A Novel Synthetic Dual Agonistic Liposomal TLR4/7 Adjuvant Promotes Broad Immune Responses in an Influenza Vaccine With Minimal Reactogenicity

Abstract

Sato-Kaneko et al.Protective Liposomal TLR4/7 Vaccine titers and cytokine levels. The combination adjuvant induced a greater diversity in B cell clonotypes of immunoglobulin heavy chain (IGH) genes in the draining lymph nodes and antibodies against a broad spectrum of HA epitopes encompassing HA head and stalk domains and with cross-reactivity against different subtypes of HA and NA. This novel combination liposomal adjuvant contributes to a more broadly protective vaccine while demonstrating an attractive safety profile.

Administration of Multivalent Influenza Virus Recombinant Hemagglutinin Vaccine in Combination-Adjuvant Elicits Broad Reactivity Beyond the Vaccine Components

“…Other than those developed especially for the elderly (85), adjuvants are not routinely used for seasonal influenza vaccines, and are consequently weakly immunogenic and typically show very limited cross-reactivity. Adjuvants, notably TLR-agonists, both increase immunogenicity and breadth of response to inactivated seasonal vaccines (86,87). Emulsions such as MF59 ® and AS03 have also been reported to broaden the response of seasonal vaccines (27,(88)(89)(90).…”

Subunit Vaccines Using TLR Triagonist Combination Adjuvants Provide Protection Against Coxiella burnetii While Minimizing Reactogenic Responses

“…Local inflammation may be the result of innate responses to adjuvants within the candidate vaccine. However, similar adjuvants and TLR agonists have been evaluated in vaccine trials against influenza, human immunodeficiency virus, and tuberculosis and did not result in the prolonged local inflammation shown in our experiments (50)(51)(52). It should be noted that these publications evaluated reactogenicity using unsensitized mice or in human trials where prior exposure to the target antigen is unlikely.…”

Small Molecule Potentiator of Adjuvant Activity Enhancing Survival to Influenza Viral Challenge

“…BALB/c female mice (n = 5/group) were intraperitoneally injected with 50 μ;g (110 nmol)/g mouse or 100 μg (220 nmol)/g mouse and body weights and behaviors were monitored for 7 days. Compound 2D216 was incorporated into a liposome formulation containing 2D216 , 1,2-dioleoyl-3-phosphatidylcholine (DOPC, Avanti polar Lipids, St. Louis, MO, United States) and cholesterol (C8667, Sigma) with a mol % ratio of 10:80:10, respectively, using the thin-film rehydration method in our laboratory to achieve high concentrations ( 17 ).…”

“…The influenza challenge test was performed at the Institute for Antiviral Research of Utah State University as previously described ( 17 ). Briefly, BALB/c mice (n = 10/group) were intramuscularly immunized with 2D216 (100 nmol/mouse) with or without MPLA (1 μg/mouse) as an adjuvant and inactivated influenza A virus [IIAV, A/California/07/2009, (H1N1)pdm09] (0.3 μg/mouse) as an antigen in a total volume of 50 µL on day 0 and intranasally challenged with approximately 1×10 5 (3×LD 50 ) cell culture infectious doses (CCID 50 ) of homologous influenza A virus, (H1N1)pdm09 in 50 µL on day 21.…”

“…Body weights and survival of mice were monitored. Virus neutralization and hemagglutination-inhibition (HAI) titers were determined by Antiviral Research of Utah State University as previously described ( 17 ).…”