Diving deep into the lineages of Bordetella pertussis, the causative agent of whooping cough, an international team of researchers has traced the organism’s evolution over nearly a century. In a study in mBio® this week, they show how B. pertussis has adapted over time to elude vaccines.
The first documented epidemic of whooping cough, or pertussis, occurred in Paris in 1578. The introduction of vaccines in most countries between 1940 and 1960 significantly reduced the pertussis burden but has not eradicated it.
Even today, pertussis is a significant cause of child mortality. Estimates from the World Health Organization suggest that, in 2008, about 16 million cases of pertussis occurred worldwide, 95 percent of which were in developing countries, and that 195,000 children died from the disease. And the years 2010 to 2012 have seen large outbreaks in Australia, the Netherlands, the United Kingdom and the United States, with significant mortality in infants. (hyperlink to mBio paper)
Possible causes for the resurgence are still unknown but include: waning vaccine-induced immunity; the switch from whole-cell vaccines (composed of whole bacterial cells that have been killed) to acellular vaccines (composed of fragments of bacterial cells thought to be best suited to stimulate a strong immune response) in the late 1990s; and adaptation of the pathogen.
For the study, the researchers applied comparative genomics to a collection of 343 B. pertussis strains from 19 countries, isolated between 1920 and 2010. Their analyses found two deep branches of B. pertussis that diverged around 2,000 years ago, suggesting either two independent introductions of the organism into the global human population from an unknown reservoir or the loss of intermediate lineages over time. Branch I contained only a small number of strains (1.7%), isolated between 1954 and 2000, while Branch II contained strains isolated between 1920 and 2010 falling into more common types.
The analysis also found that many adaptive mutations occurred in the period in which whole-cell vaccines were used, suggesting that vaccination was the major force driving changes in B. pertussis populations. A mutation causing a variant called pertussis toxin promoter allele, or ptxP3, occurred once in the 1980s and strains carrying this allele spread worldwide in 25 to 30 years.
The team also found that the worldwide B. pertussis population has changed significantly during the last 60 years. Most changes resulted in genetic divergence from vaccine strains. The group found that virulence-associated genes and genes coding for surface-exposed proteins were important for adaptation. And they identified other, less obvious genes with potentially adaptive mutations.
“The study shows that pertussis has evolved to respond to the use of both whole-cell and acellular vaccines,” says senior study author Julian Parkhill, head of pathogen genomics at The Sanger Institute, a non-profit genome research institute primarily funded by the Wellcome Trust. “The data does help to determine how modern vaccines can be adapted to respond in turn by reflecting the antigenic changes evident in the population.”
Still, adds Parkhill, “The take-home message for the public is that vaccines do work -- this is evident from the fact that the pathogen has to evolve in order to evade them. This study should contribute to the continual process of vaccine improvement. Current vaccines are still hugely better than no vaccine.”
The work was supported by the Wellcome Trust, the RIVM (National Institute for Public Health and the Environment), and the National Health and Medical Research Council of Australia.
-- Karen Blum