the design and impact of clinical studies, and expand the cadre of HBV 

researchers across NIH. 

NIH will continue to leverage existing research activities, resources, and human cohorts. For 

example, researchers continue to analyze data from the NIDDK, which conducted clinical 

studies of disease characteristics and treatment approaches in both adults and children, in 

collaboration with several industry partners. The HBRN and its repository help researchers 

explore the mechanisms of viral pathogenesis, including immunology and HBV/HIV co-infection. 

A new Liver Cirrhosis Network, supported by the NIDDK in collaboration with the NCI and 

NIAAA, is building upon this work by establishing a longitudinal cohort of people with cirrhosis, 

including those with chronic hepatitis B. This Network plans to test new therapeutic approaches 

to cirrhosis, such as the use of statin drugs. 

Objective 3.3 Evaluate curative approaches in diverse populations 

Any cure strategy developed, whether a single or a combination approach, will need to be 

evaluated among diverse populations. Factors such as sex, gender, race and ethnic background, 

socio-economic status, and country of birth need to be considered when evaluating potential 

cures and the long-term clinical residual risk of liver disease progression and HCC. For example, 

the risk of progression from cirrhosis to HCC is considerably higher in men than in women, and 

higher in Hispanic men in the southern Texas border area compared to other areas in the 

United States. Furthermore, many people with chronic hepatitis B are immigrants from Africa 

or Asia and are often not perceived as at-risk for infection due to lack of awareness among 

clinicians. Other important subpopulations include chronically infected women of childbearing 

age, who risk transmitting the virus to their infants during childbirth or in early childhood; and 

injection drug users and men who have sex with men, two groups at higher risk of HBV 

infection. These vulnerable populations should be prioritized when considering the testing of 

potential cures. 

Any potential cure will need to be evaluated in HBV-infected individuals with other 

complicating medical conditions or coinfections to ensure effectiveness in these populations, 

especially considering that the therapy itself may result in cytotoxicity and liver inflammation. 

Examination of interactions between therapies is also needed specifically for patients whose 

immune systems are suppressed because of cancer treatment, treatment with biologic 

therapies, or immunodeficiency disorders, since immunosuppression sharply increases the risk 

of HBV reactivation. 

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Dietary, behavioral, and sociocultural variables also affect the clinical impact of a cure. For 

example, heavy alcohol consumption is an independent risk factor for cirrhosis and HCC. The 

risk of developing alcohol-associated HCC is increased in the context of chronic HBV infection. 

Individuals with alcohol use disorders as well as those who engage in injection drug use, who 

are at increased risk of HBV infection, may be particularly difficult to reach with potentially 

curative therapies. Furthermore, obesity, type 2 diabetes, and other factors can contribute to 

non-alcoholic steatohepatitis (NASH), a form of fatty liver disease that may lead to cirrhosis and 

HCC. The risk of developing HBV-related cirrhosis and HCC thus may be increased in people with 

NASH-related liver damage. These considerations will affect the public health impact of a cure 

and inform the development of guidelines for its implementation. 

NIH will continue to support the development of improved clinical trial designs with the 

appropriate clinical endpoints, including validated surrogate markers to assess efficacy. These 

studies could be implemented by leveraging the clinical research networks listed in Strategic 

Priority 2 and existing NIH-sponsored networks such as the HIV clinical trial networks. 

Objective 3.4 Develop effective strategies to screen and vaccinate diverse 

populations and ensure follow-up to care and adherence to treatment 

Innovative, effective strategies to screen populations at high risk for HBV infection, including 

underserved and hard-to-reach populations, must be devised and implemented. Improved 

access to the existing and highly effective HBV vaccine is critical to eliminating hepatitis B. 

Improved screening, vaccination of uninfected individuals, and treatment of HBV-infected 

individuals will reduce the number of HBV infections and the complications and deaths due to 

long-term sequelae of chronic HBV infection. 

In 2017, the U.S. Food and Drug Administration (FDA) approved the Heplisav-B vaccine—which 

requires only two shots over one month instead of three shots over six months and that may 

facilitate the implementation of the new guidelines and protect more adults from hepatitis B 

and liver cancer. Despite this advancement, the CDC estimates that only 25% of adults in the 

United States are currently vaccinated for hepatitis B. As of November 2021, CDC ACIP 

guidelines recommend the vaccination of all children and adults up to age 60. Current HBV 

vaccines are nearly 100% effective after three doses in most populations, especially children. In 

2021, the FDA approved an HBV vaccine, PreHevbrio, that has higher response rates with three 

doses in adults, who are more likely to be poor responders due to complicating comorbidities 

or coinfections (e.g., obesity, HIV, renal failure, transplantation). Implementing the new U.S. 

recommendations to vaccinate adults should decrease the incidence of both infection and 

transmission. 

Implementation of the current guidelines for HBV prevention is a particularly important issue 

for underserved and hard-to-reach populations in the United States. Improved approaches are 

needed to vaccinate and screen people from HBV-endemic countries who have moved to the 

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United States, and to treat infected individuals. Strategies are needed to overcome vaccine 

hesitancy and improve vaccine uptake, especially among diverse populations. New strategies to 

decrease infection could be considered, such as free mobile vaccination clinics, or screening 

clinics for adults. Screening also will serve to inform people and communities about HBV 

infection and limit further transmission. Other strategies will need to be tailored to reach 

specific high-risk groups. For instance, systematically screening patients for HBV infection prior 

to cancer chemotherapy or immunosuppressive treatment would decrease the risk of HBV 

reactivation, which in some cases may lead to acute liver failure. 

Interventions are needed to better implement HBV treatment guidelines and to facilitate 

clinical follow-up and adherence to treatment in high-risk populations. Public health strategies 

to promote follow-up to care and adherence to treatment for individuals who test positive for 

HBV and are eligible for treatment—and thereby reduce viral transmission—must also be part 

of the global effort to control the hepatitis B epidemic. These strategies need to address the 

stigma of chronic HBV infection in some populations, which poses challenges for achieving 

effective screening and follow-up to care. Long-term adherence to treatment to control HBV 

infection is challenging, especially in hard-to-reach populations, and resource-limited settings, 

where both the cost and availability of existing antiviral therapies are current barriers to care. 

Improved approaches to monitor long-term complications, and the development of a cure, will 

help alleviate these challenges. 

Once effective cure regimens have been developed, a coordinated international effort will be 

required to develop strategies for implementation at both the U.S. and global levels. These 

strategies may need to be modified to address HBV genetic variability over time and under the 

pressure of therapy. 

Conclusion 

NIH will continue to advance research to find a cure for hepatitis B using available mechanisms 

and resources to address this critical health threat. Addressing gaps in HBV research and 

developing needed resources and tools will facilitate the development of strategies to cure and 

prevent hepatitis B. 

This Strategic Plan for NIH Research to Cure Hepatitis B 2022 Update aligns with the HHS Viral 

Hepatitis National Strategic Plan and builds on recommendations from the U.S. National 

Academies of Science, Engineering and Medicine; the Hepatitis B Foundation Roadmap for a 

Cure; the International Coalition to Eliminate HBV; the American Association for the Study of 

Liver Diseases; the European Association for the Study of Liver; the American Liver Foundation; 

the ACTG Hepatitis Transformative Sciences Group; the International Network for Strategic 

Initiatives in Global HIV Trials (INSIGHT); the Alaska Native Tribal Health Consortium Liver 

Disease and Hepatitis Program; and other groups. It furthermore supports the HHS and WHO 

goals to eliminate hepatitis B by 2030 by strengthening the research foundation that will inform 

new approaches to prevent, diagnose, treat, and cure this disease. 

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A dedicated strategy will require coordination of hepatitis B research across NIH Institutes, 

Centers, and Offices to build on the existing portfolio of resources and investments in 

biomedical research to strengthen the NIH hepatitis B research program. These efforts will 

continue to strengthen hepatitis B research, expanding understanding of hepatitis B biology, 

developing tools and resources to advance HBV research, and creating strategies to cure and 

prevent hepatitis B. 

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Appendix 1. NIH Hepatitis B Cure Strategic Plan Working 

Group Members 

IC 

NIAID 

Last Name 

Alston-Smith 

First Name 

Beverly 

Position 

Chief, Complications and Co-Infections 

Research Branch, Therapeutics Research 

Program, Division of AIDS 

NIAID Azeez Olumayowa Health Science Policy Analyst, Policy, 

Planning and Evaluation Branch, OD 

NIAID Bushar Nicholas Chief, Policy, Planning and Reporting 

Section, Policy, Planning and Evaluation 

Branch, OD 

NIAID Caviston Juliane Health Science Policy Analyst, Policy, 

Planning and Evaluation Branch, OD 

(now at NIH Office of Research on 

Women’s Health) 

NIAID Challberg Mark Chief, Virology Branch, Division of 

Microbiology and Infectious Diseases 

NIAID Chiou Christine Medical Officer, Complications and CoInfections Research Branch, Therapeutics 

Research Program, Division of AIDS 

NIAID Deckhut Alison Chief, Basic Immunology Branch, Division of 

Allergy, Immunology, and Transplantation 

NIAID Farci Patrizia Chief, Hepatic Pathogenesis Section, 

Laboratory of Infectious Diseases, Division 

of Intramural Research 

NIAID Koshy Rajen Viral Hepatitis Program Officer, Virology 

Branch, Division of Microbiology and 

Infectious Diseases 

NIAID Miers Sarah Program Analyst, Office of Scientific 

Coordination and Program Operations, 

Division of Microbiology and Infectious 

Diseases 

NIAID Patterson Jean Chief, Translational Research Section, 

Virology Branch, Division of Microbiology 

and Infectious Diseases 

NIAID Robinson Daphne Health Science Policy Analyst, Policy, 

Planning and Evaluation Branch, OD (now 

at NIH's National Institute of Arthritis and 

Musculoskeletal and Skin Diseases) 

NIAID Schneider Johanna Chief, Policy, Planning and Evaluation 

Branch, OD 

20 
 

 

 

IC Last Name First Name Position 

NCI Lam Tram Kim Program Director, Environmental 

Epidemiology Branch, Epidemiology and 

Genomics Research Program, Division of 

Cancer Control and Population Sciences 

NCI Nothwehr Steve Program Director, Translational Research 

Program, Division of Cancer Treatment and 

Diagnosis 

NCI Read-Connole Betsy Cancer Etiology Section Chief, Cancer 

Immunology, Hematology, and Etiology 

Branch, Division of Cancer Biology 

NCI Rinaudo Jo Ann Program Director, Cancer Biomarkers 

Research Group, Division of Cancer 

Prevention 

NIAAA Wang Joe Program Director, Division of Metabolism & 

Health Effects 

NIDA Cotto Jessica Health Science Policy Analyst, Science 

Policy Branch 

NIDA Hartsock Peter Research Scientist Officer, Epidemiology 

Research Branch 

NIDDK Sherker Averell Scientific Advisor for Viral Hepatitis and 

Liver Diseases, Liver Diseases Research 

Branch 

NIDDK Singh Megan Health Science Policy Analyst, Office of 

Scientific Program and Policy Analysis 

NIMHD Das Rina Program Director, Division of Integrative 

Biological and Behavioral Sciences 

NIMHD Farhat Tilda Director, Office of Science Policy, Planning, 

Evaluation, and Reporting, Reporting, and 

Data 

OD Kuhn Ira Health Science Policy Analyst, Office of 

Evaluation, Performance, and Reporting, 

Division of Program Coordination, Planning, 

and Strategic Initiatives 

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Appendix 2. Analysis of Public Comments to Request for 

Information (RFI) 

NIH sought input from stakeholders in the scientific research community and the general 

public regarding the proposed priorities through a Request for Information (RFI). The RFI (NOTAI-22-018) was open for comments from December 27, 2021 to January 31, 2022. Comments 

were submitted through a web-based form or by email. Comments were requested on, but 

were not limited to, the following four topics regarding hepatitis B cure research: 

• Recent significant research advances in hepatitis B as well as in other areas that could 

have implications for the development of a hepatitis B cure 

• Impact of COVID-19 pandemic on hepatitis B research, and possible solutions 

• Emerging research questions and/or barriers 

• Resources necessary to advance basic, translational, and clinical research to cure 

hepatitis B. 

NIH received 5 responses to the RFI, including a detailed, coordinated response from 23 

advocacy groups. Other responses originated from academia and private companies, 

representing 27 organizations in total. Overall, the submissions supported both the effort to 

update the plan and the specific priorities. No new priorities were suggested. Comments 

provided further details on what to include within each priority. 

Strategic Priority 1 – Understanding Hepatitis B Biology 

• Understand HBV cccDNA biology 

• Explore the roles of HBx, HBsAg, HBcAg, and HBeAg in pathobiology 

• Characterize the variety of immune responses to HBV 

• Understand the impact of various HBV genotypes 

• Address the role of HBV DNA integration in HCC development, and improve HCC 

treatment 

Strategic Priority 2 – Developing Tools and Resources 

• Consider the impact and treatment of co-infection with HDV and HIV, including 

systematically assessing drug interactions 

• Develop biomarkers of disease, especially to reflect disease reactivation and flare-ups 

• Improve and create new animal models that enable evaluation of potential therapies 

Strategic Priority 3 – Creating Strategies to Cure and Prevent Hepatitis B 

• Explore new strategies for prevention as well as immune-therapeutic intervention and 

ways of producing therapeutic proteins in target organs, such as mRNA vaccines 

• Systematically design and evaluate potential combination therapies 

• Incorporate more patient-friendly strategies, such as telehealth visits for clinical 

research 

22 
 

 

 

 

• Conduct research to understand the barriers to linkage to care, especially among 

immigrants from Africa and Asia and those with limited English proficiency 

• Coordinate with community partners (community leaders and people living with HBV) to 

develop evidence-based, culturally appropriate interventions for HBV screening, 

vaccination, and treatment 

• Explore the possibility of an Undetectable=Untransmittable approach for hepatitis B 

The NIH working group members carefully considered all the suggestions and incorporated 

them in the updated plan as appropriate. Many of the RFI responses mentioned research areas 

included in the original plan that underscored the importance of understanding hepatitis B 

biology, developing animal models and identifying biomarkers. RFI responses related to Priority 

3 reflected an increased awareness of health disparities and new approaches to research 

developed during the COVID-19 pandemic. These are reflected in the updated plan. 

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Appendix 3. NIH-Supported Research Resources 

Resource Name Description 

AIDS Reagent Program Acquires, develops, and produces state-ofthe-art reagents and provides these reagents 

at no cost to qualified investigators 

throughout the world 

BEI Resources Repository Central repository that supplies organisms and 

reagents to the broad community of 

microbiology and infectious diseases 

researchers 

Bioinformatics Resource Centers Collects, archives, updates, and integrates 

research data with user-friendly interfaces 

and computational analysis tools 

NIAID Clinical Genomics Program Provides centralized resources to be used for 

genomics and related research 

Cooperative Centers on Human Immunology Conduct mechanistic studies to advance 

understanding of human immunity; also 

supports technology development to improve 

immunologic analyses of human samples 

Genomic Centers for Infectious Disease 

Resources 

Provides innovative application of genomic 

technologies and rapid, cost-efficient 

production of high-quality genome sequences 

for pathogens, and hosts 

Hepatitis B Research Network (HBRN) NIDDK-funded network conducts ongoing 

analyses of completed research on chronic 

hepatitis B to better understand the 

pathobiology of the disease and develop 

effective treatment strategies with currently 

available therapies, accompanied by a 

resource for data and biosamples related to 

HBV, through the NIDDK HBRN repository 

HIV/AIDS Clinical Trials Networks Group of clinical trials networks addressing 

HIV scientific priorities, including therapeutics 

for coinfections 

Human Immunology Project Consortium 

(HIPC) 

Conducts detailed immune profiling/systems 

immunology analyses of human immune 

system at steady state and before/after 

infection, vaccination, or adjuvant treatment. 

HIPC-generated datasets and analyses are 

publicly available through ImmuneSpace. 

24 
 

 

 

 

 

 

 

 

 

 

 

Resource Name 

ImmPort 

Description 

Platform to share and analyze immunology 

data generated from human and animal 

models 

Immune Epitope Database and Analysis 

Resource Immune Epitope Database and 

Analysis Resource 

Database with detailed information for more 

than 1,000,000 unique immune epitopes 

(antibody/B cell and T cell) related to 

infectious and immune-mediated diseases 

ImmuneSpace Powerful data management and analysis 

engine for the HIPC program that enables 

integrative analyses and visualization of 

human immunological data 

Interventional Agent Development Services to facilitate preclinical development 

of therapeutics and new in vivo diagnostics for 

infectious disease–causing pathogens and/or 

toxins 

International Clinical Sciences Support Center Support services, including consultation and 

protocol development, site assessment, and 

data management for clinical investigators 

supported by NIAID 

International Epidemiology Databases to 

Evaluate AIDS Cohort Consortium (IeDEA) 

Generates large, harmonized HIV/AIDS data 

sets from seven international regional data 

centers to help address high-priority research 

questions 

International Network for Strategic Initiatives 

in Global HIV Trials (INSIGHT) 

International network conducting HIV 

treatment trials 

Liver Cirrhosis Network (LCN) Network funded by the NIDDK, in 

collaboration with the NCI and NIAAA, to 

establish a longitudinal cohort of adults with 

cirrhosis, including those with chronic 

hepatitis B, and test new therapeutic 

approaches. 

NCI AIDS Cancer Specimen Resource Provides biospecimens from persons with a 

wide spectrum of HIV/AIDS-related diseases, 

particularly cancers 

NCI Developmental Therapeutics Program Provides services and resources to research 

communities worldwide to facilitate the 

discovery and development of new cancer 

therapeutic agents 

NIH Tetramer Core Facility Produces and distributes major 

histocompatibility complex tetramers and 

related reagents to the research community 

25 
 

 

 

 

 

Resource Name Description 

NIH Webinar Series on Moving from Hepatitis 

Discovery to Elimination 

This series, led by NCI and the Coalition for 

Global Hepatitis Elimination in partnership 

with other NIH Institutes and Centers, has 

featured webinars on HBV and HDV. 

Phase I Clinical Trial Units for Therapeutics Support design, development, 

implementation, and conduct of Phase I 

clinical trials against viral (other than HIV), 

bacterial, parasitic, and fungal pathogens 

PhenX Toolkit Example of standardized measures for social 

determinants of health 

Preclinical Models of Infectious Disease 

Program 

Provides development, screening, and efficacy 

testing in preclinical infectious diseases 

models, including traditional lab species, 

nonhuman primates, and non-traditional 

models 

REVEAL cohort in Taiwan Community-based prospective study of 

hepatitis B and hepatitis C 

Structural Genomics Centers for Infectious 

Diseases 

Applies state-of-the-art 

technologies/methodologies to characterize 

3-D atomic structures of molecules to support 

infectious disease research 

Therapeutic Development Services: 

Biopharmaceutical Product Development 

Services 

Offers services for biotechnology products, 

such as planning, product characterization, 

process development, formulation, Good 

Manufacturing Practice, and Chemistry, 

Manufacturing and Control documentation 

Therapeutic Development Services: 

Interventional Agent Development Services 

Facilitates development of therapeutics, 

including lead identification and development, 

chemistry and manufacturing, toxicology, and 

pharmacokinetics 

Vaccine and Treatment Evaluation Units Support efforts to develop new and improved 

vaccines and therapies against infectious 

diseases 

Virus Pathogen Resource Database, bioinformatics analysis and 

visualization tools to support the research of 

viral pathogens 

26 
 

 

Appendix 4. Abbreviations 

Abbreviation 

ACIP 

Definition 

Advisory Committee on Immunization Practise 

ALT Alanine aminotransferase 

ASOs Antisense oligonucleotides 

cccDNA Covalently closed circular DNA 

CDC Centers for Disease Control and Prevention 

COVID-19 Coronavirus disease 2019 

DNA Deoxyribonucleic acid 

FDA Food and Drug Administration 

GWAS Genome-wide association studies 

HBcAg Hepatitis B core antigen 

HBcrAg Hepatitis B core-related antigen 

HBeAg Hepatitis B e antigen 

HBsAg Hepatitis B surface antigen 

HBV Hepatitis B virus 

HBx Hepatitis B protein x 

HCC Hepatocellular carcinoma 

HCV Hepatitis C virus 

HDV Hepatitis D virus 

HIV Human immunodeficiency virus 

NAPs/STOPs Nucleic acid polymers/ S-antigen transport-inhibiting oligonucleotide 

polymers 

NASH Non-alcoholic steatohepatitis 

NCI National Cancer Institute 

NIAID National Institute of Allergy and Infectious Diseases 

NIDDK National Institute of Diabetes and Digestive and Kidney Diseases 

NIMHD National Institute of Minority Health and Health Disparities 

NTCP Sodium taurocholate co-transporting polypeptide 

OD Office of the Director 

PCR Polymerase chain reaction 

pgRNA Pre-genomic RNA 

RNA Ribonucleic acid 

SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus 2 

siRNAs Small interfering RNA 

WHO World Health Organization 

WHV Woodchuck hepatitis virus 

27