TY - JOUR
T1 - Effect of childhood vaccination and antibiotic use on pneumococcal populations and genome-wide associations with disease among children in Nepal
T2 - an observational study
AU - Kandasamy, Rama
AU - Lo, Stephanie
AU - Gurung, Meeru
AU - Carter, Michael J
AU - Gladstone, Rebecca
AU - Lees, John
AU - Shrestha, Sonu
AU - Thorson, Stephen
AU - Bijukchhe, Sanjeev
AU - Gautam, Madhav C
AU - Shrestha, Reetu
AU - Gurung, Sunaina
AU - Khadka, Bibek
AU - McGee, Lesley
AU - Breiman, Robert F
AU - Murdoch, David R
AU - Kelly, Dominic F
AU - Shrestha, Shrijana
AU - Bentley, Stephen D
AU - Pollard, Andrew J
N1 - Funding Information:
RK receives a National Health and Medical Research Council (NHMRC) Emerging Leader Fellowship (GNT1174010). MJC is a National Institute for Health Research (NIHR) Academic Clinical Lecturer and was funded by a Wellcome Trust Clinical Fellowship (104439/Z/14/Z) for part of this work. AJP is Chair of UK Department of Health and Social Care's (DHSC) Joint Committee on Vaccination & Immunisation (JCVI). He is a member of WHO's Strategic Advisory Group of Experts. AJP is an NIHR Senior Investigator. The views expressed in this Article do not necessarily represent the views of DHSC, JCVI, NIHR, or WHO. AJP is chief investigator on clinical trials of Oxford University's COVID-19 vaccine funded by NIHR. Oxford University has entered a joint COVID-19 vaccine development partnership with AstraZeneca.
Funding Information:
This study was funded by Gavi the vaccine alliance, WHO, the Bill and Melinda Gates Foundation (grant code OPP1034556), the Wellcome Sanger Institute (core Wellcome grants 098051 and 206194) and the US Centers for Disease Control and Prevention. We thank all members of the Global Pneumococcal Sequencing Consortium for their contributions to create this rich global dataset so as to make some of the overarching analyses in this Article possible. We are also grateful for the technical support from Wellcome Sanger Institute sequencing facility and Pathogen Informatics team. The findings and conclusions in this Article are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention.
Publisher Copyright:
© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
PY - 2022/7/1
Y1 - 2022/7/1
N2 - Background: Pneumococcal disease is a leading cause of bacterial pneumonia and invasive bacterial disease among children globally. The reason some strains of pneumococci are more likely to cause disease, and how interventions such as vaccines and antibiotics affect pneumococcal strains is poorly understood. We aimed to identify genetic regions under selective pressure and those associated with disease through the analysis of pneumococcal whole-genome sequences. Methods: Whole-genome sequencing was performed on pneumococcal isolates collected between January, 2005, and May, 2018, in Kathmandu, Nepal, which included programmatic ten-valent pneumococcal conjugate vaccine (PCV10) introduction in 2015. Isolates were from three distinct cohorts: nasopharyngeal swabs of healthy community-based children, nasopharyngeal swabs of children admitted to hospital with pneumonia, and sterile-site cultures from children admitted to hospital. Across these cohorts we examined serotype distribution, antibiotic resistance, strain distribution, and regions of recombination to determine genes that were undergoing diversifying selection. Genome-wide association studies comparing pneumonia and sterile-site isolates with healthy carriage were used to determine novel variants associated with disease. Findings: After programmatic introduction of PCV10, there was a decline in vaccine covered serotypes; however, strains that had expressed these serotypes continued to exist in the post-PCV population. We identified GPSC9 to be a strain of concern due to its high prevalence in disease, multidrug resistance, and ability to switch to an unencapsulated phenotype via insertion of virulence factor pspC into the cps locus. Antibiotic resistance loci to co-trimoxazole were found to be prevalent (pre-PCV10 78% vs post-PCV10 81%; p=0·27) and increasingly prevalent to penicillin (pre-PCV10 15% vs post-PCV10 32%; p<0·0001). Regions with multiple recombinations were identified spanning the surface protein virulence factors pspA and pspC and antibiotic targets pbpX, folA, folC, folE, and folP. Furthermore, we identified variants in lacE2 to be strongly associated with isolates from children with pneumonia and PRIP to be strongly associated with isolates from sterile sites. Interpretation: Our work highlights the effect of pneumococcal conjugate vaccines, antibiotics, and host–pathogen interaction in pneumococcal variation, and the pathogen's capability of adapting to these factors at both population-wide and strain-specific levels. Ongoing surveillance of disease-associated strains and further investigation of lacE2 and PRIP as serotype-independent targets for therapeutic interventions is required. Funding: Gavi, The Vaccine Alliance; WHO; Bill & Melinda Gates Foundation; Wellcome Sanger Institute; and US Centers for Disease Control and Prevention.
AB - Background: Pneumococcal disease is a leading cause of bacterial pneumonia and invasive bacterial disease among children globally. The reason some strains of pneumococci are more likely to cause disease, and how interventions such as vaccines and antibiotics affect pneumococcal strains is poorly understood. We aimed to identify genetic regions under selective pressure and those associated with disease through the analysis of pneumococcal whole-genome sequences. Methods: Whole-genome sequencing was performed on pneumococcal isolates collected between January, 2005, and May, 2018, in Kathmandu, Nepal, which included programmatic ten-valent pneumococcal conjugate vaccine (PCV10) introduction in 2015. Isolates were from three distinct cohorts: nasopharyngeal swabs of healthy community-based children, nasopharyngeal swabs of children admitted to hospital with pneumonia, and sterile-site cultures from children admitted to hospital. Across these cohorts we examined serotype distribution, antibiotic resistance, strain distribution, and regions of recombination to determine genes that were undergoing diversifying selection. Genome-wide association studies comparing pneumonia and sterile-site isolates with healthy carriage were used to determine novel variants associated with disease. Findings: After programmatic introduction of PCV10, there was a decline in vaccine covered serotypes; however, strains that had expressed these serotypes continued to exist in the post-PCV population. We identified GPSC9 to be a strain of concern due to its high prevalence in disease, multidrug resistance, and ability to switch to an unencapsulated phenotype via insertion of virulence factor pspC into the cps locus. Antibiotic resistance loci to co-trimoxazole were found to be prevalent (pre-PCV10 78% vs post-PCV10 81%; p=0·27) and increasingly prevalent to penicillin (pre-PCV10 15% vs post-PCV10 32%; p<0·0001). Regions with multiple recombinations were identified spanning the surface protein virulence factors pspA and pspC and antibiotic targets pbpX, folA, folC, folE, and folP. Furthermore, we identified variants in lacE2 to be strongly associated with isolates from children with pneumonia and PRIP to be strongly associated with isolates from sterile sites. Interpretation: Our work highlights the effect of pneumococcal conjugate vaccines, antibiotics, and host–pathogen interaction in pneumococcal variation, and the pathogen's capability of adapting to these factors at both population-wide and strain-specific levels. Ongoing surveillance of disease-associated strains and further investigation of lacE2 and PRIP as serotype-independent targets for therapeutic interventions is required. Funding: Gavi, The Vaccine Alliance; WHO; Bill & Melinda Gates Foundation; Wellcome Sanger Institute; and US Centers for Disease Control and Prevention.
KW - Anti-Bacterial Agents/pharmacology
KW - Carrier State/epidemiology
KW - Genome-Wide Association Study
KW - Humans
KW - Nepal/epidemiology
KW - Streptococcus pneumoniae/genetics
KW - United States
KW - Vaccination
KW - Vaccines, Conjugate/pharmacology
UR - http://www.scopus.com/inward/record.url?scp=85133267710&partnerID=8YFLogxK
U2 - 10.1016/S2666-5247(22)00066-0
DO - 10.1016/S2666-5247(22)00066-0
M3 - Article
C2 - 35779566
SN - 2666-5247
VL - 3
SP - e503-e511
JO - The Lancet Microbe
JF - The Lancet Microbe
IS - 7
ER -
