The influence of conjugation variables on the design and immunogenicity of a glycoconjugate vaccine against Salmonella Typhi

Abstract

In recent years there have been major efforts to develop glycoconjugate vaccines based on the Vi polysaccharide that will protect against Salmonella enterica Typhi infections, particularly typhoid fever, which remains a major public health concern in low-income countries. The design of glycoconjugate vaccines influences the immune responses they elicit. Here we systematically test the response in mice to Vi glycoconjugates that differ in Vi chain length (full-length and fragmented), carrier protein, conjugation chemistry, saccharide to protein ratio and size. We show that the length of Vi chains, but not the ultimate size of the conjugate, has an impact on the anti-Vi IgG immune response induced. Full-length Vi conjugates, independent of the carrier protein, induce peak IgG responses rapidly after just one immunization, and secondary immunization does not enhance the magnitude of these responses. Fragmented Vi linked to CRM197 and diphtheria toxoid, but not to tetanus toxoid, gives lower anti-Vi antibody responses after the first immunization than full-length Vi conjugates, but antibody titres are similar to those induced by full-length Vi conjugates following a second dose. The chemistry to conjugate Vi to the carrier protein, the linker used, and the saccharide to protein ratio do not significantly alter the response. We conclude that Vi length and carrier protein are the variables that influence the anti-Vi IgG response to immunization the most, while other parameters are of lesser importance.

Structural and immunological characterization of E. coli derived recombinant CRM197 protein used as carrier in conjugate vaccines

“…The Anti-Vi IgG elicited by Vi-rCRM 197 conjugate vaccine was more than four-fold higher than the response generated by unconjugated Vi which is one of the benchmark for a protective typhoid conjugate vaccine [ 41 ]. The comparative immunogenicity of Vi polysaccharide conjugated to other carrier protein like tetanus toxoid (TT), diphtheria toxoid (DT) and C7 CRM 197 is already published [ 44 ]. The immunogenicity of Vi-rCRM 197 showed the comparable result in terms of overall fold change in Anti-Vi IgG over Vi and booster impact.…”

Potential targets for next generation antimicrobial glycoconjugate vaccines

“…Hydrogen peroxide has been used also for depolymerization of Salmonella Typhi (Vi CPS) (Arcuri et al. 2017 ).…”

Glycoconjugate vaccines: some observations on carrier and production methods

“…enterica serovar typhi, the Vi-polysaccharide of different lengths were assessed as an antigen conjugated to a number of different carriers. Short chain Vi polysaccharide was less able to develop a robust immune response than long chain, but only when conjugated to DT or CRM197, and only on primary infection (Arcuri et al, 2017). Quantification of free Vi polysaccharide has also been used to assess the stability of conjugates (Giannelli et al, 2017).…”