Self-assembling influenza nanoparticle vaccines drive extended germinal center activity and memory B cell maturation
Hannah G. Kelly, Hyon-Xhi Tan, Jennifer A. Juno, Robyn Esterbauer, Yi Ju, Wenbo Jiang, Verena C. Wimmer, Brigette C. Duckworth, Joanna R. Groom, Frank Caruso, Masaru Kanekiyo, Stephen J. Kent, Adam K. Wheatley
Hannah G. Kelly, Hyon-Xhi Tan, Jennifer A. Juno, Robyn Esterbauer, Yi Ju, Wenbo Jiang, Verena C. Wimmer, Brigette C. Duckworth, Joanna R. Groom, Frank Caruso, Masaru Kanekiyo, Stephen J. Kent, Adam K. Wheatley
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Research Article Immunology Vaccines

Self-assembling influenza nanoparticle vaccines drive extended germinal center activity and memory B cell maturation

Abstract

Protein-based, self-assembling nanoparticles elicit superior immunity compared with soluble protein vaccines, but the immune mechanisms underpinning this effect remain poorly defined. Here, we investigated the immunogenicity of a prototypic ferritin-based nanoparticle displaying influenza hemagglutinin (HA) in mice and macaques. Vaccination of mice with HA-ferritin nanoparticles elicited higher serum antibody titers and greater protection against experimental influenza challenge compared with soluble HA protein. Germinal centers in the draining lymph nodes were expanded and persistent following HA-ferritin vaccination, with greater deposition of antigen that colocalized with follicular dendritic cells. Our findings suggest that a highly ordered and repetitive antigen array may directly drive germinal centers through a B cell–intrinsic mechanism that does not rely on ferritin-specific T follicular helper cells. In contrast to mice, enhanced immunogenicity of HA-ferritin was not observed in pigtail macaques, where antibody titers and lymph node immunity were comparable to soluble vaccination. An improved understanding of factors that drive nanoparticle vaccine immunogenicity in small and large animal models will facilitate the clinical development of nanoparticle vaccines for broad and durable protection against diverse pathogens.

Authors

Hannah G. Kelly, Hyon-Xhi Tan, Jennifer A. Juno, Robyn Esterbauer, Yi Ju, Wenbo Jiang, Verena C. Wimmer, Brigette C. Duckworth, Joanna R. Groom, Frank Caruso, Masaru Kanekiyo, Stephen J. Kent, Adam K. Wheatley

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Figure 5

Superior immunity of HA-ferritin is not driven by ferritin-specific TFH cells.

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Superior immunity of HA-ferritin is not driven by ferritin-specific TFH ...
(A) C57BL/6 (n = 10 mice per group) mice were immunized with HA-ferritin (5 or 0.5 μg) or a molar equivalent of soluble HA (3.8 or 0.38 μg), or 1.2 μg ferritin alone, adjuvanted with AddaVax. Fourteen days following vaccination, draining iliac (left) and inguinal (right) LNs were harvested. The proportion of TFH cells (identified as CXCR5+PD-1+) within the CD4+ T cell population was determined by flow cytometry. Data shown are combined from 2 independent experiments. Fourteen days after mice were vaccinated as in A, inguinal and iliac LNs were harvested and pooled for each mouse (n = 5 mice per group). Lymph node suspensions were cultured for 18 hours with pools of overlapping peptides spanning HA or ferritin proteins (final concentration of each peptide, 2 μg/mL) or DMSO alone. Antigen specificity was determined by the proportion of TFH cells positive for ligand CD154 (B) or activation markers (CD25+OX40+) (C) following subtraction of DMSO background. Data represent mean ± SD. *P < 0.05, determined by a Mann-Whitney U test.