Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Nov 12;12(11):1272.
doi: 10.3390/vaccines12111272.

Design of a Glycoconjugate Vaccine Against Salmonella Paratyphi A

Renzo Alfini  1 , Martina Carducci  1 , Luisa Massai  1 , Daniele De Simone  1 , Marco Mariti  2 , Omar Rossi  1 , Simona Rondini  1 , Francesca Micoli  1 , Carlo Giannelli  1
Affiliations

Design of a Glycoconjugate Vaccine Against Salmonella Paratyphi A

Renzo Alfini et al. Vaccines (Basel). .

Abstract

Background/objectives: Typhoid and paratyphoid fever together are responsible for millions of cases and thousands of deaths per year, most of which occur in children in South and Southeast Asia. While typhoid conjugate vaccines (TCVs) are licensed, no vaccines are currently available against S. Paratyphi A. Here we describe the design of a S. Paratyphi A conjugate.

Methods: The serovar-specific O-antigen (O:2) was linked to the CRM197 carrier protein (O:2-CRM197) and a panel of conjugates differing for structural characteristics were compared in mice and rabbits.

Results: We identified the O-antigen molecular size, polysaccharide to protein ratio, conjugate cross-linking, and O:2 O-acetylation level as critical quality attributes and identified optimal design for a more immunogenic vaccine.

Conclusions: This work guides the development of the O:2-CRM197 conjugate to be combined with TCV in a bivalent formulation against enteric fever.

Keywords: 1-cyano-4-dimethylaminopyridine tetrafluoroborate (CDAP); O-antigen (O:2); Salmonella Paratyphi A; acetylation; conjugate; critical quality attribute (CQA); immunogenicity; molecular size.

PubMed Disclaimer

Conflict of interest statement

GSK Vaccines Institute for Global Health Srl is an affiliate of GlaxoSmithKline Biologicals; R.A., M.C., L.M., D.D.S., M.M., O.R., S.R., F.M., and C.G. are employees of the GSK group of companies.

Figures

Figure 1
Figure 1
Chemical approach based on CDAP chemistry for the conjugation of O:2 to CRM197 carrier protein.
Figure 2
Figure 2
Summary graphs of anti-O:2 IgG geometric mean units (bars) and individual antibody levels (dots) are reported. (A) Impact on the immune response in mice of S. Paratyphi A O:2 size: O:2–CRM197 conjugates synthesized using O:2 with different sizes (16 kDa, 100 kDa, and 16 kDa + 100 kDa) and with a similar O:2/CRM197 w/w ratio were compared. (B) Impact of O:2/CRM197 w/w ratio: O:2–CRM197 conjugates synthesized from O:2 of a certain size but showing a different O:2/CRM197 w/w ratio were compared. (C) Impact of O:2 activation degree: O:2–CRM197 conjugates synthesized from O:2[16kDa+100kDa] with a different activation degree were compared.
Figure 3
Figure 3
(A) Impact of O-acetylation level on anti-O:2 IgG response elicited in mice by O:2–CRM197 conjugates. Five different levels of O-acetylation were compared for O:2 [16kDa+100kDa] and two different levels for O:2[16kDa]. Summary graphs of anti-O:2 IgG geometric mean units (bars with 95% CI) and individual antibody levels (dots) are reported. (B) Linear regression analysis for Log EU (Day 42) vs. OAc % with 95% CI.
Figure 4
Figure 4
Immune response induced in rabbits by O:2–CRM197 conjugates differing in O:2 size. (A) Summary graphs of anti-O:2 IgG geometric mean units (bars with 95% CI) and individual antibody levels (dots) are reported. (B) Summary graphs of SBA titers as geometric mean units (bars with 95% CI) and individual SBA titers (dots) are reported.
Figure 5
Figure 5
O-acetylation models obtained from the Šesták–Berggren truncated equation at different temperatures, with 95% prediction intervals for pH 6.5 and 7.4.
See this image and copyright information in PMC

References

    1. Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis. Lancet. 2022;399:629–655. doi: 10.1016/S0140-6736(21)02724-0. - DOI - PMC - PubMed
    1. Sallam M., Snygg J., Allam D., Kassem R. From Protection to Prevention: Redefining Vaccines in the Context of Antimicrobial Resistance. Cureus. 2024;16:e60551. doi: 10.7759/cureus.60551. - DOI - PMC - PubMed
    1. Hasso-Agopsowicz M., Sparrow E., Cameron A.M., Sati H., Srikantiah P., Gottlieb S., Bentsi-Enchill A., Le Doare K., Hamel M., Giersing B.K., et al. The role of vaccines in reducing antimicrobial resistance: A review of potential impact of vaccines on AMR and insights across 16 vaccines and pathogens. Vaccine. 2024;42:S1–S8. doi: 10.1016/j.vaccine.2024.06.017. - DOI - PubMed
    1. Zavaleta-Monestel E., Hasselmyr Hasselmyr S., García-Montero J., Arguedas-Chacón S., Rojas-Chinchilla C., Díaz-Madriz J.P. The Impact of Vaccination as a Strategy to Combat Bacterial Antimicrobial Resistance. Cureus. 2024;16:e65840. doi: 10.7759/cureus.65840. - DOI - PMC - PubMed
    1. Patel P.D., Liang Y., Meiring J.E., Chasweka N., Patel P., Misiri T., Mwakiseghile F., Wachepa R., Banda H.C., Shumba F., et al. Efficacy of typhoid conjugate vaccine: Final analysis of a 4-year, phase 3, randomised controlled trial in Malawian children. Lancet. 2024;403:459–468. doi: 10.1016/S0140-6736(23)02031-7. - DOI - PMC - PubMed

LinkOut - more resources