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.

Background Appropriate storage and transport conditions are crucial for ensuring bacterial viability within biological specimens. Nasopharyngeal carriage studies are common for Streptococcus pneumoniae . However, storing or transporting specimens at ultra-low temperatures as recommended by the World Health Organization is not possible in all settings. Here, we assess the impact of alternative storage conditions on pneumococcal viability and density using laboratory-prepared samples. Methods Flocked swabs were inoculated with low (n = 395) or medium (n = 395) loads of single pneumococcal isolates. Twenty different serotypes were tested. Swabs were stored in skim milk, tryptone, glucose and glycerol (STGG) medium at -80°C (gold standard), -20°C and 4°C, and in silica desiccant packets (SDPs) at 4°C and 30°C. Viable counts were performed at inoculation (baseline), and 2, 7, 14, 21 and 28 days post storage. A subset of samples from baseline and 28 days post storage were assessed for pneumococcal detection and density using culture-independent, molecular methods. Results Using culture-based methods, pneumococcal recovery was high (≥ 80%) up to 28 days when samples were stored at -20°C and − 80°C in STGG. Samples stored at 4°C in both STGG and SDPs had inconsistent recovery (< 80%) by 28 days, and samples stored at 30°C in SDPs had very low recovery (< 15%) at all timepoints. Overall, when compared by culture to the inoculum load, density was substantially reduced when alternative storage conditions were used. When density was assessed by lytA qPCR, pneumococci could be detected for most (99%) samples in select storage conditions. Conclusions Improper storage of specimens may lead to underestimations of pneumococcal prevalence and density, especially when culture-based methods are used. Given this, study outcomes and methods of testing should be considered when determining feasible transport and storage conditions. We identified alternative storage conditions to the gold standard that could enable studies in remote or complex settings.

BACKGROUND:Correlates of protection for pneumococcal carriage, a precursor for invasive pneumococcal disease, are not well defined. The relationship between memory B cells (Bmem) with carriage remains unclear. We assessed serotype-specific Bmem, IgG and opsonophagocytic (OPA) responses following different infant schedules of 10-valent pneumococcal conjugate vaccine (PCV10, Synflorix) and their association with pneumococcal carriage. METHODS:We analysed secondary outcome data from a phase II/III randomised controlled trial in Viet Nam (trial registration NCT01953510). Infants received PCV10 in a 3+1 (2-3-4-9 months), 3+0 (2-3-4 months) or 2+1 (2-4-9.5 months) schedule. Serotype-specific Bmem, IgG and OPA were measured at 10 months (all) and 18 months (Bmem and IgG only). Carriage was assessed from nasopharyngeal swabs at 12-18-24 months with additional carriage episodes identified by seroincidence. Associations between immunological parameters at 10 months and subsequent carriage were evaluated using multivariable logistic regression. RESULTS:At 10 months, Bmem levels were similar across vaccine arms, but IgG and OPA were higher in the 3+1/2+1 than 3+0 arm. At 18 months, Bmem and IgG waned for most serotypes in all vaccine arms. There were minimal associations between the immunological parameters and subsequent carriage. Only IgG was negatively associated with serotype 19A carriage, when defined as carriage and/or seroincidence ≥2-fold (odds ratio: 0.31, 95% confidence interval: 0.10-0.94, p=0.038), and carriage and/or seroincidence of any increase (odds ratio: 0.13, 95% confidence interval: 0.04-0.40, p<0.001). CONCLUSIONS:We found no substantive evidence linking Bmem, IgG and OPA with pneumococcal carriage. Larger studies are needed to identify associations between different immunological parameters and carriage.

Background:Streptococcus pneumoniae (the pneumococcus) is one of the main causes of childhood mortality. Understanding pneumococcal serotype and lineage distribution in children is important for vaccine decision-making. We undertook a secondary analysis of nasopharyngeal swabs collected from unvaccinated children as part of pneumococcal vaccine studies to provide a comprehensive picture of pneumococcal carriage epidemiology in Vietnamese children during the first 60 months of life. Methods:We analysed 4375 nasopharyngeal swabs from unvaccinated children to assess overall and vaccine-type pneumococcal carriage at 6, 12, 18, 24, and 60 months of age. For the latter three age groups, serotype distribution and genetic lineages (Global Pneumococcal Sequence Cluster, GPSCs) were described overall and by age. We also evaluated the prevalence of antimicrobial resistance (AMR) genes and multi-drug resistance (MDR), comparing vaccine-type and non-vaccine-type pneumococci. Findings:Overall pneumococcal carriage was 21·7% (952/4375) with a total of 27 serotypes detected. Serotype coverage was similar across products Pneumosil (68·6% [95% CI 65·5-71·7%], 595/867), Prevenar13 (70·0% [95% CI 67·0-73·1%], 607/867), and Vaxneuvance (70·0% [95% CI 67·0-73·1%], 607/867), and lower for Synflorix (41·5% [95% CI 38·2-44·8%], 360/867) p < 0·05 vs Pneumosil, Prevenar13 or Vaxneuvance. In total, 2444 swabs were tested at 18, 24, and 60 months. Thirty distinct GPSCs were identified, with their distribution remaining stable across these ages. AMR genes were highly prevalent, detected in 98·9% (360/364) of samples. Interpretation:Synflorix provided lower serotype coverage than other PCVs, largely driven by the prevalence of serotype 6A, which is not included in Synflorix formulation. Serotype, lineage distribution, and prevalence of AMR genes across the sampled age groups remained consistent, indicating that these distributions are broadly representative of young unvaccinated children, helping to guide optimal approaches for pneumococcal surveillance in low- and middle-income countries. Funding:National Health and Medical Research Council, Bill & Melinda Gates Foundation, Murdoch Children's Research Institute.

Objective Pneumococcal carriage is a prerequisite for invasive pneumococcal disease (IPD). Interleukin (IL)-17 A and IL-17 A-producing cells are involved in the clearance of pneumococcal carriage in adults, but their role in children is unclear. This study aims to examine the relationship between IL-17 A, IL-17 A-related cytokines (IL-22, IL-23, IFNγ) and IL-17 A-producing cells and pneumococcal carriage in children aged under two years. Methods Blood samples (n = 143) collected from unvaccinated children at 18 months (m) of age and nasopharyngeal swabs collected from unvaccinated children at 2, 6, 9, 12, 18, 24 m in the Vietnam Pneumococcal Project (ClinicalTrials.gov, NCT01953510) were included in this analysis. Pneumococcal carriage was previously determined. Plasma cytokine concentrations were measured by multiplex bead array or ELISA. Flow cytometry was used to measure IL-17 A/IFNγ-producing cells in peripheral blood mononuclear cells. Results IL-17 A, IL-22, IL-23 and IFNγ plasma cytokine concentrations were 1.7 to 2.6-fold higher among pneumococcal carriers at 18 m of age compared with non-carriers. Two-to four-fold higher IL-17 A, IL-22, IL-23 concentrations were observed in children carrying two or more pneumococcal serotypes at 18 m compared with children who only carried one pneumococcal serotype or non-carriers. Pneumococcal carriers at 18 m of age had 1.6 to 2-fold higher IL-17 A, IL-22, IL-23 compared with carriers at earlier timepoints (≤12 m). No differences in the frequencies of IL-17 A-producing cells were observed between carriers and non-carriers at 18 m of age. IL-17 A and related cytokines at 18 m of age did not appear to influence clearance of pneumococcus at 24 m of age. Conclusion Pneumococcal carriage is associated with higher plasma IL-17 A, IL-22 and IL-23 concentrations in children aged under two years.

Background:Vaccination of infants with pneumococcal conjugate vaccines is recommended by the World Health Organization. Evidence is mixed regarding the differences in immunogenicity and efficacy of the different pneumococcal vaccines. Objectives:The primary objective was to compare the immunogenicity of pneumococcal conjugate vaccine-10 versus pneumococcal conjugate vaccine-13. The main secondary objective was to compare the seroefficacy of pneumococcal conjugate vaccine-10 versus pneumococcal conjugate vaccine-13. Methods:We searched the Cochrane Library, EMBASE, Global Health, MEDLINE, ClinicalTrials.gov and trialsearch.who.int up to July 2022. Studies were eligible if they directly compared either pneumococcal conjugate vaccine-7, pneumococcal conjugate vaccine-10 or pneumococcal conjugate vaccine-13 in randomised trials of children under 2 years of age, and provided immunogenicity data for at least one time point. Individual participant data were requested and aggregate data used otherwise. Outcomes included the geometric mean ratio of serotype-specific immunoglobulin G and the relative risk of seroinfection. Seroinfection was defined for each individual as a rise in antibody between the post-primary vaccination series time point and the booster dose, evidence of presumed subclinical infection. Each trial was analysed to obtain the log of the ratio of geometric means and its standard error. The relative risk of seroinfection ('seroefficacy') was estimated by comparing the proportion of participants with seroinfection between vaccine groups. The log-geometric mean ratios, log-relative risks and their standard errors constituted the input data for evidence synthesis. For serotypes contained in all three vaccines, evidence could be synthesised using a network meta-analysis. For other serotypes, meta-analysis was used. Results from seroefficacy analyses were incorporated into a mathematical model of pneumococcal transmission dynamics to compare the differential impact of pneumococcal conjugate vaccine-10 and pneumococcal conjugate vaccine-13 introduction on invasive pneumococcal disease cases. The model estimated the impact of vaccine introduction over a 25-year time period and an economic evaluation was conducted. Results:In total, 47 studies were eligible from 38 countries. Twenty-eight and 12 studies with data available were included in immunogenicity and seroefficacy analyses, respectively. Geometric mean ratios comparing pneumococcal conjugate vaccine-13 versus pneumococcal conjugate vaccine-10 favoured pneumococcal conjugate vaccine-13 for serotypes 4, 9V and 23F at 1 month after primary vaccination series, with 1.14- to 1.54-fold significantly higher immunoglobulin G responses with pneumococcal conjugate vaccine-13. Risk of seroinfection prior to the time of booster dose was lower for pneumococcal conjugate vaccine-13 for serotype 4, 6B, 9V, 18C and 23F than for pneumococcal conjugate vaccine-10. Significant heterogeneity and inconsistency were present for most serotypes and for both outcomes. Twofold higher antibody after primary vaccination was associated with a 54% decrease in risk of seroinfection (relative risk 0.46, 95% confidence interval 0.23 to 0.96). In modelled scenarios, pneumococcal conjugate vaccine-13 or pneumococcal conjugate vaccine-10 introduction in 2006 resulted in a reduction in cases that was less rapid for pneumococcal conjugate vaccine-10 than for pneumococcal conjugate vaccine-13. The pneumococcal conjugate vaccine-13 programme was predicted to avoid an additional 2808 (95% confidence interval 2690 to 2925) cases of invasive pneumococcal disease compared with pneumococcal conjugate vaccine-10 introduction between 2006 and 2030. Limitations:Analyses used data from infant vaccine studies with blood samples taken prior to a booster dose. The impact of extrapolating pre-booster efficacy to post-booster time points is unknown. Network meta-analysis models contained significant heterogeneity which may lead to bias. Conclusions:Serotype-specific differences were found in immunogenicity and seroefficacy between pneumococcal conjugate vaccine-13 and pneumococcal conjugate vaccine-10. Higher antibody response after vaccination was associated with a lower risk of subsequent infection. These methods can be used to compare the pneumococcal conjugate vaccines and optimise vaccination strategies. For future work, seroefficacy estimates can be determined for other pneumococcal vaccines, which could contribute to licensing or policy decisions for new pneumococcal vaccines. Study registration:This study is registered as PROSPERO CRD42019124580. Funding:This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/148/03) and is published in full in Health Technology Assessment; Vol. 28, No. 34. See the NIHR Funding and Awards website for further award information.

The use of pneumococcal conjugate vaccine (PCV) schedules with fewer doses are being considered to reduce costs and improve access, particularly in low- and middle-income countries. While several studies have assessed their immunogenicity, there are limited data on their potential for long-term immune protection, as assessed by pneumococcal serotype-specific memory B cell (Bmem) responses. This current study reports secondary outcome data that aims to compare Bmem responses following reduced-dose (0 + 1 and 1 + 1) schedules of PCV10 and PCV13 in Vietnamese infants from our randomised-controlled trial (trial registration number NCT03098628). Following vaccination at 12 months of age, Bmem levels for most serotypes peaked seven days post-vaccination and were higher in magnitude for the 1 + 1 than 0 + 1 schedules and for PCV13 than PCV10. Furthermore, Bmem did not wane as rapidly as IgG levels by 24 months of age. Further studies are needed to assess the use of Bmem as markers of long-term protection against pneumococcal carriage and disease, which is crucial to generate data for immunisation program decision-making. As part of a randomized controlled trial in Viet Nam, this study finds that pneumococcal-specific memory B cells (Bmem) are higher following a 1 + 1 compared to a 0 + 1 pneumococcal conjugate vaccine (PCV) schedule and higher for PCV13 compared to PCV10. Bmem did not wane as rapidly as IgG by 24 months of age.

Background Vaccination of infants with pneumococcal conjugate vaccines (PCV) is recommended by the World Health Organization. Evidence is mixed regarding the differences in immunogenicity and efficacy of the different pneumococcal vaccines. Methods In this systematic-review and network meta-analysis, we searched the Cochrane Library, Embase, Global Health, Medline, clinicaltrials.gov and trialsearch.who.int up to February 17, 2023 with no language restrictions. Studies were eligible if they presented data comparing the immunogenicity of either PCV7, PCV10 or PCV13 in head-to-head randomised trials of young children under 2 years of age, and provided immunogenicity data for at least one time point after the primary vaccination series or the booster dose. Publication bias was assessed via Cochrane's Risk Of Bias due to Missing Evidence tool and comparison-adjusted funnel plots with Egger's test. Individual participant level data were requested from publication authors and/or relevant vaccine manufacturers. Outcomes included the geometric mean ratio (GMR) of serotype-specific IgG and the relative risk (RR) of seroinfection. Seroinfection was defined for each individual as a rise in antibody between the post-primary vaccination series time point and the booster dose, evidence of presumed subclinical infection. Seroefficacy was defined as the RR of seroinfection. We also estimated the relationship between the GMR of IgG one month after priming and the RR of seroinfection by the time of the booster dose. The protocol is registered with PROSPERO, ID CRD42019124580. Findings 47 studies were eligible from 38 countries across six continents. 28 and 12 studies with data available were included in immunogenicity and seroefficacy analyses, respectively. GMRs comparing PCV13 vs PCV10 favoured PCV13 for serotypes 4, 9V, and 23F at 1 month after primary vaccination series, with 1.14-to 1.54-fold significantly higher IgG responses with PCV13. Risk of seroinfection prior to the time of booster dose was lower for PCV13 for serotype 4, 6B, 9V, 18C and 23F than for PCV10. Significant heterogeneity and inconsistency were present for most serotypes and for both outcomes. Two-fold higher antibody after primary vaccination was associated with a 54% decrease in risk of seroinfection (RR 0.46, 95% CI 0.23-0.96). Interpretation Serotype-specific differences were found in immunogenicity and seroefficacy between PCV13 and PCV10. Higher antibody response after vaccination was associated with a lower risk of subsequent infection. These findings could be used to compare PCVs and optimise vaccination strategies. 2023;61:

Background Interest in reduced-dose pneumococcal conjugate vaccine (PCV) schedules is growing, but data on their ability to provide direct and indirect protection are scarce. We evaluated 1 + 1 (at 2 months and 12 months) and 0 + 1 (at 12 months) schedules of PCV10 or PCV13 in a predominately unvaccinated population. Methods In this parallel, single-blind, randomised controlled trial, healthy infants aged 2 months were recruited from birth records in three districts in Ho Chi Minh City, Vietnam, and assigned (4:4:4:4:9) to one of five groups: PCV10 at 12 months of age (0 + 1 PCV10), PCV13 at 12 months of age (0 + 1 PCV13), PCV10 at 2 months and 12 months of age (1 + 1 PCV10), PCV13 at 2 months and 12 months of age (1 + 1 PCV13), and unvaccinated control. Outcome assessors were masked to group allocation, and the infants' caregivers and those administering vaccines were not. Nasopharyngeal swabs collected at 6 months, 12 months, 18 months, and 24 months were analysed for pneumococcal carriage. Blood samples collected from a subset of participants (200 per group) at various timepoints were analysed by ELISA and opsonophagocytic assay. The primary outcome was the efficacy of each schedule against vaccine-type carriage at 24 months, analysed by intention to treat for all those with a nasopharyngeal swab available. This trial is registered at ClinicalTrials.gov, NCT03098628. Findings 2501 infants were enrolled between March 8, 2017, and July 24, 2018 and randomly assigned to study groups (400 to 0 + 1 PCV10, 400 to 0 + 1 PCV13, 402 to 1 + 1 PCV10, 401 to 1 + 1 PCV13, and 898 to control). Analysis of the primary endpoint included 341 participants for 0 + 1 PCV10, 356 0 + 1 PCV13, 358 1 + 1 PCV10, 350 1 + 1 PCV13, and 758 control. At 24 months, a 1 + 1 PCV10 schedule reduced PCV10-type carriage by 58% (95% CI 25 to 77), a 1 + 1 PCV13 schedule reduced PCV13-type carriage by 65% (42 to 79), a 0 + 1 PCV10 schedule reduced PCV10-type carriage by 53% (17 to 73), and a 0 + 1 PCV13 schedule non-significantly reduced PCV13-type carriage by 25% (-7 to 48) compared with the unvaccinated control group. Reactogenicity and serious adverse events were similar across groups. Interpretation A 1 + 1 PCV schedule greatly reduces vaccine-type carriage and is likely to generate substantial herd protection and provide some degree of individual protection during the first year of life. Such a schedule is suitable for mature PCV programmes or for introduction in conjunction with a comprehensive catch-up campaign, and potentially could be most effective given as a mixed regimen (PCV10 then PCV13). A 0 + 1 PCV schedule has some effect on carriage along with a reasonable immune response and could be considered for use in humanitarian crises or remote settings. Funding Bill & Melinda Gates Foundation. Copyright & COPY; The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

Background WHO recommends a three-dose infant pneumococcal conjugate vaccine (PCV) schedule administered as a two-dose primary series with booster (2 + 1) or a three-dose primary series (3 + 0). Data on carriage impacts of these and further reduced PCV schedules are needed to inform PCV strategies. Here we evaluate the efficacy against carriage of four different PCV10 schedules.Methods Participants within an open-label, randomised controlled trial in Ho Chi Minh City, Vietnam, were allocated to receive PCV10 in a 3 + 1 (2,3,4,9 months, n = 152), 3 + 0 (2,3,4 months, n = 149), 2 + 1 (2,4,9.5 months, n = 250) or novel two-dose (2,6 months, n = 202) schedule, or no infant doses of PCV (two control groups, n = 197 and n = 199). Nasopharyngeal swabs collected between 2 and 24 months were analysed (blinded) for pneumococcal carriage and serotypes. Trial registration: ClinicalTrials.gov NCT01953510.Findings Pneumococcal carriage prevalence was low (10.6-14.1% for vaccine-type (VT) at 12-24 months in unvaccinated controls). All four PCV10 schedules reduced VT carriage compared with controls (the 2 + 1 schedule at 12, 18, and 24 months; the 3 + 1 and two-dose schedules at 18 months; and the 3 + 0 schedule at 24 months), with maximum reductions of 40.1%-64.5%. There were no differences in VT carriage prevalence at 6 or 9 months comparing three-dose and two-dose primary series, and no differences at 12, 18, or 24 months when comparing schedules with and without a booster dose.Interpretation In Vietnamese children with a relatively low pneumococcal carriage prevalence, 3 + 1, 2 + 1, 3 + 0 and two-dose PCV10 schedules were effective in reducing VT carriage. There were no discernible differences in the effect on carriage of the WHO-recommended 2 + 1 and 3 + 0 schedules during the first two years of life. Together with the previously reported immunogenicity data, this trial suggests that a range of PCV schedules are likely to generate significant direct and indirect protection.Funding NHMRC, BMGFCopyright (c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

There are 100 known serotypes of Streptococcus pneumoniae,1 and pneumococcal conjugate vaccines (PCVs) are highly effective at protecting against disease from serotypes included in the vaccine. PCVs contain selected pneumococcal polysaccharides that are individually conjugated to carrier proteins. The first PCV, licensed in 2000, contained seven serotypes (PCV7), while the most recently approved contains 20 (PCV20), with several other higher valency PCVs in development. Increasing valency has obvious benefits in terms of broader disease coverage, but comes at the cost of decreasing immunogenicity due to carrier suppression.

The pneumococcus is a major cause of mortality globally. Implementation of NPIs during the COVID-19 pandemic led to reductions in invasive pneumococcal disease in many countries.

Background: Interest in reduced-dose pneumococcal conjugate vaccine (PCV) schedules is growing, but data on their ability to provide direct and indirect protection are limited. Here we evaluate 1+1 (at 2&12m) and 0+1 (at 12m) schedules of PCV10 or PCV13 in a predominately unvaccinated population.Methods: In this parallel, open-label, randomised controlled trial, healthy 2-month-old infants were assigned (4:4:4:4:9) to: 0+1 PCV10, 0+1 PCV13, 1+1 PCV10, 1+1 PCV13, and controls. NP swabs collected at 6, 12, 18, and 24m were analysed for pneumococcal carriage. Blood samples collected from a subset of participants (n=200/group) at various timepoints were analysed by ELISA and opsonophagocytic assay. The primary outcome was the efficacy of each schedule against vaccine-type carriage at 24m.Findings: 2501 infants were enrolled between March 2017 and July 2018. At 24m, a 1+1 PCV10-schedule reduced PCV10-type carriage by 58% (95%CI 25-77), a 1+1 PCV13-schedule reduced PCV13-type carriage by 65% (42-79), a 0+1 PCV10-schedule reduced PCV10-type carriage by 53% (17-73), and a 0+1 PCV13-schedule reduced PCV13-type carriage by 25% (-7-48) compared with unvaccinated controls. All schedules were immunogenic. GMCs were generally higher with PCV10 after the 2m-dose and with PCV13 after the 12m-dose, and higher with a 1+1 than 0+1 schedule after 12m. Reactogenicity and serious adverse events were similar across groups.Interpretation: A 1+1 PCV schedule dramatically reduces vaccine-type carriage and is likely to generate substantial herd protection and provide some degree of individual protection during the first year of life. Such a schedule is suitable for mature PCV programs or for introduction in conjunction with a comprehensive catch-up campaign, and potentially could be most effective given as a mixed regimen (PCV10 then PCV13). A 0+1 PCV schedule provides some impact on carriage along with a reasonable immune response and could be valuable in humanitarian crises or remote settings.Trial Registration: The trial was overseen by a Data Safety and Monitoring Board and is registered at ClinicalTrials.gov (NCT03098628).Funding Information: This work was supported by the Bill & Melinda Gates Foundation (grant number INV-008627).Declaration of Interests: The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: All authors except JB and JH received salary support from the Bill & Melinda Gates Foundation grant. KM, CS, and CN are investigators on a clinical research collaboration with Pfizer on PCV vaccination in Mongolia and are investigators on a Merck Investigator Studies Program grant funded by MSD on pneumococcal serotype epidemiology in children. JB provided a report on pneumococcal carriage in Northern Australia to MSD Australia. JH receives project grant funding from Pfizer and is co-founder and board member of BUGS Bioscience Ltd. We declare no other competing interests.Ethics Approval Statement: The protocol was approved by the IRB at the Pasteur Institute of HCMC, and ethical approval was obtained from the Royal Children’s Hospital Melbourne HREC and the Vietnam MoH Ethics Committee.

Non-pharmaceutical interventions (NPIs) implemented to contain SARS-CoV-2 have decreased invasive pneumococcal disease. We undertook an observational study to evaluate the impact of NPIs on pneumococcal carriage and density, drivers of transmission and disease, during the COVID-19 pandemic in Ho Chi Minh City, Vietnam. While NPIs did not significantly impact pneumococcal carriage, mean capsular pneumococcal density decreased by up to 91.5% (1.07 log10genome equivalents/mL, 95% Confidence Interval: 0.74-1.41) after NPI introduction compared with the pre-COVID-19 period. As higher pneumococcal density is a risk factor for disease, the observed decline provides a plausible mechanism for the reductions in invasive pneumococcal disease.### Competing Interest StatementCS is a lead investigator, and KM and CN are co-investigators, on a Merck Investigator Studies Program grant funded by MSD outside of this work. KM is a lead investigator, and CS and CN are co-investigators, on a Pfizer funded study outside of this work. CN is on a Data Safety Monitoring Board outside of this work (no payment). JB prepared a report on pneumococcal serotypes for MSD outside of this work. JH receives project grants from Pfizer that are outside of this work, and is a co-founder and board member of BUGS Bioscience Ltd., a not-for-profit spin-out company (no personal payment). KM is a member of WHO SAGE committee (no payment) and KM and CS are Board members of ISPPD (no payment). None of the other authors have any competing interests to declare.### Funding StatementThe vaccine trial was supported by the Bill & Melinda Gates Foundation (grant number OPP-1116833/INV-008627). We also acknowledge the Victorian Governments Operational Infrastructure Support Program.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethical approval was obtained for the vaccine trial from the Human Research Ethics Committee of the Royal Childrens Hospital Melbourne, the Institutional Review Board at the Pasteur Institute of Ho Chi Minh City, and the Vietnam Ministry of Health Ethical Review Committee for Biomedical Research. The vaccine trial is registered at clinicaltrials.gov ([NCT03098628][1]).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesDeidentified data are available upon reasonable request. Requests must be compliant with the vaccine trial ethical approvals. Requests should be directed to Professor Kim Mulholland (https://orcid.org/0000-0001-7947-680X). [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03098628&atom=%2Fmedrxiv%2Fearly%2F2022%2F05%2F07%2F2022.05.05.22274646.atom

Background: Pneumococcal conjugate vaccines (PCVs) generate herd protection by reducing nasopharyngeal (NP) carriage. Two PCVs, PCV10 and PCV13, have been in use for over a decade, yet there are few data comparing their impact on carriage. Here we report their effect on carriage in a 2+1 schedule, compared with each other and with unvaccinated controls. Methods: Data from four groups within a parallel, open-label randomised controlled trial in Ho Chi Minh City contribute to this article. Three groups were randomised to receive a 2+1 schedule of PCV10 (n = 250), a 2+1 schedule of PCV13 (n = 251), or two doses of PCV10 at 18 and 24 months (controls, n = 197). An additional group (n = 199) was recruited at 18 months to serve as controls from 18 to 24 months. NP swabs collected at 2, 6, 9, 12, 18, and 24 months were analysed (blinded) for pneumococcal carriage. This study aimed to determine if PCV10 and PCV13 have a differential effect on pneumococcal carriage, a secondary outcome of the trial. We also describe the serotype distribution among unvaccinated participants. Trial registration: ClinicalTrials. gov NCT01953510. Findings: Compared with unvaccinated controls, a 2+1 schedule of PCV10 reduced PCV10-type carriage by 45-62% from pre-booster through to 24 months of age, and a 2+1 schedule of PCV13 reduced PCV13-type carriage by 36-49% at 12 and 18 months of age. Compared directly with each other, there were few differences between the vaccines in their impact on carriage. Vaccine serotypes accounted for the majority of carriage in unvaccinated participants. Interpretation: Both PCV10 and PCV13 reduce the carriage of pneumococcal vaccine serotypes. The introduction of either vaccine would have the potential to generate significant herd protection in this population. (C) 2021 The Author(s). Published by Elsevier Ltd.

Background Data are scarce from low-income and middle-income countries (LMICs) to support the choice of vaccination schedule for the introduction of pneumococcal conjugate vaccines (PCV). We aimed to compare the immunogenicity of four different infant PCV10 schedules in infants in Vietnam. Methods In this single-blind, parallel-group, open-label, randomised controlled trial, infants aged 2 months were recruited by community health staff in districts 4 and 7 of Ho Chi Minh City, Vietnam. Eligible infants had no clinically significant maternal or prenatal history and were born at or after 36 weeks' gestation. Participants were randomly assigned (3:3:5:4:5:4) using block randomisation, stratified by district, to one of six PCV10 or PCV13 vaccination schedules. Here we report results for four groups: group A, who were given PCV10 at ages 2, 3, 4, and 9 months (a 3 + 1 schedule); group B, who were vaccinated at ages 2, 3, and 4 months (3 + 0 schedule); group C, who were vaccinated at ages 2, 4, and 9middot5 months (2 + 1 schedule); and group D, who were vaccinated at ages 2 and 6 months (two-dose schedule). Laboratory-based assessors were masked to group allocation. Blood samples were collected at different prespecified timepoints between ages 3-18 months depending on group allocation, within 27-43 days after vaccination, and these were analysed for serotype-specific IgG and opsonophagocytic responses. Participants were followed-up until age 24 months. The primary outcome was the proportion of infants with serotype-specific IgG levels of 0middot35 mu g/mL or higher at age 5 months, analysed as a non-inferiority comparison (10% margin) of the two-dose and three-dose primary series (group C vs groups A and B combined). We also compared responses 4 weeks after two doses administered at either ages 2 and 4 months (group C) or at ages 2 and 6 months (group D). The primary endpoint was analysed in the per-protocol population. Reactogenicity has been reported previously. This study is registered with ClinicalTrials.gov, NCT01953510, and is now closed to accrual. Findings Between Sept 30, 2013, and Jan 9, 2015, 1201 infants were enrolled and randomly assigned to group A (n=152), group B (n=149), group C (n=250), group D (n=202), or groups E (n=251) and F (n=197). In groups A-D, 388 (52%) of 753 participants were female and 365 (48%) were male. 286 (95%) participants in groups A and B combined (three-dose primary series) and 237 (95%) in group C (two-dose primary series) completed the primary vaccination series and had blood samples taken within the specified time window at age 5 months (per-protocol population). At this timepoint, a two-dose primary series was non-inferior to a three-dose primary series for eight of ten vaccine serotypes; exceptions were 6B (84middot6% [95% CI 79middot9-88middot6] of infants had protective IgG concentrations after three doses [groups A and B combined] vs 76middot8% [70middot9-82middot0] of infants after two doses [group C]; risk difference 7middot8% [90% CI 2middot1-13middot6]) and 23F (90middot6% [95% CI 86middot6-93middot7] vs 77middot6% [71middot8-82middot2]; 12middot9% [90% CI 7middot7-18middot3]). Two doses at ages 2 and 6 months produced higher antibody levels than two doses at ages 2 and 4 months for all serotypes except 5 and 7F. Interpretation A two-dose primary vaccination series was non-inferior to a three-dose primary vaccination series while two doses given with a wider interval between doses increased immunogenicity. The use of a two-dose primary vaccination schedule using a wider interval could be considered in LMIC settings to extend protection in the second year of life. Funding Australian National Health and Medical Research Council, and The Bill & Melinda Gates Foundation. Copyright (c) 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4. 0 license

INTRODUCTION:Reduced-dose schedules offer a more efficient and affordable way to use pneumococcal conjugate vaccines (PCVs). Such schedules rely primarily on the maintenance of herd protection. The Vietnam Pneumococcal Trial II (VPT-II) will evaluate reduced-dose schedules of PCV10 and PCV13 utilising an unvaccinated control group. Schedules will be compared in relation to their effect on nasopharyngeal carriage and immunogenicity. METHODS AND ANALYSIS:VPT-II is a single-blind open-label randomised controlled trial of 2500 infants in three districts of Ho Chi Minh City, Vietnam. Eligible infants have no clinically significant maternal or perinatal history and are born at or after 36 weeks' gestation. Participants are recruited at 2 months of age and randomly assigned (4:4:4:4:9) using block randomisation, stratified by district, to one of five groups: four intervention groups that receive PCV10 in a 0+1 (at 12 months) or 1+1 (at 2 and 12 months) schedule or PCV13 in the same 0+1 or 1+1 schedule; and a control group (that receives a single dose of PCV10 at 24 months). Participants are followed up to 24 months of age. The primary outcome is vaccine-type pneumococcal carriage at 24 months of age. Secondary outcomes are carriage at 6, 12 and 18 months of age and the comparative immunogenicity of the different schedules in terms of antibody responses, functional antibody responses and memory B cell responses. ETHICS AND DISSEMINATION:Ethical approval has been obtained from the Human Research Ethics Committee of the Royal Children's Hospital Melbourne and the Vietnam Ministry of Health Ethics Committee. The results, interpretation and conclusions will be presented to parents and guardians, at national and international conferences and published in peer-reviewed open access journals. TRIAL REGISTRATION NUMBER:NCT03098628.

BackgroundThis study investigated the immunogenicity and impact on nasopharyngeal carriage of a single dose of PCV10 given to 18-month-old Vietnamese children. This information is important for countries considering catch-up vaccination during PCV introduction and in the context of vaccination during humanitarian crises.MethodsTwo groups of PCV-naïve children within the Vietnam Pneumococcal Project received PCV10 (n=197) or no PCV (unvaccinated; n=199) at 18 months of age. Blood samples were collected at 18, 19, and 24 months of age, and nasopharyngeal swabs at 18 and 24 months of age. Immunogenicity was assessed by measuring serotype-specific IgG, opsonophagocytosis (OPA) and memory B cells (Bmem). Pneumococci were detected and quantified using real-time PCR and serotyped by microarray.FindingsAt 19 months of age, IgG and OPA responses were higher in the PCV10 group compared with the unvaccinated group for all PCV10 serotypes and cross-reactive serotypes 6A and 19A. This was sustained out to 24 months of age, at which point PCV10-type carriage was 60% lower in the PCV10 group than the unvaccinated group. Bmem levels increased between 18 and 24 months of age in the vaccinated group.InterpretationWe demonstrate strong protective immune responses in vaccinees following a single dose of PCV10 at 18 months of age, and a potential impact on herd protection through a substantial reduction in vaccine-type carriage. A single dose of PCV10 in the second year of life could be considered as part of catch-up campaigns or in humanitarian crises to protect children at high-risk of pneumococcal disease.