Drug-Resistant Invasive Pneumococcal Bacteria Increased After Vaccine

On May 25, 2017, the CDC published a report that found a nonvaccine, penicillin-nonsusceptible strain of pneumococcal bacteria that causes invasive pneumococcal disease (IPD) increased during the years that pneumococcal 7-valent conjugate vaccine was available (2001–2009) and increased further after implementation of pneumococcal 13-valent conjugate vaccine in 2010.


A pneumococcal conjugate vaccine is a vaccine created by attaching capsule sugars of bacteria strains to a protein to elicit a stronger immune response used to protect people against disease caused by the bacterium Streptococcus pneumoniae. The pneumococcal 7-valent conjugate vaccine (PCV7 or Prevnar) contains the cell capsule sugars of seven serotypes of the bacteria S. pneumoniae (4, 6B, 9V, 14, 18C, 19F and 23F). The pneumococcal 13-valent conjugate vaccine (PCV13 or Prevnar 13) contains the cell capsule sugars of thirteen serotypes of the bacteria S. pneumoniae (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F).


Researchers used whole-genome sequencing to characterize 199 nonvaccine serotype 35B pneumococcal strains that caused IPD in the United States during 2015–2016. Researchers then compared these findings to previous serotype 35B IPD data. The comparison revealed that penicillin-nonsusceptible 35B IPD increased during the years that pneumococcal 7-valent conjugate vaccine was available (2001–2009) and increased further after implementation of pneumococcal 13-valent conjugate vaccine in 2010. This increase was caused primarily by one strain (the 35B/sequence type (ST) 558 lineage or 35B/ST558) that can develop into another strain (35B/ST156). This is of concern because in the past ST156 strains have become globally predominant. The researchers concluded that protection against serotype 35B should be considered in next-generation pneumococcal vaccines.


Although the dramatic protective effect of the pneumococcal 7-valent conjugate vaccine (PCV7) against IPD persisted a full decade after its introduction in the United States in 2000, the emergence of 19A and other non-PCV7 serotypes reduced the overall benefit. Before PCV7 implementation, researchers observed only two different 35B lineages through the CDC’s Active Bacterial Core Surveillance (ABCs)/Emerging Infections Program Network. Both lineages were relatively rare causes of IPD, but were geographically widespread in the United States before and after PCV7 introduction. One 35B lineage was antimicrobial-susceptible and multilocus sequence type (MLST) 452 (35B/ST452), and the second strain was penicillin-nonsusceptible 35B/ST558. During 1995–2001, the penicillin-nonsusceptible 35B/ST558 lineage accounted for 69% of serotype 35B ABCs isolates. During 1999–2007 in the United States, the proportion of penicillin-nonsusceptible IPD isolates within serotype 35B increased to 84%; 35B/ST558 accounted for this increase.


After introduction of the 13-valent conjugate vaccine (PCV13) in 2010, 35B became the most common serotype in ABCs. Consistent with its status as a major cause of IPD in the post-PCV13 era, the 35B/ST558 lineage is currently commonly found in disease and asymptomatic pneumococcal carriage in many countries.


The increased incidence of 35B IPD during the post-PCV7 period (2.1–3.7 cases/million population during 2001–2009 vs. 1.2–1.3 cases/million population during 1998–1999) and the post-PCV13 period (3.3–4.8 cases/million population during 2011–2015), combined with the consistent trend of markedly increased proportions of penicillin-nonsusceptible 35B IPD isolates throughout the conjugate vaccine era, is consistent with reported increased 35B/ST558 in IPD and carriage.


An increase of penicillin-nonsusceptible serotype 35B IPD and carriage caused by 35B/ST558 has been apparent in the United States since the introduction of PCV7 in 2000, and it has shown a major increase after PCV13 implementation. This finding is of concern because even strains that are rarely detected in IPD sometimes rapidly emerge. For example, the 19A/ST320 strain was not detected during extensive characterization of pre-PCV7 ABCs isolates, yet it became the predominant invasive pneumococcal strain during 2005–2009.


The recent identification of the antimicrobial-resistant 35B/ST156 lineage and its subsequent detection within 6 ABCs sites is a cause for concern. The ST156 lineage has shown a remarkable propensity to persist through undergoing serotype-switch events. The penicillin-resistant 9V/ST156 lineage was the predominant serotype 9V cause of IPD in the United States during the pre-PCV7 era. Soon after introduction of PCV7, serotype 9V IPD became rare, and 19A became the predominant representative of the ST156 lineage within ABCs. After introduction of PCV13, 35B has become the predominant serotype of the ST156 lineage within the United States.


Although conjugate vaccines have a history of providing effective and durable protection against IPD, the continued emergence and expansion of serotype 35B into different clonal complexes supports continued development of wider spectrum pneumococcal vaccines. Serotype 19A IPD, although relatively uncommon in the pre-PCV7 era, rapidly became the predominant invasive serotype in the post-PCV7 period. Serotype 35B strains have several of the same features that were found among serotype 19A strains before implementation of PCV7 in 2000. These features that could predispose for serotype 35B to continue its increasing trend as a cause of IPD include its lack of inclusion within conjugate vaccine, high carriage rates within children, antimicrobial resistance, clonal expansion, and serotype switching. An experimental 15-valent conjugate vaccine in development includes serotypes 22F and 33F, which have increased as causes of IPD in the postconjugate vaccine era. Serotypes 15A, 15B, and 23A are expressed by moderately antimicrobial-resistant clones and are not uncommon causes of IPD. Although less resistant to β-lactam antimicrobial drugs than 35B/ST558 and 35B/ST156, these strains also present a challenge to address through more encompassing pneumococcal vaccines.


See the CDC Report


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