Methylglycol chitosan and a synthetic TLR4 agonist enhance immune responses to influenza vaccine administered sublingually

Abstract

Influenza is a vaccine-preventable contagious respiratory illness caused by influenza (flu) viruses which can lead to hospitalization and sometimes even death. Current flu vaccines delivered intramuscularly (IM) or intradermally (ID) are less effective at eliciting protective mucosal immune responses and vaccines delivered intranasally (IN) possess potential safety concerns. Sublingual (SL) vaccination is a promising alternative route for vaccine delivery which has been indicated as safe and effective at inducing protective immune responses in both systemic and mucosal compartments. We evaluated the efficacy of methylglycol chitosan (MGC) and a synthetic toll-like receptor 4 agonist (CRX-601), alone or in combination, for improving systemic and mucosal immune responses to a monovalent detergent-split flu virus vaccine delivered SL. SL vaccination of mice with split-flu vaccine formulated with either MGC or CRX-601 resulted in specific serum IgG and mucosal IgA titers that were significantly greater than titers from non-adjuvanted vaccination and equivalent to or greater than titers in mice vaccinated IM. Our results demonstrate that SL vaccination utilizing MGC or CRX-601 as adjuvants is a viable alternative route of vaccination for flu which can elicit systemic immune responses equivalent to or greater than IM vaccination with the added benefit of stimulating a robust specific mucosal immune response.

Noninvasive vaccination against infectious diseases

“… 51 , 52 Nevertheless, these routes of immunization are less effective in stimulating mucosal immunity, 53 , 54 and a split-flu vaccine in combination with the adjuvant methylglycol chitosan and/or CRX601 administered sublingually was recently found to improve the systemic and mucosal immune responses equivalently or to a greater extent than intramuscular vaccination. 55 …”

Commentary on the Development and Application of Chitosan in Immunochemistry

“…Furthermore, the coating of modified liposomes with methylglycol chitosan produced the most effective flu-specific immune response. These results demonstrate efficient sublingual vaccine delivery utilizing a combination of a muco-adhesive and surface neutral liposomes to achieve a robust mucosal and systemic immune response [14]. A novel delivery system was described comprised of chitosan-functionalized gold nanoparticles and saponin-containing botanical adjuvant, which established the possible role of immunomodulatory adjuvants in particulate delivery systems for mucosal delivery of vaccines [15].…”

Disruption of nasal bacteria enhances protective immune responses to influenza A virus and SARS-CoV-2 infection in mice

“…Although CT and LT are effective adjuvants to enhance mucosal immune responses including secretory IgA responses, they have some side effects in humans, including Bell's palsy and nasal discharge (Mutsch et al, 2004). Therefore, several adjuvants that are as effective as CT or LT and are also safe for human use have been developed for clinical application with intranasal influenza vaccine (Ainai et al, 2010;Bracci et al, 2005;Ichinohe et al, 2005;Sjolander et al, 2001;Skountzou et al, 2010;Spinner et al, 2015). In this study, (Cat#08456-65; Nacalai Tesque) supplemented with 10% FBS, penicillin (100 U/ml), streptomycin (100 μg/ml), and G418 (1mg/ml) (Matsuyama et al, 2020).…”

“…Therefore, induction of the virus-specific secretory IgA in the upper respiratory tract by intranasal vaccination has a great advantage in conferring protection against an unpredictable pandemic of viral pathogens such as the swine-origin H1N1 and avian-origin H7N9 influenza A viruses, or zoonotic origin of SARS-CoV-2 (Gao et al, 2013;Neumann, Noda, & Kawaoka, 2009). In the effort to develop effective intranasal vaccines, several adjuvants such as cholera toxin (Watanabe et al, 2002), synthetic double-stranded RNA poly(I:C) (Ichinohe et al, 2005), synthetic toll-like receptor 4 agonist (Spinner et al, 2015), zymosan (Ainai et al, 2010), flagellin (Skountzou et al, 2010), immune stimulating complexes (ISCOMs) (Sjolander et al, 2001), or type-I interferons (Bracci et al, 2005) have been developed to enhance the vaccine-specific nasal IgA response. While upper respiratory tract contains commensal bacteria (Bassis et al, 2015;Clark, 2020), intranasal administration of split vaccine alone was insufficient to induce the vaccine-specific nasal IgA response (Ichinohe et al, 2005;Jangra et al, 2020), suggesting that the amounts of commensal bacteria in upper respiratory tract are insufficient to stimulate the vaccine-specific nasal IgA response.…”