title: Co-delivery of GPI-anchored CCL28 and influenza HA in chimeric virus-like particles induces cross-protective immunity against H3N2 viruses.
abstract: Influenza infection typically initiates at respiratory mucosal surfaces. Induction of immune responses at the sites where pathogens initiate replication is crucial for the prevention of infection. We studied the adjuvanticity of GPI-anchored CCL28 co-incorporated with influenza HA-antigens in chimeric virus-like particles (cVLPs), in boosting strong protective immune responses through an intranasal (i.n.) route in mice. We compared the immune responses to that from influenza VLPs without CCL28, or physically mixed with soluble CCL28 at systemic and various mucosal compartments. The cVLPs containing GPI-CCL28 showed in-vitro chemotactic activity towards spleen and lung cells expressing CCR3/CCR10 chemokine receptors. The cVLPs induced antigen specific endpoint titers and avidity indices of IgG in sera and IgA in tracheal, lung, and intestinal secretions, significantly higher (4-6 fold) than other formulations. Significantly higher (3-5 fold) hemagglutination inhibition titers and high serum neutralization against H3N2 viruses were also detected with CCL28-containing VLPs compared to other groups. The CCL28-containing VLPs showed complete and 80% protection, when vaccinated animals were challenged with A/Aichi/2/1968/H3N2 (homologous) and A/Philippines/2/1982/H3N2 (heterologous) viruses, respectively. Thus, GPI-anchored CCL28 in influenza VLPs act as a strong immunostimulator at both systemic and mucosal sites, boosting significant cross-protection in animals against heterologous viruses across a large distance.
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, 1518 Clifton Road, Atlanta, GA 30322, USA; Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, 100 Piedmont Ave SE, Atlanta, GA 30303, USA.
authors.forename: Teena
authors.initials: T
authors.lastname: Mohan
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, 1518 Clifton Road, Atlanta, GA 30322, USA.
authors.forename: Jongrok
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, 1518 Clifton Road, Atlanta, GA 30322, USA; Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, 100 Piedmont Ave SE, Atlanta, GA 30303, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Berman
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, 1518 Clifton Road, Atlanta, GA 30322, USA.
authors.forename: Shelly
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, 1518 Clifton Road, Atlanta, GA 30322, USA.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Compans
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, 1518 Clifton Road, Atlanta, GA 30322, USA; Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, 100 Piedmont Ave SE, Atlanta, GA 30303, USA. Electronic address: bwang3@emory.edu.
authors.forename: Bao-Zhong
authors.initials: BZ
authors.lastname: Wang
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D000956:Antigens, Viral / Q000008:administration & dosage*; D002460:Cell Line; D019742:Chemokines, CC / Q000008:administration & dosage*; D004285:Dogs; D005260:Female; D058851:GPI-Linked Proteins / Q000008:administration & dosage*; D006389:Hemagglutinins, Viral / Q000008:administration & dosage*; D007070:Immunoglobulin A / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology*; D061985:Madin Darby Canine Kidney Cells; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000517:prevention & control; D018411:Spodoptera; D058425:Vaccines, Virus-Like Particle / Q000008:administration & dosage*; D014763:Viral Matrix Proteins / Q000008:administration & dosage*
chemical_list: D000914:Antibodies, Viral; D000956:Antigens, Viral; C511142:Ccl28 protein, mouse; D019742:Chemokines, CC; D058851:GPI-Linked Proteins; D006389:Hemagglutinins, Viral; D007070:Immunoglobulin A; D007074:Immunoglobulin G; C488936:M1 protein, Influenza A virus; D058425:Vaccines, Virus-Like Particle; D014763:Viral Matrix Proteins
keywords: Antibody avidity; Hemagglutination; Influenza; Mucosal adjuvant; Neutralization; Virus-like particles (VLPs)