Saturday, April 27, 2024
4/27/2024
SUMMARY RSV is responsible for >100,000 deaths in children worldwide, and significant morbidity and mortality in the elderly and immune-compromised. A past vaccine trial using inactivated virus failed to protect and caused virus-enhanced lung disease (VED) upon exposure to RSV. Since then, achieving an efficaceous vaccine that is also safe has proven enormously challenging. Absent of an approved vaccine, both live and non-live vaccine approaches are pursued, with each approach presenting unique qualities and hurdles. Among non-live approaches, virus-like-particles (VLPs) are gaining traction, due to successes with commercial VLP vaccines and recent reports showing protective anti-RSV immunity without VED and with improved memory in animal models using VLPs without adjuvants. In part because little is known about RSV particle assembly, all VLP approaches currently in preclinical trials are based on heterologous VLP systems, with most expressing the RSV fusion (F) protein, one of two major RSV glycoproteins. It is by now well recognized that the F protein is unstable and shifts to a post-fusion (non-functional) conformation during vaccine preparation. In recent developments, a pre-fusion stabilized F form (preF) was formulated, and was shown to induce a higher proportion of RSV-neutralizing antibodies than wildtype F, making preF a critical vaccine antigen. A large body of work however shows that other RSV antigens can significantly contribute to, and will likely enhance, preF-based protection across strains. Furthermore, even a successful single-antigen vaccine can induce resistant viruses in the population, as demonstrated with Palivizumab studies in cotton rats and in humans. One avenue to broaden efficacy and simultaneously avoid dependence on a singular antigen is to use a homologous RSV VLP platform including multiple RSV antigens. In the past years, we have learned to generate RSV-based VLPs that are morphologically indistinguishable from wildtype RSV. Recently, we have been able to generate two unique RSV-based VLPs, one displaying on its surface the preF protein, the other a conserved region of the attachment protein G. G is an important antigen as anti-G antibodies can neutralize virus and reduce lung pathology. G is quite variable between strains, except for the central conserved region (G-CCR). We have developed VLPs that exclusively, and recognizably, display the G-CCR on their surface, to augment the immune response to this important region, which also contains a receptor binding domain. Here, we propose a vaccine consisting of combinations of authentic RSV VLPs, separately displaying the preF protein or the G-CCR. By using distinct RSV-based VLPs, an optimal ratio of F to G antigenicity can be determined. Additionally, these VLPs include conserved core RSV antigens for which antibodies and/or CD8 T cell responses were observed in humans. Our hypothesis is that the induced response should be more efficaceous, better protective against divergent strains, better avoid escape viruses than an F-alone based approach, and be devoid of the immune dysregulation observed with live virus and hence be more durable.
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