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Sequencing Study Follows Pneumococcal Population Dynamics after Vaccine Introduction

NEW YORK (GenomeWeb News) – A new Nature Genetics study has taken a look at Streptococcus pneumoniae population patterns in Massachusetts in the years following the introduction of a vaccine targeting several pneumococcal infection-causing forms of the bug.

Researchers from the Harvard School of Public Health, the Wellcome Trust Sanger Institute, Addenbrooke's Hospital at the University of Cambridge, and elsewhere did whole-genome sequencing on hundreds of S. pneumoniae isolates. The sample set represented samples collected between 2000 and 2007 in Massachusetts from individuals showing no obvious signs of infection.

With this data, the team was able to see shifts in the pneumococcal strains in the years after a polysaccharide-protein conjugate vaccine targeting seven S. pneumoniae serotypes came into regular use in the region in 2000.

"The widespread use of whole genome sequencing will allow better surveillance of bacterial populations — even those that are genetically diverse — and improve understanding of their evolution," Harvard School of Public Health's Marc Lipsitch, co-senior author on the study, said in a statement.

"In this study, we were even able to see how quickly these bacteria transmit between different regions within Massachusetts," he noted, "and identify genes associated with bacteria in children of different ages."

Though it's not uncommon for individuals to carry S. pneumoniae without incident, the bug can cause dangerous conditions such as pneumonia and meningitis under certain circumstances. Some forms of the bug seem especially apt to cause these serious infections. In 2000 a vaccine called PCV7 that targets seven such serotypes was introduced in the US.

Data from Massachusetts suggests the number of children carrying pneumococci without showing disease symptoms has stayed relatively constant in the years since PCV7 vaccination became routine, authors of the new study noted. But the overall rates of invasive pneumococcal disease have declined dramatically.

The prevalence of multi-drug resistant pneumococcal strains seems to have dipped in the wake of PCV7 vaccination, too, though antibiotic resistance appears to be ticking back up since the mid-2000s.

All in all, these and other patterns have researchers wondering about the genetic processes at play in post-vaccine pneumococcal populations, particularly for understanding whether more-invasive, vaccine-vulnerable serotypes are primarily being replaced by non-vaccine-targeted serotypes or whether some are turning to genetic strategies that help them dodge PCV7.

"[T]he ability of the pneumococcus to recombine by natural transformation suggests that successful lineages that were mainly vaccine type before PCV7 may persist through the acquisition of non-[vaccine type] capsules," they wrote, "a process called serotype or capsule switching that has been observed throughout the history of pneumococcus."

To look at this in more detail, the team used Illumina's HiSeq 2000 instrument to do whole-genome sequencing on 616 S. pneumoniae isolates from asymptomatic individuals in Massachusetts. The collection included 133 isolates from 2001 — the year after PCV7 was introduced. Another 203 isolates represented circulating S. pneumoniae bugs from 2004 and the remaining 280 isolates were collected in 2007.

"In terms of their serotype distribution, these populations represent the pneumococcal community at the point at which PCV7 was introduced, a community with increased diversity after the introduction of the vaccine, and a return to equilibrium, respectively," study authors noted.

Using de novo genome assemblies developed for the isolates, the researchers tallied up more than 1.2 million predicted protein-coding genes, which fell into 5,442 clusters of orthologous genes.

Of those, 1,194 orthologous gene clusters were shared across isolates, they reported, apparently comprising a core S. pneumoniae genome.

Using polymorphisms peppering those core sequences, it was possible to take a look at the phylogeny of the isolates, which clustered into 15 groups. Together with genome alignments, these S. pneumoniae relationships over time pointed to dramatic change in S. pneumoniae populations in the years since pneumonococcal vaccine use began.

Consistent with lower rates of invasive infections, for instance, the team found that the seven serotypes targeted by PCV7 all but disappeared in the years after PCV7 use began.

On the other hand, serotypes not targeted by the vaccine quickly became more prevalent and spread in Massachusetts in the wake of PCV7 vaccinations — strain dynamics that the researchers were able to track with their genomic data.

Their data also unearthed examples of genetic similarities between vaccine serotypes of S. pneumoniae and those not targeted by the vaccine, including instances of serotype swapping via transformation of polysaccharide capsule sequences. For the most part, though, such similarities seem to stem from interactions between strains prior to PCV7 introduction.

In addition, despite the dramatic serotype changes — and corresponding drop in invasive pneumococcal infection rates — much of the accessory genome remained relatively stable over time in S. pneumoniae isolates tested.

"Comparison of the pooled data from 2001 and 2007 identifies a detectable vaccine effect on only a few genes associated with one of the vaccine serotypes," Lipsitch and co-authors noted, "demonstrating the importance of assigning genomic data to specific taxa rather than using pooled shotgun reads in studying strain dynamics."

"That both populations are composed of distinct strains, themselves representing different combinations of similar loci, while the [invasive pneumocococcal disease] rate decreases indicates that subtle differences within [clusters of orthologous genes] or the consequences of interactions between them are crucial in determining the rate at which pneumococci cause disease within a carrier."