Multistrain influenza protection induced by a nanoparticulate mucosal immunotherapeutic

Abstract

All commercial influenza vaccines elicit antibody responses that protect against seasonal infection, but this approach is limited by the need for annual vaccine reformulation that precludes efficient responses against epidemic and pandemic disease. In this study we describe a novel vaccination approach in which a nanoparticulate, liposome-based agent containing short, highly conserved influenza-derived peptides is delivered to the respiratory tract to elicit potent innate and selective T cell-based adaptive immune responses. Prepared without virus-specific peptides, mucosal immunostimulatory therapeutic (MIT) provided robust, but short-lived, protection against multiple, highly lethal strains of influenza in mice of diverse genetic backgrounds. MIT prepared with three highly conserved epitopes that elicited virus-specific memory T-cell responses but not neutralizing antibodies, termed MITpep, provided equivalent, but more durable, protection relative to MIT. Alveolar macrophages were more important than dendritic cells in determining the protective efficacy of MIT, which induced both canonical and non-canonical antiviral immune pathways. Through activation of airway mucosal innate and highly specific T-cell responses, MIT and MITpep represent novel approaches to antiviral protection that offer the possibility of universal protection against epidemic and pandemic influenza.

Essential role for autophagy in the maintenance of immunological memory against influenza infection

“…Together, these data suggest that immunization of B/ Atg7 −/− mice failed to induce protective humoral immunity to control influenza virus re-infection. Despite an important role for antibodies in the protection against influenza infections, T cell responses may also confer certain degrees of protection 56–58 . B/ Atg7 −/− mice surviving the reinfection still showed defective anti-HA antibody responses but displayed increased T cell expansion (Supplementary Fig.…”

“…Mice were administered intranasally with 50 μl influenza A/Hong Kong/8/68 (H3N2) 58 (A/HK/68) at a sub-lethal dose of 7.5 TCID 50 . For intranasal challenge, aliquots of influenza virus were diluted in Dulbecco’s modified Eagle’s medium (DMEM) to achieve the indicated number of influenza virus per 50 μl volume.…”

Immunization with Biodegradable Nanoparticles Efficiently Induces Cellular Immunity and Protects against Influenza Virus Infection

“…Nanoparticles (NPs) offer a new method for the design of vaccine systems. They are considered to be efficient Ag carriers and are being widely investigated for their biological potential (12)(13)(14). Recently, we generated biodegradable calcium phosphate (CaP) NPs that coencapsulate the TLR9 ligand CpG and a MHC class IIrestricted influenza virus hemagglutinin (HA) peptide.…”

A model for homeopathic remedy effects: low dose nanoparticles, allostatic cross-adaptation, and time-dependent sensitization in a complex adaptive system

“…These findings include remedy-induced changes in heat shock proteins [7,17,146], cytokines [147-149], immune [150-153], metabolic [12,131], and nervous system [154-162] function, as well as gene expression patterns [9,163,164]. Nanoparticles per se can and do mobilize components of the allostatic network [165-167]. Because of the interconnected network nature of the allostatic network, however, in vivo studies, which allow the brain and body to carry on their usual bidirectional homeostatic interactions with one another, are most likely to capture the hypothesized role of the allostatic network in adaptation [96] after remedy administration.…”

“…For instance, an infectious agent or environmental nanoparticles would likely interact first with elements of the immune system [165,167], but then the cytokines released as part of the immune and inflammatory response in the allostatic network would modulate brain function, leading to changes in emotional state, mood and energy levels [136,170]. In the “other” direction from above downward in the stress response network, chronic disturbances in brain function such as sleep deprivation can mobilize sympathetic nervous system tone, inflammatory cytokine release, and glucocorticoid activity [171].…”