Inducing effective vaccination responses in aging

Objective. Aging-related decline in immune functions, termed immunosenescence, is a primary cause of reduced vaccine efficiency in the elderly, due to impaired induction of cellular and humoral responses to new antigens, especially if the response is T cell dependent. Consequently, the elderly are susceptible to a more severe morbidity following infections, and exhibit more prolonged and frequent hospitalization, and a higher mortality rate than in the general population. Therefore, there is an increasing need to develop vaccination strategies that overcome immunosenescence, especially for aging-related diseases such as Alzheimer`s disease (AD). This study aimed to develop a new vaccination strategy that harnesses memory-based immunity, which is less affected by aging.

Methods. Aged 5xFAD mice, which model early onset AD, as well as aged wildtype mice exhibit a dramatic reduction in anti-Amyloid-beta (A-beta) antibody (Ab) production. We therefore aimed to reverse this process by inducing memory response at a young age. To this end, young mice were primed with a DNA vaccination against the vaccine carrier Hepatitis B surface antigen (HBsAg). At an advanced age, primed mice were immunized with an A-beta1-11 fused to HBsAg.

Results. This vaccination scheme elicited a markedly higher A-beta specific antibody titer than vaccinating aged unprimed mice with the same construct. Importantly, this vaccine strategy more efficiently reduced cerebral A-beta levels and altered microglial phenotype.

Conclusions. Overall, we provide evidence that priming with an exogenous antigen carrier can overcome impaired humoral responses to self-antigens in the elderly, paving the route for a potent immunotherapy to AD.