Prevalence and serotype distribution of nasopharyngeal carriage of Streptococcus pneumoniae in Vietnam: a systematic review and meta-analysis

Summary

Background

Streptococcus pneumoniae (S. pneumoniae) is a leading cause of childhood morbidity and mortality worldwide. While pneumococcal conjugate vaccines (PCVs) have significantly reduced the global burden of pneumococcal disease, Vietnam has yet to introduce PCV into their National Immunisation Program. Better understanding of pneumococcal disease in Vietnamese children is key to informing vaccination policy, including PCV product selection. The aim of this study was to assess the prevalence, serotype distribution, and antimicrobial susceptibility patterns of nasopharyngeal carriage of S. pneumoniae among children in Vietnam.

Methods

We conducted a systematic review and meta-analysis of S. pneumoniae carriage studies in Vietnamese children under 18 years of age. Seven international biomedical research databases and 13 key Vietnamese-language journals were searched without language or publication date restrictions. The Joanna Briggs Institute critical appraisal tools were used to assess the quality of articles. We extracted data on the prevalence of S. pneumoniae carriage and the serotype distribution. Where available, we also extracted the proportions of isolates that were non-susceptible to selected antibiotics. The pooled prevalence, serotype distribution, and antibiotic resistance rates were calculated with 95% confidence intervals (CIs) using random-effects models.

Findings

A total of 1197 studies were searched, of which 594 unique studies were identified and screened. 15 studies, conducted between 1996 and 2020, were included in the systematic review and meta-analysis. The pooled prevalence of nasopharyngeal carriage of S. pneumoniae among Vietnamese children was 33% (95% CI: 28%–39%). The most common vaccine serotypes associated with colonisation were 6A (23%), 19F (17%), 6B (15%), 23F (10%), 14 (8%), and 19A (3%). High non-susceptibility rates were observed for penicillin (64%), macrolides (70%–91%), sulfamethoxazole–trimethoprim (70%), tetracycline (84%), and several other antibiotics. Moderate to low non-susceptibility rates were observed for amoxicillin (22%), amoxicillin-clavulanate (6%), moxifloxacin (1%), vancomycin (1%), and rifampicin (0%).

Interpretation

The prevalence of S. pneumoniae nasopharyngeal carriage in children, a surrogate for potential invasive disease, was high in Vietnam, with substantial antimicrobial resistance detected. The predominant serotypes circulating in the community are covered by available PCVs. Inclusion of PCV into the country's National Immunisation Program at the earliest opportunity will have a large impact on childhood disease.

Funding

Gavi, the Vaccine Alliance, and Australia’s Department of Foreign Affairs and Trade (DFAT) provided funding support for this project.

Research in context.

Evidence before this study

While pneumococcal conjugate vaccine (PCV) introduction has substantially reduced the global burden of pneumococcal disease and mortality in over three-quarters of the countries in the world, Vietnam has not yet introduced PCV into its National Immunisation Program. Understanding the epidemiology of pneumococcal carriage and disease in Vietnam is key to informing immunisation policy, including PCV product selection.

Before this study, data on invasive pneumococcal disease (IPD) causing serotypes in Vietnam were limited and unrepresentative, as reporting on IPD cases in Vietnam has typically been passive and limited to ad hoc studies with small sample sizes. To provide high-quality local evidence to support evidence-based decision-making (EBDM), we conducted this systematic review on prevalence and serotype distribution of Streptococcus pneumoniae nasopharyngeal carriage—a key surrogate for potential invasive disease.

We systematically searched seven international databases (MEDLINE, EMBASE, Global Health, Scopus, Web of Science, Global Index Medicus, and the Cochrane Library) and 13 Vietnamese-language journals, without restriction on language or publication date. The 15 included studies, conducted between 1996 and 2020, involved over 13,000 children under 18 years of age, and covered northern, central, and southern Vietnam. The pooled prevalence of nasopharyngeal carriage of S. pneumoniae among Vietnamese children under 18 years of age was 33% (95% CI: 28%–39%). The most common vaccine serotypes associated with colonisation were 6A (23%), 19F (17%), 6B (15%), 23F (10%), 14 (8%), and 19A (3%).

Added value of this study

This study provides up-to-date, representative, and robust evidence on the serotype distribution of S. pneumoniae in Vietnamese children. Our findings provide key data to estimate serotype-specific PCV coverage, essential parameters for future economic models and cost-effectiveness analyses, and robust local evidence to support PCV product selection. The main strengths of this study are its comprehensive and broad search strategy and its strong consistency with the serotype distribution from local IPD cases.

Implications of all the available evidence

Taking swift action to include PCV into the National Immunisation Program in Vietnam, with high population-based uptake to ensure herd immunity benefits, would assist in addressing the heavy pneumococcal disease burden and high antimicrobial resistance in Vietnam. Both PCV13 and PCV10–SII cover the six most prevalent vaccine serotypes (6A, 6B, 14, 19A, 19F, and 23F) among Vietnamese children. A three-dose vaccination schedule, recommended by the WHO Strategic Advisory Group of Experts on Immunisation (SAGE), is important at the introduction phase.

Introduction

Streptococcus pneumoniae (S. pneumoniae) is the leading cause of bacterial pneumonia, meningitis, sepsis, and other severe infections in young children, and is associated with high rates of morbidity and mortality.¹ Pneumococcal disease was estimated to be responsible for 97.9 million low respiratory infection episodes and 505,000 deaths in 2021.² In countries where pneumococcal conjugate vaccines (PCVs) has been part of the infant National Immunisation Program schedules, there has been a remarkable decline in pneumococcal disease and deaths.³

Three PCVs have received WHO prequalification for use in children, with clinical trials and post-implementation studies demonstrating their safety, immunogenicity, and effectiveness: (1) the 13-valent PCV manufactured by Pfizer (PCV13), (2) a 10-valent PCV from GlaxoSmithKline (PCV10-GSK), and (3) a 10-valent PCV from Serum Institute of India (PCV10-SII). PCV13 and PCV10-SII are both conjugated to CRM₁₉₇, while PCV10-GSK is conjugated to Protein D, which may provide additional protection against non-typeable Haemophilus influenzae (NTHi).⁴ As shown in Fig. 1, these vaccines differ in their serotype compositions. PCV13 includes the serotypes present in both PCV10-GSK and PCV10-SII, with the addition of serotype 3. However, data on PCV13 impact on serotype 3 are inconclusive, with most studies showing no impact.^5,6 Cross-protection has been observed against serotype 6A in PCV10-GSK (conferred by the inclusion of serotype 6B), and against serotype 6C in PCV13 (conferred by the inclusion of serotype 6A).^5,6 Although higher-valency vaccines, such as PCV15 and PCV20, are now being used in some high-income countries, their cost is likely to exceed the budget constraints of most National Immunisation Program schedules and there is limited evidence on their real-world effectiveness in Vietnam to inform cost-effectiveness analyses.

Fig. 1.

Serotype coverage of the three WHO-prequalified pneumococcal conjugate vaccines.

Vietnam is planning a phased introduction of PCV into its National Immunisation Program beginning in 2025.⁷ While PCV has been used in the private market in Vietnam, no national data is available on the extent of uptake. The selection of a PCV product for population-based programs should be based, alongside other factors, on local pneumococcal disease data, especially the proportions of invasive pneumococcal disease (IPD) in children caused by serotypes included in the respective PCVs.⁵ However, implementing robust IPD surveillance programs in resource-constrained settings is challenging due to its labour- and resource-intensive nature.⁸ A previous review highlighted a lack of data on IPD causing serotypes in Vietnam, with the main limitations being the small number of sterile site isolates routinely obtained and lack of representativeness.^9,10 These data are insufficient to support the decision-making regarding the selection of the PCV in Vietnam.9, 10, 11, 12

Carriage of S. pneumoniae in the nasopharynx plays an important role in the transmission of this pathogen and resultant pneumococcal disease, and is a necessary precursor to IPD.¹³ Carriage studies are relatively more feasible in resource-constrained settings and have been effectively used as an alternative method for IPD surveillance¹⁴ to ascertain circulating serotypes including monitoring changes post PCV introduction.⁹ In Vietnam, a robust evaluation of the serotype distribution of S. pneumoniae nasopharyngeal carriage could provide valuable evidence to inform the selection of an appropriate PCV product. In addition, given previously reported high rates of antimicrobial resistance in Vietnam, it is also important to assess resistance patterns of carriage specimens as nasopharyngeal carriage can serve as a reservoir for antibiotic-resistant S. pneumoniae clones.¹⁵

The primary aim of this systematic review was to assess the overall prevalence and serotype distribution of nasopharyngeal carriage of S. pneumoniae among children in Vietnam. The secondary aim of this review was to describe antimicrobial resistance patterns of the S. pneumoniae nasopharyngeal isolates.

Methods

This systematic review was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO) (Registration ID: CRD42024612665). The review process and its reporting adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guideline.¹⁶ The study was approved by the Sydney Children's Hospitals Network Human Research Ethics Committee, Sydney, Australia. Human Research Ethics Committee Reference Number: 2024/ETH02633.

Search strategy and selection criteria

Seven databases (Ovid MEDLINE, Ovid EMBASE, Ovid Global Health, Scopus, Web of Science, Global Index Medicus, and the Cochrane Library) were systematically searched for published articles in December 2024. Additionally, 13 key Vietnamese journals (the Vietnam Medical Journal, Journal of Preventive Medicine, Journal of Medical Research, Journal of Practice Medicine, Vietnam Journal of Public Health, Ho Chi Minh City Medical Journal, Journal of Paediatric Research and Practice, Vietnam National University Journal of Science, Journal of Military Medicine and Pharmacy, Hue Journal of Medicine and Pharmacy, Journal of Clinical Medicine—Hue Central Hospital, Journal of Community Medicine, and Vietnam Pediatrics Associations) were hand-searched in January 2025 to identify published articles that may not be indexed in biomedical databases. Tailored search strategies were developed, tested, and applied for each database to ensure comprehensive retrieval of relevant literature (Supplementary File S1). No language or publication date restrictions were applied.

The pre-defined inclusion criteria were: (1) study was conducted in Vietnam or contained Vietnam study sites, (2) subjects were children <18 years of age; (3) subjects were recruited from community settings (e.g., including schools, households, communes) so as to be representative of vaccine target population; (4) subjects were not vaccinated with PCV; (5) samples were collected from nasal, nasopharyngeal or oropharyngeal swabs; (6) study contained extractable data on S. pneumoniae carriage. The exclusion criteria were: (1) animal study; (2) study did not contain data on S. pneumoniae; (3) subjects were adults only; (4) subjects were recruited from hospital settings; (5) subjects previously received one or more doses of PCV; (6) study lacked sufficient data for meaningful extraction.

All independent reviewers (XT, KS, TTN, HTTD, LTD, THMD) participated in a standardised study protocol training session to ensure consistency. The team used Covidence software to facilitate screening and resolved any disagreements through discussion.

Data extraction

Two researchers (XT and KS) extracted the following data independently: (1) General information: first author, year of publication, study period, study location, study population, type of swab, identification method for S. pneumoniae, number of participants, and number of participants with S. pneumoniae carriage. We also extracted age-specific carriage prevalence rate when studies reported disaggregated data at specific age points (e.g., at 9 months) or by age groups (e.g., 0–5 years). When the mean age was not reported, the midpoint value was calculated as the average of the minimum and maximum ages within each age group. (2) Serotype data: serotyping method, number of isolates that underwent serotyping, number of different serotype isolates; (3) Antimicrobial susceptibility data: standards for antimicrobial susceptibility testing, total number of isolates tested for antimicrobial susceptibility, number of resistant, intermediate, susceptible, and non-susceptible isolates. We used the publicly available tool WebPlotDigitizer (version 5) to extract numerical data from studies that presented results in graphical form only and whose authors could not be contacted for additional data. When a study reported only proportions, we estimated the absolute numbers based on the total sample size.

Quality assessment

An appraisal tool adopted from the Joanna Briggs Institute's Checklist for Prevalence Studies was used to assess the quality of the eligible studies.¹⁷ The quality assessment was performed by two independent reviewers (XT, KS), and any disagreement was solved by discussion.

Meta-analysis

The meta-analysis synthesised extracted data from all eligible studies. Based on the high heterogeneity (I² > 75%) observed in previous meta-analyses on this topic in other countries,18, 19, 20 DerSimonian and Laird random-effects models were used to calculate the pooled prevalence and proportions and the 95% confidence intervals (CIs). Subgroup analyses were performed to explore whether study and patient characteristics of interest were associated with the variation in the carriage prevalence. Sensitivity analyses were performed to assess the robustness of pooled estimates. For the serotype distribution meta-analysis, we calculated the proportion of carriage due to individual serotypes. We divided the total number of isolates of specific serotype by the total number of positive S. pneumoniae isolates that underwent serotyping. We considered all serotypes included in the PCV13 vaccine as vaccine types (VT) and the others as non-vaccine types (NVT). For the antimicrobial resistance meta-analysis, we calculated the rates of non-susceptibility by dividing the total number of both resistant and intermediate isolates by the total number of isolates that underwent antimicrobial testing. To avoid changes in definitions associated with the revision of Clinical and Laboratory Standards Institute (CLSI) standards,²¹ and for consistency with the European Committee on Antimicrobial Susceptibility Testing (EUCAST),²² we defined penicillin susceptibility according to oral, non-meningitis breakpoints (susceptible: ≤0.06 μg/mL; intermediate 0.12–1.0 μg/mL; resistant: ≥2.0 μg/mL). Where applicable, we also distinguished susceptibility standards for meningitis, non-meningitis, and oral antibiotic use. As the studies included in our meta-analysis were observational and descriptive in nature, the risk of publication bias was less significant. Nonetheless, we evaluated the potential publication bias by examining funnel plots. STATA version 18.0 was used to perform all statistical analyses.

Role of the funding source

The funders of the study had no direct or indirect role in the study design, data collection, data analysis, interpretation, or manuscript writing.

Results

Study selection

Fig. 2 provides an overview of the study selection process. The initial database search identified 771 records from international biomedical databases and 428 records from key Vietnamese-language journals. After deduplication, 594 unique records remained. Of these, 567 studies were excluded at title and abstract screening, and 12 were excluded at full-text screening. A total of 15 eligible studies were included in this review and meta-analysis.

Fig. 2.

PRISMA flow diagram for inclusion of studies in the review.

Characteristics of included studies and quality assessment

Table 1 summarises the main characteristics and quality assessment scores of the included studies. Pneumococcal carriage studies conducted between 1996 and 2020 were geographically distributed across Vietnam's three principal regions: the Northern region (centered around Hanoi), the Central region (around Nha Trang), and the Southern region (around Ho Chi Minh City). Five studies used a convenience sampling method by recruiting children who attended schools on the day of survey, seven studies used a census-based sampling method with participants selected randomly using the census data, and three studies were randomised controlled PCV trials. The three included PCV trials (Smith-Vaughan 2023,³⁴ Yoshida 2024,³⁵ Temple 2023³⁶) provided extractable carriage data from their unvaccinated control groups. The PCV trials recruited infants and toddlers under 2 years of age, while the remaining studies included children either up to 5 years or <18 years of age. Five studies specifically enrolled ‘healthy’ children who had no symptoms of respiratory infection and no recent antibiotic use, whereas the remaining ten studies applied broader criteria with no restrictions on participants' health status. Additional details on the types of swabs collected, study settings, and serotyping methods are provided in Supplementary Table S1.

Table 1.

Study and participant characteristics of included studies in the systematic review (n = 15).

Study	Sample year	Location/s	Sampling method	Age range	Recruitment criteriaa	Spn carriage identification method	Positive/Total samples, prevalence of Nasopharyngeal carriage of Spn	Quality score
Parry 200023	1996–1999	HCMC Dong Nai Province Khanh Hoa Province	Convenience sampling in schools and communities	1–16 years	All children	Optochin susceptibility	404/911, 44%	7
Lee 200124	1998–1999	HCMC	Convenience sampling in schools and communities	<5 years	Healthy children only	Optochin susceptibility; Bile solubility	104/295, 35%	6
Larsson 200025	1999	Hanoi	Census-based sampling	1–5 years	All children	Optochin susceptibility	87/200, 44%	7
Quagliarello 200326	1999	HCMC Dong Nai Province	Convenience sampling in schools and communities	<18 years	All children	Optochin susceptibility	150/529, 28%	6
Ahn 200727	2001–2002	Hanoi	Convenience sampling in schools and communities	<5 years	Healthy children only	Unclear	7/70, 10%	4
Schultsz 200728	2003–2004	HCMC Binh Phuoc Province Khanh Hoa Province	Convenience sampling in schools and communities	<7 years	All children	Optochin susceptibility; Bile solubility	536/1422, 38%	7
Hoa 201029	2007	Hanoi	Census-based sampling	6–60 months	All children	Optochin susceptibility	421/818, 51%	8
Dhoubhadel 201430	2008	Nha Trang	Census-based sampling	<5 years	Healthy children only	Optochin susceptibility; lytA real-time PCR	140/350, 40%	7
Nguyen 201931	2008	Nha Trang	Census-based sampling	<5 years	Healthy children only	Optochin susceptibility; Bile solubility	95/331, 29%	9
Vu 201132	2008	Nha Trang	Census-based sampling	<5 years	Healthy children only	Multiplex PCR	176/350, 50%	9
Larsson 202133	2013–2014	Hanoi	Census-based sampling	6–59 months	All children	Optochin susceptibility	221/546, 40%	8
Smith-Vaughan 202334	2013–2016	HCMC	Unvaccinated control group of PCV RCT	2–24 months	All children	Optochin susceptibility; lytA real-time PCR	225/1306, 17%	8
Yoshida 202435	2016	Nha Trang	Unvaccinated control group of PCV RCT	4–24 months	All children	lytA real-time PCR	953/3123, 31%	9
Temple 202336	2017–2020	HCMC	Unvaccinated control group of PCV RCT	6–24 months	All children	Optochin susceptibility; lytA real-time PCR	591/3085, 19%	8
Tran 202237	2018–2019	Binh Luc District, Ha Nam Province	Census-based sampling	<10 years	All children	Optochin susceptibility	73/307, 24%	7

Note: Spn, Streptococcus pneumoniae; HCMC, Hoi Chi Minh City; RCT, randomised controlled trial.

^aHealthy children were defined as those who showed no signs of respiratory infections and had no history of antibiotic use within a specified period prior to enrolment.

The quality assessment of the 15 included studies using the Joanna Briggs Institute's checklist for prevalence studies is presented in Supplementary Table S2. Three studies met all nine quality assessment criteria, 11 studies scored between 6 and 8, and one study (Ahn 2007²⁷) with small sample size (n = 70) and insufficient description on collection, culture, and storage of samples, was rated with a low score of 4 (Table 1).

Carriage prevalence and serotype distributions

All 15 eligible studies, involving 13,643 children under 18 years of age, were included in the meta-analysis. The pooled prevalence of nasopharyngeal carriage of S. pneumoniae among Vietnamese children was 33% (95% CI: 28%–39%) (Fig. 3). The meta-analysis of carriage prevalence showed considerable variation between studies (study prevalence ranged between 10% and 51%) and high heterogeneity (I² = 98.2%). As shown in Table 2, the most prevalent vaccine type serotypes identified were 6A (23%), 19F (17%), 6B (15%), 23F (10%), 14 (8%), and 19A (3%).

Fig. 3.

Pooled prevalence of nasopharyngeal carriage of S. pneumoniae from 15 included studies among 13,643 children in Vietnam aged <18 years.

Table 2.

Vaccine-type serotype distribution of nasopharyngeal carriage of S. pneumoniae.

Serotype	Proportion (95% CI)	Total no. of samples being serotyped	No. of samples of each serotype	No. of included studies	I2	P	References
1	0% (0%, 0%)	1986	5	5	7.86%	0.36	23,24,34, 35, 36
3	0% (0%, 1%)	1986	10	5	0.00%	0.42	23,24,34, 35, 36
4	0% (0%, 0%)	1861	3	4	0.00%	0.48	24,34, 35, 36
5	0% (0%, 0%)	1861	0	4	0.00%	0.88	24,34, 35, 36
6A	23% (14%, 31%)	1769	446	3	93.86%	<0.01	34, 35, 36
6B	15% (12%, 18%)	1769	253	3	65.49%	0.06	34, 35, 36
7F	0% (0%, 0%)	1769	0	3	0.00%	0.86	34, 35, 36
9V	0% (0%, 1%)	1945	9	4	31.51%	0.22	32,34, 35, 36
14	8% (5%, 10%)	2572	153	9	83.85%	<0.01	23,24,28,30, 31, 32,34, 35, 36
18C	0% (0%, 0%)	1769	3	3	0.00%	0.37	34, 35, 36
19A	3% (1%, 5%)	2085	82	5	93.57%	<0.01	30,32,34, 35, 36
19F	17% (12%, 21%)	2177	377	6	83.46%	<0.01	30, 31, 32,34, 35, 36
23F	10% (7%, 13%)	2177	240	6	74.22%	<0.01	30, 31, 32,34, 35, 36

Note: I², I-squared index for heterogeneity; P, P value for heterogeneity.

Subgroup analyses of carriage prevalence

Subgroup analysis by age range of study participants (Supplementary Figure S1) showed that the three PCV RCTs enrolling young infants and toddlers (>50% under 1 year of age) had significantly lower carriage prevalence (22%, 95% CI: 14%–30%) compared to other studies involving older children (P for heterogenicity = 0.02). Age-specific data from individual studies showed a sharp increase in pneumococcal carriage prevalence rates from birth to 12 months, a plateau between 12 and 24 months, and a gradual decline beyond 24 months (Fig. 4). Four studies showed notable heterogeneity compared with the others (Supplementary Figure S2). Three were PCV trials that recruited young infants and toddlers (P for heterogenicity = 0.02), and one was a low-quality study. After excluding these studies, we found no significant different across studies with different recruitment criteria on health status (P for heterogeneity = 1.00), type of swabs (P = 0.54), sampling method (P = 0.54), study setting (P = 0.92), and study period (P = 0.54) (Supplementary Figure S3).

Fig. 4.

Age-specific prevalence of nasopharyngeal carriage of S. pneumoniae. Note: Two studies reported carriage prevalence at specific ages (e.g., at 6 months), and seven studies reported prevalence by age groups (e.g., 0–5 years). For the latter, the midpoint value was calculated as the average of the minimum and maximum ages within each reported age group.

Publication bias

The symmetrical funnel plot, after excluding the four heterogenous studies, showed no evidence of publication bias on the reported prevalence of nasopharyngeal carriage (Supplementary Figure S4).

Antimicrobial resistance patterns

As shown in Table 3, eight studies, conducted between 1996 and 2024, reported data of antimicrobial resistance to a range of antibiotics. These nasopharyngeal samples of S. pneumoniae in Vietnamese children showed high, but variable non-susceptibility rates to several antibiotic classes. Almost all isolates were non-susceptible to gentamicin (98%), ciprofloxacin (98%), and cefaclor (95%). High non-susceptibility rates were observed across all three macrolides–erythromycin (70%), clarithromycin (90%), and azithromycin (91%)–as well as for two carbapenems (imipenem [63%] and meropenem [75%]). Most cephalosporins also showed high non-susceptibility (>30%), except for cefotaxime (non-meningitis, 22%) and ceftriaxone (meningitis, 12%). Other antibiotics with high non-susceptibility included clindamycin (86%), tetracycline (84%), sulfamethoxazole–trimethoprim (70%), penicillin (64%), ofloxacin (48%), and chloramphenicol (44%). Moderate non-susceptibility rates were found for amoxicillin (22%) and low non-susceptibility rates were observed for rifampicin (0%), moxifloxacin (1%), vancomycin (1%), and amoxicillin-clavulanate (6%). The meta-analysis of non-susceptibility rates included only studies conducted before 2014; therefore, the interpretation of the pooled estimates should be approached with caution.

Table 3.

Proportion of non-susceptibility in S. pneumoniae samples from nasopharyngeal carriage (1996–2014).

Antibiotics	Non-susceptible proportion (95% CI)	No. of included studies	Total no. of samples tested	No. of non-susceptible samples
β-Lactam antibiotics: Penicillins
Amoxicillin	22% (13%, 30%)	1	93	20
Amoxicillin-clavulanate	6% (0%, 16%)	2	197	13
Penicillin (Oral)	64% (47%, 80%)	8	1964	1229
Macrolides
Azithromycin	91% (86%, 97%)	1	93	85
Clarithromycin	90% (84%, 96%)	1	93	84
Erythromycin	70% (54%, 85%)	7	1818	1217
β-Lactam antibiotics: Cephalosporins
2nd Gen: Cefaclor	95% (90%, 99%)	1	93	88
3rd Gen: Cefotaxime (meningitis)	41% (16%, 66%)	3	418	186
3rd Gen: Cefotaxime (non-meningitis)	22% (0%, 54%)	2	514	59
3rd Gen: Ceftriaxone (meningitis)	12% (6%, 19%)	3	1063	116
3rd Gen: Cefuroxime (Oral)	52% (45%, 59%)	2	197	103
4th Gen: Cefepime (meningitis)	73% (64%, 82%)	1	93	68
4th Gen: Cefepime (non-meningitis)	33% (24%, 43%)	1	93	31
β-Lactam antibiotics: Carbapenems
Imipenem	63% (36%, 90%)	2	197	122
Meropenem	75% (67%, 84%)	1	93	70
Quinolone antibiotics: Fluoroquinolones
Ciprofloxacin	98% (96%, 100%)	3	704	686
Moxifloxacin	1% (0%, 3%)	1	221	3
Ofloxacin	48% (38%, 59%)	1	93	45
Others
Chloramphenicol	44% (34%, 54%)	5	786	334
Clindamycin	86% (79%, 93%)	1	93	80
Gentamicin	98% (95%, 100%)	1	62	61
Rifampicin	0% (0%, 2%)	1	93	0
Tetracycline	84% (76%, 92%)	6	1300	1048
Sulfamethoxazole–trimethoprim	70% (54%, 85%)	6	1164	867
Vancomycin	1% (0%, 3%)	3	376	6

Note: The 95% confidence interval lower bound was truncated at 0% and the upper bound at 100%.

Discussion

This study is the first systematic review and meta-analysis to assess the prevalence and serotype distribution of S. pneumoniae nasopharyngeal carriage among children in Vietnam, with inclusion of studies in both English and Vietnamese language. The 15 included studies, conducted between 1996 and 2020, involved over 13,000 children under 18 years of age, and were evenly distributed across northern, central, and southern Vietnam. The pooled prevalence of pneumococcal carriage was 33% (95% CI: 28%–39%). The common serotypes circulating in the community that are contained in PCV13 were 6A (23%), 19F (17%), 6B (15%), 23F (10%), 14 (8%), and 19A (3%).

Pneumococcal carriage prevalence varies considerably across regions due to socio-demographic and environmental factors, as well as related to methodological factors in different studies. Sensitivity analysis excluding the four heterogenous studies involving extremely young participants and with low quality yielded an even higher pooled carriage prevalence of 39% (95% CI: 33%–44%) (Supplementary Figure S3). A systematic review of studies conducted prior to PCV introduction in ten low and lower-middle income countries reported that S. pneumoniae carriage rates among children ranged from 6.5% to 93.4%.³⁸ A more recent review also showed that the carriage rates among children ranged from 26.7% to 90.5% in pre-PCV studies in 15 low and lower-middle income countries.³⁹ A meta-analysis estimated the pooled prevalence of S. pneumoniae in healthy children <5 years of age from eight out of the 11 countries in the South East Asia Region (Vietnam included) to be 36% (95% CI: 34%–38%),⁴⁰ which is close to the pooled prevalence observed in our study.

Our study found a distinct age-related pattern in pneumococcal carriage prevalence among Vietnamese children, characterised by a sharp increase during the first year of life, a plateau during the second year, and a gradual decline thereafter. This trend was most clearly demonstrated in the unvaccinated control groups in two PCV trials conducted in Ho Chi Minh City, which collected carriage data at specific age points: 2, 6, 9, 12, 18, and 24 months.^34,36 However, the different peak age of pneumococcal carriage did vary: Smith-Vaughan et al. observed a peak carriage rate of 25% at 12 months,²⁹ and Temple et al. observed a peak of 22% at 18 months.³¹ A systematic review of nasopharyngeal S. pneumoniae carriage among unvaccinated infants from 49 cohort studies and randomised controlled trials in 23 countries showed an even earlier peak at 4–6 months of age.⁴¹ In contrast, a systematic review conducted in China found the highest carriage rates among kindergarten children (2–5 years of age).²⁰ Nevertheless, all studies reported persistent exposure to S. pneumoniae after the first year of life, highlighting the importance of infant vaccination as well as the need for continued PCV protection beyond infancy. This finding underscores the critical importance of implementing a three-dose vaccination schedule, whether following a three primary doses with no booster (3p+0) or two primary doses with one booster (2p+1) regimen, both of which are recommended by WHO and demonstrate the capacity to provide sustained immunological protection.⁴² Experience from Australia indicates the advantage of the more recently adopted 2p+1 schedule over their prior 3p+0 schedule when the third-dose coverage is high, as the booster dose between 9 and 18 months of age has reduced breakthrough IPD cases in children >12 months.⁴³

We identified six common S. pneumoniae carriage serotypes among Vietnamese children that are covered by both PCV13 and PCV10–SII: 6A (23%), 19F (17%), 6B (15%), 23F (10%), 14 (8%), and 19A (3%); these constituted 76% overall of all pooled isolates. A review of six studies on pneumococcal carriage in Vietnamese children <5 years with respiratory infections reported similar findings, with the most common serotypes being 6A/B, 14, 19F, and 23F.⁹ Similarly, four studies with a limited number of pneumococcal isolates obtained from IPD cases and lower respiratory tract specimens from patients of all ages in Vietnam found the same predominant serotypes.⁹ Between 2015 and 2016, Khanh Hoa General Hospital from Central Vietnam identified serotypes 6A/B (35.9%), 19F (23.7%), 23F (12.7%), 14 (6.5%), and 19A (1.5%) as the most common vaccine serotypes among the 401 S. pneumoniae isolates from 1300 nasopharyngeal swabs collected from paediatric acute respiratory infection cases.⁴⁴ Between 2012 and 2018, 25 bacterial isolates from children under five years of age with meningitis in Southern Vietnam were serotyped. The most frequently identified vaccine serotypes were 19F (32%), 6A (16%), 6B (12%), 23F (12%), and 14 (8%).¹² More recently, from 2019 to 2022, the Vietnam National Children's Hospital in Northern Vietnam reported 6A/B (20.6%), 19A (17.0%), 23F (15.6%), 19F (14.2%), and 14 (9.9%) as the most common vaccine serotypes among the 141 S. pneumoniae isolates (45 blood samples and 96 cerebrospinal fluid samples) obtained from 274 paediatric IPD cases.¹¹ Overall, our findings from community-based studies are consistent with those from limited studies of IPD in children. Together this provides a comprehensive analysis of available data on S. pneumoniae in Vietnam.

Serotype-specific coverage is one of the key considerations for PCV product choice.⁵ However, reporting on IPD in Vietnam has usually been passive, and limited to ad hoc studies with small sample sizes. There is a pressing need to enhance the IPD surveillance in Vietnam to better assess serotypes causing invasive disease, generate high-quality evidence to inform ongoing PCV-related policy, and monitor serotype replacement post-PCV introduction.

The level of cross-protection against serotype 6A conferred by serotype 6B in PCV10-GSK will be a key variable in estimating the current serotype-specific coverage in Vietnam, given that serotype 6A accounts for 23% of all S. pneumoniae nasopharyngeal carriage in Vietnam. The global surveillance analysis (PSERENADE project), which included 15 PCV10-GSK sites and 31 PCV13 sites, demonstrated comparable reductions in IPD caused by serotype 6A by introduction of both vaccines (children <5 years: 83–99% decline; adults ≥65 years: 54–96% decline).⁶ However, PCV10-GSK (without prior PCV7 use) was not able to eradicate serotype 6A IPD incidence, unlike other scenarios introducing PCV13. A head-to-head immunogenicity study also showed that the serotype 6A responses to PCV13 and PCV10–SII were considerably higher than the cross-reactive responses to serotypes 6B generated by PCV10-GSK.⁴⁵ Although cross-reactive immunity against serotype 6A IPD has been observed with serotype 6B-containing PCVs (PCV7, PCV10-GSK) in many studies, direct inclusion of serotype 6A into PCVs offers several advantages: (1) improved protection against serotype-specific IPD, (2) reduced nasopharyngeal colonisation promoting indirect protection for unvaccinated individuals, and (3) potential cross-protection against serotype 6C IPD. Thus, serotype 6A-containing vaccines (PCV 13 and PCV10–SII) may be prioritised in settings like Vietnam, where serotype 6A is highly prevalent.

Vietnam is one of the countries that face the highest levels of antimicrobial resistance in the world,⁴⁶ which is largely driven by the unrestricted use of antibiotics at all levels of the health care system, in aquaculture and livestock production, and in the community.¹⁵ Our study found high levels of non-susceptibility to several antibiotic classes in S. pneumoniae isolates from Vietnamese children, a population often underrepresented in antimicrobial resistance studies. Multiple studies included in our review reported that over half of the general paediatric population recruited from community settings, had received antibiotics in the four weeks preceding the study.^25,26,29,33 A global study has shown that implementation of PCVs successfully led to reductions of around 10% in the non-susceptibility of S. pneumoniae to many first-line antibiotics, through reductions in antimicrobial prescribing.⁴⁷ While not precluding the need for wider strategies to comprehensively address antimicrobial resistance in Vietnam, taking swift action to include PCV into the National Immunisation Program in Vietnam, with high national population-based uptake to ensure herd immunity benefits, would assist in addressing this serious issue.⁴⁸

This study has several limitations. First, our review of S. pneumoniae serotype distribution was based on carriage studies rather than IPD cases and therefore should be interpreted with caution when informing the PCV product choice. It is well-established that pneumococcal serotypes differ in their disease potential.⁴⁹ For example, serotype 1 is rarely detected in nasopharyngeal colonisation but is the most common causes of IPD in sub-Saharan Africa.⁵⁰ However, the six common serotypes identified in our systematic review are consistent with findings from carriage studies in hospitalised children with respiratory tract infections, as well as with limited IPD studies from different regions of Vietnam. In addition, two smaller systematic reviews showed that serotypes 6A, 6B, 14, 19A, 19F, and 23F were present at similar proportions in both non-IPD and IPD cases.^18,19 Second, the included studies used different antimicrobial susceptibility testing standards, with varying zone diameter and minimum inhibitory concentration (MIC) interpretive criteria for S. pneumoniae, making analysis challenging. In our study, we defined penicillin susceptibility according to oral, non-meningitis breakpoints to avoid changes in definitions associated with the 2009 revision of CLSI standards, and for consistency with the EUCAST.⁴⁷ In addition, we distinguished susceptibility standards for meningitis, non-meningitis isolates where possible.

Conclusion

One in three children in Vietnam have positive nasopharyngeal carriage of S. pneumoniae, a condition that may lead to pneumonia, meningitis, sepsis, and other severe infections. The most common vaccine serotypes identified in our review were 6A, 6B, 14, 19A, 19F, and 23F which are vaccine preventable. We recommend taking prompt action to introduce PCV into Vietnam's National Immunisation Program schedule.

Contributors

XT, CK, PW, SJ, and Kristine M conceptualised the study. CK and HTTD conducted literature search. XT, KS, TTN, HTTD, LTD, THMD conducted screening and eligibility assessment. XT and KS conducted data extraction, quality assessment, accessed and verified the data. XT conducted the data analysis and drafted the manuscript. XT, KS, CK, TTN, TN, PW, SJ, BT, Kim M, and Kristine M reviewed the manuscript. All co-authors contributed to the writing of the manuscript and approved the final version. All authors attest that they meet the authorship criteria.

Data sharing statement

Data is available upon reasonable request to the corresponding author.

Declaration of interests

We declare no competing interests.