Researchers’ study show advancements in GP38 contributions to CCHFV and monoclonal antibody therapies

A recent study published in Science Translational Medicine involving scientists from the U.S. Army Medical Research Institute of Infectious Diseases in collaboration with scientists from the Albert Einstein College of Medicine and the University of California-Berkeley have advanced discoveries surrounding the viral glycoprotein GP38 expressed by the Crimean-Congo hemorrhagic fever virus (CCHFV).

CCHFV is endemic to Africa, the Balkans, the Middle East and Asia, and considered a priority pathogen by the World Health Organization. The virus is primarily transmitted to people from ticks and livestock animals with a case fatality rate of up to 40%. There are currently no approved vaccines against the virus.

Historically GP38 has been considered an important target for vaccines or other treatments. However, the lack of knowledge regarding GP38s function during infection has hindered efforts to develop CCHFV-specific medical countermeasures.

The new research sheds light on GP38’s role in viral infections and pathogenesis, and how GP38-specific antibodies particularly mediate protection in vivo.

“This study is focused on demonstrating that GP38 alone can act as a ‘viral toxin’ and trigger vascular leakage to occur,” says Andrew Herbert, a senior author of the study and USAMRIID branch chief. “It is also focused largely on understanding the mechanism of protective efficacy for antibodies targeting GP38.”

Evidence also shows that GP38 has a direct role in viral pathogenesis that is independent of its function in viral glycoprotein biogenesis. It emphasizes the importance of including GP38 in CCHFV vaccine design and provides a starting point for the rational design of GP38-targeting anti-CCHF therapeutics.

Additional research backs this evidence by treating CCHFV-challenged mice with exogenous GP38, further enhancing vascular leak in the context of infection, suggesting that GP38 functions as a secreted viral toxin in the induction of vascular leak.

In previous work, published in July 2024 Monticelli and Herbert, along with collaborators from academia and industry, isolated a large panel of GP38-targeting mAbs from human survivors of natural infection, and showed some of these to be protective in animal models of infection against multiple diverse isolates of CCHFV. While this study provided some evidence of protective epitopes on GP38, it did not provide a clear understanding of the mechanism of protection of these anti-GP38 antibodies.

“From the previous study, we didn’t know how the antibodies were mediating protection,” says Stephanie Monticelli, co-first author of the publication and a research scientist at USAMRIID. “By determining a mechanism of action for protective GP38-specific monoclonal antibody therapies, we can better understand how to target this protein for the development of potent medical countermeasures.”

This recent publication showed that non-neutralizing GP38-specific mAbs targeting the N-terminal region of GP38 (region 2) were the most protective against lethal challenge, the most potent at reducing circulating GP38, diminishing vascular leak, and curtailing viral dissemination to distal tissues. The moderate effect of the virus-neutralizing anti-Gc mAb indicates that the observed reduction in vascular leak upon treatment with GP38-binding mAbs is not only a result of overall reduction in viral load but rather is specific to a reduction in circulating GP38 and direct blockade of the function of GP38 in inducing vascular leak.

These discoveries show a clear significance of the virus-host relationship, specifically when working with the CCHFV-challenged subjects.

“Virus host interactions are very complex and teasing apart complex processes that occur during a viral infection can be tricky,” says Herbert. “Viral proteins often perform more than one function during infection, and they can also ‘collaborate’ with other viral proteins, or even host proteins, to perform a specific function that is beneficial for the virus.”

This study is part of the Prepositioning Optimized Strategies for Vaccines and Immunotherapeutics Against Diverse Emerging Infectious Threats - PROVIDENT consortium.

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Since 1969, USAMRIID has provided leading edge medical capabilities to deter and defend against current and emerging biological threat agents. The Institute is the only laboratory in the Department of Defense equipped to safely study highly hazardous pathogens requiring maximum containment at Biosafety Level 4. Research conducted at USAMRIID leads to vaccines, drugs, diagnostics, and training programs that protect both Warfighters and civilians. The Institute's unique science and technology base serves not only to address current threats to our Armed Forces but is an essential element in the medical response to any future biological threats that may confront our nation.