title: A virus-like particle vaccination strategy expands its tolerance to H3N2 antigenic drift by enhancing neutralizing antibodies against hemagglutinin stalk.
abstract: Seasonal influenza viruses impact public health annually due to their continual evolution. However, the current inactivated seasonal vaccines provide poor protection against antigenically drifted viruses and require periodical reformulation through hit-and-miss predictions about which strains will circulate during the next season. To reduce the impact caused by vaccine mismatch, we investigated the drift-tolerance of virus-like particles (VLP) as an improved vaccine candidate. The cross-protective humoral immunity elicited by the H3N2-VLP vaccine constructed for the 2011-2012 season was examined against viruses isolated from 2010 to 2015 in Taiwan evolving chronologically through clades 1, 4, 5, 3B and 3C, as well as viruses that were circulating globally in 2005, 2007 and 2009. Mouse immunization results demonstrated that H3N2-VLP vaccine elicited superior immunological breadth in comparison with the cognate conventional whole-inactivated virus (WIV) vaccine. Titers of neutralizing antibodies against heterologous strains representing each epidemic period in the VLP group were significantly higher than in the WIV group, indicating the antibody repertoire induced by the H3N2-VLPs was insensitive to viral antigenic drift over a span of at least 10 years. Noticeably, H3N2-VLP elicited higher levels of anti-stalk antibodies than H3N2-WIV, which offset the ineffectiveness caused by antigenic drift. This advantageous effect was attributed to the uncleaved precursor of their HA proteins. These results suggest a mechanism through which VLP-induced humoral immunity may better tolerate the evolutionary dynamics of influenza viruses and point to the possible use of a VLP vaccine as a method by which the requirement for annual updates of seasonal influenza vaccines may be diminished.
authors.affiliation: Institute of Biotechnology, National Taiwan University, Taipei, Taiwan; Center for Research, Diagnostics and Vaccine Development, Centers for Disease Control, Taipei, Taiwan; Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Ji-Rong
authors.initials: JR
authors.lastname: Yang
authors.affiliation: Center for Research, Diagnostics and Vaccine Development, Centers for Disease Control, Taipei, Taiwan.
authors.forename: Chieh-Yu
authors.initials: CY
authors.lastname: Cheng
authors.affiliation: Center for Research, Diagnostics and Vaccine Development, Centers for Disease Control, Taipei, Taiwan.
authors.forename: Chih-Yuan
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Center for Research, Diagnostics and Vaccine Development, Centers for Disease Control, Taipei, Taiwan.
authors.forename: Chao-Hua
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Center for Research, Diagnostics and Vaccine Development, Centers for Disease Control, Taipei, Taiwan.
authors.forename: Chuan-Yi
authors.initials: CY
authors.lastname: Kuo
authors.affiliation: Center for Research, Diagnostics and Vaccine Development, Centers for Disease Control, Taipei, Taiwan.
authors.forename: Hsiang-Yi
authors.initials: HY
authors.lastname: Huang
authors.affiliation: Center for Research, Diagnostics and Vaccine Development, Centers for Disease Control, Taipei, Taiwan.
authors.forename: Fu-Ting
authors.initials: FT
authors.lastname: Wu
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Yang
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Chia-Ying
authors.initials: CY
authors.lastname: Wu
authors.affiliation: Center for Research, Diagnostics and Vaccine Development, Centers for Disease Control, Taipei, Taiwan. Electronic address: mtliu@cdc.gov.tw.
authors.forename: Ming-Tsan
authors.initials: MT
authors.lastname: Liu
authors.affiliation: Institute of Biotechnology, National Taiwan University, Taipei, Taiwan; Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan. Electronic address: pwhsiao@gate.sinica.edu.tw.
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Hsiao
mesh_terms: D057134:Antibodies, Neutralizing / Q000097:blood*; D000914:Antibodies, Viral; D000940:Antigenic Variation / Q000235:genetics*; D056738:Cross Protection; D006385:Hemagglutination Inhibition Tests; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D053122:Influenza A Virus, H3N2 Subtype / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D007252:Influenza Vaccines / Q000276:immunology; D007251:Influenza, Human; D013624:Taiwan; D014611:Vaccination; D015164:Vaccines, Inactivated / Q000276:immunology; D058425:Vaccines, Virus-Like Particle / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; D015164:Vaccines, Inactivated; D058425:Vaccines, Virus-Like Particle
keywords: Antigenic drift; Cross-protective antibody; Influenza A(H3N2) virus; Virus-like particle vaccine