Vaccine Escape Recombinants Emerge after Pneumococcal Vaccination in the United States

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Abstract
The heptavalent pneumococcal conjugate vaccine (PCV7) was introduced in the United States (US) in 2000 and has significantly reduced invasive pneumococcal disease; however, the incidence of nonvaccine serotype invasive disease, particularly due to serotype 19A, has increased. The serotype 19A increase can be explained in part by expansion of a genotype that has been circulating in the US prior to vaccine implementation (and other countries since at least 1990), but also by the emergence of a novel “vaccine escape recombinant” pneumococcal strain. This strain has a genotype that previously was only associated with vaccine serotype 4, but now expresses a nonvaccine serotype 19A capsule. Based on prior evidence for capsular switching by recombination at the capsular locus, the genetic event that resulted in this novel serotype/genotype combination might be identifiable from the DNA sequence of individual pneumococcal strains. Therefore, the aim of this study was to characterise the putative recombinational event(s) at the capsular locus that resulted in the change from a vaccine to a nonvaccine capsular type. Sequencing the capsular locus flanking regions of 51 vaccine escape (progeny), recipient, and putative donor pneumococci revealed a 39 kb recombinational fragment, which included the capsular locus, flanking regions, and two adjacent penicillin-binding proteins, and thus resulted in a capsular switch and penicillin nonsusceptibility in a single genetic event. Since 2003, 37 such vaccine escape strains have been detected, some of which had evolved further. Furthermore, two new types of serotype 19A vaccine escape strains emerged in 2005. To our knowledge, this is the first time a single recombinational event has been documented in vivo that resulted in both a change of serotype and penicillin nonsusceptibility. Vaccine escape by genetic recombination at the capsular locus has the potential to reduce PCV7 effectiveness in the longer term. The 7-valent pneumococcal conjugate vaccine is a remarkable public health success story. It has significantly reduced invasive pneumococcal disease in the United States not only by protecting vaccinated children, but also by protecting unvaccinated older children and adults by herd immunity. However, there was always a concern that use of a limited-valency vaccine would result in an increase in disease due to nonvaccine serotypes, and this has now occurred in the US. The predominant nonvaccine serotype causing invasive disease is 19A, and this increase is partially explained by “vaccine escape” pneumococci, strains that have exchanged the genes that encode a vaccine serotype 4 capsule for genes that encode a nonvaccine serotype 19A capsule. These strains are then able to escape vaccine-induced immunity. Characterisation of the genetic event that resulted in these vaccine escape strains was the focus of our study and the results were surprising. The results of this study have important relevance to the long-term effectiveness of the current vaccine and to the development of future pneumococcal vaccines.