Vaccine Escape Recombinants Emerge after Pneumococcal Vaccination in the United States

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.

Current Trends in Streptococcus pneumoniae Infections and Their Treatment

“…Capsular switching from vaccine serotype to nonvaccine serotype can occur as a result of genetic recombination and lead to serotype replacement disease [4 •• ]. Following PCV7, vaccine escape serotypes have emerged due to recombinant exchanges [44]. The emergence of many clones of pneumococcal serotype 19A is a result of capsular switching [15].…”

Vaccination with the pneumococcal 7-valent conjugate: a successful experiment but the species is adapting

“…Capsular switching events that have occurred owing to recombinational replacement of the capsular biosynthetic locus in the pre-PCV7 era have been characterized at the molecular level and were seen to involve PCV7 serotype donors and recipients [8]. Recent data are also suggestive of capsular switching in the post-PCV7 era, involving non-PCV7 serotype donors and PCV7 serotype recipients [9][10][11]. A capsular switch event is initially suggested without DNA sequence analysis of crossover regions when a strain of a given serotype exhibits a genetic type that is normally highly associated with a different serotype.…”

“…A capsular switch event is initially suggested without DNA sequence analysis of crossover regions when a strain of a given serotype exhibits a genetic type that is normally highly associated with a different serotype. Regardless of whether switching events occurred before or after vaccine introduction, evidence suggests that in the post-PCV7 era, serotype 19A, a serotype for which the vaccine provides no protection, has become more genetically diverse owing to the expansion of clonal complexes formerly highly associated with PCV7 serotypes [9,10]. In a relatively short period after PCV7 introduction, serotype 19A has become the prevalent invasive serotype within the USA [9,11,12].…”

“…A very interesting serotype 19A serotype switch variant recovered in the USA during the postvaccine era possesses the multilocus ST (ST695) that identifies the major antibiotic-susceptible invasive serotype 4 clone [9][10][11]. It is interesting that the ST695 type 19A strain, unlike the putative serotype 4 parental strain, is intermediately penicillin resistant [11].…”

“…It is interesting that the ST695 type 19A strain, unlike the putative serotype 4 parental strain, is intermediately penicillin resistant [11]. This is apparently due to a single double-crossover event, resulting in recombinational replacement of the cps locus, as well as the flanking pbp2x and pbp1a genes in the ST695 type 4 clone, with the cps locus and mosaic pbp gene counterparts from the major serotype 19A clone donor [10]. These current data suggest that the immune escape mechanism of serotype switching may contribute to the emergence of antibiotic resistance within new clonal types owing to the hitch-hiking effect of the flanking pbp genes.…”