Design of Three-Component Vaccines against Group A Streptococcal Infections: Importance of Spatial Arrangement of Vaccine Components

Immunological assessment of group A streptococcal (GAS) branched lipopeptides demonstrated the impact of spatial arrangement of vaccine components on both the quality and quantity of their immune responses. Each lipopeptide was composed of three components: a GAS B-cell epitope (J14), a universal CD...

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Veröffentlicht in:Journal of medicinal chemistry 2010-11, Vol.53 (22), p.8041-8046
Hauptverfasser: Abdel-Aal, Abu-Baker M, Zaman, Mehfuz, Fujita, Yoshio, Batzloff, Michael R, Good, Michael F, Toth, Istvan
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Sprache:eng
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Zusammenfassung:Immunological assessment of group A streptococcal (GAS) branched lipopeptides demonstrated the impact of spatial arrangement of vaccine components on both the quality and quantity of their immune responses. Each lipopeptide was composed of three components: a GAS B-cell epitope (J14), a universal CD4+ T-cell helper epitope (P25), and an immunostimulant lipid moiety that differs only in its spatial arrangement. The best systemic immune responses were demonstrated by a lipopeptide featuring the lipid moiety at the lipopeptide C-terminus. However, this candidate did not achieve protection against bacterial challenge. The best protection (100%) was shown by a lipopeptide featuring a C-terminal J14, conjugated through a lysine residue to P25 at the N-terminus, and a lipid moiety on the lysine side chain. The former candidate features α-helical conformation required to produce protective J14-specific antibodies. Our results highlight the importance of epitope orientation and lipid position in the design of three-component synthetic vaccines.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm1007787