Wild-type and single-O-antigen repeat outer-membrane vesicles induce equivalent protection against homologous and heterologous Salmonella challenge

Alshayea, A. I.; Jossi, S.; Marcial-Juarez, E.; Perez-Toledo, M.; Persaud, R.; Schager, A. E.; Larsen, D. N.; Gutishvili, G.; Pillaye, J.; Escobar-Riquelme, F.; Aksu, K.; Bryant, J. A.; Horsnell, W. G.; Banzhaf, M.; Kaczmarek, J. Z.; Hojrup, P.; C. Gumbart, J.; Henderson, I. R.; Bavro, V. N.; Lopez-Macias, C.; Cunningham, A. F.

doi:10.1101/2024.07.03.601871

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bioRxiv · 10.1101/2024.07.03.601871

Wild-type and single-O-antigen repeat outer-membrane vesicles induce equivalent protection against homologous and heterologous Salmonella challenge

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Abstract

Lipopolysaccharide O-antigen is an immunodominant target of protective antibodies. Variation in O-antigen structures limits antibody-mediated cross-protection between closely-related pathogens including Salmonella Typhimurium (STm) and S. Enteritidis (SEn). Bacterial outer membrane vesicles (OMV) are vaccine platforms presenting surface antigens in their natural conformations. To assess how O-antigen lengths impact antibody responses and control of homologous or heterologous infection, mice were immunized with STm-OMV containing wild-type O-antigen unit repeats (wt-OMV), [≤]1 O-antigen unit (wzy-OMV), or no O-antigen units (wbaP-OMV) respectively and challenged with either STm or SEn. Unexpectedly, anti-STm LPS IgG and protection to STm were comparable after immunization with either wt-OMV or wzy-OMV. Anti-porin responses were elevated after immunization with wzy-OMV and wbaP-OMV. A single immunization with any OMV induced minimal cross-protection against SEn, except in blood. In contrast, boosting with O-antigen-expressing OMV enhanced control of SEn infections by >10-fold. These results suggest that i) Antibody to single or variable-length O-antigen units are comparably protective against Salmonella; ii) Antigens other than immunodominant O-antigens may be targets of cross-reactive antibodies that moderate bacterial burdens; iii) Boosting can enhance the level of cross-protection against related Salmonella serovars and iv) High tissue burdens of Salmonella can be present in the absence of detectable bacteraemia.

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Alshayea, A. I., Jossi, S., Marcial-Juarez, E., Perez-Toledo, M., Persaud, R., Schager, A. E., Larsen, D. N., Gutishvili, G., Pillaye, J., Escobar-Riquelme, F., Aksu, K., Bryant, J. A., Horsnell, W. G., Banzhaf, M., Kaczmarek, J. Z., Hojrup, P., C. Gumbart, J., Henderson, I. R., Bavro, V. N., Lopez-Macias, C., Cunningham, A. F.. 2024-07-05. Wild-type and single-O-antigen repeat outer-membrane vesicles induce equivalent protection against homologous and heterologous Salmonella challenge. https://doi.org/10.1101/2024.07.03.601871

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