Typhoid fever remains a major public health concern in low-income countries affecting millions of people each year. Research on effective vaccines against Salmonella Typhi has been directed toward the development of glycoconjugates. Several conjugation parameters affect the magnitude, quality and persistence of immune response. A systematic investigation of the effect of each variable on immunogenicity was conducted, synthesizing and testing in mice a panel of Vi-based conjugates differing for saccharide size, carrier protein, saccharide to protein ration and conjugation chemistry. Saccharide size and carrier protein were the parameters mainly impacting immunogenicity. Differently from full-length Vi (165 kDa) conjugates, fragmented Vi (< 82 kDa) –CRM₁₉₇ showed anamnestic response and induced minimal antibody responses in T-cell knockout mice. Unexpectedly, fragmented Vi conjugates induced lower persistent antibody levels compared to full-length Vi conjugates. Fragmented Vi conjugates offer benefits in terms of manufacture, and random chemistry is preferable because of higher conjugation yields obtained compared to selective chemistry. In view of Vi conjugate vaccine introduction into vaccination schedules, CRM₁₉₇ may have advantages as an optimal carrier protein to avoid any negative effect of pre-existing anti-carrier immunity. Therefore, this systematic investigation of conjugation parameters represents a model for rational design of glycoconjugates.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:723389 |
| Date | January 2017 |
| Creators | Arcuri, Melissa |
| Publisher | University of Birmingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://etheses.bham.ac.uk//id/eprint/7736/ |
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