Development Of New Approaches To Vaccines Against Neurotropic Flaviviruses

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

The pathogenesis of flaviviral neuroinfection is complex and depends on a series of events involving (1) virus replication in the periphery to produce and sustain the level of viremia sufficient for neuroinvasion, (2) virus entry into the CNS (neuroinvasiveness), (3) virus replication, spread, and introduction of neuropathology once in the CNS (neurovirulence), and (4) virus-mediated stimulation of innate and adaptive immune responses of the host both in the periphery and within the CNS. To prevent the virus entry into the CNS (neuroinvasiveness) and to restrict its replication in the neurons (neurovirulence) or in peripheral organs, we have explored several different approaches and developed the vaccine candidates using the strategies based on (1) chimerization of a neurovirulent virus (JEV, WNV, SLEV or TBEV) with a non-neuroinvasive mosquito-borne dengue type 4 flavivirus (DEN4) or naturally attenuated tick-borne Langat virus (LGT) and (2) targeting of viral genome for cellular microRNAs (miRNAs) expressed in the tissue of interest (etc., brain, reproductive organs, placenta) for selective control of virus tropism. The promising and most attenuated vaccine candidates were then evaluated for safety, immunogenicity, and their ability to protect mice and monkeys against challenge with wild-type virulent parental virus. In addition, a miRNA targeting approach was adapted to design environmentally safe vaccine viruses restricted in their ability to infect and be transmitted by permissive arthropod vectors (mosquitoes or ticks). West Nile virus (WNV) is a mosquito-borne neurotropic flavivirus that has emerged as a human pathogen of global scale and now is a leading cause of viral encephalitis in US. There are no approved vaccines against WNV, clinical management of the disease in humans remains only supportive, and our current understanding of the disease neuropathogenesis is yet to be translated into effective treatments. Building on our methodological approaches and recent findings that helped to fill the gaps in our understanding of WNV neuropathogenesis in nonhuman primates, in FYI 2022 we initiated efforts to obtain the brain and spinal cord tissues from human cases of WNV encephalitis in the US. We are working on the design and implementation of multiple studies to address the outstanding questions regarding WNV neuropathogenesis and its short- and long-term impacts on humans. To address these questions, we engage multiple colleagues from the NIAID Division of Intramural Research and Research Technology Branch (both in Bethesda, Maryland and Hamilton, Montana) to employ informative existing and emerging methodologies including histopathology, immunohistochemistry, digital pathology, electron microscopy, transcriptomics, in situ RNA detection, and spatial protein profiling. We hope that new findings using integration of these scientific approaches may provide a better understanding of the pathophysiology of the disease of the central nervous system caused by WNV infection and prompt a new thinking in a search for effective therapeutic approaches.