Abstract
Routine use of pneumococcal conjugate vaccines (PCV) in South Africa caused a decline in vaccine-associated invasive pneumococcal disease (IPD), followed by the emergence of non-PCV serotypes, driven mainly by pre-existing lineages. We determined the molecular epidemiology of isolates causing IPD among adults in South Africa from 2020 to 2025 before and following the implementation of PCV in 2009. We performed whole-genome sequencing on randomly selected isolates causing IPD among adults aged ≥18 years (N=1 581) during the four vaccine periods [pre-PCV (2005-2008), PCV7 (2009-2010), early-PCV13 (2011-2014) and late-PCV13 (2015-2020)]. We assigned in silico serotype, multi-locus sequence type, clonal complex (CC) and global pneumococcal sequence cluster (GPSC) and determined antimicrobial non-susceptibility profiles in silico. Poisson regression was used to calculate incidence rate ratios of imputed individual GPSC lineages using IPD incidence rate estimated per year for the three vaccine periods (PCV7, early-PCV13 and late-PCV13), compared to the pre-PCV period. Overall, our dataset represented 3.7% (n=270), 3.4% (n=128), 4.9% (n=287) and 13.5% (n=896) of adult pneumococcal isolates received during the four periods, respectively. We identified 135 GPSCs with the majority of isolates [68.7%(1 086/1 581)] clustering into 1 of 23 dominant GPSCs defined as GPSCs that comprised ≥20 genomes in the dataset. Compared to the pre-PCV7 period, a decrease in incidence of vaccine type lineages normally associated with vaccine serotypes was observed during the late-PCV13 period. GPSC2 (serotype 1) declined from 1.4 to 0.039/100,000 population (P<0.001). Some non-PCV lineages increased. GPSC26 (serotype 12F) increased from 0.07 to 0.3 (P<0.001). Of the 23 dominant GPSCs, 11 expressed ≥2 serotypes. While the majority of GPSC5/CC172 isolates expressed serotype 23F during the pre-PCV period (61.5%, 7/12), serotype 35B was the most common serotype (57.1%, 12/21) expressed by GPSC5/CC172 isolates during the late-PCV13 period. All GPSC9/CC63 isolates sequenced from the pre-PCV period (n=3) expressed serotype 14; however, during the late-PCV13 period, nearly all (88.2%, 15/17) were serotype 15A. The emergence among non-PCV13 serotypes, of lineages usually associated with PCV13 serotypes (such as GPSC5/CC172 and GPSC9/CC63), warrants continued genomic surveillance in South Africa, more so as PCV10 (Pneumosil) replaced PCV13 in South Africa in 2024.