This blog is the second in a series about the future of NIAID's HIV clinical research enterprise. For more information, please visit the /research/hiv-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 Next NIAID HIV Networks.

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-developed Vaccines May Provide Flexibility and Choice Among Ebola Vaccines

Ebola viruses cause devastating disease in people, resulting in severe and often fatal hemorrhagic fever called Ebola virus disease. Of the four species of Ebola viruses that cause disease in people, Zaire ebolavirus (EBOV) and Sudan ebolavirus (SUDV) have caused more than 30 known outbreaks in the last century, killing more than half of those with the disease. Scientists at NIAID’s Vaccine Research Center (VRC) developed novel vaccines to combat these viruses, which were advanced to clinical trials in response to the 2014-2016 Ebola epidemic in the West African countries of Guinea, Liberia, and Sierra Leone. In two phase 1/1b trials conducted in the United States and Uganda, the researchers evaluated combinations of the experimental vaccines against Ebola disease in healthy adults, finding them safe, tolerable, and capable of producing immune responses. Comparisons between the different vaccine regimens revealed important data on how the vaccines could be administered in routine and outbreak settings. The results of the trials were published last week in npj Vaccines.

In a Springer Nature Research Communities blog post published after the research article, the authors discussed how the vaccines were rapidly brought to clinical trials amid reports that cases of Ebola virus disease were spreading in Guinea in March 2014. At the time, there were no approved vaccines or therapeutics for Ebola virus disease. When outbreaks occur, Ebola virus spreads quickly, and severe symptoms and death can occur within weeks of infection. The rapid progression of Ebola virus disease in individuals often causes outbreaks to be short but deadly, although the threat of larger epidemics looms large. In 2014, the Ebola outbreak spread to Liberia and Sierra Leone, with a small number of travel-related cases in the U.S. and several African and European countries. Public health officials around the world feared the outbreak could become a global pandemic.

At the same time, researchers at the VRC were preparing to bring new investigational Ebola vaccines, called cAd3-EBO, cAd3-EBOZ, and MVA-EbolaZ, to clinical trials. The scientists and their collaborators worked hard to accelerate the process and launch a clinical trial in the U.S. to test whether a two-dose vaccine regimen could be used in the event of a prolonged outbreak. The researchers also launched a similar clinical trial in Uganda. The two trials enrolled 230 healthy people, 174 of whom had already received an Ebola vaccine in previous studies.

The trials evaluated “prime-boost” vaccine regimens, which first use a “prime” vaccine followed by a different “boost” vaccine. Each of the vaccines uses a portion of a protein from the surface of Ebola viruses called Ebola glycoprotein (GP) as the immunogen—the part of the vaccine that trains the body to generate an immune response without causing disease. The prime vaccines used in the trial were cAd3-EBOZ and cAd3-EBO, which use a vaccine vector based on a chimpanzee adenovirus not capable of replicating inside the human body, called cAd3. The cAd3 vaccines included either EBOV GP (the cAd3-EBOZ vaccine) or a combination of EBOV and SUDV GPs (the cAd3-EBO vaccine). The boost vaccine was MVA-EbolaZ, which uses EBOV GP with a different vector, modified vaccinia virus Ankara (MVA). Preclinical studies had shown the combination of vaccines could produce strong, protective immunity against Ebola virus disease in animals.

Combining the results of the U.S. and Uganda trials, the researchers found the vaccines to be safe and tolerable in people with and without prior Ebola vaccinations. Additionally, the cAd3 Ebola vaccines produced immune responses in people, stimulating the production of antibodies against Ebola that reach high levels as soon as two weeks after vaccination and lasting up to 48 weeks after the prime and boost vaccinations. The researchers also found that different time intervals between the prime and boost vaccinations influenced the magnitude of antibody and cellular immune responses.

The 2014 Ebola outbreak was larger than any previously reported. When it was declared over in 2016, the disease had claimed 11,325 lives among the 28,652 reported cases. Several clinical trials evaluating Ebola vaccines, including cAd3 vaccines, were launched at the time, providing much-needed countermeasures against this deadly disease. Since then, new vaccines against Ebola virus disease have emerged, with one approved for use in the U.S., the European Union (EU), and several African countries, and a prime-boost regimen that was authorized for use in the EU.

Given the unpredictable nature of Ebola outbreaks, several different vaccination strategies could be useful. These include routine vaccinations in regions where Ebola virus disease is known to occur, pre-exposure vaccinations of frontline workers during outbreaks, emergency vaccinations of people in outbreak zones, as well as the availability of multiple vaccines for different individuals. According to the researchers, these findings demonstrate that the cAd3 and MVA Ebola vaccines could make useful additions to countermeasures against Ebola virus disease, allowing for choice and flexibility among the currently available vaccines. Additionally, they note that the findings will inform the development of vaccine campaigns and emergency response strategies during Ebola outbreaks.

References:

M Happe, AR Hofstetter, et al. “Heterologous cAd3-Ebola and MVA-EbolaZ vaccines are safe and immunogenic in US and Uganda phase 1/1b trials.” npj Vaccines DOI: 10.1038/s41541-024-00833-z (2024).

AR Hofstetter, M Happe, et al. “Clinical Testing of the cAd3-Ebola and MVA-EbolaZ vaccines.” Springer Nature Research Communities (2024).

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