Researchers at Vanderbilt University Medical Center, in collaboration with Takeda Vaccines Inc., have reported a major advance in understanding and potentially preventing dengue, a devastating, mosquito-borne tropical viral infection that is spreading across the globe.
Their technique, called neutralization fingerprinting, characterizes the diverse, “poly-clonal” antibody responses to dengue infections and vaccines in a way that should help guide further vaccine development and optimization.
While the Dengvaxia vaccine has been approved for use in certain geographic regions, it does not offer complete protection against all four of the dengue viruses (called dengue “serotypes”) that elicit different immune responses.
This is important, because antibodies generated against one serotype can enhance a subsequent infection by a different serotype.
This antibody-dependent enhancement of infection increases the risk for dengue hemorrhagic fever and dengue shock syndrome, characterized by fever, vomiting, internal bleeding and potentially fatal circulatory collapse.
“The existence of multiple dengue virus serotypes presents a formidable challenge for the human immune system to elicit broadly protective responses,” said Ivelin Georgiev, PhD, co-corresponding author with Robert Carnahan, PhD, of the paper published Dec. 13 in the journal Cell Reports.
“A better understanding of the complexity of the immune response to dengue vaccines is needed,” said Georgiev, who directs the Vanderbilt Program in Computational Microbiology and Immunology.
“Our technology offers a unique opportunity to decipher the key ingredients in the responses to dengue vaccines, providing a roadmap for further vaccine optimization.”
The neutralizing fingerprinting technology (NFP) was developed several years ago by Georgiev and colleagues, then at the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, to “deconvolute” the polyclonal antibody responses to infection by the human immunodeficiency virus (HIV), which causes AIDS.
In the current study, Georgiev, Carnahan, and their colleagues examined the neutralization patterns of polyclonal antibodies responding to the investigational TAK-003 vaccine, which is now licensed in Indonesia and Asia.
Using their NFP algorithm, they discovered that antibody neutralization patterns in individuals who had been previously infected by various dengue serotypes prior to vaccination differed significantly from the patterns observed in previously uninfected individuals who received the vaccine.
The technique predicted amplification by the vaccine of pre-existing neutralizing antibody specificities in previously infected, seropositive individuals, thus quantifying the role of immunologic imprinting in driving antibody responses to dengue virus vaccines.
Georgiev, associate professor of Pathology, Microbiology & Immunology, Biomedical Informatics, and Computer Science, has pioneered computational methods to model antibody-antigen interactions.
Carnahan, professor of Pediatrics and of Radiology & Radiological Sciences, and associate director of the Vanderbilt Vaccine Center, has advanced the use of human monoclonal antibodies to prevent life-threatening viral infections.
VUMC co-authors included Nagarajan Raju, PhD, Xiaoyan Zhan, PhD, and James E. Crowe, Jr., MD. Takeda Vaccines collaborators included Subash Das, DVM, PhD, Lovkesh Karwal, MS, and Hansi J. Dean, PhD.
