Adjuvants that stimulate TLR3 or NLPR3 pathways enhance the efficiency of influenza virus-like particle vaccines in aged mice

Abstract

There is intense interest in the design and use of vaccine strategies against influenza to enhance protective immune responses in the elderly. To address the need for improved influenza vaccines for the aged, two inflammatory adjuvants, Imject(®) alum (a stimulator of the Nod-like receptor, Nalp3) and poly I:C (a toll-like receptor type 3 ligand), were used during vaccination with novel influenza virus-like particles (VLP). Adult (4 month old) or aged (24 month old) mice were vaccinated with VLPs alone or in combination with adjuvant. VLP-vaccinated adult mice were protected from a lethal influenza virus challenge without the use of either adjuvant. In contrast, only aged mice that were vaccinated with VLPs plus adjuvant survived challenge, whereas ∼33% of the mice vaccinated with VLP only survived challenge. Mice vaccinated with adjuvant only did not survive challenge despite similar levels of activation of CD11b(+)/CD11c(+) dendritic cells in the lungs. The protection was not associated with HAI titers or HA specific CD8(+) T cells, since both adjuvants boosted the VLP-induced serum HAI titers and CD8(+) responses in adult mice, but not aged mice. Influenza VLPs used in combination with two different inflammatory adjuvants during vaccination allow for the immune system to overcome the deficiency in the aged immune system to influenza virus infection.

Role of human Toll‐like receptors in naturally occurring influenza A infections

“…Our results, together with emerging reports on other pattern recognition receptors33, 36, 42, strongly support further clinical studies on the roles of innate immunity in controlling influenza and to explore potential applications of receptor targeting, especially as preventive interventions 2, 4, 37…”

“…Nevertheless, recent studies have shown that TLR's role in regulating the adaptive responses can be harnessed to boost immunogenicity of influenza vaccines (e.g., TLR9 or TLR7 ligands as adjuvants). This may be particularly useful in the elderly and the immunologically naïve vaccinees 4, 33, 34, 35, 36, 37, 38, 39, 40. Our data in natural influenza provide additional support to this new vaccination approach.…”

The avian influenza vaccine Emerflu. Why did it fail?

“…This was an unexpected finding, yet to be explained or confirmed, but which similar to SU inactivated influenza vaccines contradicted findings from animal studies [87]. Given our current experience from clinical studies with alum-adjuvanted influenza A/H5N1 vaccines in humans and animals, preformulation studies of alum-adjuvanted vaccines will likely be beneficial and minimize potential issues related to suboptimal formulations.…”

Adjuvant formulations for virus-like particle (VLP) based vaccines

“…In the context of VLP vaccinology, Poly I:C has been shown to enhance the protective ability of a VLP-based vaccine against a lethal challenge in a mouse model using a mouse-adapted flu virus [84]. In addition, a VLP-based vaccine for Ebola virus was more efficacious in mice and guinea pigs when adjuvanted with Poly ICLC adjuvant (Hiltonol, Oncovir Inc.) which is a stable combination of Poly IC and Poly lysine [85].…”