Global impact of ten-valent and 13-valent pneumococcal conjugate vaccines on invasive pneumococcal disease in all ages (the PSERENADE project): a global surveillance analysis.

Background: Pneumococcal conjugate vaccines (PCVs) that are ten-valent (PCV10) and 13-valent (PCV13) became available in 2010. We evaluated their global impact on invasive pneumococcal disease (IPD) incidence in all ages.

Methods: Serotype-specific IPD cases and population denominators were obtained directly from surveillance sites using PCV10 or PCV13 in their national immunisation programmes and with a primary series uptake of at least 50%.

SARS-CoV-2 human challenge reveals biomarkers that discriminate early and late phases of respiratory viral infections.

Blood transcriptional biomarkers of acute viral infections typically reflect type 1 interferon (IFN) signalling, but it is not known whether there are biological differences in their regulation that can be leveraged for distinct translational applications. We use high frequency sampling in the SARS-CoV-2 human challenge model to show induction of IFN-stimulated gene (ISG) expression with different temporal and cellular profiles. MX1 gene expression correlates with a rapid and transient wave of ISG expression across all cell types, which may precede PCR detection of replicative infection.

Evaluating methods for identifying and quantifying co-colonization using next-generation sequencing data.

Detection of multiple pneumococcal serotype carriage can enhance monitoring of pneumococcal vaccine impact, particularly among high-burden childhood populations. We assessed methods for identifying co-carriage of pneumococcal serotypes from whole-genome sequences. Twenty-four nasopharyngeal samples were collected during community carriage surveillance from healthy children in Blantyre, Malawi, which were then serotyped by microarray.

Radiographically confirmed pneumonia in Malawian children and associated pneumococcal carriage after introduction of the 13-valent pneumococcal conjugate vaccine.

Background: The 13-valent pneumococcal conjugate vaccine (PCV-13) was introduced in Malawi in 2011 with an expected impact of reducing pneumococcal pneumonia in children. We aimed to describe clinical characteristics and nasopharyngeal (NP) carriage of pneumococcus by serotype in children hospitalized with primary end-point pneumonia (PEP) between 2013 and 19 after the introduction of PCV-13.

Methods: We conducted a secondary analysis of children aged under-5-years hospitalized with acute respiratory illness (ARI) in Malawi.

Integration and validation of host transcript signatures, including a novel 3-transcript tuberculosis signature, to enable one-step multiclass diagnosis of childhood febrile disease.

Background: Whole blood host transcript signatures show great potential for diagnosis of infectious and inflammatory illness, with most published signatures performing binary classification tasks. Barriers to clinical implementation include validation studies, and development of strategies that enable simultaneous, multiclass diagnosis of febrile illness based on gene expression.

Methods: We validated five distinct diagnostic signatures for paediatric infectious diseases in parallel using a single NanoString nCounter® experiment.

Modelling Salmonella Typhi in high-density urban Blantyre neighbourhood, Malawi, using point pattern methods.

Salmonella Typhi is a human-restricted pathogen that is transmitted by the faecal-oral route and causative organism of typhoid fever. Using health facility data from 2016 to 2020, this study focuses on modelling the spatial variation in typhoid risk in Ndirande township in Blantyre. To pursue this objective, we developed a marked inhomogeneous Poisson process model that allows us to incorporate both individual-level and environmental risk factors.

Clonal Expansion of a Streptococcus pneumoniae Serotype 3 Capsule Variant Sequence Type 700 With Enhanced Vaccine Escape Potential After 13-Valent Pneumococcal Conjugate Vaccine Introduction.

Background: Streptococcus pneumoniae serotype 3 remains a problem globally. Malawi introduced 13-valent pneumococcal conjugate vaccine (PCV13) in 2011, but there has been no direct protection against serotype 3 carriage. We explored whether vaccine escape by serotype 3 is due to clonal expansion of a lineage with a competitive advantage.

Expansion of pneumococcal serotype 23F and 14 lineages with genotypic changes in capsule polysaccharide locus and virulence gene profiles post introduction of pneumococcal conjugate vaccine in Blantyre, Malawi.

Since the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) in Malawi in 2011, there has been persistent carriage of vaccine serotype (VT) , despite high vaccine coverage. To determine if there has been a genetic change within the VT capsule polysaccharide (cps) loci since the vaccine's introduction, we compared 1022 whole-genome-sequenced VT isolates from 1998 to 2019. We identified the clonal expansion of a multidrug-resistant, penicillin non-susceptible serotype 23F GPSC14-ST2059 lineage, a serotype 14 GPSC9-ST782 lineage and a novel serotype 14 sequence type GPSC9-ST18728 lineage.

serovar Typhimurium ST313 sublineage 2.2 has emerged in Malawi with a characteristic gene expression signature and a fitness advantage.

Invasive non-typhoidal (iNTS) disease is a serious bloodstream infection that targets immune-compromised individuals, and causes significant mortality in sub-Saharan Africa. serovar Typhimurium ST313 causes the majority of iNTS in Malawi. We performed an intensive comparative genomic analysis of 608 .

Evaluating the relationship between ciprofloxacin prescription and non-susceptibility in Salmonella Typhi in Blantyre, Malawi: an observational study.

Background: Ciprofloxacin is the first-line drug for treating typhoid fever in many countries in Africa with a high disease burden, but the emergence of non-susceptibility poses a challenge to public health programmes. Through enhanced surveillance as part of vaccine evaluation, we investigated the occurrence and potential determinants of ciprofloxacin non-susceptibility in Blantyre, Malawi.

Methods: We conducted systematic surveillance of typhoid fever cases and antibiotic prescription in two health centres in Blantyre, Malawi, between Oct 1, 2016, and Oct 31, 2019, as part of the STRATAA and TyVAC studies.

Efficacy of typhoid conjugate vaccine: final analysis of a 4-year, phase 3, randomised controlled trial in Malawian children.

Background: Randomised controlled trials of typhoid conjugate vaccines among children in Africa and Asia have shown high short-term efficacy. Data on the durability of protection beyond 2 years are sparse. We present the final analysis of a randomised controlled trial in Malawi, encompassing more than 4 years of follow-up, with the aim of investigating vaccine efficacy over time and by age group.

A retrospective analysis of 20,178 adult neurological infection admissions to United Kingdom critical care units from 2001 to 2020.

Background: Neurological infection is an important cause of critical illness, yet little is known on the epidemiology of neurological infections requiring critical care.

Methods: We analysed data on all adults with proven or probable neurological infection admitted to UK (NHS) critical care units between 2001 and 2020 reported to the Intensive Care National Audit and Research Centre. Diagnoses, physiological variables, organ support and clinical outcomes were analysed over the whole period, and for consecutive 5-year intervals within it.

The metabolic, virulence and antimicrobial resistance profiles of colonising Streptococcus pneumoniae shift after PCV13 introduction in urban Malawi.

Streptococcus pneumoniae causes substantial mortality among children under 5-years-old worldwide. Polysaccharide conjugate vaccines (PCVs) are highly effective at reducing vaccine serotype disease, but emergence of non-vaccine serotypes and persistent nasopharyngeal carriage threaten this success. We investigated the hypothesis that following vaccine, adapted pneumococcal genotypes emerge with the potential for vaccine escape.

Global diversity and antimicrobial resistance of typhoid fever pathogens: Insights from a meta-analysis of 13,000 Typhi genomes.

Background: The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000).

Methods: This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch.

A Randomized Controlled Clinical Trial of Nasal Immunization with Live Virulence Attenuated Strains Using Human Infection Challenge.

Pneumococcal pneumonia remains a global health problem. Pneumococcal colonization increases local and systemic protective immunity, suggesting that nasal administration of live attenuated (Spn) strains could help prevent infections. We used a controlled human infection model to investigate whether nasopharyngeal colonization with attenuated strains protected against recolonization with wild-type (WT) Spn (SpnWT).

Cross-sectional health centre and community-based evaluation of the impact of pneumococcal and malaria vaccination on antibiotic prescription and usage, febrile illness and antimicrobial resistance in young children in Malawi: the IVAR study protocol.

Introduction: Vaccination is a potentially critical component of efforts to arrest development and dissemination of antimicrobial resistance (AMR), though little is known about vaccination impact within low-income and middle-income countries. This study will evaluate the impact of vaccination on reducing carriage prevalence of resistant and extended spectrum beta-lactamase-producing and species. We will leverage two large ongoing cluster-randomised vaccine evaluations in Malawi assessing; first, adding a booster dose to the 13-valent pneumococcal conjugate vaccine (PCV13) schedule, and second, introduction of the RTS,S/AS01 malaria vaccine.

The challenges of defining the human nasopharyngeal resistome.

The nasopharynx is an important microbial reservoir for the emergence and spread of antibiotic-resistant organisms. The nasopharyngeal resistome is an extensive, adaptable reservoir of antibiotic-resistance genes (ARGs) within this niche. Metagenomic sequencing decodes the genetic material of all organisms within a sample using next-generation technologies, permitting unbiased discovery of novel ARGs and associated mobile genetic elements (MGEs).