Network Research Priority Areas

Every seven years, NIH competitively renews its funding of the HIV clinical research networks operating in the United States and internationally. For the next funding cycle starting in fiscal year 2021, NIAID is soliciting applications for the following four HIV/AIDS Clinical Trials Networks: HIV Prevention Clinical Trials Network, HIV Vaccines Clinical Trials Network, HIV/AIDS Adult Therapeutics Clinical Trials Network, and the HIV/AIDS Maternal, Adolescent and Pediatric Therapeutics Clinical Trials Network. This page provides descriptions of the research priorities for each of the four networks.

Table of Contents

HIV Prevention Clinical Trials Network: Research Priority Areas

For more information, see RFA AI-19-005 in the NIH Guide.

The specific scientific priorities of NIH that will be addressed by the Leadership and Operation Center’s (LOC’s) proposed scientific research agenda are as follows (not in priority order):

Novel Antiretroviral (ARV)-Based HIV Prevention Methods and Delivery Systems
Focus on delivery methods that help to address the challenges of adherence including and not limited to long-acting agents and sustained release systems is encouraged.  The delivery method should achieve systemic protection from infection or protection from all routes of sexual exposure for the target key population. However, products that do not achieve complete systemic protection but do address an agreed-upon compelling specific public health need can be considered on a case-by-case basis if the scientific data support moving them forward to clinical testing.

Key populations to be considered are young cisgender women in southern Africa; men who have sex with men (MSM); transgender people; persons with injection and non-injection substance use and substance use disorders; sex workers; groups demonstrating age, racial/ethnic, or gender-based disparities; adolescents; and pregnant women. The following types of evaluations of these products are considered responsive to this funding opportunity announcement (FOA):

  • Early stage acceptability/desirability research to optimize and select candidate products and delivery systems
  • Pharmacokinetic/pharmacodynamic assessments
  • Safety evaluation to include maternal and pregnancy outcomes
  • Efficacy testing
  • Bridging studies for additional populations

As part of any ARV-based prevention product development, there is a critical need to determine end-user preferred characteristics using appropriate methodologies to increase prevention product uptake, recognizing that there is a significant gap between intention/acceptance and uptake. Prevention product desirability is the goal, and the proposed research should include expertise and use of methodologies from the disciplines of behavioral and social science as well as human-centered design by using ethnographic and other such techniques, as appropriate.

Multipurpose Prevention Technologies (MPTs)
MPTs are defined as the coformulation and/or simultaneous delivery of a licensed pregnancy and/or sexually transmitted infection (STI) prevention strategy with a HIV prevention method.

Included are the following types of clinical product development activities for MPTs:

  • Early stage acceptability/desirability research to optimize and select candidate products and delivery systems
  • Pharmacokinetics/pharmacodynamic assessments
  • Safety
  • Efficacy

As with ARV-based prevention product development, there is also a need with MPTs to determine end-user preferred characteristics using appropriate methodologies as described above.

The HIV prevention component of MPTs must impart or confer systemic protection against HIV acquisition. However, products that do not achieve complete systemic protection but do address an agreed-upon compelling specific public health need can be considered on a case-by-case basis if the scientific data support moving them forward to clinical testing.

Development of MPTs also will require substantial engagement of regulatory agencies to chart a Product Development Plan that will be acceptable from a regulatory requirement perspective.

Integrated Biomedical and Socio-Behavioral Prevention Strategies
In partnership with other NIH Institutes and Centers, U.S. government agencies, and non-governmental foundations and organizations, NIAID seeks to pioneer and improve the effective delivery of proven prevention tools through strategies that integrate and optimize their implementation. Examples of potential populations of high importance for integrated prevention strategies include

  • Young, cisgender women in southern Africa
  • MSM
  • Transgender people
  • Persons with injection and non-injection substance use and substance use disorders
  • Sex workers
  • Groups demonstrating age, racial/ethnic, or gender-based disparities in HIV prevention product use and outcomes
  • Adolescents
  • Pregnant women

Cross-Network Collaborative Research Area
Research related to passive administration of antibodies will continue to be at the scientific interface of HIV vaccine- and non-vaccine prevention. Consequently, it is anticipated for this research area there will be continued productive collaboration and joint scientific leadership by NIH-supported networks devoted to clinical trials of HIV vaccines and non-vaccine prevention strategies. This includes passive immunization strategies to administer

  • Single monoclonal antibodies
  • Combinations of multiple monoclonal antibodies of different specificities and binding sites or different protective mechanisms
  • Combinations of antibody molecules with antiretroviral drugs and other prevention modalities
  • Engineered molecules derived from or related to antibodies that have novel binding specificities, altered half-life or host interaction profiles, or altered mechanisms of protection
  • Vectors encoding one or more antibody or antibody-related molecules capable of sustained in vivo antibody expression
  • Polyclonal antibody mixtures derived directly from humans or from biotechnological engineering
  • When addressing clinical research questions in specific populations, the two leading networks will be expected also to collaborate with additional population-specific research networks as needed to ensure access to the required scientific and clinical expertise.

HIV Vaccines Clinical Trials Network: Research Priority Areas

For more information, see RFA AI-19-006 in the NIH Guide.

Through this solicitation, NIAID will support an HIV Vaccines Clinical Trials Network LOC that will work collaboratively with a Laboratory Center (LC), Statistical and Data Management Center (SDMC), and network-affiliated Clinical Trials Units (CTUs)/Clinical Research Sites (CRSs) and where applicable, with other HIV/AIDS clinical trials networks to implement and update, as needed, a scientific strategic plan that addresses NIAID’s research priorities in areas primarily related to preventive HIV vaccines, as well as cross-network collaborative research on other preventive modalities, including passive administration of antibodies to prevent HIV acquisition and TB vaccines.

NIAID has identified the following scientific research priority areas for the HIV Vaccines Network:

  • Design and conduct Phase I clinical trials to address scientific questions critical to the development of efficacious vaccines to prevent HIV infection, and based upon predefined criteria, advance selected concepts to Phase II evaluation
  • Conduct Phase II evaluation of selected candidate vaccines, vaccine combinations, adjuvants and delivery systems through standardized protocols, reagents and assays to assess immune responses so that comparisons between competing vaccine strategies approaches are possible
  • Design and execute "fast-track"-type small iterative Phase I studies to address pressing research questions on immunogen design to advance the field
  • With partners, design and conduct Phase IIb and III clinical trials to evaluate whether promising vaccine candidates/combinations can significantly prevent HIV infection (and/or limit progression of infection)
  • Evaluate possible laboratory correlates of immune protection in the context of Phase IIb/III clinical trials that demonstrate significant vaccine efficacy
  • Assess both virus and host genetic variability and their potential impact on immunogen response and efficacy, when feasible and practical
  • Regularly exchange information on progress and plans with basic and preclinical researchers, particularly those working with preclinical animal models, especially non-human primates, to maximize the insights that clinical and basic/developmental sciences can provide each other to advance progress in HIV vaccines
  • Incorporate research on epidemiological, behavioral and social aspects of preventive vaccine interventions, where applicable including vaccine acceptability and regimen adherence

Cross-Network Collaborative Research Areas
Several clinical research areas related to preventive HIV vaccines are inherently cross-disciplinary, requiring close collaborations of HIV immunology researchers with other NIAID-supported clinical researchers working in related areas, such as non-vaccine prevention of HIV infection, pediatric infectious diseases, treatment of HIV infection, and non-HIV infectious diseases highly relevant to the HIV epidemic. The NIAID scientific priorities described below are integral to the scientific agenda for HIV preventive vaccines, as well as to the research agendas of other NIAID-supported clinical trial networks.

Research related to passive immunization by administration of antibodies will continue to be at the scientific interface of HIV vaccine- and non-vaccine prevention. Consequently, it is anticipated for this research area there will be continued productive collaboration and joint scientific leadership by NIH-supported networks devoted to clinical trials of HIV vaccines and non-vaccine prevention strategies. This includes passive immunization strategies to administer

  • Single monoclonal antibodies
  • Combinations of multiple monoclonal antibodies of different specificities and binding sites or different protective mechanisms
  • Combinations of antibody molecules with antiretroviral drugs and other prevention modalities
  • Engineered molecules derived from or related to antibodies that have novel binding specificities, altered half-life or host interaction profiles, or altered mechanisms of protection
  • Vectors encoding one or more antibody or antibody-related molecules capable of sustained in vivo antibody expression
  • Polyclonal antibody mixtures derived directly from humans or from biotechnological engineering

When addressing clinical research questions in specific populations, the two leading networks (HIV vaccines and non-vaccine prevention) will be expected also to collaborate with additional population-specific research networks as needed to ensure access to the required scientific and clinical expertise.

A research agenda of limited scope should be included for pediatric HIV vaccination. Pediatric clinical trials of vaccines for HIV prevention should include HIV-exposed or unexposed children after candidate vaccines are determined to be safe and sufficiently efficacious in adults. Candidate vaccines meeting these criteria should be evaluated for safety, immunogenicity and response durability in pediatric populations, as well as examining unique characteristics of pediatric immunity for developing broadly neutralizing antibody vaccine responses. Pediatric studies of vaccine protective efficacy, including age de-escalation studies (from adults into the pediatric population), will only be undertaken once clear evidence supports high plausibility of protection. Pediatric vaccine trials will rely on the same expertise in vaccine clinical trial design, conduct, and analysis as for those vaccines in other populations, i.e., the HIV Vaccines Clinical Trials Network will provide scientific leadership with collaborative support as needed from other population-specific networks that work with children or adolescents.

The evaluation of tuberculosis (TB) vaccines is a research area that requires expertise across clinical trial networks. The HIV Vaccines Clinical Trials Network is expected to provide scientific leadership for TB vaccine clinical trials that evaluate vaccine immunogenicity and use in the prevention of TB infection in adults, adolescents and children. However, for trials assessing vaccines for prevention of disease, prevention of recurrence, and therapeutic vaccine trials in adults, in which diagnosis and management of clinical disease is necessary, the Adult Therapeutics Clinical Trials Network will take the lead for adult populations with collaborative support from the HIV Vaccines Clinical Trials Network. For trials assessing vaccines for prevention of disease in pediatric populations, the Maternal, Adolescent and Pediatric Therapeutics Clinical Trials Network will take the lead with collaborative support from the HIV Vaccines Clinical Trials Network.

Follow-up of women who become pregnant while enrolled in HIV or TB prevention of infection vaccine trials, as well as their infants born during the trial, will continue to be a priority of the HIV vaccine network, with collaborative support provided as needed from other networks working with women and infants.

HIV/AIDS Adult Therapeutics Clinical Trials Network: Research Priority Areas

For more information, see RFA AI-19-003 in the NIH Guide.

NIAID has identified the following scientific research priority areas for the HIV/AIDS Adult Therapeutics Clinical Trials Network:

Novel and Durable Interventions for Treatment of HIV

Achieve durable HIV suppression for all adults by investigating

  • Novel drugs and biologics, including long-acting formulations and antibody-based approaches
  • Novel combinations of biomedical and behavioral interventions  

With other funders, as appropriate opportunities arise,

  • Evaluate and/or demonstrate effectiveness of integrated behavioral, mental health, biomedical and structural interventions to increase durability of virally suppressive combination antiretroviral therapy (cART) therapy for people living with HIV

ART-Free Remission
Identify and evaluate strategies to eradicate HIV or sustain virologic remission, including:

  • Immune-based interventions, including therapeutic vaccines and antibodies
  • Gene/cell therapies
  • Interventions that activate or suppress latent provirus

Within the context of clinical trials

  • Investigate host, viral or other factors that influence HIV persistence and immune response
  • Investigate behavioral and ethical issues to inform and enhance trial conduct

Complications and Co-Infections

  • When appropriate preclinical and clinical evidence for potential efficacy exists, evaluate therapeutic strategies that target the mechanisms that lead to host cell, tissue and organ dysfunction
  • With other stakeholders, identify and evaluate strategies to prevent and treat end-organ disease associated with HIV infection or its treatment
  • Evaluate curative strategies for hepatitis B virus co-infection

Tuberculosis
Research may be conducted in people living with HIV or people without HIV.

  • Evaluate novel drugs and combination treatments for drug-sensitive and drug-resistant TB to shorten therapy, improve tolerance and reduce long term morbidity
  • Evaluate new formulations and delivery routes, e.g., long-acting agents and inhaled administration
  • As opportunities arise, evaluate adjunctive host-directed therapies and therapeutic vaccines, including vaccines to prevent activation of disease from the latent state
  • Improve therapies targeting extra-pulmonary TB, e.g., TB meningitis
  • Develop improved treatments for HIV and TB co-infection
  • With other stakeholders, improve therapies for TB in the setting of co-morbidities that worsen TB outcomes, e.g. diabetes
  • Evaluate strategies to improve the effectiveness and tolerance, and to shorten duration of chemoprevention for drug-sensitive and multi-drug resistant TB
  • Within the context of clinical trials:
    • Evaluate prognostic biomarkers for disease progression and treatment response and new diagnostics/drug susceptibility testing, including point-of-care methodologies, for both pulmonary and extrapulmonary TB disease
    • Conduct TB and TB/HIV pathogenesis and translational research

For each of the four scientific research priority areas described above, applicants are expected to incorporate processes to rapidly implement small proof-of-concept or Phase I (single site) clinical trials when such trials of high priority are identified. To support early-stage pilot trials of novel products and approaches, the clinical research infrastructure must also provide opportunities for intensive sampling of potential tissue reservoirs of HIV, and specialized laboratory capabilities for virologic and immunologic analyses.

When appropriate and feasible, treatment-related protocols should incorporate valid assessments of treatment adherence, strategies to promote adherence to clinical trial protocols and investigational therapies, and concurrent scientific expertise.

Cross-Network Collaborative Research Areas

  • Where appropriate for HIV and TB treatment, partner with pediatric and maternal therapeutics network to extend clinical investigations across the lifespan
  • The evaluation of TB vaccines is a research area that requires expertise across clinical trial networks. The HIV Vaccines Clinical Trials Network is expected to provide scientific leadership for TB vaccine clinical trials that evaluate vaccine immunogenicity and use in the prevention of TB infection in adults, adolescents and children. However, for trials assessing vaccines for prevention of disease, prevention of recurrence, and therapeutic vaccine trials in adults, in which diagnosis and management of clinical disease is necessary, the Adult Therapeutics Clinical Trials Network will take the lead for adult populations with collaborative support from the HIV Vaccines Clinical Trials Network. For trials assessing vaccines for prevention of disease in pediatric populations, the Maternal, Adolescent and Pediatric Therapeutics Clinical Trials Network will take the lead with collaborative support from the HIV Vaccines Clinical Trials Network.

The network’s research agenda in the required four areas described above will be potentially revised by NIAID staff to ensure optimal synergy with existing NIH programs, particularly in the areas of TB and viral hepatitis.

HIV/AIDS Maternal, Adolescent and Pediatric Therapeutics Clinical Trials Network: Research Priority Areas

For more information, see RFA AI-19-004 in the NIH Guide.

The network will focus its research on infants, children, adolescents and pregnant/postpartum women with HIV or tuberculosis, and HIV-associated infections of high priority for NIAID and its partner Institutes. Scientific research priority areas to be addressed by the LOC include the following (not listed in priority order):

Novel and Durable Interventions for Treatment of HIV

  • Accelerate evaluation (pharmacokinetic [PK], safety, antiviral efficacy) and licensure of promising antiviral drugs:
    • In pediatric HIV-infected populations from newborns to adolescents
    • In maternal populations including HIV-infected pregnant, postpartum and lactating women for optimization of ART for maternal and newborn health and around the critical period of vertical transmission risk
    • Using rational and strategic selection and prioritization of ARVs towards accelerated path to licensure
  • Advance evaluation of long-acting and novel drug delivery strategies with extended dosing intervals for HIV-infected maternal, pediatric and adolescent populations.
  • With federal and non-federal partners, demonstrate effectiveness of these approaches as integrated behavioral, biomedical, and structural interventions with an emphasis for adolescent populations.

ART-Free Remission

  • Evaluate novel therapeutic interventions and strategies to achieve ART-free remission in pediatric populations from newborns to adolescents including
    • Antibodies
    • Therapeutic vaccines
    • Novel strategies for early treatment in the immediate newborn period
    • Other approaches as the safety profile emerges in adult populations such as latency reactivating agents, cell therapies, gene therapy
  • Within the context of clinical trials
    • Evaluate and characterize host and viral processes involved in reservoir establishment and maintenance
    • Evaluate tools and approaches to identify, characterize and measure HIV reservoirs

Tuberculosis

  • Evaluate (PK, safety, efficacy) new anti-tuberculous drugs and regimens, for treatment and prevention of drug-sensitive and drug-resistant TB disease, both pulmonary and extrapulmonary (including central nervous system [CNS]) forms
    • In pediatric and adolescent populations, with and without HIV infection
    • In maternal populations including HIV-infected and uninfected pregnant, postpartum and lactating women
    • Within the context of clinical trials, evaluate diagnostic, prognostic and/or treatment response and sequelae biomarkers for TB disease with a focus on clinical presentations in young children, including assessment of non-sputum samples, and suitability for POC platforms.
  • Where feasible, partner with the adult therapeutics network to extend clinical investigations across the lifespan.

Complications and Co-Infections

  • Investigate potential neuroprotective and neurotoxic effects of combination ART (cART) to preserve neurocognitive development and mental health in infants, children and adolescents.
    • In the context of clinical trials, refine and optimize evaluation and treatment of neurocognitive and mental health disorders particularly depression and anxiety.
  • Working with NIAID and other partners, evaluate novel preventive and/or therapeutic approaches for high-priority diseases of importance to pediatric HIV-infected/affected populations such as respiratory syncytial virus (RSV) disease.
  • With other partner NIH Institutes, evaluate other co-morbidities and complications of importance for pediatric, adolescent and pregnant populations.

Additional areas that should be fostered include:

  • Strengthening of community partnership and involvement in all aspects of the research
  • Strengthening of collaboration with commercial or non-commercial product developers in order to facilitate licensure of new ARVs in all pediatric populations
  • Collaboration with implementors and normative bodies to guide rational and strategic product prioritization and to facilitate, enable and accelerate scale up of efficacious interventions towards maximizing effectiveness.

Cross-Network Collaborative Research Areas
In addition to assuming the lead on the scientific research priority areas listed above, the HIV/AIDS Maternal, Adolescent, and Pediatric Therapeutics Clinical Trials Network is expected to collaborate with other HIV/AIDS networks and lend its expertise in pediatric and maternal populations to support scientific areas where other networks will serve as the lead.

In support of the preventive HIV vaccine network, these scientific research areas include

  • Evaluation of preventive HIV vaccine candidates for which there are sufficient safety data and an adequate efficacy signal, and that leverage unique characteristics of pediatric immunity to develop broad and durable neutralizing antibody and cellular immune responses
  • Evaluation of passive antibody administration for HIV prevention in pregnant women
  • Evaluation of TB vaccines for safety, immunogenicity and prevention of infection (POI) in pediatric populations including young children and adolescents
  • Follow-up of women who become pregnant in HIV vaccine trials for maternal, pregnancy and infant outcomes

In support of the HIV prevention network, these scientific research areas include

  • Development of products and strategies for the purpose of HIV prevention in HIV-uninfected at-risk adolescent populations
  • Evaluation of pre-exposure prophylaxis (PrEP) interventions in adolescents as bridging studies or alongside or as part of efficacy studies in adults
  • Development and evaluation of PrEP interventions including passive antibody administration in HIV-uninfected pregnant and lactating women
  • Follow-up of women who become pregnant in PrEP trials for pregnancy and infant outcomes

The evaluation of TB vaccines is a research area that requires expertise across clinical trial networks. The HIV Vaccines Clinical Trials Network is expected to provide scientific leadership for TB vaccine clinical trials that evaluate vaccine immunogenicity and use in the prevention of TB infection in adults, adolescents and children. However, for trials assessing vaccines for prevention of disease, prevention of recurrence, and therapeutic vaccine trials in adults, in which diagnosis and management of clinical disease is necessary, the Adult Therapeutics Clinical Trials Network will take the lead for adult populations with collaborative support from the HIV Vaccines Clinical Trials Network. For trials assessing vaccines for prevention of disease in pediatric populations, the Maternal, Adolescent and Pediatric Therapeutics Clinical Trials Network will take the lead with collaborative support from the HIV Vaccines Clinical Trials Network.

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