Capsular switching and emergence of vaccine escape variants after PCV introduction

Impact of PCV7 and PCV13 implementation
Introduction of the 7-valent and 13-va­lent PCVs (PCV7 in 2000 and PCV13 in 2010, respectively) substantially decreased invasive pneumococcal disease (IPD) inci­dence, especially in children. Despite the effectiveness of PCVs against vaccine-type (VT) pneumococcal serotypes, emergence of NVT pneumococci has continued to drive the development of higher-valent vaccines, such as PCV20, offering broad­er serotype coverage. [Emerg Infect Dis 2021;27:1627-1636; Pediatr Infect Dis J 2024;43:596-603]

What is capsular switching?
The serotype of Streptococcus pneu­moniae is primarily determined by its poly­saccharide capsule, which is encoded by the capsule polysaccharide synthesis (cps) locus. The capsule is the target of current PCVs; it plays a crucial role in virulence by protecting the bacteria against phagocyto­sis during invasive disease and may also prevent clearance during nasopharyngeal colonization. [J Infect Dis 2013;207:439- 449]

The postvaccination increase in NVT pneumococci can be attributed to sero­type replacement and/or serotype switching. Serotype replacement involves the ex­pansion of pre-existing NVT strains, while serotype switching refers to a change of serotype within a single clone by alteration or exchange of its cps locus. It is worth noting that capsular switching events have been regular occurrences among pneu­mococci even before the introduction of PCVs. [J Infect Dis 2013;207:439-449]

Pneumococci are classified using Multi-Locus Sequence Typing (MLST) into different sequence types (STs), which are then grouped into clonal complexes (CCs) based on shared genetic similarity. Isolates within the same CC but with different sero­types may represent capsular switch vari­ants. [J Infect Dis 2013;207:439-449]

Emergence of vaccine escape serotype 3
Despite being included in PCV13, S. pneumoniae serotype 3 remains a signifi­cant global health concern because of its high tendency to recombine and form new clones through capsule switching, which allows it to evade vaccine protection. Since the introduction of PCV13, CC180 has emerged as the most prevalent lineage of serotype 3 worldwide. [PLoS Pathog 2018;14:e1007438]

A study conducted in Malawi explored the genomic and phenotypic characteris­tics of a S. pneumoniae serotype 3 variant after the introduction of PCV13. The analyses found clonal expansion of the Global Pneumococcal Sequence Cluster 10 (GPSC10)-ST700 serotype 3 lineage, which lacked six genes in its cps locus and exhibited enhanced vaccine escape po­tential. Specifically, the ST700 variant ex­hibited increased antimicrobial resistance and possessed clusters of virulence genes involved in pathogenicity and colonization. When tested against serum samples from vaccinated individuals, the ST700 variant showed lower susceptibility to opsono­phagocytic killing (the process by which phagocytic cells engulf and destroy bacte­ria tagged with opsonins, such as antibod­ies and complement proteins) compared with the reference ST5435 strain that has the full-length cps locus. The median opsonic indices for ST700 and ST5435 were 25.5 and 83.5, respectively (p=0.02; Mann-Whitney test). (Figure 1) [J Infect Dis 2024;230:e189-e198]

The authors proposed that the GP­SC10-ST700 serotype 3 lineage may have emerged initially from serotype 19A/19F through capsular switching events involv­ing gene loss, thus resulting in a modified capsule that is less susceptible to opsono­phagocytosis, and contributing to immune evasion among PCV13-vaccinated indi­viduals. [J Infect Dis 2024;230:e189-e198]

Rise in serotype 3–related IPD in HK children
In Hong Kong, IPD caused by sero­type 3 among children has increased in the post-PCV13 era. This is largely attributed to the emergence and spread of a novel ST6011 clone. A local study examined the impact of PCV implementation on IPD incidence among young children. IPD and serotype data were collected from multi­ple sources covering four periods of PCV availability: period 1 in 1995–2004 (pre-PCV), period 2 in 2006–2009 (private mar­ket, PCV7 only), period 3 in 2010–2014 (mixed use of PCV7, PCV10 and PCV13), and period 4 in 2015–2017 (>5 years of PCV13 only). [Hum Vaccin Immunother 2019;15:455-458]

During the entire study period, there was a 97 percent decrease in IPD caused by PCV7 serotypes. However, IPD incidence for PCV13-nonPCV7 serotypes increased substantially, and was attributed to a rise in disease caused by serotype 3. (Figure 2) [Hum Vaccin Immunother 2019;15:455-458]

Serotype 3 caused 59 percent of the IPD in period 4. Susceptibility data, avail­able for 52 serotype 3 isolates, showed erythromycin resistance rates of 74 percent in period 3 and 100 percent in period 4. Molecular analysis of 27 of the serotype 3 isolates from periods 3 and 4 revealed that 19 were of ST6011, and all were pos­itive for the ermB gene (which is associat­ed with macrolide resistance). However, the study’s authors advised caution in interpreting the proportion of serotype 3 disease attributed to the ST6011 lineage, as only half of the serotype 3 isolates from periods 3 and 4 were retrievable for mo­lecular analysis. [Hum Vaccin Immunother 2019;15:455-458]

ST6011 has been identified in both serotype 3 and serogroup 15 strains of S. pneumococci, which suggests its capacity for capsular switching and vaccine escape. [Hum Vaccin Immunother 2019;15:455-458]

Real-world impact of higher-valent PCVs
Both PCV10 and PCV13 have been implemented as part of paediatric national immunization programmes in several coun­tries. In immunogenicity trials, these vaccines missed noninferiority (NI) for certain PCV7 serotypes. However, a retrospective analysis using IPD surveillance data from nine countries showed high effectiveness of both higher-valent vaccines against IPD due to the respective PCV7 serotypes. [Expert Rev Vaccines 2024;23:879-886]

These findings suggest that immuno­genicity studies do not adequately predict real-world effectiveness of a vaccine programme, and may have implications for the 20-valent PCV (PCV20). In Hong Kong, PCV20’s indication has been recently expanded to include the paediatric population (6 weeks to <18 years of age). [PREVNAR20 Hong Kong Prescribing In­formation, July 2024]

In a phase III clinical trial, PCV20 induced robust immune responses compared with PCV13. For immunoglobulin G (IgG) geometric mean concentrations (GMCs) after both post-primary dose (PPD) (dose 3) and post-toddler dose (PTD) (dose 4), all 20 serotypes met the NI criteria. For percentage of participants with pre­defined IgG concentrations after PPD, NI was met for 8/13 matched serotypes and 6/7 additional serotypes. After PPD and PTD, PCV20 induced opsonophagocytic activity (OPA) geometric mean titres (GMTs) comparable to PCV13 for the 13 matched serotypes, and substantially higher GMTs for the 7 additional serotypes. PCV20 also induced OPA boosting in all serotypes mirroring the IgG boosting responses, in­dicating that the vaccine elicits functional memory responses after the infant doses. [Pediatr Infect Dis J 2024;43:596-603]