Genetic manipulation perfects vaccine design
Staphylococcus aureus and Streptococcus pyogenes pose a great threat to human health. With the increasing incidence of antibiotic resistance, it is now more than ever necessary to develop safe and efficacious vaccines. A further complication of existing vaccines against Streptococcus pyogenes is the potential risk of cross-reactivity of vaccine-induced antibodies with human tissue. This results in the immune-mediated disease rheumatic fever, which is a major cause of chronic heart disease and mortality. Scientists on the EU-funded 'Gram positive surface proteins in immune evasion' (SURFACE) project proposed to target surface-exposed antigens as vaccine targets. The work focused on the surface-expressed polysaccharide Group A carbohydrate (GAC), the major constituent of the bacterial cell wall. Although GAC had been previously validated as a universal group A Streptococcus vaccine, theoretical concerns regarding the cross-reactivity of the generated antibodies with human tissue had prohibited its further development. The SURFACE study proceeded with delineating the biological function of the GAC antigen. Researchers generated specific gene deletion bacteria through genetic mutation expressing modified GAC structures that lacked the specific epitope that induced the cross-reactivity. The knockout bacteria were tested in a series of assays and animal models, showing that they are more susceptible to immune clearance. Compared to wild-type bacteria they also caused reduced mortality and morbidity. Finally, the SURFACE research team tested the capacity of the modified carbohydrate to be an effective vaccine antigen. Vaccination experiments illustrated the capacity of this modified antigen to provide broad coverage against all group A Streptococcus serotypes without the risk of inducing autoimmunity. The SURFACE vaccine is covered by an international patent and should soon be tested in the clinic. The overall approach demonstrated how genetic and functional insight into antigens could contribute to rational vaccine design.
Keywords
Vaccine, Staphylococcus aureus, Streptococcus pyogenes, virulence, Group A carbohydrate
