Harrison, H. F. | Search bioRxiv

bioRxiv2024

The TLR7/8 agonist INI-4001 enhances the immunogenicity of a Powassan virus-like-particle vaccine

Powassan virus (POWV) is a pathogenic tick-borne flavivirus that causes fatal neuroinvasive disease in humans. There are currently no approved therapies or vaccines for POWV infection. Here, we develop a POW virus-like-particle (POW-VLP) based vaccine adjuvanted with the novel synthetic Toll-like receptor 7/8 agonist INI-4001. We demonstrate that INI-4001 outperforms both alum and the Toll-like receptor 4 agonist INI-2002 in enhancing the immunogenicity of a dose-sparing POW-VLP vaccine in mice. INI-4001 increases the magnitude and breadth of the antibody response as measured by whole-virus ELISA, induces neutralizing antibodies measured by FRNT, reduces viral burden in the brain of infected mice measured by RT qPCR, and confers 100% protection from lethal challenge with both lineages of POWV. We show that the antibody response induced by INI-4001 is more durable than standard alum, and 80% of mice remain protected from lethal challenge 9-months post-vaccination. Lastly, we show that the protection elicited by INI-4001 adjuvanted POW-VLP vaccine is unaffected by either CD4+ or CD8+ T cell depletion and can be passively transferred to unvaccinated mice indicating that protection is mediated through humoral immunity. This study highlights the utility of novel synthetic adjuvants in VLP-based vaccines. Author summaryPowassan virus (POWV) is an emerging pathogenic tick-borne flavivirus for which there is no vaccine. Current tick-borne flavivirus vaccines are less than ideal and use formalin-inactivated virus adjuvanted with alum. These vaccines require thorough inactivation of the antigen and frequent boosting to maintain immunity. In this study, we describe the development of a POWV vaccine using Powassan virus-like-particles (POW-VLPs) adjuvanted with either of two novel Toll-like receptor (TLR) agonists, the TLR4 agonist INI-2002 or the TLR7/8 agonist INI-4001. We show that INI-4001 enhances the antibody response, reduces POWV neuroinvasion, and elicits full protection from lethal POWV infection in mice prime-boost vaccinated with low doses of POW-VLP. We further show that this protection is mediated by a humoral immune response which is both broader and more durable than a POW-VLP vaccine formulated with alum. These findings demonstrate the effectiveness of the novel synthetic TLR7/8 agonist INI-4001 as an adjuvant for low-dose VLP-based vaccines and the ability of this vaccine platform to improve upon current tick-borne flavivirus vaccine methodology.

immunology↗

bioRxiv2024

Systemic exposure to COVID-19 virus-like particles modulates firing patterns of cortical neurons in the living mouse brain

Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) causes a systemic infection that affects the central nervous system. We used virus-like particles (VLPs) to explore how exposure to the SARS-CoV-2 proteins affects brain activity patterns in wild-type (WT) mice and in mice that express the wild-type human tau protein (htau mice). VLP exposure elicited dose-dependent changes in corticosterone and distinct chemokine levels. Longitudinal two-photon microscopy recordings of primary somatosensory and motor cortex neurons that express the jGCaMP7s calcium sensor tracked modifications of neuronal activity patterns following exposure to VLPs. There was a substantial short-term increase in stimulus-evoked activity metrics in both WT and htau VLP-injected mice, while htau mice showed also increased spontaneous activity metrics and increase activity in the vehicle-injected group. Over the following weeks, activity metrics in WT mice subsided, but remained above baseline levels. For htau mice, activity metrics either remain elevated or decreased to lower levels than baseline. Overall, our data suggest that exposure to the SARS-CoV-2 VLPs leads to strong short-term disruption of cortical activity patterns in mice with long-term residual effects. The htau mice, which have a more vulnerable genetic background, exhibited more severe pathobiology that may lead to more adverse outcomes.

neuroscience↗