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.

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)

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. 

This blog is the second 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 impact of clinical research is often measured by its outcomes. From trials that provide groundbreaking evidence of efficacy to those stopped early for futility, the end results of clinical trials shape practice and future research priorities. However, years of effort from scientists, study teams and study participants while a trial is underway are sometimes overshadowed by final study outcomes. In this regard, trial implementation requires clinical research sites’ operational excellence for the duration of a study. Access to relevant populations depends on the location of each clinical research site as well as investigators' and clinical care providers’ engagement with the local community and understanding of their needs and preferences. A high-functioning clinical research site anchored in the communities it works in and comprised of cohesive, well-integrated components is essential to producing high-quality outputs. 

Currently, NIAID supports four research networks as part of its HIV clinical research enterprise. The networks are made up of more than 100 clinical research sites, each with local experts, robust research infrastructure, and well-trained, cross-functional staff who maintain standardized procedures and quality controls aligned with their network.

Every seven years, NIAID 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. Subsequent NIAID HIV research investments build on the conclusions of these discussions. This process includes examining the networks’ infrastructure model, which the Institute updates and refines to stay aligned with its scientific priorities. 

The HIV clinical trials network sites have made tremendous contributions to NIH’s scientific priorities by offering direct access to and consultation with populations most affected by HIV globally, and by delivering high-quality clinical research with strong connections to trusted community outreach platforms. Their approach to community engagement anchors clinical research sites beyond the scope of any individual study, and when possible, aligns scientific questions and study protocols based on local context. 

Since the start of the 2020 research network grant cycle, HIV clinical research sites have enrolled about 93,000 participants across 78 clinical trials in 25 countries. The networks were able to quickly pivot to support NIAID’s emerging infectious disease priority areas, including COVID-19 and mpox. Of the 93,000 participants since 2020, approximately 78,000 were enrolled into COVID-19 clinical trials sponsored by NIAID’s Division of AIDS. 

Clinical trials sites currently operate with a hub-and-spoke model, with each hub providing centralized support to their linked clinical research sites. This model leverages shared resources where possible and practical, and ensures robust oversight to promote high-quality clinical trial operations. Hubs provide infrastructure and services including laboratory, pharmacy, regulatory, data management, and training to support execution of NIAID-sponsored clinical research. 

Future networks will need to maintain core strengths of current models while expanding capacity in areas vital to further scientific progress. These include operations that inform pandemic responses and extending our reach within communities impacted by HIV, including populations historically underrepresented in clinical research. Additionally, there may be opportunities for clinical research sites and other partners to conduct implementation science research based on their capacity and access to relevant populations in the context of specific scientific questions. 

Make seamless progress on established and emerging scientific priorities

Our goals include maintaining the strength and flexibility of our current network model and infrastructure to support established scientific priorities that improve the practice of medicine, including high-impact registrational trials to identify new biomedical interventions and support changes to product labelling. The networks also must remain capable of directing operations to generate evidence on interventions for pandemic responses. 

Engage underserved populations for more representative studies 

Building on its current reach, NIAID and its partners have identified opportunities to expand or strengthen our connections to medically underserved populations affected by HIV, and to increase representation of geographic areas with limited access to current clinical trials sites. We also are seeking clinical research sites with longstanding community relationships and experience conducting randomized clinical trials that include Black gay, bisexual, and other men who have sex with men, transgender people, people who sell sex, people who use drugs, and adolescent girls and young women, as well as populations in African countries with a high HIV prevalence. 

Integrate implementation science within clinical research practice

Implementation science is the scientific study of methods and strategies that facilitate the uptake of evidence-based practice and research into regular use by practitioners and policymakers. As biomedical HIV prevention, treatment, and diagnostic options expand, our scientific questions must expand to address not only whether an intervention works, but how it can be delivered to offer health care choices that people need, want and are able to use. This expanded scientific scope calls for research sites to have a diverse reach and skill sets, including experience and capacity for conducting implementation science research and fostering and maintaining partnerships with organizations that conduct implementation science research on key topics and interventions on which implementers seek stronger evidence.

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.

NIAID’s VRC, S. Africa’s Afrigen Kick Off Vaccine-Sharing Efforts
Training Aimed at Making mRNA Technology Available Globally 

A team of vaccine production experts from South Africa recently finished training in Maryland as part of a global mRNA vaccine collaboration. The experts are working with scientists at NIAID’s Vaccine Research Center (VRC) to produce vaccines against a list of troubling infectious diseases.

The mRNA vaccine platform, which became commonly used during the COVID-19 pandemic, works by delivering a piece of genetic material to cells that instructs the body to make a protein fragment resembling one from a target pathogen (such as a virus). The immune system then recognizes and remembers the fragment, enabling it to mount a strong response if the body is exposed to that pathogen. The mRNA vaccine production process involves inserting the selected virus protein gene into a plasmid (a circular piece of DNA), the production of which was the topic of the visit from the South African scientists.

The seven-member team from Afrigen Biologics and Vaccines, a biotechnology company based in Cape Town, South Africa, arrived on July 21 for two weeks of collaboration and learning with VRC scientists. They focused on vaccine manufacturing at the VRC’s Vaccine Clinical Materials Program in Frederick, Maryland. Specific aspects included topics such as: inoculum growth, nutrient feeding, quality control, and other steps needed to make an mRNA vaccine. The Afrigen team also met with VRC leadership, including the recently appointed VRC Director, Dr. Ted Pierson. 

The visit represented a significant milestone for an ongoing research collaboration established in March 2022 between NIAID and Afrigen. Their objective is to share knowledge, expertise, and data to expedite mRNA vaccine production globally. As part of the collaboration, NIAID – specifically scientists at the VRC – are making plasmid DNA that will be used for Afrigen’s in vitro transcription process. Additionally, the VRC is providing technology transfer and training on plasmid DNA manufacturing, which the Afrigen group observed during the visit. In turn, Afrigen is sharing knowledge and expertise with NIAID scientists about the in vitro transcription and lipid nanoparticle formulation processes. The mutually beneficial scientific collaboration will advance each institution’s work toward establishing mRNA vaccine production capabilities to support their respective missions.

The World Health Organization, the COVAX Vaccine Manufacturing Taskforce, and the Medicines Patent Pool established a formal agreement in July 2021 to build capacity in low- and middle-income countries to make mRNA vaccines, now known as the mRNA technology transfer programme. Afrigen was chosen as a center of excellence and training, or “technology transfer hub,” as part of the mRNA technology transfer programme. The hub is designed to improve the health and security of member nations by creating sustainable, locally owned mRNA vaccine manufacturing in those nations. Because mRNA vaccines can be cheaper to produce, quickly developed in response to outbreaks, and easily modified when new variants of pathogens emerge, the ability to produce these vaccines in low- and middle-income nations will contribute significantly to global health security.

Afrigen is working to establish mRNA vaccine production technology—initially for a COVID-19 vaccine candidate—and will work with local partners to conduct research to evaluate the vaccines, along with manufacturing the vaccines at scale. The eventual goal is to be able to share this established process with manufacturers across multiple countries. 

Though the effort began with COVID-19 in mind, the scientists are mutually hoping to use the mRNA vaccine platform to develop and test vaccines against an array of infectious diseases found globally, such as HIV, tuberculosis, malaria, influenza, cancer-associated viruses and more.

Afrigen scientists spent time getting to know colleagues at the Vaccine Research Center’s Vaccine Production Program (VPP) and Vaccine Clinical Materials Program (VCMP), including during a meet-and-greet with VRC leadership and staff at the VCMP pilot plant in Frederick, Maryland.

Credit: NIAID