Comparison of adjuvants to optimize influenza neutralizing antibody responses. Issue 42 (30th September 2019)

• Record Type: Journal Article
• Authors: Rudicell, Rebecca S.; Garinot, Marie; Kanekiyo, Masaru; Kamp, Heather D.; Swanson, Kurt; Chou, Te-hui; Dai, Shujia; Bedel, Olivier; Simard, Daniel; Gillespie, Rebecca A.; Yang, Kanwen; Reardon, Michael; Avila, Luis Z.; Besev, Magnus; Dhal, Pradeep K.; Dharanipragada, Ram; Zheng, Lingyi; Duan, Xiaochu; Dinapoli, Joshua; Vogel, Thorsten U.; Kleanthous, Harry; Mascola, John R.; Graham, Barney S.; Haensler, Jean; Wei, Chih-Jen; Nabel, Gary J.
• Is Part Of: Vaccine. Volume 37:Issue 42(2019)
• Page Start: 6208
• Page End: 6220
• Publication Date: 2019-09-30
• Subjects: Influenza vaccine -- Nanoparticles -- Adjuvants -- TLR agonists -- STING agonists -- AF03; HA-NP hemagglutinin on a ferritin nanoparticle -- TLR toll-like receptor -- STING stimulator of interferon genes -- IIV inactivated influenza virus -- LAIV live-attenuated influenza virus -- HA hemagglutinin -- NA neuraminidase -- PAMP pathogen-associated molecular patterns -- HAI hemagglutination inhibition -- MN microneutralization -- TEV tobacco etch virus -- SEC size exclusion chromatography -- DLS dynamic light scattering -- ELISA enzyme-linked immunosorbent assay -- SDS-PAGE sodium dodecyl sulfate polyacrylamide gel electrophoresis -- MPLA monophosphoryl Lipid A -- SAS Sigma Adjuvant System -- GLA glucipyranosyl lipid adjuvant -- PBS phosphate-buffered saline -- HRP horseradish peroxidase -- TMB 3, 3′, 5, 5′-tetramethylbenzidine -- TMPRSS2 transmembrane serine protease 2 -- RDE Receptor-Destroying Enzyme -- DBCO dibenzocyclooctyne -- PEG polyethylene glycol -- TOF-MS time of flight mass spectrometry -- LC-MS liquid chromatography mass spectrometry -- MPA mobile phase A -- MPB mobile phase B -- ANOVA analysis of variance -- cGAMP cyclic guanosine monophosphate-adenosine monophosphate -- NC99 New Caledonia 1999 -- NHP non-human primates -- LPS lipopolysaccharide -- HBV hepatitis B virus -- HPV human papilloma virus -- VZV varicella zoster virus -- DC pDC plasmacytoid dendritic cells -- CTL cytotoxic T lymphocyte -- RSV respiratory syncytial virus -- HIV human immunodeficiency virus; Vaccines -- Periodicals; 615.372
• DOI: 10.1016/j.vaccine.2019.08.030
• Languages: English
• ISSNs: 0264-410X

Abstract

Abstract: Seasonal influenza vaccines represent a positive intervention to limit the spread of the virus and protect public health. Yet continual influenza evolution and its ability to evade immunity pose a constant threat. For these reasons, vaccines with improved potency and breadth of protection remain an important need. We previously developed a next-generation influenza vaccine that displays the trimeric influenza hemagglutinin (HA) on a ferritin nanoparticle (NP) to optimize its presentation. Similar to other vaccines, HA-nanoparticle vaccine efficacy is increased by the inclusion of adjuvants during immunization. To identify the optimal adjuvants to enhance influenza immunity, we systematically analyzed TLR agonists for their ability to elicit immune responses. HA-NPs were compatible with nearly all adjuvants tested, including TLR2, TLR4, TLR7/8, and TLR9 agonists, squalene oil-in-water mixtures, and STING agonists. In addition, we chemically conjugated TLR7/8 and TLR9 ligands directly to the HA-ferritin nanoparticle. These TLR agonist-conjugated nanoparticles induced stronger antibody responses than nanoparticles alone, which allowed the use of a 5000-fold-lower dose of adjuvant than traditional admixtures. One candidate, the oil-in-water adjuvant AF03, was also tested in non-human primates and showed strong induction of neutralizing responses against both matched and heterologous H1N1 viruses. These data suggest that AF03, along with certain TLR agonists, enhance strong neutralizing antibody responses following influenza vaccination and may improve the breadth, potency, and ultimately vaccine protection in humans.