Stimulating the immune system to fight Group A Streptococcus (strep) is a delicate business. Strep is an inviting target, since it causes more than 700 million infections worldwide each year, leading to cases of strep throat, necrotizing fasciitis (flesh-eating disease), and rheumatic heart disease. Yet scientists have approached strep vaccines only gingerly.
The fear has been that a vaccine might contain the “wrong” antigens. According to some studies, such antigens could account for a sobering observation: Some patients with strep infections produce antibodies that cross-react with their own heart valve tissue, leading to rheumatic fever and heart damage.
Hopes for a safe and effective vaccine, however, have been revived by a new study completed by researchers at the University of California, San Diego School of Medicine. The study’s results appeared June 11 in Cell Host & Microbe, in an article entitled “The Classical Lancefield Antigen of Group A Streptococcus Is a Virulence Determinant with Implications for Vaccine Design.”
The study suggests a way to circumvent the damaging autoimmune response triggered by strep. Specifically, the researchers noted that the cell wall of strep is composed primarily of a single molecule known as the Lancefield group A carbohydrate (or GAC) which, in turn, is built from repeating units of the bacterial sugar rhamnose and the human-like sugar N-acetylglucosamine (GlcNAc).
Previous research has indicated that GlcNAc sugars present in GAC may be responsible for triggering production of heart-damaging antibodies in some patients. Senior author Victor Nizet, M.D., said the latest findings corroborate this model, and suggest that eliminating the pathogen’s ability to add GlcNAc sugars to GAC could be the basis for a safe vaccine.
“In this study, we discovered the strep genes responsible for the biosynthesis and assembly of GAC, the very molecule that defines the pathogen in clinical diagnosis,” added first author Nina van Sorge, PharmD, Ph.D., a former postdoctoral fellow at UC San Diego who now leads her own laboratory at Utrecht University Medical Center in the Netherlands. “This discovery allowed us to generate mutant bacterial strains and study the contribution of GAC to strep disease.”
According to the researchers, “an isogenic mutant of the glycosyltransferase gacI, which is defective for GlcNAc side-chain addition, is attenuated for virulence in two infection models, in association with increased sensitivity to neutrophil killing, platelet-derived antimicrobials in serum, and the cathelicidin antimicrobial peptide LL-37.” The mutant strep was easily killed when exposed to human white blood cells or serum. It also lost the ability to produce severe disease in animal infection models.
The researchers also identified a way to remove the problematic GlcNAc sugar so that a mutant form of the bacteria with only rhamnose-containing GAC could be purified and tested as a vaccine antigen. “Antibodies to GAC lacking the GlcNAc side chain and containing only polyrhamnose,” explained the authors, “promoted opsonophagocytic killing of multiple GAS serotypes and protected against systemic GAS challenge after passive immunization.”
Researchers plan to assess the new modified antigen against other candidates in advanced strep throat vaccine tests in nonhuman primates beginning later this year in Atlanta, GA, funded by the National Health and Medical Research Council of Australia.
“We showed that antibodies produced against mutant GAC antigen helped human white blood cells kill the pathogen and protected mice from lethal strep infection," said Jason Cole, Ph.D., a visiting project scientist from the University of Queensland, Australia, and co-lead author of the paper. “Because GAC is present in all strep strains, this may represent a safer antigen for inclusion in a universal strep vaccine.”
“Our studies showed that the GlcNAc sugar of GAC is a critical virulence factor allowing strep to spread in the blood and tissues,” Dr. van Sorge said. “This is likely important for the rare, but deadly, complications of strep infection such as pneumonia, necrotizing fasciitis, and toxic shock syndrome.”