Looking down the road: development and distribution of a future syphilis vaccine.
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syphilis↗
Biomedical subjects
Mathew A Beale
Publications and source records attributed to Mathew A Beale.
Effect of repeated mass drug administration on the transmission of yaws: a retrospective genomic epidemiology study.
BACKGROUND: Yaws, a neglected tropical disease caused by Treponema pallidum subspecies pertenue (T p pertenue), has evaded eradication, in part due to a high proportion of asymptomatic cases. Repeated mass drug administration (MDA), whereby an entire population is repeatedly treated irrespective of disease, could provide a solution. Here, we aimed to investigate the effect of MDA on the genomic epidemiology of T p pertenue. METHODS: We conducted a retrospective genomic epidemiology study on samples collected during a cluster-randomised trial of mass administration of azithromycin for yaws eradication in the Namatanai District of Papua New Guinea. Participants were in 38 wards (administrative units encompassing several villages) in three local-level government areas (LLGs). The experimental group received an initial round of MDA followed by two further rounds 6 months and 12 months after the first round. The control group received one round of MDA followed by two rounds of treatment targeting clinical cases and contacts only, on the same schedule as the MDA in the experimental group. A follow-up survey on both groups was done 18 months after the first MDA round. Swab samples were collected at each round from ulcerative and nodular skin lesions, and blood was collected by finger-prick for serological testing at 18 months. Metadata on ulcer size (cm) and duration (days) were recorded at each round, and treponemal and non-treponemal antibodies were recorded at 18 months. Samples from swabs positive for T p pertenue underwent library preparation and whole-genome sequencing. We examined the phylogenetic relationships between genomes, linking them with geospatial and patient metadata to understand the impact of MDA on T p pertenue diversity and transmission. FINDINGS: Swabs collected from 297 individuals with active yaws from April 30, 2018, to Nov 2, 2019, yielded 222 good-quality Tp pertenue genomes. We identified 20 sublineages of T p pertenue in the control group and 21 in the experimental group at the beginning of the study. At the end of the study, there were 13 sublineages in the control group and three in the experimental group, of which two persisted in both groups. Three sublineages not detected at baseline were observed in the control group after commencing MDA. The two sublineages that persisted in both groups had non-synonymous mutations in penicillin-binding proteins. One of these sublineages evolved macrolide resistance in three individuals and was associated with lowered treponemal antibody (p=0·0036) and longer ulcer duration (p=0·015). Despite the study taking place within a small island, sublineages were geographically clustered, with pairs of samples from the same ward (odds ratio 7·1, 95% CI 5·7-8·8; p<0·0001) or neighbouring wards (4·3, 3·3-5·4; p<0·0001) more likely to share the same sublineages compared with pairs from different LLGs. Additionally, older individuals were more likely to share sublineages than were younger individuals (1·5, 1·2-1·9; p<0·0001). INTERPRETATION: Repeated MDA was successful in reducing and maintaining the genetic diversity of T p pertenue at a low level but was associated with the development of macrolide resistance. Yaws re-emergence after MDA was attributed to multiple sublineages, of which the majority were detected in the population before MDA. Participants within the same ward were more likely to share sublineages than those that were more widely geographically separated, suggesting that re-emergence was driven by local transmission. These findings could inform future yaws elimination strategies. FUNDING: European Research Council, EU, Provincial Deputation of Barcelona, Barberà Solidària Foundation, Wellcome, and Fundació "la Caixa".
Adolescent↗
Transmission of extended spectrum β-lactamase-producing Escherichia coli and antimicrobial resistance gene flow across One Health compartments in eastern Africa: a whole-genome sequence analysis from a prospective cohort study.
BACKGROUND: The One Health paradigm considers interdependence of human, animal, and environmental health. However, there is little evidence from high-income countries to support the importance of a One Health approach to addressing spread of antimicrobial resistance (AMR). Given AMR is a global threat, understanding how the close interactions of humans with animals and the environment in low-income settings affect the spread of AMR is important. We aimed to investigate diversity and transmission of extended spectrum β-lactamase (ESBL)-producing Escherichia coli across household-linked One Health compartments using genomic data. METHODS: We sequenced whole genomes of ESBL-producing E coli isolates from humans, animals, and the environment from a prospective, longitudinal cohort study conducted in Malawi (April 29, 2019, to Dec 3, 2020) and Uganda (July 16, 2020, to Aug 6, 2021). In the cohort study, 259 households were enrolled at baseline in Malawi and 92 in Uganda from a mix of urban, peri-urban, and rural areas. Households were followed up at months 1, 3, and 6 in Malawi and at months 1, 2, and 4 in Uganda. Samples collected at each visit included human and animal stool, environmental samples from hand-contact areas, food, and water, and broader environmental samples such as river water. Samples were cultured in buffered peptone water and then ESBL chromogenic agar to isolate ESBL-producing E coli. ESBL-producing E coli isolates underwent whole-genome sequencing. We performed phylogenetic analyses, and in-silico multi-locus sequence typing, characterised AMR determinants and linked genotypes with sample location, ecological source, and other covariates. We performed fine-scale single nucleotide polymorphism (SNP) and network analysis to infer strain and plasmid transmission across ecological compartments. The primary outcome was colonisation with ESBL-producing E coli. Secondary outcomes were genomic clusters and ESBL genomic determinants within and between One Health compartments. FINDINGS: We found high diversity of ESBL-producing E coli, with 170 sequence types and 166 genomic clusters identified from 2344 genomes, including 1814 genomes from Malawi (907 human, 221 animal, and 686 environmental) and 530 genomes from Uganda (380 human, 147 animal, and three environmental). Sequence type (ST)131 dominated in Malawi (209 [11·5%] of 1814 genomes), and ST10 dominated in Uganda (45 [8·5%] of 530 genomes). Common ESBL genes blaCTX-M-15 (1604 [68·4%] of 2344 genomes) and blaCTX-M-27 (336 [14·3%] of 2344 genomes) were carried on a complex network of 55 and 30 different plasmids. This diversity of plasmids presented multiple pathways for dissemination and revealed high force of selection. Phylogenetic analyses revealed common intermixing of isolates between humans, animals, and the environment. SNP transmission analysis revealed ecologically overlapping clusters, suggesting ESBL-producing E coli co-circulation both within and between compartments with frequent spillover events. Applying a five-SNP threshold, we inferred 463 human-environment transmission events, 146 human-animal events, and 142 animal-environment events. INTERPRETATION: Our work suggests that a One Health approach is crucial to addressing AMR in eastern Africa. Improving water, sanitation, and hygiene systems will create a safer environment, reduce spillovers of AMR bacteria between compartments, and eventually reduce AMR reservoirs in the environment and in animals. FUNDING: Medical Research Council, National Institute for Health and Care Research, and Wellcome Trust.
Humans↗
SPARKI: a tool for the statistical analysis of pathogen identification results.
MOTIVATION: Many pathogen identification and microbiome analysis tools have been developed in recent years, with Kraken 2 being one of the most popular. While tools downstream of Kraken 2 can assist in the interpretation of its outputs, a statistical framework to assess the likelihood that a taxon/organism is present in a single sample alongside an automated end-to-end analysis pipeline has not yet been fully implemented. RESULTS: Here, we introduce SPARKI, an R package that performs statistical analysis of Kraken 2 outputs and aids in the identification of pathogens present in next-generation sequencing samples. SPARKI adds to the field by bringing a probabilistic view to Kraken 2 data, serving as a discovery tool and complementing other methods such as KrakenTools, Bracken, and Pavian. AVAILABILITY AND IMPLEMENTATION: SPARKI code is available on GitHub at https://github.com/team113sanger/sparki. SPARKI is also part of an end-to-end pathogen identification pipeline, sparki-nf, which is available at https://github.com/team113sanger/sparki-nf. An additional pipeline for further exploration and validation of SPARKI results is also available at https://github.com/team113sanger/map-to-genome.
Software↗
Diversity of Salmonella enterica isolates from urban river and sewage water in Blantyre, Malawi.
BACKGROUND: Salmonella enterica encompasses over 2,600 serovars, including several commonly associated with severe infection in humans. Salmonella is a major cause of sepsis in Africa; however, diagnosis requires clinical microbiology facilities. Environmental surveillance has the potential to play a role in Salmonella surveillance. METHODS: We undertook water-based environmental surveillance in Blantyre, Malawi, from 2018-2020, taking samples from rivers (87.9%), a sewage plant (8.85%) and other water sources (3.24%), isolating and storing 1,042 non-typhoidal Salmonella (NTS) isolates in this period. Of these, 341 NTS isolates were whole genome sequenced, genome quality was checked, duplicate genomes from any given sample were removed and core genome phylogeny was reconstructed. AMRFinder, PathogenWatch and SISTR were used to further investigate serovar, sequence type and antimicrobial resistance determinants. RESULTS: After quality checks, and removal of duplicate genomes, 270 NTS genomes remained for further analysis. Multiple Salmonella serovars associated with human infection were detected, of which S. Typhimurium (55/270 isolates) was the most common, including 44 of Sequence Type (ST) 313, a serovar commonly associated with severe invasive disease (iNTS). Six lineage 2 ST313 genomes possessed AMR genes predicting multidrug resistance (MDR), while 29 lineage 3 isolates contained no AMR predictive genes. PCR based detection of staG has been proposed as a diagnostic marker of S. Typhi; however, all eight genomes that contained staG identified as Salmonella enterica serovar Orion, raising concerns about the specificity of this marker as a monoplex for environmental surveillance of S. Typhi. DISCUSSION: The study identified diverse Salmonella serovars in the environment, including those reported to cause invasive disease, emphasizing the complex but potentially valuable contribution of implementing environmental surveillance for Salmonella in high burden areas lacking diagnostic microbiology capacity.
Sewage↗