Effect of Pneumococcal Conjugate Vaccine on Pneumonia Incidence Rates among Children 2-59 Months of Age, Mongolia, 2015-2021.

Starting in June 2016, the 13-valent pneumococcal conjugate vaccine (PCV13) was introduced into the routine immunization program of Mongolia by using a 2+1 dosing schedule, phased by district. We used prospective hospital surveillance to evaluate the vaccine's effect on pneumonia incidence rates among children 2-59 months of age over a 6-year period. Of 17,607 children with pneumonia, overall adjusted incidence rate ratios showed decreased primary endpoint pneumonia, very severe pneumonia, and probable pneumococcal pneumonia until June 2021. Results excluding and including the COVID-19 pandemic period were similar. Pneumonia declined in 3 districts that introduced PCV13 with catch-up campaigns but not in the 1 district that did not. After PCV13 introduction, vaccine-type pneumococcal carriage prevalence decreased by 44% and nonvaccine-type carriage increased by 49%. After PCV13 introduction in Mongolia, the incidence of more specific pneumonia endpoints declined in children 2-59 months of age; additional benefits were conferred by catch-up campaigns.

Insights Into Pneumococcal Pneumonia Using Lung Aspirates and Nasopharyngeal Swabs Collected From Pneumonia Patients in The Gambia.

BACKGROUND: We investigated the pathogenesis of pneumococcal pneumonia using clinical specimens collected for pneumonia surveillance in The Gambia. METHODS: Lung aspirates and nasopharyngeal swabs from 31 patients were examined by culture, quantitative polymerase chain reaction (qPCR), whole genome sequencing, serotyping, and reverse-transcription qPCR. RESULTS: Five lung aspirates cultured pneumococci, with a matching strain identified in the nasopharynx. Three virulence genes including ply (pneumolysin) were upregulated >20-fold in the lung compared with the nasopharynx. Nasopharyngeal pneumococcal density was higher in pediatric pneumonia patients compared with controls (P < .0001). CONCLUSIONS: Findings suggest that changes in pneumococcal gene expression occurring in the lung environment may be important in pathogenesis.

Nasopharyngeal Pneumococcal Colonization Density Is Associated With Severe Pneumonia in Young Children in the Lao People's Democratic Republic.

BACKGROUND: No studies have explored the association between pneumococcal nasopharyngeal density and severe pneumonia using the World Health Organization (WHO) 2013 definition. In Lao People's Democratic Republic (Lao PDR), we determine the association between nasopharyngeal pneumococcal density and severe pneumonia in children. METHODS: A prospective observational study was undertaken at Mahosot Hospital, Vientiane, from 2014 to mid-2018. Children <5 years admitted with acute respiratory infections (ARIs) were included. Clinical and demographic data were collected alongside nasopharyngeal swabs for pneumococcal quantification by lytA real-time quantitative polymerase chain reaction. Severe pneumonia was defined using the 2013 WHO definition. For pneumococcal carriers, a logistic regression model examined the association between pneumococcal density and severe pneumonia, after adjusting for potential confounders including demographic and household factors, 13-valent pneumococcal conjugate vaccine status, respiratory syncytial virus co-detection, and preadmission antibiotics. RESULTS: Of 1268 participants with ARI, 32.3% (n = 410) had severe pneumonia and 36.9% (n = 468) had pneumococcal carriage. For pneumococcal carriers, pneumococcal density was positively associated with severe pneumonia (adjusted odds ratio, 1.4 [95% confidence interval, 1.1-1.8]; P = .020). CONCLUSIONS: Among children with ARIs and pneumococcal carriage, pneumococcal carriage density was positively associated with severe pneumonia in Lao PDR. Further studies may determine if pneumococcal density is a useful marker for pneumococcal conjugate vaccine impact on childhood pneumonia.

Association of pneumococcal carriage in infants with the risk of carriage among their contacts in Nha Trang, Vietnam: A nested cross-sectional survey.

BACKGROUND: Infants are at highest risk of pneumococcal disease. Their added protection through herd effects is a key part in the considerations on optimal pneumococcal vaccination strategies. Yet, little is currently known about the main transmission pathways to this vulnerable age group. Hence, this study investigates pneumococcal transmission routes to infants in the coastal city of Nha Trang, Vietnam. METHODS AND FINDINGS: In October 2018, we conducted a nested cross-sectional contact and pneumococcal carriage survey in randomly selected 4- to 11-month-old infants across all 27 communes of Nha Trang. Bayesian logistic regression models were used to estimate age specific carriage prevalence in the population, a proxy for the probability that a contact of a given age could lead to pneumococcal exposure for the infant. We used another Bayesian logistic regression model to estimate the correlation between infant carriage and the probability that at least one of their reported contacts carried pneumococci, controlling for age and locality. In total, 1,583 infants between 4 and 13 months old participated, with 7,428 contacts reported. Few infants (5%, or 86 infants) attended day care, and carriage prevalence was 22% (353 infants). Most infants (61%, or 966 infants) had less than a 25% probability to have had close contact with a pneumococcal carrier on the surveyed day. Pneumococcal infection risk and contact behaviour were highly correlated: If adjusted for age and locality, the odds of an infant's carriage increased by 22% (95% confidence interval (CI): 15 to 29) per 10 percentage points increase in the probability to have had close contact with at least 1 pneumococcal carrier. Moreover, 2- to 6-year-old children contributed 51% (95% CI: 39 to 63) to the total direct pneumococcal exposure risks to infants in this setting. The main limitation of this study is that exposure risk was assessed indirectly by the age-dependent propensity for carriage of a contact and not by assessing carriage of such contacts directly. CONCLUSIONS: In this study, we observed that cross-sectional contact and infection studies could help identify pneumococcal transmission routes and that preschool-age children may be the largest reservoir for pneumococcal transmission to infants in Nha Trang, Vietnam.

Age-related differences in SARS-CoV-2 binding factors: An explanation for reduced susceptibility to severe COVID-19 among children?

CONTEXT: In contrast with other respiratory viruses, children infected with SARS-CoV-2 are largely spared from severe COVID-19. OBJECTIVES: To critically assess age-related differences in three host proteins involved in SARS-CoV-2 cellular entry: angiotensin-converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2) and furin. METHODS: We systematically searched Medline, Embase, and PubMed databases for relevant publications. Studies were eligible if they evaluated ACE2, TMPRSS2 or furin expression, methylation, or protein level in children. RESULTS: Sixteen papers were included. Age-dependent differences in membrane-bound and soluble ACE2 were shown in several studies, with ACE2 expression increasing with age. TMPRSS2 and furin are key proteases involved in SARS-CoV-2 spike protein cleavage. TMPRSS2 expression is increased by circulating androgens and is thus low in pre-pubertal children. Furin has not currently been well researched. LIMITATIONS: High levels of study heterogeneity. CONCLUSIONS: Low expression of key host proteins may partially explain the reduced incidence of severe COVID-19 among children, although further research is needed.

Evaluation of the impact of childhood 13-valent pneumococcal conjugate vaccine introduction on adult pneumonia in Ulaanbaatar, Mongolia: study protocol for an observational study.

BACKGROUND: Community-acquired pneumonia is an important cause of morbidity and mortality in adults. Approximately one-third of pneumonia cases can be attributed to the pneumococcus. Pneumococcal conjugate vaccines (PCVs) protect against colonisation with vaccine-type serotypes. The resulting decrease in transmission of vaccine serotypes leads to large indirect effects. There are limited data from developing countries demonstrating the impact of childhood PCV immunisation on adult pneumonia. There are also insufficient data available on the burden and severity of all-cause pneumonia and respiratory syncytial virus (RSV) in adults from low resource countries. There is currently no recommendation for adult pneumococcal vaccination with either pneumococcal polysaccharide vaccine or PCVs in Mongolia. We describe the protocol developed to evaluate the association between childhood 13-valent PCV (PCV13) vaccination and trends in adult pneumonia. METHODS: PCV13 was introduced into the routine childhood immunisation schedule in Mongolia in a phased manner from 2016. In March 2019 we initiated active hospital-based surveillance for adult pneumonia, with the primary objective of evaluating trends in severe hospitalised clinical pneumonia incidence in adults 18 years and older in four districts of Ulaanbaatar. Secondary objectives include measuring the association between PCV13 introduction and trends in all clinically-defined pneumonia, radiologically-confirmed pneumonia, nasopharyngeal carriage of S. pneumoniae and pneumonia associated with RSV or influenza. Clinical questionnaires, nasopharyngeal swabs, urine samples and chest radiographs were collected from enrolled patients. Retrospective administrative and clinical data were collected for all respiratory disease-related admissions from January 2015 to February 2019. DISCUSSION: Establishing a robust adult surveillance system may be an important component of monitoring the indirect impact of PCVs within a country. Monitoring indirect impact of childhood PCV13 vaccination on adult pneumonia provides additional data on the full public health impact of the vaccine, which has implications for vaccine efficiency and cost-effectiveness. Adult surveillance in Mongolia will contribute to the limited evidence available on the burden of pneumococcal pneumonia among adults in low- and middle-income countries, particularly in the Asia-Pacific region. In addition, it is one of the few examples of implementing prospective, population-based pneumonia surveillance to evaluate the indirect impact of PCVs in a resource-limited setting.

Aspirin-triggered resolvin D1 reduces pneumococcal lung infection and inflammation in a viral and bacterial coinfection pneumonia model.

Formyl peptide receptor 2/lipoxin A4 (LXA4) receptor (Fpr2/ALX) co-ordinates the transition from inflammation to resolution during acute infection by binding to distinct ligands including serum amyloid A (SAA) and Resolvin D1 (RvD1). Here, we evaluated the proresolving actions of aspirin-triggered RvD1 (AT-RvD1) in an acute coinfection pneumonia model. Coinfection with Streptococcus pneumoniae and influenza A virus (IAV) markedly increased pneumococcal lung load and neutrophilic inflammation during the resolution phase. Fpr2/ALX transcript levels were increased in the lungs of coinfected mice, and immunohistochemistry identified prominent Fpr2/ALX immunoreactivity in bronchial epithelial cells and macrophages. Levels of circulating and lung SAA were also highly increased in coinfected mice. Therapeutic treatment with exogenous AT-RvD1 during the acute phase of infection (day 4-6 post-pneumococcal inoculation) significantly reduced the pneumococcal load. AT-RvD1 also significantly reduced neutrophil elastase (NE) activity and restored total antimicrobial activity in bronchoalveolar lavage (BAL) fluid (BALF) of coinfected mice. Pneumonia severity, as measured by quantitating parenchymal inflammation or alveolitis was significantly reduced with AT-RvD1 treatment, which also reduced the number of infiltrating lung neutrophils and monocytes/macrophages as assessed by flow cytometry. The reduction in distal lung inflammation in AT-RvD1-treated mice was not associated with a significant reduction in inflammatory and chemokine mediators. In summary, we demonstrate that in the coinfection setting, SAA levels were persistently increased and exogenous AT-RvD1 facilitated more rapid clearance of pneumococci in the lungs, while concurrently reducing the severity of pneumonia by limiting excessive leukocyte chemotaxis from the infected bronchioles to distal areas of the lungs.

No long-term evidence of hyporesponsiveness after use of pneumococcal conjugate vaccine in children previously immunized with pneumococcal polysaccharide vaccine.

BACKGROUND: A randomized controlled trial in Fiji examined the immunogenicity and effect on nasopharyngeal carriage after 0, 1, 2, or 3 doses of 7-valent pneumococcal conjugate vaccine (PCV7; Prevnar) in infancy followed by 23-valent pneumococcal polysaccharide vaccine (23vPPV; Pneumovax) at 12 months of age. At 18 months of age, children given 23vPPV exhibited immune hyporesponsiveness to a micro-23vPPV (20%) challenge dose in terms of serotype-specific IgG and opsonophagocytosis, while 23vPPV had no effect on vaccine-type carriage. OBJECTIVE: This follow-up study examined the long-term effect of the 12-month 23vPPV dose by evaluating the immune response to 13-valent pneumococcal conjugate vaccine (PCV13) administration 4 to 5 years later. METHODS: Blood samples from 194 children (now 5-7 years old) were taken before and 28 days after PCV13 booster immunization. Nasopharyngeal swabs were taken before PCV13 immunization. We measured levels of serotype-specific IgG to all 13 vaccine serotypes, opsonophagocytosis for 8 vaccine serotypes, and memory B-cell responses for 18 serotypes before and after PCV13 immunization. RESULTS: Paired samples were obtained from 185 children. There were no significant differences in the serotype-specific IgG, opsonophagocytosis, or memory B-cell response at either time point between children who did or did not receive 23vPPV at 12 months of age. Nasopharyngeal carriage of PCV7 and 23vPPV serotypes was similar among the groups. Priming with 1, 2, or 3 PCV7 doses during infancy did not affect serotype-specific immunity or carriage. CONCLUSION: Immune hyporesponsiveness induced by 23vPPV in toddlers does not appear to be sustained among preschool children in this context and does not affect the pneumococcal carriage rate in this age group.

Investigation of Streptococcus salivarius-mediated inhibition of pneumococcal adherence to pharyngeal epithelial cells.

BACKGROUND: Pneumococcal adherence to the nasopharyngeal epithelium is a critical step in colonisation and disease. The probiotic bacterium, Streptococcus salivarius, can inhibit pneumococcal adherence to epithelial cells in vitro. We investigated the mechanism(s) of inhibition using a human pharyngeal epithelial cell line (Detroit 562) following pre-administration of two different strains of S. salivarius. RESULTS: Whilst the bacteriocin-encoding megaplasmids of S. salivarius strains K12 and M18 were essential to prevent pneumococcal growth on solid media, they were not required to inhibit pneumococcal adherence. Experiments testing S. salivarius K12 and two pneumococcal isolates (serotypes 19F and 6A) showed that inhibition of 19F may involve S. salivarius-mediated blocking of pneumococcal binding sites: a negative correlation was observed between adherence of K12 and 19F, and no inhibition occurred when K12 was prevented from contacting epithelial cells. K12-mediated inhibition of adherence by 6A may involve additional mechanisms, since no correlation was observed between adherence of K12 and 6A, and K12 could inhibit 6A adherence in the absence of cell contact. CONCLUSIONS: These results suggest that S. salivarius employs several mechanisms, including blocking pneumococcal binding sites, to reduce pneumococcal adherence to pharyngeal epithelial cells. These findings extend our understanding of how probiotics may inhibit pneumococcal adherence and could assist with the development of novel strategies to prevent pneumococcal colonisation in the future.

The PneuCarriage Project: A Multi-Centre Comparative Study to Identify the Best Serotyping Methods for Examining Pneumococcal Carriage in Vaccine Evaluation Studies.

BACKGROUND: The pneumococcus is a diverse pathogen whose primary niche is the nasopharynx. Over 90 different serotypes exist, and nasopharyngeal carriage of multiple serotypes is common. Understanding pneumococcal carriage is essential for evaluating the impact of pneumococcal vaccines. Traditional serotyping methods are cumbersome and insufficient for detecting multiple serotype carriage, and there are few data comparing the new methods that have been developed over the past decade. We established the PneuCarriage project, a large, international multi-centre study dedicated to the identification of the best pneumococcal serotyping methods for carriage studies. METHODS AND FINDINGS: Reference sample sets were distributed to 15 research groups for blinded testing. Twenty pneumococcal serotyping methods were used to test 81 laboratory-prepared (spiked) samples. The five top-performing methods were used to test 260 nasopharyngeal (field) samples collected from children in six high-burden countries. Sensitivity and positive predictive value (PPV) were determined for the test methods and the reference method (traditional serotyping of >100 colonies from each sample). For the alternate serotyping methods, the overall sensitivity ranged from 1% to 99% (reference method 98%), and PPV from 8% to 100% (reference method 100%), when testing the spiked samples. Fifteen methods had ≥70% sensitivity to detect the dominant (major) serotype, whilst only eight methods had ≥70% sensitivity to detect minor serotypes. For the field samples, the overall sensitivity ranged from 74.2% to 95.8% (reference method 93.8%), and PPV from 82.2% to 96.4% (reference method 99.6%). The microarray had the highest sensitivity (95.8%) and high PPV (93.7%). The major limitation of this study is that not all of the available alternative serotyping methods were included. CONCLUSIONS: Most methods were able to detect the dominant serotype in a sample, but many performed poorly in detecting the minor serotype populations. Microarray with a culture amplification step was the top-performing method. Results from this comprehensive evaluation will inform future vaccine evaluation and impact studies, particularly in low-income settings, where pneumococcal disease burden remains high.

Immunization with a whole cell vaccine reduces pneumococcal nasopharyngeal density and shedding, and middle ear infection in mice.

Pneumococcal Conjugate Vaccines (PCVs) have substantially reduced the burden of disease caused by Streptococcus pneumoniae (the pneumococcus). However, protection is limited to vaccine serotypes, and when administered to children who are colonized with pneumococci at the time of vaccination, immune responses to the vaccine are blunted. Here, we investigate the potential of a killed whole cell pneumococcal vaccine (WCV) to reduce existing pneumococcal carriage and mucosal disease when given therapeutically to infant mice colonized with pneumococci. We show that a single dose of WCV reduced pneumococcal carriage density in an antibody-dependent manner. Therapeutic vaccination induced robust immune responses to pneumococcal surface antigens CbpA, PspA (family 1) and PiaA. In a co-infection model of otitis media, a single dose of WCV reduced pneumococcal middle ear infection. Lastly, in a two-dose model, therapeutic administration of WCV reduced nasal shedding of pneumococci. Taken together, our data demonstrate that WCV administered in colonized mice reduced pneumococcal density in the nasopharynx and the middle ear, and decreased shedding. WCVs would be beneficial in low and middle-income settings where pneumococcal carriage in children is high.

Evaluation of a multiplex-qPCR for paediatric pleural empyema-An observational study in hospitalised children.

Pleural empyema is a serious complication of pneumonia in children. Negative bacterial cultures commonly impede optimal antibiotic therapy. To improve bacterial identification, we developed a molecular assay and evaluated its performance compared with bacterial culture. Our multiplex-quantitative PCR to detect Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus and Haemophilus influenzae was assessed using bacterial genomic DNA and laboratory-prepared samples (n = 267). To evaluate clinical performance, we conducted the Molecular Assessment of Thoracic Empyema (MATE) observational study, enrolling children hospitalised with empyema. Pleural fluids were tested by bacterial culture and multiplex-qPCR, and performance determined using a study gold standard. We determined clinical sensitivity and time-to-organism-identification to assess the potential of the multiplex-qPCR to reduce the duration of empiric untargeted antibiotic therapy. Using spiked samples, the multiplex-qPCR demonstrated 213/215 (99.1%) sensitivity and 52/52 (100%) specificity for all organisms. During May 2019-March 2023, 100 children were enrolled in the MATE study; median age was 3.9 years (IQR 2-5.6). A bacterial pathogen was identified in 90/100 (90%) specimens by multiplex-qPCR, and 24/100 (24%) by bacterial culture (P <0.001). Multiplex-qPCR identified a bacterial cause in 68/76 (90%) culture-negative specimens. S. pneumoniae was the most common pathogen, identified in 67/100 (67%) specimens. We estimate our multiplex-qPCR would have reduced the duration of untargeted antibiotic therapy in 61% of cases by a median 20 days (IQR 17.5-23, range 1-55). Multiplex-qPCR significantly increased pathogen detection compared with culture and may allow for reducing the duration of untargeted antibiotic therapy.

Respiratory Syncytial Virus and Influenza Infections in Children in Ulaanbaatar, Mongolia, 2015-2021.

BACKGROUND: Data available for RSV and influenza infections among children < 2 years in Mongolia are limited. We present data from four districts of Ulaanbaatar from April 2015 to June 2021. METHODS: This study was nested in an enhanced surveillance project evaluating pneumococcal conjugate vaccine (PCV13) impact on the incidence of hospitalized lower respiratory tract infections (LRTIs). Our study was restricted to children aged < 2 years with arterial O2 saturation < 93% and children with radiological pneumonia. Nasopharyngeal (NP) swabs collected at admission were tested for RSV and influenza using qRT-PCR. NP swabs of all patients with radiological pneumonia and of a subset of randomly selected NP swabs were tested for S. pneumoniae (S.p.) by qPCR and for serotypes by culture and DNA microarray. RESULTS: Among 5705 patients, 2113 (37.0%) and 386 (6.8%) had RSV and influenza infections, respectively. Children aged 2-6 months had a higher percentage of very severe RSV infection compared to those older than 6 months (42.2% versus 31.4%, p-value Fisher's exact = 0.001). S.p. carriage was detected in 1073/2281 (47.0%) patients. Among S.p. carriage cases, 363/1073 (33.8%) had S.p. and RSV codetection, and 82/1073 (7.6%) had S.p. and influenza codetection. S.p. codetection with RSV/influenza was not associated with more severe LRTIs, compared to only RSV/influenza cases. CONCLUSION: In Mongolia, RSV is an important pathogen causing more severe LRTI in children under 6 months of age. Codetection of RSV or influenza virus and S.p. was not associated with increased severity.

Streptococcus pneumoniae serotype 33G: genetic, serological, and structural analysis of a new capsule type.

IMPORTANCE: Streptococcus pneumoniae (the pneumococcus) is a bacterial pathogen with the greatest burden of disease in Asia and Africa. The pneumococcal capsular polysaccharide has biological relevance as a major virulence factor as well as public health importance as it is the target for currently licensed vaccines. These vaccines have limited valency, covering up to 23 of the >100 known capsular types (serotypes) with higher valency vaccines in development. Here, we have characterized a new pneumococcal serotype, which we have named 33G. We detected serotype 33G in nasopharyngeal swabs (n = 20) from children and adults hospitalized with pneumonia, as well as healthy children in Mongolia. We show that the genetic, serological, and biochemical properties of 33G differ from existing serotypes, satisfying the criteria to be designated as a new serotype. Future studies should focus on the geographical distribution of 33G and any changes in prevalence following vaccine introduction.

Detection of group a streptococcal pharyngitis by quantitative PCR.

BACKGROUND: Group A streptococcus (GAS) is the most common bacterial cause of sore throat. School-age children bear the highest burden of GAS pharyngitis. Accurate diagnosis is difficult: the majority of sore throats are viral in origin, culture-based identification of GAS requires 24-48 hours, and up to 15% of children are asymptomatic throat carriers of GAS. The aim of this study was to develop a quantitative polymerase chain reaction (qPCR) assay for detecting GAS pharyngitis and assess its suitability for clinical diagnosis. METHODS: Pharyngeal swabs were collected from children aged 3-18 years (n = 91) and adults (n = 36) located in the Melbourne area who presented with sore throat. Six candidate PCR assays were screened using a panel of reference isolates, and two of these assays, targeting speB and spy1258, were developed into qPCR assays. The qPCR assays were compared to standard culture-based methods for their ability to detect GAS pharyngitis. GAS isolates from culture positive swabs underwent emm-typing. Clinical data were used to calculate McIsaac scores as an indicator of disease severity. RESULTS: Twenty-four of the 127 samples (18.9%) were culture-positive for GAS, and all were in children (26%). The speB qPCR had 100% sensitivity and 100% specificity compared with gold-standard culture, whereas the spy1258 qPCR had 87% sensitivity and 100% specificity. Nine different emm types were found, of which emm 89, 3, and 28 were most common. Bacterial load as measured by qPCR correlated with culture load. There were no associations between symptom severity as indicated by McIsaac scores and GAS bacterial load. CONCLUSIONS: The speB qPCR displayed high sensitivity and specificity and may be a useful tool for GAS pharyngitis diagnosis and research.

A systematic review of pneumococcal conjugate vaccine impact on pneumococcal nasopharyngeal colonisation density in children under 5 years of age.

BACKGROUND: High pneumococcal carriage density has been associated with severe pneumonia in some settings. The impact of pneumococcal conjugate vaccines (PCVs) on pneumococcal carriage density has been variable. The aim of this systematic literature review is to describe the effect of PCV7, PCV10 and PCV13 on pneumococcal colonisation density in children under five years old. METHODS: We included peer reviewed English literature published between 2000 and 2021 to identify relevant articles using Embase, Medline and PubMed. Original research articles of any study design in countries where PCV has been introduced/studied were included. Quality (risk) assessment was performed using tools developed by the National Heart Brain and Lung Institute for inclusion in this review. We used a narrative synthesis to present results. RESULTS: Ten studies were included from 1941 articles reviewed. There were two randomised controlled trials, two cluster randomised trials, one case control study, one retrospective cohort study and four cross sectional studies. Three studies used semiquantitative culture methods to determine density while the remaining studies used quantitative molecular techniques. Three studies reported an increase in density and three studies found a decrease in density among vaccinated compared with unvaccinated children. Four studies found no effect. There was considerable heterogeneity in the study populations, study design and laboratory methods. CONCLUSION: There was no consensus regarding the impact of PCV on pneumococcal nasopharyngeal density. We recommend the use of standardised methods to evaluate PCV impact on density.

Efficacy against pneumococcal carriage and the immunogenicity of reduced-dose (0 + 1 and 1 + 1) PCV10 and PCV13 schedules in Ho Chi Minh City, Viet Nam: a parallel, single-blind, randomised controlled trial.

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. TRANSLATION: For the Vietnamese translation of the abstract see Supplementary Materials section.

Effect of different schedules of ten-valent pneumococcal conjugate vaccine on pneumococcal carriage in Vietnamese infants: results from a randomised controlled trial.

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, BMGF.