A Critical Insight: Dengue Human Challenge Model Prevents Potential Vaccine Missteps

In a recent study led by Kirsten E. Lyke, MD, Professor of Medicine at the University of Maryland School of Medicine Center for Vaccine Development and Global Health, researchers used the Dengue Human Infection Model (DHIM) with Dengue Virus serotype 1 for the first time to evaluate the efficacy and safety of a dengue virus vaccine.

Dengue is one of the most significant arboviral diseases affecting humans globally, with about half of the world's population at risk. The World Health Organization has listed dengue as one of the top ten global health threats. The disease, caused by the dengue virus, has four different serotypes, contributing to its complexity and the challenges in vaccine development. Aedes mosquitoes, thriving in urban and semi-urban areas and spreading due to climate change, transmit the virus.

In January 2021, researchers enrolled ten eligible participants in the study. Six participants received a purified inactivated vaccine followed by a live-attenuated vaccine booster, while four participants in the control group received no vaccine. Approximately three years after the booster dose, the researchers exposed these participants to a weakened form of the dengue virus serotype one. Five out of six vaccine recipients and all controls developed dengue fever. The dengue vaccine recipients, however, not only remained unprotected against the Dengue Virus but also suffered earlier infections and more severe symptoms and showed increased inflammatory responses compared to the controls, indicating possible antibody-dependent enhancement. This phenomenon occurs when pre-existing but partial immunity to dengue leads to more severe disease. This approach demonstrated the complex nature of the human response to the dengue vaccine. It underscored the significance of using small cohort, human challenge models to study dengue pathogenesis and mitigate risks before vaccine widespread deployment.

"These results underscored the effectiveness of small human challenge models," said Dr. Lyke. "In our small study group, we identified that the vaccine might lead to Antibody-Dependent Enhancement—a risky complication that can lead to serious adverse effects if the vaccine had progressed to broader field trials. That's precisely why this trial was crucial. The key takeaway isn't that the vaccine failed to offer protection; rather, it's that we successfully halted its development early enough to prevent potential harm to volunteers in later-stage trials."

The Study's Findings:

The trial's results were revealing and pivotal. Despite the vaccine's initial promise, vaccinated participants exposed to the dengue virus displayed insufficient protection compared to their unvaccinated counterparts. The findings indicated the potential for Antibody-Dependent Enhancement (ADE), where pre-existing antibodies could worsen the infection.

Antibody-Dependent Enhancement is a phenomenon where the antibodies generated during an immune response to certain viruses can paradoxically enhance the infection rather than protect against it. This phenomenon raises significant concerns in vaccine development and treatment strategies for viral infections, as it challenges the traditional assumption that having antibodies against a virus is always beneficial.

U.S. Army's Response:

These insights prompted a strategic pivot in the U.S. Army's vaccine development approach, emphasizing the model's value in preemptively identifying risks. The Army's decision to deprioritize the vaccine's development before field trials underscored a proactive commitment to safety and efficacy, sparing potential adverse effects on a larger scale.

The Broader Implication:

This study underscores the DHIM's vital role in vaccine development, particularly for complex diseases like dengue, where the immune response can be unpredictable. By providing a controlled environment to identify potential issues like ADE, the DHIM acts as a crucial buffer, ensuring that only the most efficacious and safe vaccines advance to widespread use.

"As we continue to innovate in vaccine development, especially for complicated infections such as dengue, we need a rigorous approach to ensure the safety and efficacy of these products before they enter larger populations," said Miriam Laufer, MD, Professor of Pediatrics, Interim Director of the Center for Vaccine Development & Global Health and Director of the Office of Student Research in the School of Medicine. "Generating evidence about vaccine safety and efficacy is vital to our mission at the Center for Vaccine Development and Global Health. We integrate rigorous pre-clinical evaluations and clinical trials to identify early safety issues and potential health impacts during wider public use. Our use of dengue human challenge models shifts the paradigm in vaccine development.  This study is a testament to the critical importance of human challenge models in the ongoing quest to combat global health threats effectively and safely."

UMSOM faculty and co-authors of the paper include Joel Chua, MD, Sudaunshu Joshi, MS, Kathleen Strauss, BA, Hernando Guitierrez-Barbosa, MS, Biraj Shrestha, MS, Christopher Culbertson, MA, Paula Bernal, PhD, Robert Edelman, MD.

Researchers and faculty from the Viral Diseases Branch and the Pilot Bioproduction Facility, Walter Reed Army Institute of Research, and the Department of Microbiology and Immunology, State University of New York Update Medical University also contributed to this research. The group comprises the Dengue Human Challenge Consortium, which is dedicated to optimizing Dengue serotypes 1-4 live virus human challenge.

Now in its third century, the University of Maryland School of Medicine was chartered in 1807 as the first public medical school in the United States. It continues today as one of the fastest growing, top-tier biomedical research enterprises in the world -- with 46 academic departments, centers, institutes, and programs, and a faculty of more than 3,000 physicians, scientists, and allied health professionals, including members of the National Academy of Medicine and the National Academy of Sciences, and a distinguished two-time winner of the Albert E. Lasker Award in Medical Research.  With an operating budget of more than $1.2 billion, the School of Medicine works closely in partnership with the University of Maryland Medical Center and Medical System to provide research-intensive, academic and clinically based care for nearly 2 million patients each year. The School of Medicine has nearly $600 million in extramural funding, with most of its academic departments highly ranked among all medical schools in the nation in research funding.  As one of the seven professional schools that make up the University of Maryland, Baltimore campus, the School of Medicine has a total population of nearly 9,000 faculty and staff, including 2,500 students, trainees, residents, and fellows. The combined School of Medicine and Medical System (“University of Maryland Medicine”) has an annual budget of over $6 billion and an economic impact of nearly $20 billion on the state and local community. The School of Medicine, which ranks as the 8th highest among public medical schools in research productivity (according to the Association of American Medical Colleges profile) is an innovator in translational medicine, with 606 active patents and 52 start-up companies.  In the latest U.S. News & World Report ranking of the Best Medical Schools, published in 2023, the UM School of Medicine is ranked #10 among the 92 public medical schools in the U.S., and in the top 16 percent (#32) of all 192 public and private U.S. medical schools.  The School of Medicine works locally, nationally, and globally, with research and treatment facilities in 36 countries around the world. Visit medschool.umaryland.edu

About the Center for Vaccine Development and Global Health at the University of Maryland School of Medicine

For over 40 years, researchers in the Center for Vaccine Development and Global Health (CVD) have worked domestically and internationally to develop, test, and deploy vaccines to aid the world’s underserved populations. CVD is an academic enterprise engaged in the full range of infectious disease intervention from basic laboratory research through vaccine development, pre-clinical and clinical evaluation, large-scale pre-licensure field studies, and post-licensure assessments. CVD has created and tested vaccines against cholera, typhoid fever, paratyphoid fever, non-typhoidal Salmonella disease, shigellosis (bacillary dysentery), Escherichia coli diarrhea, nosocomial pathogens, tularemia, influenza, coronaviruses, malaria, dengue, ebola and other infectious diseases. CVD’s research covers the broader goal of improving global health by conducting innovative, leading research in Baltimore and around the world. Our researchers are developing new and improved ways to diagnose, prevent, treat, control, and eliminate diseases of global impact, including COVID-19. In addition, CVD’s work focuses on the ever-growing challenge of antimicrobial resistance.