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Group A Streptococcus Vaccine Target Candidates Identified From Global Genome Set

NEW YORK (GenomeWeb) – By sequencing thousands of globally-collected isolates of Group A Streptococcus, a team led by investigators in the UK and Australia has focused in on potential targets for developing a vaccine against the pathogen, also known as S. pyogenes.

"This research has the potential to fast-track a much-needed Strep A vaccine as developers and the wider scientific community can now use our database to identify the most common genes as vaccine targets," senior and co-corresponding author Mark Walker, a researcher at the University of Queensland and director of the Australian Infectious Diseases Research Centre, said in a statement.

The researchers sequenced the genomes of more than 2,000 isolates collected in 22 countries over a decade, including resource-limited locales where Strep A is endemic and involved in conditions ranging from impetigo to acute rheumatic fever and related heart disease. Their findings, published online this week in Nature Genetics, pointed to the existence of some 290 diverse clinical Group A Streptococcus phylogroups.

By looking at regions that resembled one another across isolates, the team also uncovered candidate antigen sequences that might prove useful in future vaccine development programs. From a set of more than two dozen suspected vaccine antigens, for example, the group identified the subset of sites with low sequence variation that were present in more than 99 percent of the strains profiled.

"Using large-scale genomic sequencing, we identified the existence of more than 290 genetically different lineages of clinically important Strep A, highlighting the challenges of designing an effective global vaccine," lead author Mark Davies, a researcher affiliated with the Wellcome Sanger Institute and the University of Melbourne, said in a statement. "However, using all the data we collected, we narrowed down common genes in almost all strains of Strep A globally."

Moreover, the newly-sequenced isolate set is expected to serve as a resource for answering broader questions about the conditions that Strep A can cause in different settings — from strep throat or scarlet fever in the UK to rheumatic heart disease in Australian Aboriginal populations, co-author Gordon Dougan, a researcher at the Sanger Institute and the University of Cambridge, explained in a statement.

"In addition to aiding research into a vaccine, genomic data from our study will help researchers understand how Strep A causes disease and why it is different in high-income areas [and] endemic regions," Dougan said.

Using Illumina instruments, the researchers performed multiplex, paired-end sequencing on 2,083 Group A Streptococcus isolates from 22 countries — spanning representatives from 484 multilocus sequence types and 150 "emm types." From there, they assembled draft versions of the genomes and annotated a Group A Streptococcus pan-genome that encompassed 1,306 predicted protein-coding genes in the bug's core genome, along with almost 3,700 accessory genes and signs of rampant recombination.

With an analysis based on 416 apparent core genes, the researchers found 299 Group A Streptococcus genetic clusters, or phylogroups, including 172 phylogroups with one or more clinical isolate and 206 phylogroups containing at least two of the isolates.

Across the collection, the team noted that just 68 isolates from 32 of the phylogroups contained sequences spanning the full Group A Streptococcus reference sequences, which have largely been compiled from sources in North America and Europe.

By incorporating amino acid sequence level variation and other clues, the researchers focused in on the potential vaccine antigens most likely to confer widespread protection from Group A Streptococcus. And with a genome-wide association analysis that included nearly 900 noninvasive isolates from the clinic and more than 1,400 invasive isolates from clinical samples, they searched for variants corresponding to invasiveness — an analysis that was partly confounded by varying population structure between geographic locations considered.

"We reveal that the global population structure of [Group A Streptococcus] is one of extensive genetic diversity, which is probably reflective of the rapid international spread of genetically diverse lineages driven by diversifying selection from the immune system and/or competition between lineages," the authors wrote.