A totally synthetic lipopeptide-based self-adjuvanting vaccine induces neutralizing antibodies against heat-stable enterotoxin from enterotoxigenic Escherichia coli.
ST-based lipopeptide vaccine candidates were constructed in which ST was chemically synthesized and folded into the correct conformation prior to ligation to a module containing a T-helper cell epitope (T(H)) and the Toll-like receptor 2 (TLR2) agonist, S-[2,3-bis(palmitoyloxy)propyl]cysteine (P2C). Two different chemistries, thioether-based and oxime-based, were then used to ligate ST to the lipidated T(H) epitope. The enterotoxic activity of synthetic ST and the ST-based lipopeptide vaccines was determined in mice followed by an evaluation of immunological efficacy. The importance of the fine detail in chemical composition used in vaccine design was demonstrated by the findings that (i) the oxime-based vaccine exhibited little or no toxicity but the thioether-based vaccine, exhibited residual toxicity in suckling mice, (ii) although each of the synthetic vaccines generated specific anti-ST antibodies, it was the low titer antibodies induced by the oxime-based vaccine that demonstrated better neutralizing activity suggesting that the chemical linkage also affects the specificity of antibodies, (iii) the geometric arrangement of ST within a vaccine can profoundly affect the specificity and biological function of the antibodies that are elicited, and (iv) the lipopeptide-based ST vaccine candidate assembled using oxime chemistry induced a better neutralizing antibody response to ST when administered by the mucosal (intranasal) route.
Department of Microbiology & Immunology, The University of Melbourne, Parkville 3010, Victoria, Australia.
Weiguang
W
Zeng
Kristy
K
Azzopardi
Dianna
D
Hocking
Chinn Yi
CY
Wong
Gorjana
G
Robevska
Marija
M
Tauschek
Roy M
RM
Robins-Browne
David C
DC
Jackson
D000276:Adjuvants, Immunologic / Q000737:chemistry*; D000281:Administration, Intranasal; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D057134:Antibodies, Neutralizing / Q000097:blood; D000918:Antibody Specificity; D001427:Bacterial Toxins / Q000138:chemical synthesis / Q000276:immunology*; D054307:Enterotoxigenic Escherichia coli / Q000276:immunology; D004768:Enterotoxins / Q000138:chemical synthesis / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology; D029968:Escherichia coli Proteins; D022361:Escherichia coli Vaccines / Q000138:chemical synthesis / Q000276:immunology*; D005260:Female; D055666:Lipopeptides / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests; D010091:Oximes / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000819:agonists; D014614:Vaccines, Synthetic / Q000276:immunology
D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D057134:Antibodies, Neutralizing; D001427:Bacterial Toxins; D004768:Enterotoxins; D018984:Epitopes, T-Lymphocyte; D029968:Escherichia coli Proteins; D022361:Escherichia coli Vaccines; D055666:Lipopeptides; D010091:Oximes; C552442:S-(2,3-bis(palmitoyloxy)propyl)cysteine; D051195:Toll-Like Receptor 2; D014614:Vaccines, Synthetic; C034151:heat stable toxin (E coli)