Impact of pneumococcal conjugate vaccines on invasive pneumococcal disease-causing lineages among South African children

Abstract

Invasive pneumococcal disease (IPD) due to non-vaccine serotypes after the introduction of pneumococcal conjugate vaccines (PCV) remains a global concern. This study used pathogen genomics to evaluate changes in invasive pneumococcal lineages before, during and after vaccine introduction in South Africa. We included genomes (N = 3104) of IPD isolates from individuals aged <18 years (2005-20), spanning four periods: pre-PCV, PCV7, early-PCV13, and late-PCV13. Significant incidence reductions occurred among vaccine-type lineages in the late-PCV13 period compared to the pre-PCV period. However, some vaccine-type lineages continued to cause invasive disease and showed increasing effective population size trends in the post-PCV era. A significant increase in lineage diversity was observed from the PCV7 period to the early-PCV13 period (Simpson's diversity index: 0.954, 95% confidence interval 0.948-0.961 vs 0.965, 0.962-0.969) supporting intervention-driven population structure perturbation. Increases in the prevalence of penicillin, erythromycin, and multidrug resistance were observed among non-vaccine serotypes in the late-PCV13 period compared to the pre-PCV period. In this work we highlight the importance of continued genomic surveillance to monitor disease-causing lineages post vaccination to support policy-making and future vaccine designs and considerations.

Fig. 1. Single nucleotide polymorphism (SNP) maximum-likelihood phylogeny (N = 3104) of invasive pneumococcal disease isolates from South African children <18 years.

The SNP tree is midpoint rooted. The 10 most predominant GPSC taxa are highlighted and listed in descending order: GPSC3 (n = 255/3104 [8%], GPSC2 (n = 226/3104 [7%], GPSC17 (n = 202/3104 [7%], GPSC14 (n = 167/3104 [5%], GPSC10 (n = 155/3104 [5%], GPSC5 (n = 142/3104 [5%], GPSC13 (n = 126/3104 [4%], GPSC1 (n = 104/3104 [3%], GPSC41 (n = 93/3104 [3%], and GPSC21 (n = 91/ 3104 [3%]. Antibiotic nonsceptibility by GPSC lineage is represented by coloured circular strips: PEN penicillin, AMO amoxicillin, CFT ceftriaxone, TAX cefotaxime, CFX cefuroxime, MER meropenem, CHL chloramphenicol, ERY erythromycin, CLI clindamycin, FLU fluoroquinolones, TET tetracycline, COT cotrimoxazole, GPSC global pneumococcal sequence clusters.

Fig. 2. Global Pneumococcal Sequence Cluster (GPSC) dynamics among invasive disease isolates from children in South Africa (N = 3104).

a children <5 years (n = 2680) and b children 5–17 years (n = 424). Invasive pneumococcal disease incidence per 100,000 population is plotted by GPSC lineages stratified into four vaccine periods (pre-PCV [2005–2008], PCV7 [2009–2010], early-PCV13 [2011–2014], and late-PCV13 [2015–2020]). Serotypes included in the 13-valent pneumococcal conjugate vaccine are shown by solid colour fills and non-vaccine serotypes by hatched pattern colour fills. Lineages with <40 isolates are not shown. A vaccine-type (VT) lineage was defined as having ≥50% vaccine serotype(s) in the pre-PCV period; non-vaccine-type (NVT) lineage as having >50% non-vaccine serotype(s) in the pre-PCV period. Lineage-specific clonal complexes (CC) and sequence types (ST) are shown underneath the graph. Either Poisson regression or negative binomial regression was used to calculate the incidence rate ratios (IRR) of GPSCs by vaccine period. If neither model fit, the IRR was calculated using the average annual incidence (Supplementary Data 2–5). Significant changes in the average incidence between the pre-PCV and PCV7 or late-PCV13 periods are represented by an asterisk or triangle, respectively. Significance was determined at <0.05 using a two-sided p-value where applicable. Multiple testing (>10 tests) was corrected using the Benjamini–Hochberg false discovery rate of 5%. Antibiotic nonsusceptibility proportions by lineage are shown in red horizontal bars. Penicillin (PEN) nonsusceptibility was predicted based on the penicillin-binding protein types: pbp1a, pbp2x, pbp2b; chloramphenicol (CHL), based on the presence of chloramphenicol acetyltransferase gene, cat; erythromycin (ERY), based on the presence of erythromycin resistance methylase gene ermB or macrolide efflux pump gene mefA; tetracycline (TET), by the presence of tetM or tetS/M gene with no promoter region interruptions; cotrimoxazole (COT), by the presence of mutation I100L in folA and/or indel within amino acid residue 56–67 in folP.

Fig. 3. Temporal trend analysis of important vaccine-type lineages causing persistent invasive disease in the late-PCV13 period inferred using skygrowth.

a–d Past population size dynamics as a function of time inclusive of the pneumococcal conjugate vaccine (PCV) introduction years shown by the grey arrows (PCV7 in 2009 and PCV13 in 2011) in South Africa. Time-calibrated phylogenies were used for inference with root dates as start time. Root probabilities and the number of analysed genomes per lineage are shown in Supplementary Data 6. The clonal complexes (CC) and serotypes expressed by each lineage are shown in each panel title. The solid line represents the posterior median population size. The shaded purple area represents the 95% credible intervals. The effective population size on the y-axis is expressed in log scale. GPSC global pneumococcal sequence cluster. *Only serotypes that had 5 or more genomes are included in the (a–d) panel titles.

Fig. 4. Clonal expansion dynamics of Global Pneumococcal Sequence Cluster (GPSC) lineages inferred using CaveDive.

Time-resolved phylogenies for GPSC9 (a) and GPSC10 (b) showing within lineage clonal expansions with clades coloured by serotype. GPSC references are coloured in grey. The parental nodes with high probabilities for clonal expansions are highlighted by the clonal expansion frequency colour scale and the estimated expansion year with 95% credible intervals is included. Other parental nodes are highlighted in grey including the root date. GPSC global pneumococcal sequence cluster, CC clonal complex.

Fig. 5. Simpson’s diversity index (SDI) estimates for invasive disease serotypes and lineages.

a Serotype diversity trends by year showing fluctuations before and after the introduction of 7- and 13-valent pneumococcal conjugate vaccines (PCV7 and PCV13) in 2009 and 2011, respectively (highlighted in light grey); the COVID-19 pandemic year (2020) is highlighted in dark grey. b Pooled serotype SDI estimates by vaccine period showing statistically significant differences between the PCV7 and early-PCV13 periods and early-PCV13 and late-PCV13 periods. c Lineage diversity trends by year before and after the introduction of PCV7 and PCV13 in 2009 and 2011, respectively (highlighted in light grey); the COVID-19 pandemic year (2020) is highlighted in dark grey. d Pooled lineage SDI estimates by vaccine period showing statistically significant differences between the PCV7 and early-PCV13 period and early-PCV13 and late-PCV13 periods. Estimates were derived at a 95% confidence interval among invasive disease isolates (N = 3104) from children <18 years in South Africa during the pre-PCV (n = 924), PCV7 (n = 457), early-PCV13 (n = 882), and late-PCV13 (n = 841) periods. SDI estimates represent the measure of diversity with standard error included at each data point.