Background
GAS results in the loss of over 500,000 lives each year. Vaccine development is hampered by antigenic diversity of the M-protein and by the risk that vaccination may lead to autoimmune pathology. With these caveats in mind, our approach was to define conserved cryptic epitopes within regions of the M-protein not critical to pathogenesis and which could induce pan-strain neutralizing antibodies.
Methods
We defined two conserved cryptic B-cell epitopes (J8, p*17) from the M-protein, and ‘S2’ (from the virulence factor, Spy-CEP). These were conjugated to either diphtheria toxoid or to CRM or lipidated for insertion into liposomes. The antigens were used in combination in murine vaccine studies. Immunity was assessed by measuring antibody and bacterial burden following intranasal or skin challenge.
Results
URT, skin, and systemic protective immunity were shown against multiple GAS strains. Protection was evident for over 12 months and correlates of immunity defined. A challenge study in HLA-transgenic mice using a community strain (emm-75) that has been used in human challenge experiments was also undertaken. Potent protection as measured in throat, NALT and lungs was evident 9 months following intramuscular vaccination, even though antibody levels had declined significantly by that time. The vaccines did not induce heart disease in an established rat valvulitis model. GMP-grade vaccine antigens were prepared and a human Phase I dose-ranging trial is slated for Q2, 2022.
Conclusions
We have defined cryptic conserved epitopes of the M-protein that are viable candidates for a safe vaccine that protects against multiple strains of GAS.