Novel insights into pneumococcal lineages in the vaccine era
Authors: Emmanuelle Varon, Robert Cohen
Journal: The Lancet Infectious Diseases (2019)

In The Lancet Infectious Diseases, Stephanie Lo and colleagues1Lo SW Gladstone RA van Tonder AJ et al.Pneumococcal lineages associated with serotype replacement and antibiotic resistance in childhood invasive pneumococcal disease in the post-PCV13 era: an international whole genome sequencing study.Lancet Infect Dis. 2019; (published online June 10.)http://dx.doi.org/10.1016/S1473-3099(19)30297-XSummary Full Text Full Text PDF PubMed Scopus (98) Google Scholar provide an interesting description of the genetic structure of 3233 pneumococcal strains causing invasive pneumococcal disease in children younger than 3 years from six countries where pneumococcal conjugate vaccines (PCVs) had been implemented. The implementation of PCVs has been a huge success, with a substantial decrease in the incidence of invasive pneumococcal disease and non-invasive infections, as well as a reduction in antibiotic resistance.2Balsells E Guillot L Nair H Kyaw MH Serotype distribution of Streptococcus pneumoniae causing invasive disease in children in the post-PCV era: A systematic review and metaanalysis.PLoS One. 2017; 12e0177113Crossref PubMed Scopus (206) Google Scholar Nevertheless, two facts have emerged: we have learned from carriage studies that Streptococcus pneumoniae remains a major bacterial species in the nasopharyngeal microbiota of children, because they carry S pneumoniae as much as they did before PCV implementation,3Cohen R Varon E Doit C et al.A 13-year survey of pneumococcal nasopharyngeal carriage in children with acute otitis media following PCV7 and PCV13 implementation.Vaccine. 2015; 33: 5118-5126Crossref PubMed Scopus (58) Google Scholar, 4Danino D Givon-Lavi N Ben-Shimol S Greenberg D Dagan R Understanding the evolution of antibiotic-nonsusceptible pneumococcal nasopharyngeal colonization following pneumococcal conjugate vaccines implementation in young children.Clin Infect Dis. 2018; (published online Oct 29.)DOI:10.1093/cid/ciy926Crossref PubMed Scopus (19) Google Scholar and pneumococci remain one of the leading causes of bacterial infections.2Balsells E Guillot L Nair H Kyaw MH Serotype distribution of Streptococcus pneumoniae causing invasive disease in children in the post-PCV era: A systematic review and metaanalysis.PLoS One. 2017; 12e0177113Crossref PubMed Scopus (206) Google Scholar To date, the surveillance programmes that aim to assess the impact of PCVs are mainly based on serotyping of capsular antigens—the same ones that are targeted by PCV-elicited antibodies. Besides showing a fall in the number of infections caused by almost all vaccine serotypes, these surveys have shown the emergence of non-vaccine serotypes, with variations in magnitude and diversity from country to country. With regard to magnitude, invasive pneumococcal disease caused by pneumococci expressing non-vaccine serotypes has substantially increased in incidence in several countries during the past 4 years, thereby eroding the impact of PCVs.2Balsells E Guillot L Nair H Kyaw MH Serotype distribution of Streptococcus pneumoniae causing invasive disease in children in the post-PCV era: A systematic review and metaanalysis.PLoS One. 2017; 12e0177113Crossref PubMed Scopus (206) Google Scholar By contrast, no substantial increase in incidence of invasive pneumococcal disease caused by non-vaccine serotypes has been reported in the USA.5Lewnard JA Hanage WP Making sense of differences in pneumococcal serotype replacement.Lancet Infect Dis. 2019; 19: e213-e220Summary Full Text Full Text PDF PubMed Scopus (74) Google Scholar With regard to serotype diversity, the emerging non-vaccine serotypes vary greatly: serotype 12F and 2 in Israel;6Rokney A Ben-Shimol S Korenman Z et al.Emergence of Streptococcus pneumoniae serotype 12F after sequential introduction of 7- and 13-valent vaccines, Israel.Emerg Infect Dis. 2018; 24: 453-461Crossref PubMed Scopus (37) Google Scholar serotypes 8, 9N, and 12F in the UK;7Ladhani SN Collins S Djennad A et al.Rapid increase in non-vaccine serotypes causing invasive pneumococcal disease in England and Wales, 2000–17: a prospective national observational cohort study.Lancet Infect Dis. 2018; 18: 441-451Summary Full Text Full Text PDF PubMed Scopus (306) Google Scholar and serotypes 24F and 12F in France.8Ouldali N Levy C Varon E et al.Incidence of paediatric pneumococcal meningitis and emergence of new serotypes: a time-series analysis of a 16-year French national survey.Lancet Infect Dis. 2018; 18: 983-991Summary Full Text Full Text PDF PubMed Scopus (56) Google Scholar We do not really understand the reason for these differences. Multi-locus sequence typing to characterising lineages has revealed the genetic diversity behind serotypes, as exemplified by serotype 19A isolates.9Hanage WP Bishop CJ Lee GM et al.Clonal replacement among 19A Streptococcus pneumoniae in Massachusetts, prior to 13 valent conjugate vaccination.Vaccine. 2011; 29: 8877-8881Crossref PubMed Scopus (35) Google Scholar Whole-genome sequencing of 240 isolates of the same multidrug-resistant clone that was identified by the Pneumococcal Molecular Epidemiology Network (PMEN) in the pre-vaccine era,10McGee L McDougal L Zhou J et al.Nomenclature of major antimicrobial-resistant clones of Streptococcus pneumoniae defined by the pneumococcal molecular epidemiology network.J Clin Microbiol. 2001; 39: 2565-2571Crossref PubMed Scopus (444) Google Scholar namely PMEN1 (Spain23F-1), revealed the dynamics of serotypes, with five capsular switches and multiple acquisitions of antibiotic resistance into this lineage over nearly three decades.11Croucher NJ Harris SR Fraser C et al.Rapid pneumococcal evolution in response to clinical interventions.Science. 2011; 331: 430-434Crossref PubMed Scopus (668) Google Scholar Furthermore, whole-genome sequencing that was used to explore a sample of 301 serotype 3 isolates of the PMEN31 clone (Netherlands3-31) revealed the emergence of a lineage expressing a higher rate of recombination, higher prevalence of antibiotic resistance, and lower resistance to opsonophagocytic killing than expressed by its ancestor.12Azarian T Mitchell PK Georgieva M et al.Global emergence and population dynamics of divergent serotype 3 CC180 pneumococci.PLoS Pathog. 2018; 14e1007438Crossref PubMed Scopus (48) Google Scholar Another milestone has been reached with the species-wide genomic study by Gladstone and colleagues13Gladstone RA Lo SW Lees JA et al.International genomic definition of pneumococcal lineages, to contextualise disease, antibiotic resistance and vaccine impact.EBioMedicine. 2019; (published online April 16.)https://doi.org/10.1016/j.ebiom.2019.04.021Summary Full Text Full Text PDF PubMed Scopus (88) Google Scholar in EBioMedicine, which preceded the study by Lo and colleagues.1Lo SW Gladstone RA van Tonder AJ et al.Pneumococcal lineages associated with serotype replacement and antibiotic resistance in childhood invasive pneumococcal disease in the post-PCV13 era: an international whole genome sequencing study.Lancet Infect Dis. 2019; (published online June 10.)http://dx.doi.org/10.1016/S1473-3099(19)30297-XSummary Full Text Full Text PDF PubMed Scopus (98) Google Scholar After analysing the genetic structure of nearly 20 000 pneumococcal isolates from both carriage and invasive pneumococcal disease from various geographical origins, Gladstone and colleagues proposed an international definition of clusters that makes it possible to track their evolution more efficiently than multi-locus sequence typing. Of interest, two-thirds of the 35 predominant clusters expressed vaccine serotypes along with non-vaccine serotypes, which indicates the potential for spread and serotype replacement in these lineages. Using this cluster definition, Lo and colleagues described serotype replacement in South Africa and Israel due to increased incidence of clusters predominantly expressing non-PCV13 serotypes (defined by the authors as non-vaccine type clusters) and expansion of non-vaccine serotypes within clusters predominantly expressing PCV13 serotypes (defined as vaccine-type clusters). One of the most striking findings is the top emerging cluster, GPSC3, which in the period following PCV13 implementation expressed serotype 8 in South Africa but serotype 33F in Israel and the USA. Similarly, cluster GPSC5 was found to express serotype 35B/D in South Africa and Malawi but serotype 19A in Israel in the post-PCV13 period. Of interest, different clusters expressing the same serotype but different antibiotic-resistance profiles are evolving differently. For example, the spread of serotype 12F in Israel is related to an increase in the prevalence of the penicillin-resistant cluster GPSC55 and a decrease in that of the cluster GPSC26, which is mostly susceptible to penicillin. The authors also report an increase in antibiotic resistance among most of the emerging non-vaccine-type clusters, which probably results from the selection of ancient multidrug-resistant PMEN clones because of antibiotic use. Lo and colleagues present a novel complex pneumococcal landscape. Such species-wide whole-genome sequencing studies will undoubtedly help us to understand how S pneumoniae is adapting to its environment, mechanisms of vaccine escape and serotype replacement, and changes in invasiveness, disease profile, and antibiotic susceptibility, beyond the prism of serotype. Certainly, the geographical representation needs to be increased to refine the picture, and some crucial questions remain. For more than 15 years, we have known that the disease potential and clinical presentation varies from among serotypes,14Levy C Varon E Ouldali N Béchet S Bonacorsi S Cohen R Changes in invasive pneumococcal disease spectrum after 13 valent pneumococcal conjugate vaccine implementation.Clin Infect Dis. 2019; (published online March 14.)DOI:10.1093/cid/ciz221Crossref Scopus (17) Google Scholar but will different clusters expressing the same non-vaccine serotypes cause the same disease? By taking advantage of clinically well documented collections of pneumococcal strains, further cluster association studies by age, clinical presentation, and underlying diseases could provide some answers. EV reports grants from the French Public Health Agency and Pfizer and personal fees from Pfizer, outside of the submitted work. RC reports research grants to ACTIV from Pfizer, GlaxoSmithKline, MSD, and Sanofi-Pasteur and personal fees from Pfizer, GlaxoSmithKline, MSD, Sanofi-Pasteur, and Astra-Zeneca, outside of the submitted work. Pneumococcal lineages associated with serotype replacement and antibiotic resistance in childhood invasive pneumococcal disease in the post-PCV13 era: an international whole-genome sequencing studyGlobally spreading lineages expressing invasive serotypes have an important role in serotype replacement, and emerging non-vaccine serotypes associated with different pneumococcal lineages in different countries might be explained by local antibiotic-selective pressures. Continued genomic surveillance of the dynamics of the pneumococcal population with increased geographical representation in the post-vaccine period will generate further knowledge for optimising future vaccine design. Full-Text PDF Open Access