Measuring Innovation: Laboratory Infrastructure to Deliver Essential HIV Clinical Trial Results

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This blog is the fifth in a series about the future of NIAID's HIV clinical research enterprise. For more information, please visit the HIV Clinical Research Enterprise page.

The outcomes of HIV clinical trials are often determined by precisely and accurately measuring how specific interventions work biologically in people. Whether tracking immune responses to a preventive vaccine candidate, monitoring changes to the amount of virus in the body, or screening for certain adverse events after administering a novel therapeutic, study teams routinely interact with clinical trial participants to safely obtain, store, transport, and analyze tissue and bodily fluid samples to answer important scientific questions about the impact of an HIV intervention in a laboratory. High quality, reliable laboratory infrastructure is critical to the accuracy and validity of clinical trial results. 

More than 150 NIAID-supported laboratories in 20 countries are addressing the diverse scientific programs of the four clinical trials networks in the Institute’s HIV clinical research enterprise. Since the start of HIV clinical research, laboratory capacities have grown in scope to support an increasing number of global clinical trials, emerging complexities in study protocol design and laboratory testing demands and evolving regulatory requirements for research and licensure.

NIAID is engaging research partners, community representatives, and other public health stakeholders in a multidisciplinary evaluation of its HIV clinical trials networks’ progress toward short- and long-term scientific goals. This process assesses knowledge gained since the networks were last awarded in 2020 to identify an essential path forward based on the latest laboratory and clinical evidence. Future NIAID HIV clinical research investments build on the conclusions of these discussions. 

In the next iteration of HIV clinical trials networks, laboratory functions will continue to evolve to align with scientific priorities and research approaches. Networks will support small early-phase trials, large registrational trials and implementation science research to examine preventive vaccine candidates and non-vaccine prevention interventions, antiviral treatments, HIV curative strategies, and therapies to improve the clinical outcomes of people affected by and living with HIV. Selected studies also will rely on high quality laboratory resources to examine interventions for tuberculosis, hepatitis, mpox and other infectious diseases. Clinical trial networks will need to employ a variety of laboratory types to achieve these objectives.  To increase flexibility and ensure the timeliness and the high quality standards the HIV field relies on for evidence that informs science, licensure and equitable practice, NIAID will have the ultimate authority for laboratory selection and approval.

Efficiency and Versatility 

Laboratory assays for HIV clinical trials continue to expand in quantity and complexity and require proportionate technical expertise and management. Future clinical research needs will include immunologic, microbiologic, and molecular testing, as well as standard chemistries and hematologic assays, with fluctuating volumes across a global collection of research sites. Balancing capacity, efficiency, scalability, and cost will require a mixed methods approach. These may include centralized laboratory testing where feasible and advantageous for protocol-specified tests; standardized processes for rapid assessment and approval of new network laboratories; and validated third-party outsourcing of routine assays to ensure timely turnaround when demands surge. 

Quality and Standardization

Ensuring consistent laboratory operations and high quality laboratory data will require continued compliance with the NIAID Division of AIDS Good Clinical Laboratory Practices and other applicable regulatory guidelines, ongoing external quality assurance monitoring, strong inventory management, importation and exportation expertise, and data and specimen management.

The research community plays an essential role in shaping NIAID’s scientific direction and research enterprise operations. We want to hear from you. Please share your questions and comments at NextNIAIDHIVNetworks@mail.nih.gov.

About NIAID’s HIV Clinical Trials Networks

The clinical trials networks are supported through grants from NIAID, with co-funding from and scientific partnerships with NIH’s National Institute of Mental Health, National Institute on Drug Abuse, National Institute on Aging, and other NIH institutes and centers. There are four networks—Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections, the HIV Vaccine Trials Network, the HIV Prevention Trials Network, and the International Maternal Pediatric Adolescent AIDS Clinical Trials Network.

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The emergence and re-emergence of infectious diseases continues to threaten the health of Americans and people worldwide. In the past two decades NIAID has mounted major research responses and developed effective countermeasures to emerging infectious diseases including those caused by SARS-CoV-1, the 2009 H1N1 influenza virus, Middle East Respiratory Syndrome coronavirus (MERS-CoV), Ebola virus, Zika virus, and most recently SARS-CoV-2. The ongoing 2020 global pandemic caused by SARS-CoV-2 further has underscored the continual threat of newly emerging and re-emerging pathogens and the critical value of research in pandemic preparedness efforts.

To prepare for future public health emergencies caused by infectious diseases, NIAID has developed a Pandemic Preparedness Plan that leverages its broad research portfolio, long-standing expertise in product development, capacity to engage both domestic and international partners, and flexible infrastructure. While it is recognized that pathogens other than viruses could lead to public health emergencies, the NIAID Pandemic Preparedness Plan focuses on viruses that could cause epidemics or pandemics.

Goals for the NIAID Pandemic Preparedness Plan

  • Systematically characterize pathogens of concern and increase research and surveillance to identify threats before they emerge
  • Shorten timelines between pathogen emergence or outbreak onset and authorization/approval of candidate diagnostics and medical countermeasures, such as therapeutics and vaccines
  • Bridge or eliminate existing gaps in research, infrastructure, and technology and expand pre-clinical and clinical testing capacity
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Pandemic Preparedness
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NIAID pandemic preparedness focuses predominantly on viruses that could cause epidemics or pandemics and prioritizes research on prototype-pathogens, representative pathogens from viral families known to infect humans, and high-priority pathogens most likely to threaten human health.
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Single Mutation in H5N1 Influenza Surface Protein Could Enable Easier Human Infection

A single modification in the protein found on the surface of the highly pathogenic avian influenza (HPAI) H5N1 influenza virus currently circulating in U.S. dairy cows could allow for easier transmission among humans, according to new research funded by the National Institutes of Health (NIH) and published today in the journal Science. The study results reinforce the need for continued, vigilant surveillance and monitoring of HPAI H5N1 for potential genetic changes that could make the virus more transmissible in humans.

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UC Irvine Receives Initial $33 Million in Federal Support for Vaccine Research

Dr. Eva Harris Is Co-Leader of Major Pandemic Preparedness Project

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Pitt Joins NIH Initiative to Facilitate Rapid Response to Emerging Virus Threats

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Sequencing of Congo Mpox Reports Highlights New Transmission Patterns in Country

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Country-led genetic analysis of samples collected through the Republic of Congo (RoC) epidemiologic surveillance system in early 2024 showed that mpox was affecting people in parts of the country where it has not been historically reported, and point to increases in human-to-human transmission across the border with the neighboring Democratic Republic of the Congo (DRC), where a large outbreak was declared a public health emergency of international concern in August of the same year. The analysis was conducted by the RoC Laboratoire National de Santé Publique (LNSP) in Brazzaville with support and scientific partnership from NIAID and was published in The Lancet

There are two known types or “clades” of monkeypox virus (MPXV), which causes mpox clinical disease. Clade I is endemic in Central Africa and can cause severe illness. Clade II, endemic in West Africa, caused the global mpox outbreak that began in 2022 and tends to result in milder illness. Each clade has two known subtypes referred to as “a” and “b.” Clade Ia has been identified in RoC and DRC intermittently for decades and Clade Ib was first identified during the active DRC outbreak. Mpox is a zoonotic disease, meaning it can be spread between animals and people. MPXV has been detected in rodents that live in areas historically affected by mpox. 

Genetic sequencing of MPXV can help determine the transmission dynamics and guide the public health response to mpox, but until recently most sequencing of MPXV was done outside of affected countries like RoC, requiring costly sample transport and delaying decision-making by local health authorities. 

To better understand whether mpox in RoC was driven by spillover from local animal hosts or cross-border human-to-human transmission from DRC, a team led by the RoC LNSP analyzed 31 samples of laboratory-confirmed MPXV collected through the country’s routine epidemiologic surveillance system between January and April of 2024. Using new in-country sequencing technology, the team determined that there were diverse circulating strains of MPXV in the country, all of the Clade Ia subtype, and some showed up to 99.9% genetic similarity to MPXV sequenced from the DRC. Moreover, MPXV samples came from provinces without historical reports of mpox. 

According to the authors, the diversity of identified stains suggest MPXV has been introduced to the human population in RoC through multiple distinct events, which could be a combination of direct zoonotic transmission from local animals as well as human-to-human transmission within and across the country’s borders. They state that current epidemiological data are insufficient to definitively confirm the directionality of MPXV transmission and that further epidemiological research is needed to understand local transmission patterns and inform the public health response in RoC. Finally, they highlight that while only 31 samples met criteria for analysis in the study, it is likely these cases represent only a fraction of the RoC mpox burden at the time of collection.

This research informed the RoC’s decision to declare a national mpox epidemic in April 2024. It is part of a longstanding scientific collaboration between NIAID’s Rocky Mountain Laboratories and the Congolese government. The U.S. Embassy in RoC, the U.S. Agency for International Development, the U.S. Centers for Disease Control and Prevention, and the World Health Organization also provided technical and laboratory support for this study. 

Learn more about NIAID’s mpox research priorities. Play a video of NIAID Director Jeanne Marrazzo discussing these priorities. 

Reference:

CK Yinda, et al. Genetic sequencing analysis of monkeypox virus clade I in Republic of the Congo: a cross-sectional, descriptive study. The Lancet DOI: 10.1016/S0140-6736(24)02188-3 (2024)

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Defining the Goals of HIV Science Through 2034

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Discovery, Development and Delivery for an Increasingly Interconnected HIV Landscape 

By Carl Dieffenbach, Ph.D., director, Division of AIDS, NIAID

This blog is the third in a series about the future of NIAID's HIV clinical research enterprise. For more information, please visit the HIV Clinical Research Enterprise page.

The NIAID HIV clinical research enterprise has celebrated important scientific advances since awards were made to the current networks in 2020. These achievements include the culminating steps in decades of research that led to approval of the first generation of long-acting medications for HIV prevention—a milestone that raises the standard for any future antiretroviral drug development to levels unimaginable even a decade ago. Our research has highlighted opportunities to maintain the overall health of people with HIV throughout their lifespans. We continue to expand the boundaries of scientific innovation in pursuit of durable technologies that could hasten an end to the HIV pandemic, especially preventive vaccines and curative therapy. During the COVID-19 public health emergency, our networks stepped forward to deliver swift results that advanced vaccines and therapeutics within a year of the World Health Organization declaring the global pandemic, while maintaining progress on our HIV research agenda. The impact of this collective scientific progress is evident worldwide.

Together with my NIH colleagues, I express sincere gratitude to the leaders and staff of current clinical trials networks, our research and civil society partners, and most importantly, clinical study participants and their loved ones, for their enduring commitment to supporting science that changes lives.

As we do every seven years, we are at a point in the funding cycle when our Institute engages research partners, community representatives, and other public health stakeholders in a multidisciplinary evaluation of network progress toward short- and long-term scientific goals. This process takes account of knowledge gained since the networks were last funded and identifies essential course corrections based on the latest scientific and public health evidence and priorities. Subsequent NIAID HIV research investments will build on the conclusions of these discussions.

Looking to the future, we envision an HIV research enterprise that follows a logical evolution in addressing new scientific priorities informed by previous research progress. We will fund our next networks to align with updated research goals to take us through the end of 2034. The HIV research community’s outstanding infrastructure is the model for biomedical research. Now, our capacity must reflect an increasing interdependence across clinical practice areas and public health contexts. Our goals for the next networks are to:

  • Maintain our support for core discovery and translational research to address gaps in biomedical HIV prevention and treatment, including a vaccine and therapeutic remission or cure. Our objective is to identify effective interventions that expand user choice and access, as well as improve quality of life across the lifespan;
  • Provide the multidisciplinary leadership required to address the intersections between HIV and other diseases and conditions throughout the lifespan, including noncommunicable diseases, such as diabetes mellitus and substance use disorder, and infectious diseases that share health determinants with HIV, such tuberculosis and hepatitis;
  • Compress protocol development and approval timelines for small and early-stage trials to enable more timely translation of research concepts to active studies; 
  • Respond to discrete implementation science research questions as defined by our implementation counterparts, including federal partners at the Centers for Disease Control and Prevention, Health Resources and Services Administration, U.S. Agency for International Development, agencies implementing the U.S. President’s Emergency Plan for AIDS Relief, and other nongovernmental funders and implementing organizations worldwide;  
  • Draw from nimble and effective partnerships at all levels to leverage the necessary combination of financial resources, scientific expertise, and community leadership and operational capacity to perform clinical research that is accessible to and representative of the populations most affected by HIV, especially people and communities that have been underserved in the HIV response; 
  • Leverage our partners’ platforms if called on to close critical evidence gaps for pandemic response; and,
  • Plan for impact by mapping clear pathways to rapid regulatory decisions, scalable production, and fair pricing before the start of any efficacy study.

Our shared goal is to produce tools and evidence to facilitate meaningful reductions in HIV incidence, morbidity and mortality globally. I invite you to continue sharing your thoughts with us to help shape the future of HIV clinical research, and to review the blogs on specialized topics that we will continue to post on the HIV Clinical Research Enterprise page in the coming weeks. Please share your feedback, comments, and questions at NextNIAIDHIVNetworks@mail.nih.gov. Submissions will be accepted through December 2024. 

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NIH Awards Establish Pandemic Preparedness Research Network

The Research and Development of Vaccines and Monoclonal Antibodies for Pandemic Preparedness network—called ReVAMPP—will focus its research efforts on “prototype pathogens,” representative pathogens from virus families known to infect humans, and high-priority pathogens that have the potential to cause deadly diseases. The pandemic preparedness research network will conduct research on high-priority pathogens most likely to threaten human health with the goal of developing effective vaccines and monoclonal antibodies.

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Research and Development of Vaccines and Monoclonal Antibodies for Pandemic Preparedness (ReVAMPP)

In the wake of COVID-19, the need for pandemic preparedness has become increasingly apparent. The Research and Development of Vaccines and Monoclonal Antibodies for Pandemic Preparedness (ReVAMPP) Network conducts basic and translational research on representative viruses within a specific virus family, with the goal of developing effective vaccines and monoclonal antibodies for other viruses within that family. By leveraging the “prototype pathogen” approach, the ReVAMPP network lay the groundwork for a faster and more effective pandemic response, should a virus from one of the targeted families emerge as a pandemic threat. Currently, there are no vaccines or targeted therapeutics for many diseases caused by the selected virus families. 

The awards have been made to seven different US based research groups and one coordinating center. The Network works with NIAID, USG and global partners to share information and collaborate. 

Main Areas of Focus

ReVAMPP is a pandemic preparedness research network designed to conduct fundamental basic through IND-enabling translational research on representative viruses, or “prototype pathogens,” within specific virus families. The virus families that the ReVAMPP network study contain many viruses that have caused human disease for millennia—many of which have a high likelihood of becoming pandemic threats in the future. 

The ReVAMPP network focuses on viruses from the Flaviviridae family, which features viruses that cause dengue and yellow fever; the Paramyxoviridae family, which contains viruses that cause measles, mumps, and Nipah-induced encephalitis; the Picornaviridae family, whose members cause poliomyelitis, foot-and-mouth disease, and myocarditis; the Togaviridae family, which contains viruses that induce Chikungunya virus-induced arthralgia or encephalitis and Venezuelan equine encephalitis; as well as viruses from 5 different families within the Bunyavirales order, including Sin Nombre virus from the Hantaviridae family and the viruses that cause Rift Valley Fever (Phenuiviridae), Crimean Congo Hemorrhagic Fever (Nairoviridae), Oropouche Fever (Peribunyaviridae), and Lassa Fever (Arenaviridae):

The 9 viral families covered by the ReVAMPP network are:

  • Flaviviridae
  • Paramyxoviridae
  • Picornaviridae
  • Togaviridae
  • Arenaviridae
  • Hantaviridae
  • Nairoviridae
  • Phenuiviridae
  • Peribunyaviridae

RTI International will lead a centralized Coordination and Data Sharing Center, to provide support and coordination for the network. By standardizing methodologies, such as reagents, animal models, and data outputs, research centers that comprise the ReVAMPP network are able to easily share their results and collaborate to enhance the network’s efforts.

Locations

The award recipients are:

Albert Einstein College of Medicine, Bronx, NY

Project title: PROVIDENT:  Prepositioning Optimized Strategies for Vaccines and Immunotherapeutics against Diverse Emerging Infectious Threats
Principal investigator: Kartik Chandran, Ph.D.
Grant: 1 U19 AI181977-01

Research Triangle Institute (RTI) International, Research Triangle Park, NC

Project title: Coordinating and Data Sharing Center - R&D of Vaccines and Antibodies for Pandemic Preparedness (ReVAMPP)
Principal investigator: Gregory D. Sempowski, Ph.D.
Grant: 1 UG3 AI181797-01

University of California, Irvine, CA

Project title: The UCI Vaccines for Pandemic Preparedness Center (VPPC)
Principal investigator: Louis Philip Felgner, Ph.D.
Grant: 1 U19 AI181968-01

University of Texas Medical Branch, Galveston, TX

Project title: Paramyxoviridae and Bunyavirales Vaccines and Antibodies Center (PABVAX)
Principal investigator: Thomas William Geisbert, Ph.D.
Grant: 1 U19 AI181930-01

University of Washington, Seattle, WA

Project title: Machine learning-enabled design of prototype pathogen vaccines and antibodies
Principal investigator: Neil King, Ph.D.
Grant: 1 U19 AI181881-01

Vanderbilt University Medical Center, Nashville, TN

Project title: Bunyavirus and Picornavirus Pandemic Pathogen Preparedness (BP4) Center
Principal investigator: James E. Crowe, Jr., M.D.
Grant: 1 U19 AI181979-01

Washington University, St. Louis, MO

Project title: Flavivirus and Alphavirus ReVAMPP (FLARE)
Principal investigator: Michael S. Diamond, M.D., Ph.D.
Grant: 1 U19 AI181960-01

Washington University, St. Louis, MO

Project title: Vaccines and Therapeutic Antibodies to Respiro, Rubula, Peribunya and Phenuiviridae (R2P2)-ReVAMPP
Principal investigator: Sean P.J. Whelan, Ph.D.
Grant: 1 U19 AI181984-01

View the ReVAMPP clinical/hospital/study and laboratory locations in a larger map

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