Sublingual immunization with adenovirus F protein-based vaccines stimulates protective immunity against botulinum neurotoxin A intoxication.
Sublingual (s.l.) vaccination is an efficient way to induce elevated levels of systemic and mucosal immune responses. To mediate mucosal uptake, ovalbumin (OVA) was genetically fused to adenovirus 2 fiber protein (OVA-Ad2F) to assess whether s.l. immunization was as effective as an alternative route of vaccination. Ad2F-delivered vaccines were efficiently taken up by dendritic cells and migrated mostly to submaxillary gland lymph nodes, which could readily stimulate OVA-specific CD4(+) T cells. OVA-Ad2F + cholera toxin (CT)-immunized mice elicited significantly higher OVA-specific serum IgG, IgA and mucosal IgA antibodies among the tested immunization groups. These were supported by elevated OVA-specific IgG and IgA antibody-forming cells. A mixed T(h)-cell response was induced as evident by the enhanced IL-4, IL-10, IFN-γ and TNF-α-specific cytokine-forming cells. To assess whether this approach can stimulate neutralizing antibodies, immunizations were performed with the protein encumbering the β-trefoil domain of C-terminus heavy chain (Hcβtre) from botulinum neurotoxin A (BoNT/A) as well as when fused to Ad2F. Hcβtre-Ad2F + CT-dosed mice showed the greatest serum IgG, IgA and mucosal IgA titers among the immunization groups. Hcβtre-Ad2F alone also induced elevated antibody production in contrast to Hcβtre alone. Plasma from Hcβtre + CT- and Hcβtre-Ad2F + CT-immunized groups neutralized BoNT/A and protected mice from BoNT/A intoxication. Most importantly, Hcβtre-Ad2F + CT-immunized mice were protected from BoNT/A intoxication relative to Hcβtre + CT-immunized mice, which only showed ∼60% protection. This study shows that s.l. immunization with Ad2F-based vaccines is effective in conferring protective immunity.
Department of Immunology and Infectious Diseases, Montana State University, Bozeman, MT 59717-3610, USA.
Sangmu
S
Jun
Beata
B
Clapp
Dagmara
D
Zlotkowska
Teri
T
Hoyt
Kathryn
K
Holderness
Massimo
M
Maddaloni
David W
DW
Pascual
D000286:Administration, Sublingual; D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis; D057134:Antibodies, Neutralizing / Q000096:biosynthesis; D000917:Antibody Formation; D019274:Botulinum Toxins, Type A / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000633:toxicity; D001906:Botulism / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D036022:Capsid Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D003014:Clostridium botulinum / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011993:Recombinant Fusion Proteins / Q000235:genetics; D012131:Respiratory Insufficiency / Q000209:etiology / Q000517:prevention & control; D014611:Vaccination
D000907:Antibodies, Bacterial; D057134:Antibodies, Neutralizing; D036022:Capsid Proteins; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins; C018315:hexon capsid protein, Adenovirus; D019274:Botulinum Toxins, Type A