Oral Presentation 14th Australian Peptide Conference 2022

A combinatorial synthetic peptide vaccine for Streptococcus pyogenes: progress towards phase I trial (#55)

Manisha Pandey 1 , Rasmus Mortensen 2 3 , Ainslie Calcutt 1 , Victoria Ozberk 1 , Jessica Powell 1 , Michael R Batzloff 1 , Simone Reynolds 1 , Jes Dietrich 2 , Michael F Good 1
  1. Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia
  2. Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, , Denmark
  3. Department of Immunology and Microbiology, University of Copenhagen, Denmark

Streptococcus pyogenes (StrepA) is a major human pathogen responsible for over 500,000 deaths per year mostly due to rheumatic heart disease or invasive (iStrepA) disease. CovR/S mutant StrepA are hypervirulent pathogens that up-regulate expression of a number of virulence factors including the chemokine protease, SpyCEP.  The hypervirulence of CovR/S mutant StrepA correlates with the strains ability to degrade CXC chemokines thus blunting neutrophil mediated killing and enabling ingress of bacteria from a superficial wound to deep tissue. iStrepA infections account for at least 663,000 cases each year, resulting in 163,000 deaths. Therefore, prevention of iStrepA infections is desperately needed.

 

While mice can be protected from infection with WT organisms by vaccination with a conserved M-protein peptide (J8), the vaccine-induced immunity was impaired against CovR/S mutant organisms.  However, inclusion of an inactive recombinant fragment of SpyCEP induced antibodies that shielded IL8 and protected mice from StrepA infection. Furthermore, we identify a B-cell epitope (20-amino acid peptide) from SpyCEP  (‘S2’) and show that this epitope was the principal target for anti-SpyCEP antibodies. We then combined S2-DT with J8-DT to create a combination vaccine, which could protect mice against hypervirulent StrepA. Histology demonstrated that the vaccine enables neutrophils to migrate to the infection site to destroy organisms that were opsonized by antibodies targeting the M protein. The combination vaccine also protected mice from StrepA isolates that caused lethal septic shock during a recent StrepA outbreak in Brisbane. Taken together our data strongly suggest that the combination vaccine targeting two independent virulence factors will be efficacious against most StrepA strains causing a range of pathology. Pre-clinical studies with the combination vaccine conjugated to CRM197 (a chemically defined DT analogue) further confirmed its efficacy. The vaccine is currently being prepared to enter into a Phase I clinical trial in Canada.