Background
Streptococcus pneumonia (
S. pneumoniae) is one of the most prominent pathogens, causing mild to life-threatening invasive diseases due to its well-known capsule pathogenicity [
1]. It has been reported that approximately 1 million people die of pneumococcal diseases annually, most of whom are children under 5 years old [
2‐
4]. Pneumococcal conjugate vaccines (PCVs) targeting 7, 10, or 13 of more than 90 serotypes of
S. pneumoniae have been successively introduced to reduce the burden of invasive pneumococcal disease (IPD) in vaccinated children in developed countries [
5,
6]. In fact, it has been reported that after licensing PCV13, pneumococcal diseases of any cause, but especially those caused by PCV13 minus PCV7 serotypes, were further decreased across each age group in the UK [
7].
In China,
S. pneumoniae is one of the most common pathogens and can cause infectious diseases, especially pneumonia, in children under 5 years of age [
8]. PCV7 was first introduced in mainland China in 2008 [
9] but due to its high price was not included as part of the national immunization schedule. Because of its high cost in the the private market [
10], and the vaccine may not be available to some low-income families, especially in western China. But a model predicted that every year, 112,629 cases of pneumococcal-related disease could be prevented in Shanghai if the PCV7 vaccine could be introduced [
11]. After employing PCV7, another multicenter study conducted in Shanghai in 2013 reported that the serotype coverage of PCV7, − 10, and − 13 was 58.6, 59.4 and 85.1%, respectively [
12].
Both genetic background and capsular type contribute to the ability of
S. pneumoniae to cause invasive diseases [
13,
14]. The aim of this study was to obtain a systematic estimate of the serotypes of
S. pneumonia and their antibiotic resistances and to determine clonal types causing IPD in mainland China.
Discussion
Epidemiological and clinical studies have shown that invasive pneumococcal diseases caused by
S. pneumoniae is a major public health burden. Based on a systematic review of the literature, Chen et al [
35] reported that approximately 700,000 children are diagnosed with pneumococcal disease each year and that approximately 30,000 deaths are attributed to
S. pneumoniae; moreover, over 50% of children with pneumonia in China died because of this pathogen. The high pneumococcal disease burden makes the investigation and evaluation of
S. pneumoniae serotypes important for providing evidence and guidance for the use of vaccines and antibiotics targeting the pathogen.
Our study revealed that the predominant serotypes circulating among Chinese children were 19F, 19A, 14, 6B and 23F. For children under 5 years old, the predominant serotypes were 19F, 19A, 14, 23F and 6B. A global serotype project confirmed that serotype 14 was the most prevalent cause of IPD among children under five in every region, including Asia; however, this systematic review did not include studies from mainland China, which contains the largest population of children under 5 years of age in the world [
36]. In that report, seven serotypes (1, 5, 6A, 6B, 14, 19F and 23F) accounted for over 50% of IPD in every region, including Asia, and our results demonstrated that 14, 19F, 6B, 23F and 19A accounted for 80.7 and 73.5% of all IPD in Chinese children 0–14 years and children under 5 years of age, respectively. The major serotype patterns of
S. pneumoniae in mainland China were consistent with the ANSORP study, which revealed that 19F, 23F, 19A, 14 and 6B were the major serotypes in Asia [
37]. Serotype 1 is reported as one of the 5 most common serotypes in many developing countries such as in South Africa Kenya and in Philippines [
37‐
39], but this serotype was infrequency in our study, which may revealed that the serotype distribution of S.pneumoniae was varied geographically [
40].
Pooled analysis of multiple surveillance sites revealed that vaccine-serotype and overall IPD rates declined consistently and significantly after PCV7 introduction, and this effect was still observed after 7 years [
41]. Unfortunately, these promising effects may not represent the important public health implications in some countries that did not implement routine immunization with PCVs, such as China [
10]. Although the PCV7 vaccine was imported into and licensed in China in 2008, this vaccine has not yet been included in the Chinese Expanded Program on Immunizations (EPI) [
42]. The PCV7 vaccine was removed from the market in 2015, though new vaccines, such as PCV10 and PCV13, have not yet been employed in the Chinese market, making the situation even worse [
10].
Our analyses revealed serotype coverage rates for PCV7, − 10, and − 13 of 60.8, 65.1, and 90.0%, respectively, for IPD among Chinese children. A cohort and case-control study conducted in Europe [
43] revealed that after the 13-valent pneumococcal conjugate vaccination was introduced, the overall IPD incidence declined in both vaccinated (hazard ratio, HR: 0.24, 95% CI: 0.14–0.40) and unvaccinated children (HR, 95% CI: 0.22, 0.09–0.55). The direct effect of PCV13 against vaccine serotypes was as high as 95%. According to two studies conducted in China, only 9.9% or 10.1% of children received a dose of PCV7 [
10,
44]. Such low vaccination may not produce satisfactory results for reducing the burden of pneumococcal diseases. A Markov simulation model conducted by Mo et al [
45] showed that PCV13 can reduce IPD by 31.3% and pneumonia by 15.3% in mainland China.
The high pneumococcal disease burden and the largest population baseline of children in China means that the cost-effectiveness of launching PCV7 or higher valence vaccines would improve if the government introduced the vaccines into the EPI. According to the mathematical model conducted by Hu et al [
46], a policy of universal PCV7 vaccination among infants in China would prevent approximately 10.8 million cases of disease and save 636,371 lives over 10 years, largely due to the indirect effectiveness of the vaccine on the unvaccinated population.
Global multi-region studies have revealed that the highest antibiotic resistance to
S. pneumoniae was consistently found in Asia [
37], and the ANSORP reports demonstrated that
S. pneumoniae isolates from mainland China had the highest antibiotic resistance rates [
37]. Indeed, it was reported that
S. pneumoniae isolated from Chinese children had the highest antibiotic resistance rates [
31]; the most predominant resistance, 96.4%, was to the antibiotic erythromycin, followed by tetracycline and sulfamethoxazole. Our study revealed
S. pneumoniae to be most frequently resistant to erythromycin, followed by clindamycin, tetracycline, and sulfamethoxazole, consistent with previous study and the ANSORP study [
37].
Our findings indicated a pooled penicillin resistance rate to
S. pneumoniae of 32.0% and a PNSP of 74.6%, which was much higher than the ANSORP study results but consistent with a study conducted in Beijing that revealed a total non-susceptibility rate of penicillin of 91.5% if based on an oral breakpoint of
Clinical and Laboratory Standards Institute (CLSI) [
31]. The limitation of our study is that we cannot estimate the resistance rate to penicillin based on revised CLSI breakpoints, as most of the included studies did not report the adaptation of the breakpoints. However, our results were partially consistent with the ANSORP study, which reported a resistance rate to penicillin of 60.0% for meningeal isolates [
37].
The snapshot from eBURST showed a great diversity among IPD strains isolated in mainland China. The predominant clones were CC271, CC876, CC81 and CC90. CC271 was the most predominant CC, and the inclusion of 11 STs, such as ST271, ST320, ST236, and ST4664, accounted for 43.6% of all the included isolates from the literature. Several studies have confirmed that this clone became prevalent prior to the introduction of PCV7 and spread rapidly among both adults and children in China [
44]. The widespread use of antibiotics has also been implicated in the emergence of serotype 19A and 19F isolates in both communities and hospitals. The two serotypes of the isolates were reported to be multidrug resistant and carriers of the
ermB and
mefA genes, making the situation even worse [
47,
48].
A significantly increased risk of CC271 strains, which caused IPD in our study, is anticipated among children and is in agreement with existing trends in the literature regarding transmission [
49]. ST236, namely the original Taiwan
19F-14 clone, was the major international antibiotic-resistant strain. In addition, long-term monitoring data revealed that ST271 and ST320 evolved rapidly and replaced ST236 due to their higher fitness and that they were becoming well established in local regions of China [
47]. It was also reported that CC271 is prevalent in Asian countries, such as Japan and Korea, due to the introduction of PCV7 [
50,
51]. After implementation of PCV7, non-vaccine-related serotypes, such as 19A, circulated among pediatric groups. This serotype was reported to be multidrug resistant due to PCV7 implementation and antibiotic selection pressure. The high prevalence of CC271 clones was consistent with the high penicillin non-susceptibility rate found in IPD isolates pooled in this study.
According to a multicenter study conducted in China, ST320, ST271, and ST876 were the prevalent types among IPD isolates collected from children [
52]. Another study showed that the CC876 prevalence increased from 0% in 1997–2000 to 96.4% in 2010–2012 in China, and the most important findings of this study were that this clone had high non-susceptibility rates to β-lactam antibiotics [
53].
CC81 comprises ST81 (Spain
23F-1, 5.2%, 19/365), and CC90 comprises ST90 (Spain
6B-2, 4.1%, 15/365), which were also found at lower frequencies in this study. These complexes are listed as internationally spread resistant CCs [
31].
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