Infections with Streptococcus pyogenes (StrepA) and their sequelae are responsible for an estimated 18 million cases of serious diseases, with 700 million new primary cases and 500,000 deaths per year. The majority of the fatalities are due to rheumatic heart disease (RHD) or invasive StrepA disease (ISD). RHD has an autoimmune aetiology, and the majority of cases occur in developing nations or amongst the Indigenous populations in developed countries. ISD has high mortality rates in even the best-equipped facilities. Despite the burden of disease, there is currently no vaccine available. Vaccine development has been hampered by antigenic diversity of the M-protein and by the risk that vaccination may lead to autoimmune pathology. To overcome these impediments, we defined conserved minimal cryptic-epitopes to create safe vaccines which could induce pan-strain opsonising antibodies.
The two conserved cryptic B-cell epitopes (J8, p*17) from the M-protein, and ‘S2’ (from Spy-CEP) were conjugated to either diphtheria toxoid or to Cross Reactive Material (CRM) and combinations formulated in Alum (‘IMVax’) or the cationic liposomes CAF01 (‘MUCOVax’). The combination vaccines were tested in murine models of the upper respiratory tract, skin, or invasive infection. Vaccination with IMVax (via three intramuscular immunisations) or with MUCOVax (using the prime-pull strategy) led to enduring and protective immunity, which was evident for over 12 months post vaccination, even though the antibody levels had declined significantly at that time. The safety of vaccines was also confirmed in a formal toxicology study as well as in a rat autoimmune valvulitis model. Furthermore, to assess the immunotherapeutic potential of vaccine-induced antibodies, the vaccine sera or the monoclonal antibodies against vaccine antigens were tested in a murine model of streptococcal toxic shock syndrome (STSS). Immunotherapy with vaccine antibodies quickly resolved established disease by acting to clear the infection and ablate the mitogenic and inflammatory activity of the M protein, holding significant implications for clinical therapeutics.
The vaccines are currently in a Phase 1 clinical trial. Following successful completion of the Phase 1 trial we will test vaccine efficacy in a controlled human challenge with StrepA.