A new mucosal adjuvant for augmenting influenza vaccines in elderly

Abstract This proposal is to investigate a newly developed mucosal adjuvant for its effectiveness in bolstering influenza (flu) vaccines in the elderly. Current flu vaccines are inefficacious in the elderly owing to the aged immune system and their poor stimulation of cell-mediated immunity (CMI). A powerful adjuvant capable of stimulating both humoral and cell immune responses in the elderly should greatly augment existing flu vaccines, better safeguarding this aging and growing population. We recently engineered a powerful mucosal adjuvant by encapsulating a natural STING agonist with pulmonary surfactant (PS)- biomimetic liposomes, named PS-GAMP, based on recent findings that activation of STING, the stimulator of IFN genes, can vigorously stimulate CMI and humoral immunity. PS-GAMP alongside inactivated H1N1 vaccine induced a wide spectrum of cross-protection against distant H1N1 and heterosubtypic H3N2, rgH5N1, and H7N9 viruses as early as 2 days after a single immunization. The cross-protection lasted for at least 6 months, concurrent with durable lung tissue resident memory (TRM) CD8+ T cells in young adult mice. We will extend the study to aged mice in this proposal and determine whether strong CD8+ T-cells (and perhaps CD4+ T cells as well) can be quickly induced by PS-GAMP/flu vaccine in aged mice. We will monitor a longevity of the heterosubtypic immunity, humoral immune responses, and lung TRM CD8+ and CD4+ memory T cells as mice age. Because the vaccination does not involve any replicating vaccine, pre-exiting immunity should have little effect on the efficacy of PS- GAMP/flu vaccination, which will be investigated to demonstrate significant advantages of the vaccine over live-attenuated intranasal flu vaccine that is ineffective in the elderly. Secondly, distinguished from most prominent adjuvants primarily targeting antigen-presenting cells (APCs) or professional immune cells, PS-GAMP activates both alveolar epithelial cells (AEC) and APCs. It would be interested to learn whether PS-GAMP-mediated AEC activation can offset the defects of aged APCs, eliciting strong heterosubtypic immunity in aged mice. The pivotal role for AEC will be also substantiated in ferret model. Aim 3 will investigate whether PS-GAMP/flu vaccination can be further improved in aged mice by suppressing inflammaging and/or removing senescence cells. Moreover, a novel, much more potent, and pan-STING agonist will be explored to enhance PS-GAMP's adjuvanticity and strengthen its clinical potential. The study, if successful, would have significant impact on the overall health and quality of the aged population not only for influenza but also for other respiratory viral infections like Covid-19.