F2F Poster 21st Lancefield International Symposium for Streptococci and Streptococcal Diseases 2022

Immunotherapy with antibodies to the conserved region of the M protein and a streptococcal superantigen cooperatively resolve toxic shock-like syndrome in HLA humanized mice (#345)

Manisha Pandey 1 , Victoria Ozberk 1 , Ainslie Calcutt 1 , Zhenjun Chen 2 , Matthew Croxen 3 , Jessica Powell 1 , Emma Langshaw 1 , Jamie-Lee Mills 1 , Freda .E.C Jen 1 , James McCluskey 2 , Jenny Robson 4 , Gregory J Tyrrell 3 , Michael F Good 1
  1. Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia
  2. Department of Microbiology and Immunology, University of Melbourne, Australia, Melbourne
  3. University of Alberta, Edmonton, Canada
  4. Sullivan and Nicolaides Pathology, Brisbane, Australia

Background. Invasive streptococcal disease (ISD) and toxic shock syndrome (STSS) result in over 160,000 deaths each year. Effective preventative or therapeutic approaches are desperately needed.

Methods. We modelled ISD and STSS in HLA-transgenic mice infected with a clinically lethal isolate expressing the SAg, Streptococcal pyrogenic exotoxin (Spe) C. We assessed if vaccination with a conserved streptococcal M protein peptide will prevent STSS like disease and protect mice. We also tested a therapeutic approach involving vaccine antibodies with or without antibodies to SpeC.

Results. We demonstrated that both SpeC and the M protein, act cooperatively in the STSS pathogenesis. Vaccination with J8 protected against STSS by causing significant reduction in bacteraemia, which was associated with the absence of SpeC and inflammatory cytokines from the blood. Passive immunotherapy with J8 antibodies, resolved established disease and ablated the mitogenic and inflammatory activity of the M protein. Immunotherapy with antibodies to SpeC additionally blocked the mitogenic activity of SpeC. Genomic analysis of 77 recent ISD isolates of StrepA, demonstrated that anti-J8 antibodies theoretically recognize at least 73, providing strong support for using J8 antibodies, with or without antibodies to SpeC, as a therapeutic approach. Recently, monoclonal antibodies against the conserved region epitope (p*17) have shown efficacy in treating STSS due to SpeA and SpeC.

Conclusion. Vaccination or a combination immunotherapy with conserved M protein-based peptide will result in toxin neutralization as well as clearance of StrepA from the blood, correlating with a rapid improvement in the clinical and pathological features of STSS-like disease.