Andrew J. Pollard, United Kingdom

University of Oxford Oxford Vaccine Group,

Author Of 22 Presentations

THE IMPACT OF PNEUMOCOCCAL CONJUGATE VACCINE INTRODUCTION IN NEPAL: A SIX-YEAR PAEDIATRIC SURVEILLANCE STUDY (ID 516)

Abstract

Background

S. pneumoniae is a major cause of bacterial pneumonia and an important cause of invasive bacterial disease (IBD) in children under-five years of age in Nepal. Pneumococcal conjugate vaccine, PCV10, was introduced in 2015 with a 2+1 schedule.

Methods

We assessed the programmatic impact of PCV10 introduction using surveillance for nasopharyngeal (NP) colonisation, pneumonia and IBD. NP swabs from pneumonia inpatients and from healthy children, blood cultures from inpatients with suspected IBD, and chest x-rays from inpatient pneumonia cases were obtained over a 6-year period (2014-2019).

Results

The proportion of pneumonia cases with radiographic endpoint-consolidation (likely bacterial) was 34% lower (95%CI 19-46%) in 2018 compared with the pre-vaccine period (2014-2015). Vaccine serotype (VT) carriage in children under 2-years of age with pneumonia in 2019 was 78% lower (95%CI 30-93%) than in the pre-vaccine period.

Among healthy 6-23 month old children (urban and rural cohorts), VT-carriage declined 74% (95%CI 43-82%) by 2019. An increase in PCV13-additional-serotype carriage was seen in 2018 among rural-children (prevalence-ratio 1.65, 95%CI 1.17-2.32), but not urban-children.

Serotype 1 remains the dominant serotype detected in cases of invasive pneumococcal disease.

Conclusions

A decrease in prevalence of endpoint-consolidation-pneumonia and a decrease in vaccine-serotype circulation have been observed post PCV introduction in Nepal.

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GENOME-WIDE ASSOCIATION STUDY OF COLONISING NASOPHARYNGEAL PNEUMOCOCCI OBTAINED FROM CHILDREN IN NEPAL TO IDENTIFY GENES ASSOCIATED WITH PNEUMONIA. (ID 729)

Abstract

Background

Identifying the molecular characteristics of pneumococci associated with disease may inform development of new clinical interventions. We aimed to perform a bacterial genome-wide association study to identify pneumococcal genes associated with carriage among children with pneumonia.

Methods

DNA from nasopharyngeal pneumococcal isolates obtained from Nepalese children admitted to hospital with pneumonia (cases) and healthy community-based children (controls), underwent whole-genome-sequencing on the Wellcome Sanger Institutes core sequencing pipeline. The association of variants from sequences mapped against the S. pneumoniae ATCC700669 genome, with cluster of orthologous groups using a fixed effects model, was performed using a python based sequence element enrichment analysis.

Results

245 case and 597 control isolates were sequenced. 405461 variants were identified and 31708 tested after filtering. 20 variants from colonising bacteria had a strong association (p<10-8) with pneumonia. 18/20 of these variants were located within the lacE2 gene. The variant with the strongest association, presence of an A allele at position 1066739, was identified in 240/597 (40%) of controls and 150/245 (61%) of cases (p=10-10).

Conclusions

In this study in Nepal the pneumococcal gene lacE2 was associated with colonisation in children with pneumonia. Studies examining the role of lacE2 in the pathogenesis of pneumococcal pneumonia are needed.

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MONITORING VACCINE IMPACT ON COMMUNITY CARRIAGE IN NEPAL REVEALS CHANGES IN THE CIRCULATING POPULATION OF PNEUMOCOCCAL SEROTYPES AND ANTIMICROBIAL RESISTANCE GENES (ID 977)

Abstract

Background

Community carriage of pneumococcal serotypes in children was assessed pre- and post-PCV10 introduction in Nepal to monitor pneumococcal vaccine impact. Molecular serotyping by microarray enabled detection of multiple-serotype carriage plus non-encapsulated pneumococcal lineages, related Streptococcus species and selected antimicrobial resistance genes.

Methods

Nasopharyngeal swabs were collected from healthy Nepalese children in 2014-15 (pre-PCV10) and 2017-18 (post-PCV10). DNA was extracted from plate sweeps of 1,241 and 1,445 swab cultures for pre- and post-vaccine periods respectively and analysed by Senti-SP molecular serotyping microarray.

Results

Comparing carriage among children pre- and post-PCV10, there was a decrease in PCV10 serotype carriage (37% vs 17%) and an increase in non-vaccine serotype carriage (67% vs 73%). There was no change for non-encapsulated pneumococcal lineages (16% vs 16%), an increase in related Streptococcal species (22% vs 25%) and an increase in detection of antimicrobial resistance genes (65% vs 74%). Multiple pneumococcal serotype carriage decreased (24% vs 16%) and multiple carriage including non-encapsulated pneumococci and related Streptococcal species also decreased (45% vs 41%).

Conclusions

Introduction of PCV10 in Nepal has resulted in a decrease in vaccine type carriage within two years. However, increases in carriage of non-vaccine types as well as antimicrobial resistance genes and related Streptococcal species were observed.

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IMPACT OF 10-VALENT PNEUMOCOCCAL CONJUGATE VACCINE INTRODUCTION ON INVASIVE PNEUMOCOCCAL DISEASE (IPD) IN NEPALESE CHILDREN (ID 563)

Abstract

Background

We assessed the distribution of pneumococcal serotypes in children with microbiologically-confirmed invasive pneumococcal disease (IPD) before (2014-2015) and after (2016-2019) PCV10 introduction in Nepal in 2015.

Methods

Children (aged 2 months to <14 years) admitted to Patan Hospital, Nepal with pneumococcus detected in blood, CSF or pleural fluid were included. Serotyping was by Quellung method.

Results

Pre-vaccine, 6/22 (27.3%) IPD cases were age <2 years; post-vaccine, 5/36 (13.9%) were <2 years. Ratio of vaccine-type to non-vaccine-type IPD among <2y olds was 5:1 pre-vaccine and 2:3 post-vaccine; among >=2y olds, the ratio was 13:1 pre-vaccine and 7:1 post-vaccine. Most (32/41, 78%) vaccine-type IPD was serotype 1: 3/7 among <2 year olds (n=1 post-vaccine); 29/34 among >=2 year olds (n=17/19 post-vaccine were >4 years old). Among 44 IPD cases detected from blood, 36 (82%) were vaccine-type (n=29 were ST1), and 7 were non-vaccine-type (6C, 10A (n=2), 19A, 24F, 38, 41). Of 13 detected from CSF (1 culture, 3 PCR and 9 Binax-only), 5 were serotyped (1, 14, 6B, 6A/B, 7F) .The 3 pleural fluid cases were serotypes 1 (n=2) and 19A.

Conclusions

Post-PCV10 introduction, IPD among <2 year olds fell; although a high proportion of ST1 IPD remains, most were >4 years old.

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GENOME-WIDE ASSOCIATION STUDY OF PNEUMOCOCCAL CARRIAGE AMONG NEPALESE CHILDREN (ID 16)

Abstract

Background

Determining the host molecular genetic characteristics of pneumococcal colonisation may inform the development of new clinical interventions which could interrupt pneumococcal transmission and establishment of disease. We performed a genome-wide association study to identify the genes associated with pneumococcal carriage.

Methods

DNA collected from healthy Nepalese children were genotyped using Illumina Global Screening Arrays. Array data underwent QC and filtering before undergoing imputation using the HRC R1.1 2016 reference panel. Nasopharyngeal swabs collected from participants were processed for the presence of pneumococci by conventional microbiological techniques. Association analysis was performed using PLINK 1.9.

Results

Following filtering, 1355 carriers (cases) and 766 non-carriers (controls) were analysed. 10 variants within a single region, were associated with pneumococcal carriage (p<10-8). The variant that had the strongest association with pneumococcal carriage (MAF carriers = 0.07 vs MAF non-carriers = 0.13, OR 0.52, 95% CI 0.42-0.64, p=2.3x10-8), is within an intergenic region between PPFIA2 and CCDC59.

Conclusions

We identified host genetic variants associated with pneumococcal carriage. Further studies confirming this association and its biological role in pneumococcal carriage are needed.

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PCV10 IMPACT ON PNEUMOCOCCAL LINEAGES ISOLATED FROM HEALTHY NEPALESE CHILDREN. (ID 736)

Abstract

Background

The 10-valent pneumococcal conjugate vaccine (PCV10) was introduced into the Nepalese infant immunisation schedule in August 2015. We aimed to examine how PCV10 introduction in affected pneumococcal lineages.

Methods

DNA from randomly selected nasopharyngeal pneumococcal isolates of healthy community-based Nepalese children in the Kathmandu valley pre- (2009-2014) and post-PCV10 (2017-2018) introduction, underwent whole-genome-sequencing on the Wellcome Sanger Institutes core sequencing pipeline. Isolates were clustered into lineages based on shared sequence and gene content using Population Partitioning Using Nucleotide K-mers (PopPUNK) software.

Results

313 and 284 pre- and post-PCV10 isolates were sequenced. There was a significant reduction in the proportion of PCV10 serotypes when comparing pre 73/313 (23.3%) with post 37/284 (13%) PCV10 samples (p=0.0014). Overall 122 distinct lineages were identified, 98 pre- and 74 post-PCV10. Simpson's index of diversity for the lineages was 0.992 and 0.987 pre- and post-PCV10 respectively. Within the 3 largest PCV10 serotype lineages there were no examples of non-PCV10 serotype isolates pre-vaccination, whereas all 3 lineages contained non-PCV10 serotypes post-vaccination.

Conclusions

PCV10 serotype prevalence significantly declined following PCV10 introduction. However, strain diversity remained high post-PCV10 and there is evidence suggestive of vaccine escape via capsular-switching among lineages possessing predominantly vaccine-covered capsules prior to PCV10 introduction.

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SEROTYPE-SPECIFIC PNEUMOCOCCAL CARRIAGE DENSITY AMONG HEALTHY NEPALESE CHILDREN POST-PCV10 INTRODUCTION (ID 1047)

Abstract

Background

The density of pneumococcal carriage provides an insight into the dynamics of transmission, colonisation and vaccine effect. We aimed to measure serotype-specific carriage density 2-3 years after 10-valent pneumococcal conjugate vaccine (PCV10) introduction, using qPCR and bacterial DNA microarray.

Methods

Nasopharyngeal swabs were collected from healthy Nepalese children from the Kathmandu Valley between April 2017 and August 2018. DNA was extracted from the swab media and qPCR performed for pneumococcal autolysin (lytA). Swab media were also plated on blood agar, incubated overnight, and plate sweeps collected. DNA was extracted from plate sweeps and molecular serotyped using the Senti-SPv1.5 microarray (BUGS Bioscience, UK).

Results

1264 swabs were collected and analysed by both microarray and qPCR. The mean density of PCV10 serotypes was significantly higher than non-PCV10 serotypes (10^3.9 vs 10^3.4 copies/ml, p=0.004). Serotypes 1 (10^4.6 copies/ml, 95% CI 10^3.4-5.9) and 6B (10^4.6 copies/ml, 95% CI 10^3.9-5.3) had the highest mean density. Serotypes 4 (10^2.8 copies/ml, 95% CI 10^1.1-4.5) and 9N (10^2.9copies/ml, 95% CI 10^2.1-3.7) had the lowest mean carriage density.

Conclusions

Serotype 1, which causes the greatest proportion of invasive pneumococcal disease in this setting, was found to have the highest carriage density. Further evaluation of the PCV10 impact on carriage density is needed.

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COMPARISON OF IMMUNOGENICITY OF TEN- AND THIRTEEN-VALENT PNEUMOCOCCAL CONJUGATE VACCINES – A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS (ID 567)

Abstract

Background

Streptococcus pneumoniae causes substantial morbidity and mortality globally, with serotype-specific disease burden varying geographically. Currently there are two widely used pneumococcal conjugate vaccines (PCV). Evidence is limited regarding their comparative serotype-specific immunogenicity and efficacy.

Methods

We conducted a systematic-review and network meta-analysis of studies in which the immunogenicity of PCVs was directly compared in head-to-head randomised trials. Network meta-analysis incorporates both direct pair-wise comparisons and indirect comparisons (e.g. PCV10 vs PCV7, and PCV13 vs PCV7) thereby increasing overall statistical precision for the main comparison of interest (PCV10 vs PCV13). The difference in immunogenicity, as measured by geometric mean ratio (GMR), was examined by serotype.

Results

27 trials were included in the network meta-analysis, 4 directly comparing PCV10 and PCV13, 7 comparing PCV7 and PCV10, and 16 comparing PCV7 and PCV13. For the 10 common serotypes, immunogenicity at 1 month after the primary vaccination series was higher for PCV13 for 7 serotypes, with GMRs ranging from 1.18 to 2.50. In contrast, serotype 5, 18C and 19F favoured PCV10. Similar results were observed post-booster dose except for serotype 5 and 7F.

Conclusions

Variation in serotype-specific immunogenicity exists between PCV10 and PCV13, indicating that further investigation into whether this translates to heterogeneity in protection is needed.

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IMPACT OF PCV10 INTRODUCTION ON NASOPHARYNGEAL CARRIAGE OF STREPTOCOCCUS PNEUMONIAE IN HEALTHY CHILDREN IN RURAL AND URBAN NEPAL (ID 531)

Abstract

Background

The ten-valent pneumococcal conjugate vaccine (PCV10) was introduced in Nepal in 2015. We compared the nasopharyngeal carriage of PCV10 and non-PCV10 serotypes of pneumococcus between pre-vaccine (2015) and post-vaccine (2017-2018) years in two different regions of Nepal.

Methods

Nasopharyngeal samples obtained in healthy Nepalese children aged 6-59 months in urban (Patan, Kathmandu) and 6-23 months in rural (Okhaldhunga) settings were transported in STGG (Skim Milk-Tryptone-Glucose-Glycerol) media, cultured for pneumococcus and serotyped by the Quellung method.

Results

The carriage prevalence decreased for all PCV10-type serotypes except 7F in both the settings. PCV10-type prevalence decreased from 29.7% in rural and 17.2% in urban children pre-vaccine to 9.0% and 8.6% post-vaccine, respectively. Pre-vaccine, the most frequently found serotypes in both settings were 19F, 6B, 14. Post-vaccine, the non-PCV10 serotypes were more common; serotypes 34, 6C, 19A and 15B were most common in rural and 6A, 34, 11A, 6C and 15B in urban settings.

Conclusions

Since the introduction of PCV10, carriage prevalence of PCV10 serotypes have reduced and non-PCV10 serotypes have increased in both settings raising the possibility of replacement disease. Continued monitoring of changes in PCV10-serotypes and non-PCV10 serotypes, especially those covered by PCV13, is important to assess vaccine impact.

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GLOBAL GENOMIC EPIDEMIOLOGY OF PNEUMOCOCCAL SEROTYPE 2 ISOLATED DURING 1989 TO 2019 (ID 1084)

Abstract

Background

Serotype 2 was a major cause of pneumococcal pneumonia about 100 years ago and then disappeared. Recently, serotype 2 re-emerged in many countries, including Bangladesh and associated with meningitis. This study aims to understand genomic and epidemiological characteristics of newly emerged serotype 2 strains.

Methods

Whole-genome sequencing was performed on 146 isolates (invasive= 125, carriage= 8 and other= 5, unknown= 8) collected between 1989 and 2017. Data were analyzed for comparative genomics, antimicrobial resistance and molecular typing.

Results

Isolates were from 16 countries, mostly in Asia (n=93), Africa (n=23) and Oceania (n=26). Bangladesh (n=66) and Papua New Guinea (n=26) contributed 63% of the isolates. Among the known clinical conditions, 80% (91/113) were from meningitis. All isolates belonged to GPSC96 lineage and descended from two predominant sequence types: ST74 found in Asia and Africa, and ST1504 found in Papua New Guinea and Israel. Almost all isolates were sensitive to all antibiotics. No significant genetic differences were detected between invasive and carriage isolates.

Conclusions

Our findings don’t explain why the recent increase in serotype 2 occurred but exclude an outbreak or emergence of an antimicrobial-resistant strain as the cause. These isolates have unusually high propensity to be invasive, mostly causing meningitis.

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ASSOCIATION BETWEEN C-REACTIVE PROTEIN LEVEL AND A RADIOLOGICAL END POINT CONSOLIDATION PNEUMONIA AMONG HOSPITALISED CHILDREN WITH SUSPECTED PNEUMONIA IN NEPAL (ID 618)

Abstract

Background

S. pneumoniae is one of the most common causes of paediatric bacterial pneumonia. In low-income countries such as Nepal, CRP level and blood culture can be useful in diagnosis assessment. We assessed the association between CRP/blood culture, and pneumonia with end-point consolidation.

Methods

We included children less than 5 years of age admitted with suspected pneumonia to Patan Hospital in 2018 and 2019, whose chest xray, CRP level and blood culture were done. CRP levels >40 mg/dl were considered elevated.

Results

There was a significant difference (p<0.001) in CRP levels between EPC-pneumonia and non-EPC pneumonia cases with a median (IQR) CRP of 46.2 (16, 215) in 141 EPC-pneumonia cases and a median (IQR) CRP of 13 (4, 35) in non-EPC pneumonia cases. The sensitivity and specificity of CRP >40mg/dl to detect EPC pneumonia were 50% and 84% respectively. The area under the ROC curve was 0.727 indicating good discrimination between EPC-pneumonia and non-EPC pneumonia. Among the EPC-pneumonia cases, 62% had elevated CRP and 3.5% had S. pneumoniae positive blood cultures.

Conclusions

There was a significant association between CRP and EPC pneumonia. Blood culture had low sensitivity to detect bacterial pneumonia, nevertheless, CRP may be a useful tool in diagnosis of bacterial pneumonia.

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IMPACT OF PNEUMOCOCCAL CONJUGATE VACCINE (PCV-10) ON RADIOLOGICAL PNEUMONIA AT A TERTIARY CARE CENTRE IN NEPAL (ID 514)

Abstract

Background

Routine immunization with 10-valent pneumococcal conjugate vaccine (PCV10) was introduced in Kathmandu in 2015 with doses administered at 6 weeks, 10 weeks and 9 months of age. We assessed the impact of PCV10 on the prevalence of radiographic changes in children aged 2 months to 14 years with a clinical diagnosis of pneumonia admitted to Patan Hospital, Kathmandu.

Methods

Digitalized chest radiographs were interpreted using standardized WHO criteria as primary endpoint pneumonia (PEP), other infiltrate or normal, by two specific readers. A third reader arbitrated upon all discordant results.

Results

From March 2014 to December 2018, 1755 children were enrolled, of whom 1692 (96%) had interpretable radiographs. The proportion of children with PEP decreased annually from 84/189 (44%) in 2014 to 105/414 (25%) in 2018 (p<0.001). PEP was associated with age, occurring in 247/1090 (22%) children <2 years of age, in comparison with 120/175 (69%) children ≥5 years of age (p<0.001), and carriage of PCV10 serotypes, occurring in 95/188 (51%) children with PCV10 carriage in comparison with 459/1504 (31%) children with non-PCV10 serotypes or no carriage (p<0.001).

Conclusions

The prevalence of PEP in children hospitalized with pneumonia decreased from 2014 to 2018 in association with the implementation of PCV10 immunization in Kathmandu.

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CONSISTENCY OF VACCINATION HISTORIES OBTAINED FROM MEDICAL RECORDS OR CAREGIVER RECALL IN NEPAL. (ID 1135)

Abstract

Background

PCV status, necessary for assessing vaccine impact, is often incomplete or unknown. For children admitted with pneumonia in Kathmandu, Nepal, we compared vaccine histories from caregivers vs medical records to determine if these provided similar estimates of coverage.

Methods

Between 2016-2019, patients aged 6 months to 14 years admitted with pneumonia at Patan Hospital, enrolled into a pneumococcal carriage study had their number of PCV doses collected by caregiver recall and/or from hospital medical records. Records, created at birth, are updated when they receive routine vaccinations there; for vaccinations administered elsewhere, vaccine history is obtained from caregivers during any hospital admission. Cases were excluded from analyses if both caregiver recall and medical records were cited as the source.

Results

Of the 1,603 inpatients enrolled, 1,201 (80%) had data from either caregiver recall or medical records. PCV coverage (3 doses) was higher for caregiver recall than medical records (43% vs 35%; p=0.03), while Hib vaccine coverage was similar (91% vs 87%; p=0.16).

Conclusions

Although caregiver recall provided statistically higher estimates of vaccine coverage than medical records, the estimates were generally similar. Medical records may be incomplete (underestimate) and caregiver recall may have recall bias (overestimate); the truth may be in between.

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