Vaccine-induced, but not natural immunity, against the Streptococcal Inhibitor of Complement protects against invasive disease

Abstract

Highly pathogenic emm1 Streptococcus pyogenes strains secrete the multidomain Streptococcal inhibitor of complement (SIC) that binds and inactivates components of the innate immune response. We aimed to determine if naturally occurring or vaccine-induced antibodies to SIC are protective against invasive S. pyogenes infection. Immunisation with full length SIC protected mice against systemic bacterial dissemination following intranasal or intramuscular infection with emm1 S. pyogenes. Vaccine-induced rabbit anti-SIC antibodies, but not naturally occurring human anti-SIC antibodies, enhanced bacterial clearance in an ex vivo whole blood assay. SIC vaccination of both mice and rabbits resulted in antibody recognition of all domains of SIC, whereas naturally occurring human anti-SIC antibodies recognised the proline-rich region of SIC only. We therefore propose a model whereby natural infection with S. pyogenes generates non-protective antibodies against the proline-rich region of SIC, while vaccination with full length SIC permits development of protective antibodies against all SIC domains.

Correlates of immunity to Group A Streptococcus: a pathway to vaccine development

“…This forms the basis of the classic "Lancefield" assay 18 , which measures the opsonophagocytic capacity of donor plasma antibodies as a marker of resistance to invasive infection. Subcutaneous [19][20][21] , intramuscular 22,23 and intranasal 24,25 vaccination with adjuvanted protein vaccines appear effective at preventing even lethal invasive infections in mouse models of infection. Furthermore, passive transfer of immunity using antisera and pooled human intravenous immunoglobulin (IVIg) have all successfully induced immunity in animal models, particularly when highly concentrated 13 .…”

“…In a longitudinal cohort of Fijian children, there was no association between the time to next Strep A skin infection and total serum IgG antibody titres to the M protein semi-conserved C-repeat region J8 peptide following primary skin infection 52 . It is important to note that vaccine-induced and natural immunity may differ significantly 23 .…”