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 the development of protective antibodies against all SIC domains.

Analysis of host-pathogen gene association networks reveals patient-specific response to streptococcal and polymicrobial necrotising soft tissue infections

“…A study by Kachroo et al [ 59 ] revealed a positive correlation between sic and genes involved in the host immune response and inflammation when they examined the dual RNA-seq transcriptomes of S. pyogenes and host skeletal muscle from infected non-human primates. In addition, vaccination-induced anti-sic antibodies were effective in bacterial clearance in rabbit, mice, and in an ex vivo whole body assay [ 60 ].…”

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 – 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 .…”

Progress towards the Elusive Mastitis Vaccines

“…In conclusion, it is clear that natural IMI itself does not elicit complete protection against reinfection, so that any vaccine would have to improve on the natural immune response. An example is provided by the antibody response to Streptococcus pyogenes inhibitor of complement SIC: natural infection does not elicit neutralizing antibodies, whereas vaccination with the recombinant protein does [44]. Accordingly, the new vaccines would protect against infectious diseases by eliciting "unnatural immunity"; that is, immune responses that are of a different nature and directed to different antigens from those elicited by natural infections [5].…”