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Pneumococcal Bacteria Sequences Suggest Vaccine Escape Isolates Contain Recombined DNA

NEW YORK (GenomeWeb News) – Pneumococcal disease-causing Streptococcus pneumoniae bacteria can dodge vaccines by swapping and recombining multiple chunks of DNA with bacteria from serotypes not recognized by the vaccine, a new study in Nature Genetics suggests.

Researchers at the University of Oxford and the US Centers for Disease Control and Prevention used custom arrays to capture sequences of interest from the genomes of 62 S. pneumoniae isolates collected in the US during nearly a decade following the introduction of Pfizer's pneumococcal conjugate vaccine PCV7.

By sequencing these selected portions of the genome from each isolate and comparing them to one another, the researchers found genetic patterns coinciding with five independent vaccine escape events in the US.

Results of the study suggest that pneumococcal bacteria from different serotypes traded and recombined multiple chunks of their genomes, including sequences that help specify the bacterial capsule features used to help define S. pneumoniae serotypes.

"Our genomic data provide strong evidence that, in each case, the recombination event generating the capsular switch involved simultaneous import of multiple and often large additional DNA fragments from locations across the genome," co-senior author Derrick Crook, a University of Oxford microbiologist, and colleagues wrote.

"This process has far-reaching consequences for the evolution of bacteria and their response to the strong selection imposed by vaccines or antimicrobials," they added.

The PCV7 vaccine, used in the US since 2000 and the UK since 2006, is a conjugated vaccine based on the polysaccharides present in the bacterial capsules surrounding S. pneumoniae from seven serotypes, the study authors explained. While its introduction led to a drop in pneumococcal diseases such as pneumonia and meningitis, it also spurred concerns over what tactics pneumococcal bugs might use to get around the vaccine.

In particular, because vaccination leads to strong selection against the seven serotypes targeted, some researchers suspected that extensive PCV7 vaccination might eventually lead to changes in capsule composition in bacteria from the serotypes targeted and/or contribute to a rise in the prevalence of the S. pneumoniae from the remaining 85 or so serotypes not targeted by the vaccine.

To look at the genetic mechanisms contributing to vaccine escape, the researchers targeted 300,000 bases of the S. pneumoniae genome sequence in 62 pneumococcal isolates using Affymetrix CustomSeq arrays followed by Illumina GAIIx sequencing. Whole-genome sequencing on a handful of the isolates was also used to verify some of their results.

The isolates were collected between 2000 and 2007 as part of the CDC's Active Bacterial Core surveillance monitoring program in the US. More than 1,900 isolates collected through the program were serotyped by multi-locus sequence typing for previous studies.

The latest findings suggest that five different episodes of vaccine escape by S. pneumoniae in the US arose independently of one another, often involving bacteria that had exchanged multiple large pieces of DNA with bugs from other serotypes.

The bacteria donating this genetic material appear to have belonged to a S. pneumoniae serotype not recognized by PCV7 called 19A, which has become more common since the vaccine's introduction, researchers noted.

Genetic and epidemiological information assessed in the study also provided clues about the spread of newly vaccine-resistant isolates, including isolates involved in one escape event that began with recombination between serotypes in New York and Connecticut and went on to move west across the country.

"These observations clarify the roles of recombination and selection in the population genomics of pneumococcus and provide proof of principle of the considerable value of combining genomic and epidemiological information in the surveillance and enhanced understanding of infectious diseases," the study's authors wrote.

Along with the insights that it offers into vaccine escape and potential mechanisms of drug resistance in pneumococcal bacteria, they explained, the work is also expected to help inform future vaccination efforts focused on controlling S. pneumoniae.

"We should now be able to understand better what happens when a pneumococcal vaccine is introduced into a new population," Crook said in a statement. "Our work suggests that current strategies for developing new vaccines are largely effective but may not have long-term effects that are as successful as hoped."

"The current vaccine strategy of targeting predominant pneumococcal serotypes is extremely effective," added CDC researcher Bernard Beall, a co-author on the study, "however our observations indicate that the organism will continue to adapt to this strategy with some measurable success."

A vaccine that recognizes 13 rather than seven S. pneumoniae serotypes has now been introduced in both the US and the UK, the study authors noted.

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