Salmonella flagellins are potent adjuvants for intranasally administered whole inactivated influenza vaccine.
Bacterial flagellins are potent inducers of innate immune responses in the mouse lung because they bind to TLR5 expressed on the apical surfaces of airway epithelial cells. TLR engagement leads to the initiation of a signaling cascade that results in a pro-inflammatory response with subsequent up-regulation of several cytokines and leads to adaptive immune responses. We examined the ability of two soluble flagellins, a monomeric flagellin expressed in Escherichia coli and a highly purified polymeric flagellin directly isolated from Salmonella, to enhance the efficacy of influenza vaccines in mice. Here we demonstrate that both flagellins co-administered intranasally with inactivated A/PR/8/34 (PR8) virus induced robust increases of systemic influenza-specific IgA and IgG titers and resulted in a more comprehensive humoral response as indicated by the increase of IgG2a and IgG2b subclass responses. Groups immunized with the adjuvanted vaccines were fully protected against high dose lethal challenge by homologous virus whereas inactivated PR8 alone conferred only partial protection. Finally we show that shortly after immunization the adjuvanted vaccines induced a dramatic increase in pro-inflammatory cytokines in the lung, resulting in extensive lung infiltration by granulocytes and monocytes/macrophages. Our results reveal a promising perspective for the use of both soluble monomeric and polymeric flagellin as mucosal vaccine adjuvants to improve protection against influenza epidemics as well as a range of other infectious diseases.
Skountzou
Ioanna
I
Department of Microbiology and Immunology and Emory Vaccine Center, Emory University School of Medicine, 1510 Clifton Rd, Atlanta, GA 30322, USA.
Martin
Maria del Pilar
Mdel P
Wang
Baozhong
B
Ye
Ling
L
Koutsonanos
Dimitrios
D
Weldon
Will
W
Jacob
Joshy
J
Compans
Richard W
RW
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D002460:Cell Line; D004285:Dogs; D004926:Escherichia coli / Q000378:metabolism; D005260:Female; D005408:Flagellin / Q000008:administration & dosage / Q000276:immunology*; D056724:Immunity, Humoral; D007071:Immunoglobulin A, Secretory; D007074:Immunoglobulin G / Q000097:blood; D007252:Influenza Vaccines / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000517:prevention & control*; D012475:Salmonella / Q000276:immunology*; D015164:Vaccines, Inactivated / Q000276:immunology
D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D007071:Immunoglobulin A, Secretory; D007074:Immunoglobulin G; D007252:Influenza Vaccines; D015850:Interleukin-6; D015164:Vaccines, Inactivated; D005408:Flagellin; D007371:Interferon-gamma