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Background: Carriage studies are an efficient means for assessing pneumococcal conjugate vaccine effect in settings where pneumococcal disease surveillance programmes are not well established. In this study the effect of 10-valent pneumococcal conjugate vaccine (PCV10) introduction on pneumococcal carriage and density among Nepalese children using a bacterial microarray and qPCR was examined., Methods: PCV10 was introduced into the Nepalese infant immunisation schedule in August 2015. Nasopharyngeal swabs were collected from healthy Nepalese children in Kathmandu between April 2014 and December 2021. Samples were plated on blood agar, incubated overnight, and DNA extracted from plate sweeps. Pneumococcal serotyping was done using the Senti-SPv1.5 microarray (BUGS Bioscience, UK). DNA was extracted from swab media and qPCR performed for pneumococcal autolysin (lytA)., Results: A significant decline in prevalence of PCV10 serotypes was observed when comparing pre-PCV10 with post-PCV10 collection periods (36.5 %, 454/1244 vs 10.3 %, 243/2353, p < 0.0001). Multiple-serotype carriage was also observed to significantly decline when comparing pre-PCV10 with post-PCV10 periods (31.4 %, 390/1244 vs 22.2 %, 522/2353, p < 0.0001). Additionally, a significant decline in median pneumococcal density was observed when comparing pre-PCV10 with post-PCV10 periods (3.3 vs 3.25 log10 GE/ml, p = 0.0196)., Conclusions: PCV10 introduction was associated with reduced, prevalence of all PCV10 serotypes, multiple serotype carriage, and pneumococcal carriage density., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Andrew J Pollard reports financial support was provided by GAVI Alliance. Rama Kandasamy reports a relationship with National Health and Medical Research Council that includes: funding grants. Rama Kandasamy reports a relationship with Sanofi that includes: funding grants. AJP is chair of the UK Joint Committee on Vaccination and Immunisation and was a member of WHOs SAGE while this study was being conducted. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The pneumococcal conjugate vaccine has had a substantial impact on invasive pneumococcal disease. Previously, we compared immunity following vaccination with the 10-valent pneumococcal conjugate vaccine (PCV10) administered at 2 slightly different schedules: at 6 and 10 weeks of age, and at 6 and 14 weeks of age, both followed by a 9-month booster. In this study, we followed up those participants to evaluate the medium-term persistence of serotype-specific pneumococcal immunity at 2-3 years of age., Method: Children from the previous studies were contacted and after taking informed consent from their parents, blood samples and nasopharyngeal swabs were collected. Serotype-specific IgG antibody concentrations were determined by enzyme-linked immunosorbent assay, for the 10 vaccine serotypes, at a WHO pneumococcal serology reference laboratory., Findings: Two hundred twenty of the 287 children who completed the primary study returned at 2-3 years of age to provide a blood sample and nasopharyngeal swab. The nasopharyngeal carriage rate of PCV10 serotypes in the 6 + 14 group was higher than the 6 + 10 group (13.4% vs. 1.9%). Nevertheless, the proportion of toddlers with serum pneumococcal serotype-specific IgG greater than or equal to 0.35 µg/mL was comparable for all PCV10 serotypes between the 6 + 10 week and 6 + 14 week groups. Similarly, the geometric mean concentrations of serum pneumococcal serotype-specific IgG levels were similar in the 2 groups for all serotypes, except for serotype 19F which was 32% lower in the 6 + 10 group than the 6 + 14 group., Conclusion: Immunization with PCV10 at 6 + 10 weeks or 6 + 14 weeks, with a booster at 9 months in each case, results in similar persistence of serotype-specific antibody at 2-3 years of age. Thus, protection from pneumococcal disease is expected to be similar when either schedule is used., Competing Interests: A.J.P. is Chair of the UK Department of Health and Social Care’s (DHSC) Joint Committee on Vaccination and Immunisation (JCVI) and is a member of the WHO’s Strategic Advisory Group of Experts. The views expressed in this article do not necessarily represent the views of DHSC, JCVI or WHO. D.F.K. receives salary support from the National Institute for Health Research Oxford Biomedical Research Centre. K.O.B. has received a research grant from Gavi, the Vaccine Alliance, the Bill & Melinda Gates Foundation, GlaxoSmithKline and Pfizer. D.G. reports 7 grants from vaccine manufacturers GlaxoSmithKline, Sanofi Pasteur and Merck, outside the submitted work. R.K. received the Robert Austrian Award in Pneumococcal Vaccinology, which was supported by Pfizer, at the 10th International Symposium on Pneumococci and Pneumococcal Diseases 2016. The remaining authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Nepalese infants receive ten-valent pneumococcal conjugate vaccine (PCV10) with a 1 month interval between priming doses for programmatic reasons. We aimed to investigate whether immune responses to PCV10 serotypes were non-inferior if the second priming dose of PCV10 was delivered at a 1 month interval as opposed to a 2 month interval., Methods: We did an open-label, randomised, parallel group trial in healthy Nepalese infants aged 40-60 days at Patan Hospital, Kathmandu, Nepal. Children were eligible for inclusion if they were healthy, were born at more than or equal to 37 weeks' gestation, were residing in Kathmandu, and had not had any previous vaccinations other than BCG, and oral polio vaccine. Participants were randomly assigned (1:1) by means of a computer-generated list with randomly varying permuted block sizes accessed through a validated web-based interface, to receive PCV10 either at 6 weeks and 10 weeks of age (6 + 10 group) or at 6 weeks and 14 weeks of age (6 + 14 group), with both groups receiving a booster at 9 months of age. Laboratory staff, masked to study intervention, analysed serum samples for antibodies against PCV10 serotypes by ELISA. The primary outcome was to determine whether the 6 + 10 schedule was non-inferior to the 6 + 14 schedule at 9 months of age, on the basis of the proportion of infants with serotype-specific IgG greater than or equal to 0·35 μg/mL. Non-inferiority was established with a 10% margin, and the primary endpoint was measured in a modified intention-to-treat population, which included only participants who successfully had a blood sample collected. This trial is registered at ClinicalTrials.gov, number NCT02385513., Findings: Between Aug 21, 2015, and April 4, 2016, 304 Nepalese children were randomly assigned to either the 6 + 10 group (n=152) or the 6 + 14 group (n=152). At 9 months of age, the 6 + 10 schedule was non-inferior for serotype 5 (79 [55·2%] of 143 vs 78 [53·4%] of 146, difference 1·82% [95% CI -9·6 to 13·25], p=0·021), serotype 9V (66 [46·1%] of 143 vs 55 [37·6%] of 146, difference 8·48% [-2·84 to 19·8], p=0·001), serotype 14 (110 [77·4%] of 142 vs 110 [74·8%] of 147, difference 2·63% [-7·27 to 12·54], p=0·006), and serotype 19F (135 [95%] of 142 vs 146 [100%] of 146, difference -4·92% [-9·86 to 0], p=0·022). At the same timepoint, non-inferiority was not shown for serotype 1 (36 [25·1%] of 143 vs 42 [28·5%] of 147, difference -3·39% [95% CI -13·56 to 6·77], p=0·102), serotype 4 (70 [48·9%] of 143 vs 87 [59·1%] of 147, difference -10·23% [-21·64 to 1·18], p=0·516), serotype 6B (96 [67·1%] of 143 vs 114 [77·5%] of 147, difference -10·41% [-20·65 to -0·18], p=0·532), serotype 7F (99 [69·2%] of 143 vs 109 [74·1%] of 147, difference -4·91% [-15·26 to 5·42], p=0·168), serotype 18C (89 [62·2%] of 143 vs 114 [77·5%] of 147, difference -15·31% [-25·78 to -4·83], p=0·840), and serotype 23F (37 [25·8%] of 143 vs 41 [27·8%] of 147, difference -2·01% [-12·19 to 8·16], p=0·062). After the booster dose, at 10 months of age, there were no significant differences in immunogenicity (proportion of children with antibody greater than or equal to 0.35 μg/mL) for any of the ten serotypes, when comparing the two schedules. Serious adverse events occurred in 32 participants, 11 (7%) of 152 in the 6 + 10 group and 21 (14%) of 152 in the 6  +  14 group., Interpretation: The 6 week, 14 week, and 9 month schedule should be implemented where possible. However, post-booster responses, which are thought to drive herd immunity, were similar in the two schedules. Therefore, the 6 week, 10 week, and 9 month schedule is an alternative that can be used when logistically necessary, and is expected to provide herd protection., Funding: Gavi, the Vaccine Alliance., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Pneumococcal conjugate vaccines (PCVs) provide direct protection against disease in those vaccinated, and interrupt transmission through the prevention of nasopharyngeal (NP) carriage., Methods: We analyzed immunogenicity data from 5224 infants who received PCV in prime-boost schedules. We defined any increase in antibody between the 1-month postpriming visit and the booster dose as an indication of NP carriage ("seroincidence"). We calculated antibody concentrations using receiver operating characteristic curves, and used generalized additive models to compute their protective efficacy against seroincidence. To support seroincidence as a marker of carriage, we compared seroincidence in a randomized immunogenicity trial in Nepal with the serotype-specific prevalence of carriage in the same community., Results: In Nepalese infants, seroincidence of carriage closely correlated with serotype-specific carriage prevalence in the community. In the larger data set, antibody concentrations associated with seroincidence were lowest for serotypes 6B and 23F (0.50 µg/mL and 0.63 µg/mL, respectively), and highest for serotypes 19F and 14 (2.54 µg/mL and 2.48 µg/mL, respectively). The protective efficacy of antibody at these levels was 62% and 74% for serotypes 6B and 23F, and 87% and 84% for serotypes 19F and 14. Protective correlates were on average 2.15 times higher in low/lower middle-income countries than in high/upper middle-income countries (geometric mean ratio, 2.15 [95% confidence interval, 1.46-3.17]; P = .0024)., Conclusions: Antibody concentrations associated with protection vary between serotypes. Higher antibody concentrations are required for protection in low-income countries. These findings are important for global vaccination policy, to interrupt transmission by protecting against carriage., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Use of pneumococcal conjugate vaccines (PCVs) in resource-poor countries has focused on early infant immunisation with little emphasis on protection in late infancy and beyond. Boosting of the immune response later in infancy might provide improved persistence of immunogenicity into early childhood, however data are scarce. The aim of this study was to investigate if a two-dose prime with booster at age 9 months compared with a three-dose prime-only PCV schedule provided non-inferior immunogenicity in early infancy and superior persistence of antibody responses in early childhood., Methods: We did an open-label, randomised, parallel group, controlled trial in healthy infants aged 40-60 days from Kathmandu, Nepal. Participants were randomly allocated (4:4:5 ratio) to receive PCV10 in addition to routine immunisations either as a two-dose prime and boost (2+1), three-dose prime (3+0), or two doses after completion of the initial study phase (0+2). We used a computer generated randomisation list with randomly varying block sizes. We followed up participants at age 2-4 years together with a group of unvaccinated controls. Sera were analysed for opsonophagocytic activity, protein D, and PCV10 serotype-specific IgG. Laboratory staff was masked to intervention group assignment. The primary outcome measure was to determine the proportion of participants in the 2+1 group at age 10 months with specific IgG for serotypes 1, 5, and 14 of at least 0·2 μg/mL in the per-protocol population. The secondary outcomes were non-inferiority (within 10% levels) at age 18 weeks for the proportion of participants in the 2+1 group compared with the 3+0 group with serotypes 1, 5, and 14 specific IgG of at least 0·2 μg/mL; the proportion of participants with PCV10 serotype-specific IgG of at least 0·2 μg/mL and opsonophagocytic activity reciprocal titre of at least 8 at ages 18 weeks and 10 months; and nasopharyngeal pneumococcal serotype-specific carriage rates at age 9 months in each study group. In the follow-up study, the primary outcome measure was the proportion of participants with IgG of at least 0·2 μg/mL for PCV10 serotypes at age 2-4 years in children previously immunised with a 3+0 schedule compared with a 2+1 schedule. The trial is registered with Current Controlled Trials, registration number ISRCTN56766232., Findings: Between May 10, 2010, and Jan 7, 2011, 390 children were randomly assigned to each group: 119 to the 2+1 group, 120 to the 3+0 group, and 151 to the 0+2 group. At age 10 months, the proportions of 2+1 participants with IgG of at least 0·2 μg/mL were 99·0% (95% CI 94·2-100·0) for serotype 1, 100% (96·2-100·0) for serotype 5, and 97·9% (92·5-99·7) for serotype 14. At age 18 weeks, non-inferiority (within 10% levels) of the 2+1 group was shown compared with the 3+0 group, and there was no difference between the 2+1 and 3+0 groups for the proportion with IgG of at least 0·2 μg/mL for any of the PCV10 serotypes. At age 10 months, proportions with IgG of at least 0·2 μg/mL for serotypes 1, 5, 6B, and 23F, were higher in the 2+1 group than in the 3+0 group. At age 18 weeks, there were no differences in opsonophagocytic activity between the 2+1 and 3+0 groups for reciprocal titres of at least 8, but at age 10 months, proportions with an opsonophagocytic reciprocal titre of at least 8 for serotypes 1, 4, 5, 6B, 18C, 19F and 23F were higher in the 2+1 group than in the 3+0 group. At age 2-4 years, there were higher proportions in the 2+1 group versus the 3+0 group with IgG of at least 0·2 μg/mL for serotypes 1, 5, 6B, and 18C., Interpretation: Use of a 2+1 PCV schedule with booster at age 9 months in a resource-poor setting improved antibody persistence through early childhood without compromising antibody responses in early infancy. This schedule is now recommended by WHO for progressive introduction across Nepal, with PCV10 introduction having commenced on Jan 18, 2015. Concurrent pre-implementation and post-implementation surveillance is being done by a GAVI Alliance funded study., Funding: This study was supported by funding from the National Institute for Public Health and the Environment, The Netherlands; Oxford Vaccine Group, University of Oxford, UK; and GlaxoSmithKline Biologicals, Belgium., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Pneumococcal disease is a significant cause of morbidity and mortality in young children in Nepal, and currently available pneumococcal conjugate vaccines offer moderate coverage of invasive disease isolates., Methods: A prevalence study of children aged 1.5 to 24 months in urban and rural Nepal was conducted. In the urban group, nasopharyngeal swabs (NPS) were transported using silica desiccant packages (SDP) with delayed processing (2 weeks), or skim-milk-tryptone-glucose-glycerin (STGG) with immediate processing (within 8 hours). Pneumococcal nasopharyngeal carriage prevalence, serogroup/type distribution and isolate genotypes (as defined by multilocus sequence typing) were determined., Results: 1101 children were enrolled into the study: 574 in the urban group and 527 in the rural group. Overall carriage prevalence based on culture from specimens transported and stored in STGG was 58.7% (337/574), compared to 40.9% (235/574) in SDP. There was concordance of detection of pneumococcus in 67% of samples. Using the SDP method, pneumococcal carriage prevalence was higher in the rural population (69.2%; 364/526) compared to the urban population (40.9%; 235/574). Serogroup/type distribution varied with geographical location. Over half of the genotypes identified in both the urban and rural pneumococcal populations were novel., Conclusion: The combination of delayed culture and transport using SDP underestimates the prevalence of pneumococcal carriage; however, in remote areas, this method could still provide a useful estimate of carriage prevalence and serogroup/type distribution. Vaccine impact is unpredictable in a setting with novel genotypes and limited serotype coverage as described here. Consequently, continued surveillance of pneumococcal isolates from carriage and disease in Nepali children following the planned introduction of pneumococcal conjugate vaccines introduction will be essential.

Invasive pneumococcal disease is one of the major causes of death in young children in resource poor countries. Nasopharyngeal carriage studies provide insight into the local prevalence of circulating pneumococcal serotypes. There are very few data on the concurrent carriage of multiple pneumococcal serotypes. This study aimed to identify the prevalence and serotype distribution of pneumococci carried in the nasopharynx of young healthy Nepalese children prior to the introduction of a pneumococcal conjugate vaccine using a microarray-based molecular serotyping method capable of detecting multi-serotype carriage. We conducted a cross-sectional study of healthy children aged 6 weeks to 24 months from the Kathmandu Valley, Nepal between May and October 2012. Nasopharyngeal swabs were frozen and subsequently plated on selective culture media. DNA extracts of plate sweeps of pneumococcal colonies from these cultures were analysed using a molecular serotyping microarray capable of detecting relative abundance of multiple pneumococcal serotypes. 600 children were enrolled into the study: 199 aged 6 weeks to <6 months, 202 aged 6 months to < 12 months, and 199 aged 12 month to 24 months. Typeable pneumococci were identified in 297/600 (49·5%) of samples with more than one serotype being found in 67/297 (20·2%) of these samples. The serotypes covered by the thirteen-valent pneumococcal conjugate vaccine were identified in 44·4% of samples containing typeable pneumococci. Application of a molecular serotyping approach to identification of multiple pneumococcal carriage demonstrates a substantial prevalence of co-colonisation. Continued surveillance utilising this approach following the introduction of routine use of pneumococcal conjugate vaccinates in infants will provide a more accurate understanding of vaccine efficacy against carriage and a better understanding of the dynamics of subsequent serotype and genotype replacement. [ABSTRACT FROM AUTHOR]

Background: Pneumococcal disease is a significant cause of morbidity and mortality in young children in Nepal, and currently available pneumococcal conjugate vaccines offer moderate coverage of invasive disease isolates. Methods: A prevalence study of children aged 1.5 to 24 months in urban and rural Nepal was conducted. In the urban group, nasopharyngeal swabs (NPS) were transported using silica desiccant packages (SDP) with delayed processing (2 weeks), or skim-milk-tryptone-glucose-glycerin (STGG) with immediate processing (within 8 hours). Pneumococcal nasopharyngeal carriage prevalence, serogroup/type distribution and isolate genotypes (as defined by multilocus sequence typing) were determined. Results: 1101 children were enrolled into the study: 574 in the urban group and 527 in the rural group. Overall carriage prevalence based on culture from specimens transported and stored in STGG was 58.7% (337/574), compared to 40.9% (235/574) in SDP. There was concordance of detection of pneumococcus in 67% of samples. Using the SDP method, pneumococcal carriage prevalence was higher in the rural population (69.2%; 364/526) compared to the urban population (40.9%; 235/574). Serogroup/type distribution varied with geographical location. Over half of the genotypes identified in both the urban and rural pneumococcal populations were novel. Conclusion: The combination of delayed culture and transport using SDP underestimates the prevalence of pneumococcal carriage; however, in remote areas, this method could still provide a useful estimate of carriage prevalence and serogroup/type distribution. Vaccine impact is unpredictable in a setting with novel genotypes and limited serotype coverage as described here. Consequently, continued surveillance of pneumococcal isolates from carriage and disease in Nepali children following the planned introduction of pneumococcal conjugate vaccines introduction will be essential. [ABSTRACT FROM AUTHOR]

Background. Streptococcus pneumoniae is a leading cause of pneumonia and meningitis in young children. Before implementation of the pneumococcal conjugate vaccine in developing countries, there is an urgent need to provide regional epidemiological data on pneumococcal disease. The aims of this study were to determine the prevalence and serotype distribution of invasive pneumococcal disease among young children hospitalized in urban Nepal. Methods. Children aged 2 months to 5 years who were admitted to Patan Hospital, Kathmandu, with fever and/or suspected pneumonia, meningitis, or bacteremia were recruited. Blood culture specimens were collected from all participants. In cases of suspected meningitis, cerebrospinal fluid specimens were cultured and were tested for S. pneutnoniae antigen. Results. A total of 885 children were recruited during the 21-month study period. Of these, 76 (9%) had meningitis and 498 (56%) had pneumonia, on the basis of clinical criteria. Radiographically confirmed pneumonia occurred in 354 (40%), and probable or definite meningitis occurred in 47 (5%). S. pneumoniae was isolated in specimens from 17 (2%) of the children. Serotypes 1 and 12A were isolated most frequently, and only 1 of 17 isolates had a serotype contained in the currently available 7-valent pneumococcal conjugate vaccine. Conclusions. More than 60% of children aged <5 years who were admitted with fever and/or suspected invasive bacterial disease in urban Nepal had the clinical syndromes of meningitis and/or pneumonia. A new generation of pneumococcal vaccines that prevent infection with a broader range of serotypes may be necessary to most effectively control pneumococcal disease in young children in Kathmandu. [ABSTRACT FROM AUTHOR]