Journal Article

Comparison of adjuvants to optimize influenza neutralizing antibody responses

Dhal, Pradeep K., Avila, Luis Z., Duan, Xiaochu, Garinot, Marie, Besev, Magnus, Bedel, Olivier, Swanson, Kurt, Dharanipragada, Ram, Haensler, Jean, Graham, Barney S., Zheng, Lingyi, Gillespie, Rebecca A., Simard, Daniel, Kanekiyo, Masaru, Rudicell, Rebecca S., Chou, Te-hui, Vogel, Thorsten U., Mascola, John R., Nabel, Gary J., Dai, Shujia, Wei, Chih-Jen, Kamp, Heather D., Reardon, Michael, Kleanthous, Harry, Dinapoli, Joshua, Yang, Kanwen

2019

Overview

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.

• Publisher: Elsevier Ltd,Elsevier Limited
• Subject: Adjuvants / Adjuvants, Immunologic - chemistry / Adjuvants, Immunologic - pharmacology / Admixtures / AF03 / Agonists / Allergy and Immunology / Aluminum / Animals / Antibodies / Antibodies, Neutralizing - immunology / antibody formation / Antigens / Chromatography / Cytokines / evolution / Female / Ferritin / Genes / HEK293 Cells / Hemagglutination Inhibition Tests / Hemagglutinins / Humans / Immune response / Immune system / Immunity / Immunization / Immunoglobulins / Influenza / Influenza A virus / influenza vaccination / Influenza vaccine / influenza vaccines / Influenza Vaccines - immunology / ligands / Lipids / Macaca mulatta / Manufacturers / Mice, Inbred BALB C / Mutation / Nanoparticles / neutralization / Neutralizing / neutralizing antibodies / Optimization / Organic chemistry / Pandemics / Plasmids / Primates / Proteins / Public health / Squalene / STING agonists / TLR agonists / TLR2 protein / TLR4 protein / TLR7 protein / TLR9 protein / Toll-like receptor 2 / Toll-like receptor 4 / Toll-like receptor 7 / Toll-like receptor 9 / Toll-like receptors / Toll-Like Receptors - agonists / Vaccine efficacy / Vaccines / Viruses