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Homogeneous Glycoconjugate Produced by Combined Unnatural Amino Acid Incorporation and Click-Chemistry for Vaccine Purposes
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Toll-like receptor 2 dependent immunogenicity of glycoconjugate vaccines containing chemically derived zwitterionic

Simona Gallorini1, Francesco Berti, Giuseppe Mancuso

  • 1Novartis Vaccines Research Center, Via Fiorentina 1, 53100 Siena, Italy.

Proceedings of the National Academy of Sciences of the United States of America
|October 7, 2009
PubMed

Insights

Zwitterionic polysaccharides (ZPS) create potent vaccines by activating antigen-presenting cells (APCs) via toll-like receptor 2 (TLR2). These ZPS-glycoconjugates enhance immune responses and protection against Group B Streptococcus (GBS) infection.

Area of Science:

  • Vaccinology
  • Immunology
  • Biochemistry

Background:

  • Group B Streptococcus (GBS) poses a significant threat to neonates, necessitating effective vaccine development.
  • Current vaccine strategies often require separate antigen and adjuvant components.
  • Zwitterionic polysaccharides (ZPS) derived from GBS exhibit intrinsic immunomodulatory properties.

Purpose of the Study:

  • To develop a novel vaccine platform combining antigen and adjuvant functions in a single molecule.
  • To investigate the immunogenicity and protective efficacy of ZPS-based glycoconjugates.
  • To elucidate the role of toll-like receptor 2 (TLR2) in ZPS-mediated immune activation.

Main Methods:

  • Chemical modification of GBS anionic polysaccharides to create zwitterionic polysaccharides (ZPS).
  • Conjugation of ZPS with carrier proteins to form ZPS-glycoconjugates.
  • Assessment of immune responses (T-cell and antibody titers) and protection in mouse models, including TLR2 knockout mice.
  • Evaluation of ZPS as standalone adjuvants with unrelated antigens.

Main Results:

  • ZPS-glycoconjugates elicited significantly higher T-cell and antibody responses compared to native polysaccharide-glycoconjugates.
  • ZPS-conjugates demonstrated enhanced activation of dendritic cells (DCs), correlating with increased immunogenicity.
  • Vaccination with ZPS-conjugates provided superior protection against lethal GBS challenge in mothers and neonates.
  • The immunomodulatory and protective effects of ZPS were dependent on TLR2 signaling.
  • ZPS co-administered with tetanus toxoid boosted specific antibody titers.

Conclusions:

  • Glycoconjugates incorporating ZPS represent potent vaccine candidates with inherent adjuvant properties.
  • ZPS function by targeting antigens to TLR2-expressing APCs, thereby enhancing adaptive immunity.
  • Rational chemical design of ZPS offers a versatile strategy for developing advanced polysaccharide-based vaccines and adjuvants.

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