This meta-analysis is performed to examine the serotype distribution and coverage and antibiotic resistance patterns of S. pneumoniae after the introduction of PCV13 as a self-funded vaccine in the pediatric population under 14 years of age in China. Our comprehensive analysis revealed that serotypes 19 F, 19 A, 6B, 14, 6 A, and 23 F were predominantly observed in both invasive and non-invasive strains. Significantly, the coverage rates of serotypes by PCV10, PCV13, PCV15, and PPSV23 vaccines were calculated to be 52.17%, 74.77%, 76.72%, and 92.90%, respectively. In addition, significant resistance was observed in S. pneumoniae to erythromycin, which was the most common, followed sequentially by azithromycin, tetracycline, clindamycin, and sulfamethoxazole, necessitating a reevaluation of current therapeutic strategies against this pathogen.
The findings of this study have several important clinical and public health implications. Firstly, the persistence of certain serotypes, such as 19 F and 19 A, despite the introduction of PCV13, underscores the need for ongoing surveillance and potential updates to vaccine formulations to include additional serotypes prevalent in the Chinese pediatric population. The high prevalence of antibiotic-resistant strains highlights the urgent need for new antibiotics and alternative treatment strategies, particularly given the limited therapeutic options available for pediatric patients.
Although PCV13 has been available since 2016 and has broader serotype coverage compared to previous formulations, its uptake in China remains low. This vaccine is an out-of-pocket expense and is not currently included in the national immunization programme, despite recommendations to do so. This limited access can have a significant impact on low socioeconomic populations and remote areas where the burden of pneumococcal disease may be higher and access to vaccines more limited. The financial burden on families in these populations may result in lower vaccination rates, further exacerbating health disparities.
Moreover, the study underscores the importance of integrating PCV13 into the national immunisation programme to ensure broader and more equitable access to vaccination. Achieving higher vaccination coverage rates is crucial for reducing the incidence of pneumococcal diseases and preventing the spread of antibiotic-resistant strains. This is particularly important in low socioeconomic and remote populations, where the burden of disease is often highest, and healthcare access is limited.
Our study also highlights the need for more carriage studies. Carriage studies are essential in understanding the transmission dynamics of S. pneumoniae and the impact of vaccination on pneumococcal ecology. They provide critical insights into the prevalence and spread of different serotypes within communities, particularly in populations where vaccine coverage is suboptimal. Future research should prioritize these studies to inform and optimize vaccination strategies.
In the context of the post-PCV13 vaccination era, our research has shown that the predominant serotypes of S pneumoniae include 19 F, 19 A, 6B, 14, 6 A, and 23 F. This serotype prevalence, although with minor variations in order, is consistent with patterns observed in pre-PCV13 vaccine studies [25,26,27]. Fu JJ, et al. [25] conducted a meta-analysis of 16 studies published before September 2016, focusing on the serotype distribution and antibiotic resistance of S. pneumoniae causing IPD in China. The study reported a predominant distribution of serotypes 19 F (27.7%), 19 A (21.2%), 14 (16.5%), 6B (8.6%), and 23 F (7.3%) in children. Similarly, Lyu S, et al. [26] conducted a systematic review that included studies from 2006 to 2016 on S. pneumoniae serotypes isolated from children aged < 14 years in mainland China. In their review of 40 studies conducted before the licensure of PCV13, the most common serotypes were 19 F, 19 A, 23 F, 14, and 6B [26]. Taken together, these findings suggest that the primary serotype profile of S. pneumoniae in the Chinese pediatric population remained unchanged after the licensing of PCV13 in 2016, suggesting a negligible effect of PCV vaccine on the predominant serotype distribution of S. pneumoniae.
Our study found that the predominant pneumococcal serotypes in the northern and southern regions of China exhibited a remarkable uniformity, suggesting a homogenous distribution pattern of these serotypes across the nation. This observation is consistent with findings from other regions of China. For example, in the northern region, Beijing demonstrated prevalence of serotypes 19 F, 19 A, 23 F, 14, and 6 A [28], while in the southern region, Liuzhou reported 19 F, 6B, 19 A, 24 F, and 14 [29]. Similar patterns were observed in Shanghai in the eastern region (19 F, 19 A, 14, and 6B) [30] and Chongqing in the western area (19 F, 61, 6B, and 19 A) [31]. In contrast, developed countries have markedly different prevalent serotypes. For instance, in the USA, the predominant serotypes include 35B, 3, 11 A, and 11D [32], whereas in the UK and Ireland, they are 3, 8, and 15 A [33], and in Japan, they are 12 F, 3 and 23 A [34]. However, slight discrepancies were observed in developing nations. Thailand reports serotypes 6B, 23 F, and 14 [35], Malaysia 14, 6B, 19 A and 6 A [36], Mexico 19 A, 3, 15B and 19 F [37], and Northern Russia 19 F, 23 F and 6 A [38]. The variation in serotype distribution may be attributed to factors such as the divergent evolutionary trajectories of native S. pneumoniae across different regions, resulting in distinct capsular genotypes; differential susceptibilities among diverse racial populations to specific S. pneumoniae serotypes; and the disparity in PCV coverage in various populations, which arguably is the most critical determinant.
Our analysis of non-vaccine serotypes revealed that the most common serotypes not covered by PCV13 were 6 C, 15B, 16 F, and 15 A. The increasing prevalence of these non-vaccine serotypes suggests potential serotype replacement, which is a concern with the widespread use of PCVs. Understanding the dynamics of non-vaccine serotypes is crucial for monitoring the long-term effectiveness of PCV13 and informing future vaccine development strategies. Continuous surveillance and updating of vaccine formulations to cover emerging non-vaccine serotypes are essential for maintaining the efficacy of pneumococcal vaccination programs.
Serotype replacement has been observed in regions where PCVs are widely available [39, 40]. An interesting finding in our study was that the PCVs-covered serotypes decreased slightly as compared to the data before the PCV13 vaccine was introduced [25, 26]. The serotype coverage rates of PCV10 and PCV13 in our study were 52.17%, and 74.77%, as compared to that of 60.8%, 65.1% and 90.0% in the studies before the introduction of PCV13 [25, 26]. These results were also reported by Yan ZY, et al. [23] who investigated the prevalence, serotypes and antibiotic susceptibility of S. pneumonia isolated from Chinese children from 2017 to 2019. In that study, the authors reported that the PCVs-covered serotypes decreased slightly (PCV10: 69.7% VS.50.8%; PCV13: 93.3% VS.77.3%), as compared to their previous data obtained before the introduction of PCV13 [41]. These may attributed to the introduction of PCV13 in 2016. Although the serotype coverage of PCV13 was slightly decreased after the introduction of PCV13, our result was still higher than that in other developed countries. For example, the serotype coverage of PCV13 was 52% in Spain [42], 41.4% in USA [39], and 37.5% in Japan [40].
An interesting finding in our study was that the coverage of PCV10, and PCV13 for IPD strains was less compared to non-IPD strains. This contrasts with a previous meta-analysis covering the period before PCV13 introduction in China, which included 85 studies (2000–2016) and found higher vaccine coverage for invasive isolates [43]. Contrarily, another U.S. meta-analysis highlighted a substantial decline in IPD rates following 5-years of PCV13 licensure, predominantly due to reductions in serotype 19 A [44]. In mainland China, despite PCV7 licensure in 2008 and PCV13 in 2016, their adoption as self-paid vaccines was limited, implying that the 20-year serotype fluctuation in China was minimally influenced by PCV introduction. The primary shifts observed were increases in serotypes 19 A and 19 F from 2000 to 2004, likely driven by antibiotic selective pressure. Notably, even with limited PCV7 usage, the rise in serotype 19 A was significant, making it a prevalent serotype across many regions in China [44]. In contrast, in the U.S., serotype 19 A, not covered by PCV7, escalated from 2.7% in 1999–2000 to 34.1% in 2010–2011 post-PCV7 licensure, a trend attributed primarily to serotype replacement post-vaccination [39, 45].
The advent of antibiotic-resistant S. pneumonia in recent years has precipitated novel complexities in clinical anti-infective regimens, particularly in pediatric populations whose liver and kidney functions are not fully developed, increasing their vulnerability to drug toxicity [46, 47]. This study observed a 27.74% resistance rate to penicillin, a notable decrease from the 45.1% reported prior to the PCV13 vaccine introduction [25]. This aligns with a study in Japan, which showed a reduction in penicillin resistance from 54.3 to 11.2% following the PCV13 introduction, correlating with the diminished prevalence of penicillin-resistant and intermediate genotypes, particularly in serotypes 6B, 14, 19 F, 23 F, and 6 A among children [48]. Furthermore, we noted that resistance rates for S. pneumonia to antibiotics such as ceftriaxone, chloramphenicol, rifampicin, moxifloxacin, meropenem, and levofloxacin were below 10.00%, consistent with previous studies [13, 14, 17, 23]. This may be linked to the lower usage of these antibiotics in treating S. pneumonia infections in this area. However, the high resistance rates to erythromycin, tetracycline, and azithromycin, all over 80%, are alarming and require immediate attention. The urgent need for new S. pneumonia vaccines is evident, with WHO recommending in 2019 the inclusion of PCVs in immunization programs to protect children’s health [49].
Strengths and limitations
This study has several strengths. Firstly, it is the first meta-analytic effort to comprehensively examine the serotype distribution and antibiotic resistance patterns of S. pneumoniae in Chinese children post-PCV13 introduction. Secondly, the inclusion of multiple databases and rigorous selection criteria ensures a broad and representative sample of studies. Thirdly, the analysis includes data from 12 studies with a total of 6593 S. pneumoniae strains for serotyping, which increases the statistical power of the results.
However, this study also has limitations. Initially, a lack of adequate data precluded the execution of a subgroup analysis distinguishing between community-acquired and hospital-acquired pneumonia. Secondly, in certain instances, the delineation between data collated post-2017 and pre-2017 was unfeasible, necessitating the exclusion of these studies from our analysis, which may have introduced a degree of bias. Thirdly, the study encountered substantial heterogeneity in several outcomes. This heterogeneity could be attributable to various factors, including geographical diversity, age discrepancies among pediatric subjects, differences in the study periods, and potentially other unidentified variables. Lastly, the studies included in this meta-analysis span from 2017 to 2024, a period that overlaps with the COVID-19 pandemic. It is plausible that the pandemic may have contributed to reduced PCV13 vaccination rates, potentially influencing outcomes like the distribution of pneumococcal serotypes and antimicrobial resistance profiles. Given these considerations, our results should be interpreted with caution.
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