Development of an Intranasal Gel for the Delivery of a Broadly Acting Subunit Influenza Vaccine

Abstract

Influenza virus is a major cause of death on a global scale. Seasonal vaccines have been developed to combat influenza; however, they are not always highly effective. One strategy to develop a more broadly active influenza vaccine is the use of multiple rounds of layered consensus buildings to generate recombinant antigens, termed computationally optimized broadly reactive antigen (COBRA). Immunization with the COBRA hemagglutinin (HA) can elicit broad protection against multiple strains of a single influenza subtype (e.g., H1N1). We formulated a COBRA H1 HA with a stimulator of interferon genes agonist cyclic guanosine monophosphate−adenosine monophosphate (cGAMP) into a nasal gel for vaccination against influenza. The gel formulation was designed to increase mucoadhesion and nasal retention of the antigen and adjuvant to promote a strong mucosal response. It consisted of a Schiff base-crosslinked hydrogel between branched polyethyleneimine and oxidized dextran. Following a prime-boost-boost schedule, an intranasal gel containing cGAMP and model antigen ovalbumin (OVA) led to the faster generation of serum IgG, IgG1, and IgG2c and significantly greater serum IgG1 levels on day 42 compared to soluble controls. Additionally, OVA-specific IgA was detected in nasal, vaginal, and fecal samples for all groups, except the vehicle control. When the COBRA HA was given intranasally in a prime-boost schedule, the mice receiving the gel containing the COBRA and cGAMP had significantly higher serum IgG and IgG2c at day 41 compared to all groups, and only this group had IgA levels above the background in vaginal, nasal, and fecal samples. Overall, this study indicates the utility of an intranasal gel for the delivery of COBRAs for the generation of serum and mucosal humoral responses.

Mucosal immune responses to infection and vaccination in the respiratory tract

“…Un-adjuvanted HA/GP nanoparticles induced innate immunity at comparable levels to CpG in mice and conferred protection against homo- and heterosubtypic influenza infection in mice ( Dong et al., 2021 ). In another recent study investigating improved IN vaccine strategies, Varma and colleagues designed and tested a hydrogel laden with cGAMP adjuvant and a broadly active HA antigen developed using the computationally optimized broadly reactive antigen (COBRA) approach ( Varma et al., 2022 ). The hydrogel was designed to increase the mucoadhesion and retention (>6 days) of the cGAMP adjuvant and, upon IN vaccination in a prime-boost schedule, resulted in significantly higher IgG and IgA levels when compared to more traditional methods ( Varma et al., 2022 ).…”

“…In another recent study investigating improved IN vaccine strategies, Varma and colleagues designed and tested a hydrogel laden with cGAMP adjuvant and a broadly active HA antigen developed using the computationally optimized broadly reactive antigen (COBRA) approach ( Varma et al., 2022 ). The hydrogel was designed to increase the mucoadhesion and retention (>6 days) of the cGAMP adjuvant and, upon IN vaccination in a prime-boost schedule, resulted in significantly higher IgG and IgA levels when compared to more traditional methods ( Varma et al., 2022 ). Due to the success of the LNP-based mRNA vaccines, ongoing studies into aerosolized LNP-based IN vaccines are also being conducted ( Zhang et al., 2020 ).…”

Hydrogels for Mucosal Drug Delivery

“…Antigens were loaded into the gel by mixing with gel precursor solutions. PEI-Ox-DEX hydrogel has shown prolonged mucoadhesion and nasal retention, leading to robust mucosal immune responses . A similar study was conducted to evaluate the effect of chitosan-hydrogel vaccine against influenza infection in mice.…”

“…PEI-Ox-DEX hydrogel has shown prolonged mucoadhesion and nasal retention, leading to robust mucosal immune responses. 196 A similar study was conducted to evaluate the effect of chitosan-hydrogel vaccine against influenza infection in mice. Mice intranasally immunized with in situ gelling chitosan hydrogel loaded with influenza-specific antigens demonstrated robust mucosal immune responses and protection after challenge with influenza virus.…”

Peptide and protein alphavirus antigens for broad spectrum vaccine design

“…Thus, our goal is to design a single vaccine that would provide protection against all AV, and overcome species specificity. Vaccines based on synthetic peptides and proteins require no mammalian cell culture and can be formulated/adjuvanted for different delivery systems [28,29].…”