Last data update: May 13, 2024. (Total: 46773 publications since 2009)
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Query Trace: Klugman KP[original query] |
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A novel mosaic tetracycline resistance gene tet(S/M) detected in a multidrug-resistant pneumococcal CC230 lineage that underwent capsular switching in South Africa (preprint)
Lo SW , Gladstone RA , van Tonder AJ , Du Plessis M , Cornick JE , Hawkins PA , Madhi SA , Nzenze SA , Kandasamy R , Ravikumar KL , Elmdaghri N , Kwambana-Adams B , Almeida SCG , Skoczynska A , Egorova E , Titov L , Saha SK , Paragi M , Everett DB , Antonio M , Klugman KP , Li Y , Metcalf BJ , Beall B , McGee L , Breiman RF , Bentley SD , von Gottberg A . bioRxiv 2019 718460 Objective We reported a novel tetracycline-resistant gene in Streptococcus pneumoniae and investigated its temporal spread in relation to nationwide clinical interventions.Methods We whole genome sequenced 12,254 pneumococcal isolates from twenty-nine countries on an Illumina HiSeq Sequencer. Serotypes, sequence types and antibiotic resistance were inferred from genomes. Phylogeny was built based on single-nucleotide variants. Temporal changes of spread were reconstructed using a birth-death model.Results We identified tet(S/M) in 131 pneumococcal isolates, 97 (74%) caused invasive pneumococcal diseases among young children (59% HIV-positive, where HIV status was available) in South Africa. A majority of tet(S/M)-positive isolates (129/131) belong to clonal complex (CC)230. A global phylogeny of CC230 (n=389) revealed that tet(S/M)-positive isolates formed a sub-lineage that exhibited multidrug-resistance. Using the genomic data and a birth-death model, we detected an unrecognised outbreak of this sub-lineage in South Africa between 2000 and 2004 with an expected secondary infections (R) of ~2.5. R declined to ~1.0 in 2005 and <1.0 in 2012. The declining epidemic coincided and could be related to the nationwide implementation of anti-retroviral treatment (ART) for HIV-infected individuals in 2004 and PCVs in late 2000s. Capsular switching from vaccine serotype 14 to non-vaccine serotype 23A was observed within the sub-lineage.Conclusions The prevalence of tet(S/M) in pneumococci was low and its dissemination was due to an unrecognised outbreak of CC230 in South Africa prior to ART and PCVs. However, capsular switching in this multidrug-resistant sub-lineage highlighted its potential to continue to cause disease in the post-PCV13 era. |
Key features of pneumococcal isolates recovered in Central and Northwestern Russia in 2011-2018 determined through whole-genome sequencing.
Egorova E , Kumar N , Gladstone RA , Urban Y , Voropaeva E , Chaplin AV , Rumiantseva E , Svistunova TS , Hawkins PA , Klugman KP , Breiman RF , McGee L , Bentley SD , Lo SW . Microb Genom 2022 8 (9) Invasive pneumococcal disease remains one of the leading causes of morbidity and mortality worldwide. In Russia, 13- valent pneumococcal conjugate vaccine (PCV13) was introduced into the childhood immunization programme nationwide in 2014. As part of the Global Pneumococcal Sequencing Project (GPS), we used genome data to characterize 179 pneumococcal isolates collected from Russia in 2011-2018 to investigate the circulating pneumococcal strains using a standardized genomic definition of pneumococcal lineages (global pneumococcal sequence clusters, GPSCs), prevalent serotypes and antimicrobial resistance profiles.We observed high serotype and lineage diversity among the 179 isolates recovered from cerebrospinal fluid (n=77), nasopharyngeal swabs (n=99) and other non-sterile site swabs (n=3). Overall, 60 GPSCs were identified, including 48 clonal complexes (CCs) and 14 singletons, and expressed 42 serotypes (including non-typable). Among PCV13 serotypes, 19F, 6B and 23F were the top three serotypes while 11A, 15B/C and 8 were the top three among non-PCV13 serotypes in the collection. Two lineages (GPSC6 and GPSC47) expressed both PCV13 and non-PCV13 serotypes that caused invasive disease, and were penicillin- and multidrug-resistant (MDR), highlighting their potential to adapt and continue to cause infections under vaccine and antibiotic selective pressure. PCV13 serotypes comprised 92 % (11/12) of the CSF isolates from the children aged below 5 years; however, the prevalence of PCV13 serotype isolates dropped to 53 % (31/58) among the nasopharyngeal isolates. Our analysis showed that 59 % (105/179) of the isolates were predicted to be non-susceptible to at least one class of antibiotics and 26 % (46/179) were MDR. Four MDR lineages (GPSC1, GPSC6, GPSC10 and GPSC47) accounted for 65 % (30/46) of the MDR isolates and expressed PCV13 serotypes (93 %, 28/30).This study provides evidence of high genetic and serotype diversity contributed by a mix of globally spreading and regionally circulating lineages in Russia. The observations suggest that the PCV13 vaccine could be important in reducing both invasive disease and antimicrobial resistance. We also identify potential lineages (GPSC6 and GPSC47) that may evade the vaccine. |
Emergence of a multidrug-resistant and virulent Streptococcus pneumoniae lineage mediates serotype replacement after PCV13: an international whole-genome sequencing study.
Lo SW , Mellor K , Cohen R , Alonso AR , Belman S , Kumar N , Hawkins PA , Gladstone RA , von Gottberg A , Veeraraghavan B , Ravikumar KL , Kandasamy R , Pollard SAJ , Saha SK , Bigogo G , Antonio M , Kwambana-Adams B , Mirza S , Shakoor S , Nisar I , Cornick JE , Lehmann D , Ford RL , Sigauque B , Turner P , Moïsi J , Obaro SK , Dagan R , Diawara I , Skoczyńska A , Wang H , Carter PE , Klugman KP , Rodgers G , Breiman RF , McGee L , Bentley SD , Almagro CM , Varon E . Lancet Microbe 2022 3 (10) e735-e743 BACKGROUND: Serotype 24F is one of the emerging pneumococcal serotypes after the introduction of pneumococcal conjugate vaccine (PCV). We aimed to identify lineages driving the increase of serotype 24F in France and place these findings into a global context. METHODS: Whole-genome sequencing was performed on a collection of serotype 24F pneumococci from asymptomatic colonisation (n=229) and invasive disease (n=190) isolates among individuals younger than 18 years in France, from 2003 to 2018. To provide a global context, we included an additional collection of 24F isolates in the Global Pneumococcal Sequencing (GPS) project database for analysis. A Global Pneumococcal Sequence Cluster (GPSC) and a clonal complex (CC) were assigned to each genome. Phylogenetic, evolutionary, and spatiotemporal analysis were conducted using the same 24F collection and supplemented with a global collection of genomes belonging to the lineage of interest from the GPS project database (n=25 590). FINDINGS: Serotype 24F was identified in numerous countries mainly due to the clonal spread of three lineages: GPSC10 (CC230), GPSC16 (CC156), and GPSC206 (CC7701). GPSC10 was the only multidrug-resistant lineage. GPSC10 drove the increase in 24F in France and had high invasive disease potential. The international dataset of GPSC10 (n=888) revealed that this lineage expressed 16 other serotypes, with only six included in 13-valent PCV (PCV13). All serotype 24F isolates were clustered in a single clade within the GPSC10 phylogeny and long-range transmissions were detected from Europe to other continents. Spatiotemporal analysis showed GPSC10-24F took 3-5 years to spread across France and a rapid change of serotype composition from PCV13 serotype 19A to 24F during the introduction of PCV13 was observed in neighbouring country Spain. INTERPRETATION: Our work reveals that GPSC10 alone is a challenge for serotype-based vaccine strategy. More systematic investigation to identify lineages like GPSC10 will better inform and improve next-generation preventive strategies against pneumococcal diseases. FUNDING: Bill & Melinda Gates Foundation, Wellcome Sanger Institute, and the US Centers for Disease Control and Prevention. |
Comparative genomics of disease and carriage serotype 1 pneumococci.
Chaguza C , Ebruke C , Senghore M , Lo SW , Tientcheu PE , Gladstone RA , Tonkin-Hill G , Cornick JE , Yang M , Worwui A , McGee L , Breiman RF , Klugman KP , Kadioglu A , Everett DB , Mackenzie G , Croucher NJ , Roca A , Kwambana-Adams BA , Antonio M , Bentley SD . Genome Biol Evol 2022 14 (4) The isolation of Streptococcus pneumoniae serotypes in systemic tissues of patients with invasive disease versus the nasopharynx of healthy individuals with asymptomatic carriage varies widely. Some serotypes are hyper-invasive, particularly serotype 1, but the underlying genetics remain poorly understood due to the rarity of carriage isolates, reducing the power of comparison with invasive isolates. Here, we use a well-controlled genome-wide association study to search for genetic variation associated with invasiveness of serotype 1 pneumococci from a serotype 1 endemic setting in Africa. We found no consensus evidence that certain genomic variation is overrepresented among isolates from patients with invasive disease than asymptomatic carriage. Overall, the genomic variation explained negligible phenotypic variability, suggesting a minimal effect on the disease status. Furthermore, changes in lineage distribution were seen with lineages replacing each other over time, highlighting the importance of continued pathogen surveillance. Our findings suggest that the hyper-invasiveness is an intrinsic property of the serotype 1 strains, not specific for a "disease-associated" subpopulation disproportionately harbouring unique genomic variation. |
A Streptococcus pneumoniae lineage usually associated with pneumococcal conjugate vaccine (PCV) serotypes is the most common cause of serotype 35B invasive disease in South Africa, following routine use of PCV.
Ndlangisa KM , du Plessis M , Lo S , de Gouveia L , Chaguza C , Antonio M , Kwambana-Adams B , Cornick J , Everett DB , Dagan R , Hawkins PA , Beall B , Corso A , Grassi Almeida SC , Ochoa TJ , Obaro S , Shakoor S , Donkor ES , Gladstone RA , Ho PL , Paragi M , Doiphode S , Srifuengfung S , Ford R , Moïsi J , Saha SK , Bigogo G , Sigauque B , Eser Ö K , Elmdaghri N , Titov L , Turner P , Kumar KLR , Kandasamy R , Egorova E , Ip M , Breiman RF , Klugman KP , McGee L , Bentley SD , von Gottberg A , The Global Pneumococcal Sequencing Consortium . Microb Genom 2022 8 (4) Pneumococcal serotype 35B is an important non-conjugate vaccine (non-PCV) serotype. Its continued emergence, post-PCV7 in the USA, was associated with expansion of a pre-existing 35B clone (clonal complex [CC] 558) along with post-PCV13 emergence of a non-35B clone previously associated with PCV serotypes (CC156). This study describes lineages circulating among 35B isolates in South Africa before and after PCV introduction. We also compared 35B isolates belonging to a predominant 35B lineage in South Africa (GPSC5), with isolates belonging to the same lineage in other parts of the world. Serotype 35B isolates that caused invasive pneumococcal disease in South Africa in 2005-2014 were characterized by whole-genome sequencing (WGS). Multi-locus sequence types and global pneumococcal sequence clusters (GPSCs) were derived from WGS data of 63 35B isolates obtained in 2005-2014. A total of 262 isolates that belong to GPSC5 (115 isolates from South Africa and 147 from other countries) that were sequenced as part of the global pneumococcal sequencing (GPS) project were included for comparison. Serotype 35B isolates from South Africa were differentiated into seven GPSCs and GPSC5 was most common (49 %, 31/63). While 35B was the most common serotype among GPSC5/CC172 isolates in South Africa during the PCV13 period (66 %, 29/44), 23F was the most common serotype during both the pre-PCV (80 %, 37/46) and PCV7 period (32 %, 8/25). Serotype 35B represented 15 % (40/262) of GPSC5 isolates within the global GPS database and 75 % (31/40) were from South Africa. The predominance of the GPSC5 lineage within non-vaccine serotype 35B, is possibly unique to South Africa and warrants further molecular surveillance of pneumococci. |
Widespread sharing of pneumococcal strains in a rural African setting: proximate villages are more likely to share similar strains that are carried at multiple timepoints.
Senghore M , Chaguza C , Bojang E , Tientcheu PE , Bancroft RE , Lo SW , Gladstone RA , McGee L , Worwui A , Foster-Nyarko E , Ceesay F , Okoi CB , Klugman KP , Breiman RF , Bentley SD , Adegbola R , Antonio M , Hanage WP , Kwambana-Adams BA . Microb Genom 2022 8 (2) The transmission dynamics of Streptococcus pneumoniae in sub-Saharan Africa are poorly understood due to a lack of adequate epidemiological and genomic data. Here we leverage a longitudinal cohort from 21 neighbouring villages in rural Africa to study how closely related strains of S. pneumoniae are shared among infants. We analysed 1074 pneumococcal genomes isolated from 102 infants from 21 villages. Strains were designated for unique serotype and sequence-type combinations, and we arbitrarily defined strain sharing where the pairwise genetic distance between strains could be accounted for by the mean within host intra-strain diversity. We used non-parametric statistical tests to assess the role of spatial distance and prolonged carriage on strain sharing using a logistic regression model. We recorded 458 carriage episodes including 318 (69.4 %) where the carried strain was shared with at least one other infant. The odds of strain sharing varied significantly across villages (χ(2)=47.5, df=21, P-value <0.001). Infants in close proximity to each other were more likely to be involved in strain sharing, but we also show a considerable amount of strain sharing across longer distances. Close geographic proximity (<5 km) between shared strains was associated with a significantly lower pairwise SNP distance compared to strains shared over longer distances (P-value <0.005). Sustained carriage of a shared strain among the infants was significantly more likely to occur if they resided in villages within a 5 km radius of each other (P-value <0.005, OR 3.7). Conversely, where both infants were transiently colonized by the shared strain, they were more likely to reside in villages separated by over 15 km (P-value <0.05, OR 1.5). PCV7 serotypes were rare (13.5 %) and were significantly less likely to be shared (P-value <0.001, OR -1.07). Strain sharing was more likely to occur over short geographical distances, especially where accompanied by sustained colonization. Our results show that strain sharing is a useful proxy for studying transmission dynamics in an under-sampled population with limited genomic data. This article contains data hosted by Microreact. |
Genomic surveillance of invasive Streptococcus pneumoniae isolates in the period pre-PCV10 and post-PCV10 introduction in Brazil.
Almeida SCG , Lo SW , Hawkins PA , Gladstone RA , Cassiolato AP , Klugman KP , Breiman RF , Bentley SD , McGee L , Brandileone MC . Microb Genom 2021 7 (10) In 2010, Brazil introduced the 10-valent pneumococcal conjugate vaccine (PCV10) into the national children's immunization programme. This study describes the genetic characteristics of invasive Streptococcus pneumoniae isolates before and after PCV10 introduction. A subset of 466 [pre-PCV10 (2008-2009): n=232, post-PCV10 (2012-2013): n=234;<5 years old: n=310, ≥5 years old: n=156] pneumococcal isolates, collected through national laboratory surveillance, were whole-genome sequenced (WGS) to determine serotype, pilus locus, antimicrobial resistance and genetic lineages. Following PCV10 introduction, in the <5 years age group, non-vaccine serotypes (NVT) serotype 3 and serotype 19A were the most frequent, and serotypes 12F, 8 and 9 N in the ≥5 years old group. The study identified 65 Global Pneumococcal Sequence Clusters (GPSCs): 49 (88 %) were GPSCs previously described and 16 (12 %) were Brazilian clusters. In total, 36 GPSCs (55 %) were NVT lineages, 18 (28 %) vaccine serotypes (VT) and 11 (17 %) were both VT and NVT lineages. In both sampling periods, the most frequent lineage was GPSC6 (CC156, serotypes 14/9V). In the <5 years old group, a decrease in penicillin (P=0.0123) and cotrimoxazole (P<0.0001) resistance and an increase in tetracycline (P=0.019) were observed. Penicillin nonsusceptibility was predicted in 40 % of the isolates; 127 PBP combinations were identified (51 predicted MIC≥0.125 mg l(-1)); cotrimoxazole (folA and/or folP alterations), macrolide (mef and/or ermB) and tetracycline (tetM, tetO or tetS/M) resistance were predicted in 63, 13 and 21.6 % of pneumococci studied, respectively. The main lineages associated with multidrug resistance in the post-PCV10 period were composed of NVT, GPSC1 (CC320, serotype 19A), and GPSC47 (ST386, serotype 6C). The study provides a baseline for future comparisons and identified important NVT lineages in the post-PCV10 period in Brazil. |
Population genetic structure, serotype distribution and antibiotic resistance of Streptococcus pneumoniae causing invasive disease in children in Argentina.
Gagetti P , Lo SW , Hawkins PA , Gladstone RA , Regueira M , Faccone D , Sireva-Argentina Group , Klugman KP , Breiman RF , McGee L , Bentley SD , Corso A . Microb Genom 2021 7 (9) Invasive disease caused by Streptococcus pneumoniae (IPD) is one of the leading causes of morbidity and mortality in young children worldwide. In Argentina, PCV13 was introduced into the childhood immunization programme nationwide in 2012 and PCV7 was available from 2000, but only in the private market. Since 1993 the National IPD Surveillance Programme, consisting of 150 hospitals, has conducted nationwide pneumococcal surveillance in Argentina in children under 6 years of age, as part of the SIREVA II-OPS network. A total of 1713 pneumococcal isolates characterized by serotype (Quellung) and antimicrobial resistance (agar dilution) to ten antibiotics, belonging to three study periods: pre-PCV7 era 1998-1999 (pre-PCV), before the introduction of PCV13 2010-2011 (PCV7) and after the introduction of PCV13 2012-2013 (PCV13), were available for inclusion. Fifty-four serotypes were identified in the entire collection and serotypes 14, 5 and 1 represented 50 % of the isolates. Resistance to penicillin was 34.9 %, cefotaxime 10.6 %, meropenem 4.9 %, cotrimoxazole 45 %, erythromycin 21.5 %, tetracycline 15.4 % and chloramphenicol 0.4 %. All the isolates were susceptible to levofloxacin, rifampin and vancomycin. Of 1713 isolates, 1061 (61.9 %) were non-susceptible to at least one antibiotic and 235(13.7 %) were multidrug resistant. A subset of 413 isolates was randomly selected and whole-genome sequenced as part of Global Pneumococcal Sequencing Project (GPS). The genome data was used to investigate the population structure of S. pneumoniae defining pneumococcal lineages using Global Pneumococcal Sequence Clusters (GPSCs), sequence types (STs) and clonal complexes (CCs), prevalent serotypes and their associated pneumococcal lineages and genomic inference of antimicrobial resistance. The collection showed a great diversity of strains. Among the 413 isolates, 73 known and 36 new STs were identified belonging to 38 CCs and 25 singletons, grouped into 52 GPSCs. Important changes were observed among vaccine types when pre-PCV and PCV13 periods were compared; a significant decrease in serotypes 14, 6B and 19F and a significant increase in 7F and 3. Among non-PCV13 types, serogroup 24 increased from 0 % in pre-PCV to 3.2 % in the PCV13 period. Our analysis showed that 66.1 % (273/413) of the isolates were predicted to be non-susceptible to at least one antibiotic and 11.9 % (49/413) were multidrug resistant. We found an agreement of 100 % when comparing the serotype determined by Quellung and WGS-based serotyping and 98.4 % of agreement in antimicrobial resistance. Continued surveillance of the pneumococcal population is needed to reveal the dynamics of pneumococcal isolates in Argentina in post-PCV13. This article contains data hosted by Microreact. |
Streptococcus pneumoniae genomic datasets from an Indian population describing pre-vaccine evolutionary epidemiology using a whole genome sequencing approach.
Nagaraj G , Govindan V , Ganaie F , Venkatesha VT , Hawkins PA , Gladstone RA , McGee L , Breiman RF , Bentley SD , Klugman KP , Lo SW , Ravikumar KL . Microb Genom 2021 7 (9) Globally, India has a high burden of pneumococcal disease, and pneumococcal conjugate vaccine (PCV) has been rolled out in different phases across the country since May 2017 in the national infant immunization programme (NIP). To provide a baseline for assessing the impact of the vaccine on circulating pneumococci in India, genetic characterization of pneumococcal isolates detected prior to introduction of PCV would be helpful. Here we present a population genomic study of 480 Streptococcus pneumoniae isolates collected across India and from all age groups before vaccine introduction (2009-2017), including 294 isolates from pneumococcal disease and 186 collected through nasopharyngeal surveys. Population genetic structure, serotype and antimicrobial susceptibility profile were characterized and predicted from whole-genome sequencing data. Our findings revealed high levels of genetic diversity represented by 110 Global Pneumococcal Sequence Clusters (GPSCs) and 54 serotypes. Serotype 19F and GPSC1 (CC320) was the most common serotype and pneumococcal lineage, respectively. Coverage of PCV13 (Pfizer) and 10-valent Pneumosil (Serum Institute of India) serotypes in age groups of ≤2 and 3-5 years were 63-75 % and 60-69 %, respectively. Coverage of PPV23 (Merck) serotypes in age groups of ≥50 years was 62 % (98/158). Among the top five lineages causing disease, GPSC10 (CC230), which ranked second, is the only lineage that expressed both PCV13 (serotypes 3, 6A, 14, 19A and 19F) and non-PCV13 (7B, 13, 10A, 11A, 13, 15B/C, 22F, 24F) serotypes. It exhibited multidrug resistance and was the largest contributor (17 %, 18/103) of NVTs in the disease-causing population. Overall, 42 % (202/480) of isolates were penicillin-resistant (minimum inhibitory concentration ≥0.12 µg ml(-1)) and 45 % (217/480) were multidrug-resistant. Nine GPSCs (GPSC1, 6, 9, 10, 13, 16, 43, 91, 376) were penicillin-resistant and among them six were multidrug-resistant. Pneumococci expressing PCV13 serotypes had a higher prevalence of antibiotic resistance. Sequencing of pneumococcal genomes has significantly improved our understanding of the biology of these bacteria. This study, describing the pneumococcal disease and carriage epidemiology pre-PCV introduction, demonstrates that 60-75 % of pneumococcal serotypes in children ≤5 years are covered by PCV13 and Pneumosil. Vaccination against pneumococci is very likely to reduce antibiotic resistance. A multidrug-resistant pneumococcal lineage, GPSC10 (CC230), is a high-risk clone that could mediate serotype replacement. |
Phylogeography and resistome of pneumococcal meningitis in West Africa before and after vaccine introduction.
Senghore M , Tientcheu PE , Worwui AK , Jarju S , Okoi C , Suso SMS , Foster-Nyarko E , Ebruke C , Sonko M , Kourna MH , Agossou J , Tsolenyanu E , Renner LA , Ansong D , Sanneh B , Cisse CB , Boula A , Miwanda B , Lo SW , Gladstone RA , Schwartz S , Hawkins P , McGee L , Klugman KP , Breiman RF , Bentley SD , Mwenda JM , Kwambana-Adams BA , Antonio M . Microb Genom 2021 7 (7) Despite contributing to the large disease burden in West Africa, little is known about the genomic epidemiology of Streptococcus pneumoniae which cause meningitis among children under 5 years old in the region. We analysed whole-genome sequencing data from 185 S. pneumoniae isolates recovered from suspected paediatric meningitis cases as part of the World Health Organization (WHO) invasive bacterial diseases surveillance from 2010 to 2016. The phylogeny was reconstructed, accessory genome similarity was computed and antimicrobial-resistance patterns were inferred from the genome data and compared to phenotypic resistance from disc diffusion. We studied the changes in the distribution of serotypes pre- and post-pneumococcal conjugate vaccine (PCV) introduction in the Central and Western sub-regions separately. The overall distribution of non-vaccine, PCV7 (4, 6B, 9V, 14, 18C, 19F and 23F) and additional PCV13 serotypes (1, 3, 5, 6A, 19A and 7F) did not change significantly before and after PCV introduction in the Central region (Fisher's test P value 0.27) despite an increase in the proportion of non-vaccine serotypes to 40 % (n=6) in the post-PCV introduction period compared to 21.9 % (n=14). In the Western sub-region, PCV13 serotypes were more dominant among isolates from The Gambia following the introduction of PCV7, 81 % (n=17), compared to the pre-PCV period in neighbouring Senegal, 51 % (n=27). The phylogeny illustrated the diversity of strains associated with paediatric meningitis in West Africa and highlighted the existence of phylogeographical clustering, with isolates from the same sub-region clustering and sharing similar accessory genome content. Antibiotic-resistance genotypes known to confer resistance to penicillin, chloramphenicol, co-trimoxazole and tetracycline were detected across all sub-regions. However, there was no discernible trend linking the presence of resistance genotypes with the vaccine introduction period or whether the strain was a vaccine or non-vaccine serotype. Resistance genotypes appeared to be conserved within selected sub-clades of the phylogenetic tree, suggesting clonal inheritance. Our data underscore the need for continued surveillance on the emergence of non-vaccine serotypes as well as chloramphenicol and penicillin resistance, as these antibiotics are likely still being used for empirical treatment in low-resource settings. This article contains data hosted by Microreact. |
Carriage Dynamics of Pneumococcal Serotypes in Naturally Colonized Infants in a Rural African Setting During the First Year of Life.
Chaguza C , Senghore M , Bojang E , Lo SW , Ebruke C , Gladstone RA , Tientcheu PE , Bancroft RE , Worwui A , Foster-Nyarko E , Ceesay F , Okoi C , McGee L , Klugman KP , Breiman RF , Barer MR , Adegbola RA , Antonio M , Bentley SD , Kwambana-Adams BA . Front Pediatr 2020 8 587730 Streptococcus pneumoniae (the pneumococcus) carriage precedes invasive disease and influences population-wide strain dynamics, but limited data exist on temporal carriage patterns of serotypes due to the prohibitive costs of longitudinal studies. Here, we report carriage prevalence, clearance and acquisition rates of pneumococcal serotypes sampled from newborn infants bi-weekly from weeks 1 to 27, and then bi-monthly from weeks 35 to 52 in the Gambia. We used sweep latex agglutination and whole genome sequencing to serotype the isolates. We show rapid pneumococcal acquisition with nearly 31% of the infants colonized by the end of first week after birth and quickly exceeding 95% after 2 months. Co-colonization with multiple serotypes was consistently observed in over 40% of the infants at each sampling point during the first year of life. Overall, the mean acquisition time and carriage duration regardless of serotype was 38 and 24 days, respectively, but varied considerably between serotypes comparable to observations from other regions. Our data will inform disease prevention and control measures including providing baseline data for parameterising infectious disease mathematical models including those assessing the impact of clinical interventions such as pneumococcal conjugate vaccines. |
Bacterial genome-wide association study of hyper-virulent pneumococcal serotype 1 identifies genetic variation associated with neurotropism.
Chaguza C , Yang M , Cornick JE , du Plessis M , Gladstone RA , Kwambana-Adams BA , Lo SW , Ebruke C , Tonkin-Hill G , Peno C , Senghore M , Obaro SK , Ousmane S , Pluschke G , Collard JM , Sigaùque B , French N , Klugman KP , Heyderman RS , McGee L , Antonio M , Breiman RF , von Gottberg A , Everett DB , Kadioglu A , Bentley SD . Commun Biol 2020 3 (1) 559 Hyper-virulent Streptococcus pneumoniae serotype 1 strains are endemic in Sub-Saharan Africa and frequently cause lethal meningitis outbreaks. It remains unknown whether genetic variation in serotype 1 strains modulates tropism into cerebrospinal fluid to cause central nervous system (CNS) infections, particularly meningitis. Here, we address this question through a large-scale linear mixed model genome-wide association study of 909 African pneumococcal serotype 1 isolates collected from CNS and non-CNS human samples. By controlling for host age, geography, and strain population structure, we identify genome-wide statistically significant genotype-phenotype associations in surface-exposed choline-binding (P = 5.00 × 10(-08)) and helicase proteins (P = 1.32 × 10(-06)) important for invasion, immune evasion and pneumococcal tropism to CNS. The small effect sizes and negligible heritability indicated that causation of CNS infection requires multiple genetic and other factors reflecting a complex and polygenic aetiology. Our findings suggest that certain pathogen genetic variation modulate pneumococcal survival and tropism to CNS tissue, and therefore, virulence for meningitis. |
Within-host microevolution of Streptococcus pneumoniae is rapid and adaptive during natural colonisation.
Chaguza C , Senghore M , Bojang E , Gladstone RA , Lo SW , Tientcheu PE , Bancroft RE , Worwui A , Foster-Nyarko E , Ceesay F , Okoi C , McGee L , Klugman KP , Breiman RF , Barer MR , Adegbola RA , Antonio M , Bentley SD , Kwambana-Adams BA . Nat Commun 2020 11 (1) 3442 Genomic evolution, transmission and pathogenesis of Streptococcus pneumoniae, an opportunistic human-adapted pathogen, is driven principally by nasopharyngeal carriage. However, little is known about genomic changes during natural colonisation. Here, we use whole-genome sequencing to investigate within-host microevolution of naturally carried pneumococci in ninety-eight infants intensively sampled sequentially from birth until twelve months in a high-carriage African setting. We show that neutral evolution and nucleotide substitution rates up to forty-fold faster than observed over longer timescales in S. pneumoniae and other bacteria drives high within-host pneumococcal genetic diversity. Highly divergent co-existing strain variants emerge during colonisation episodes through real-time intra-host homologous recombination while the rest are co-transmitted or acquired independently during multiple colonisation episodes. Genic and intergenic parallel evolution occur particularly in antibiotic resistance, immune evasion and epithelial adhesion genes. Our findings suggest that within-host microevolution is rapid and adaptive during natural colonisation. |
Visualizing variation within Global Pneumococcal Sequence Clusters (GPSCs) and country population snapshots to contextualize pneumococcal isolates.
Gladstone RA , Lo SW , Goater R , Yeats C , Taylor B , Hadfield J , Lees JA , Croucher NJ , van Tonder AJ , Bentley LJ , Quah FX , Blaschke AJ , Pershing NL , Byington CL , Balaji V , Hryniewicz W , Sigauque B , Ravikumar KL , Almeida SCG , Ochoa TJ , Ho PL , du Plessis M , Ndlangisa KM , Cornick JE , Kwambana-Adams B , Benisty R , Nzenze SA , Madhi SA , Hawkins PA , Pollard AJ , Everett DB , Antonio M , Dagan R , Klugman KP , von Gottberg A , Metcalf BJ , Li Y , Beall BW , McGee L , Breiman RF , Aanensen DM , Bentley SD . Microb Genom 2020 6 (5) Knowledge of pneumococcal lineages, their geographic distribution and antibiotic resistance patterns, can give insights into global pneumococcal disease. We provide interactive bioinformatic outputs to explore such topics, aiming to increase dissemination of genomic insights to the wider community, without the need for specialist training. We prepared 12 country-specific phylogenetic snapshots, and international phylogenetic snapshots of 73 common Global Pneumococcal Sequence Clusters (GPSCs) previously defined using PopPUNK, and present them in Microreact. Gene presence and absence defined using Roary, and recombination profiles derived from Gubbins are presented in Phandango for each GPSC. Temporal phylogenetic signal was assessed for each GPSC using BactDating. We provide examples of how such resources can be used. In our example use of a country-specific phylogenetic snapshot we determined that serotype 14 was observed in nine unrelated genetic backgrounds in South Africa. The international phylogenetic snapshot of GPSC9, in which most serotype 14 isolates from South Africa were observed, highlights that there were three independent sub-clusters represented by South African serotype 14 isolates. We estimated from the GPSC9-dated tree that the sub-clusters were each established in South Africa during the 1980s. We show how recombination plots allowed the identification of a 20 kb recombination spanning the capsular polysaccharide locus within GPSC97. This was consistent with a switch from serotype 6A to 19A estimated to have occured in the 1990s from the GPSC97-dated tree. Plots of gene presence/absence of resistance genes (tet, erm, cat) across the GPSC23 phylogeny were consistent with acquisition of a composite transposon. We estimated from the GPSC23-dated tree that the acquisition occurred between 1953 and 1975. Finally, we demonstrate the assignment of GPSC31 to 17 externally generated pneumococcal serotype 1 assemblies from Utah via Pathogenwatch. Most of the Utah isolates clustered within GPSC31 in a USA-specific clade with the most recent common ancestor estimated between 1958 and 1981. The resources we have provided can be used to explore to data, test hypothesis and generate new hypotheses. The accessible assignment of GPSCs allows others to contextualize their own collections beyond the data presented here. |
A mosaic tetracycline resistance gene tet(S/M) detected in an MDR pneumococcal CC230 lineage that underwent capsular switching in South Africa.
Lo SW , Gladstone RA , van Tonder AJ , Du Plessis M , Cornick JE , Hawkins PA , Madhi SA , Nzenze SA , Kandasamy R , Ravikumar KL , Elmdaghri N , Kwambana-Adams B , Almeida SCG , Skoczynska A , Egorova E , Titov L , Saha SK , Paragi M , Everett DB , Antonio M , Klugman KP , Li Y , Metcalf BJ , Beall B , McGee L , Breiman RF , Bentley SD , von Gottberg A . J Antimicrob Chemother 2019 75 (3) 512-520 OBJECTIVES: We reported tet(S/M) in Streptococcus pneumoniae and investigated its temporal spread in relation to nationwide clinical interventions. METHODS: We whole-genome sequenced 12 254 pneumococcal isolates from 29 countries on an Illumina HiSeq sequencer. Serotype, multilocus ST and antibiotic resistance were inferred from genomes. An SNP tree was built using Gubbins. Temporal spread was reconstructed using a birth-death model. RESULTS: We identified tet(S/M) in 131 pneumococcal isolates and none carried other known tet genes. Tetracycline susceptibility testing results were available for 121 tet(S/M)-positive isolates and all were resistant. A majority (74%) of tet(S/M)-positive isolates were from South Africa and caused invasive diseases among young children (59% HIV positive, where HIV status was available). All but two tet(S/M)-positive isolates belonged to clonal complex (CC) 230. A global phylogeny of CC230 (n=389) revealed that tet(S/M)-positive isolates formed a sublineage predicted to exhibit resistance to penicillin, co-trimoxazole, erythromycin and tetracycline. The birth-death model detected an unrecognized outbreak of this sublineage in South Africa between 2000 and 2004 with expected secondary infections (effective reproductive number, R) of approximately 2.5. R declined to approximately 1.0 in 2005 and <1.0 in 2012. The declining epidemic could be related to improved access to ART in 2004 and introduction of pneumococcal conjugate vaccine (PCV) in 2009. Capsular switching from vaccine serotype 14 to non-vaccine serotype 23A was observed within the sublineage. CONCLUSIONS: The prevalence of tet(S/M) in pneumococci was low and its dissemination was due to an unrecognized outbreak of CC230 in South Africa. Capsular switching in this MDR sublineage highlighted its potential to continue to cause disease in the post-PCV13 era. |
Putative novel cps loci in a large global collection of pneumococci.
van Tonder AJ , Gladstone RA , Lo SW , Nahm MH , du Plessis M , Cornick J , Kwambana-Adams B , Madhi SA , Hawkins PA , Benisty R , Dagan R , Everett D , Antonio M , Klugman KP , von Gottberg A , Breiman RF , McGee L , Bentley SD . Microb Genom 2019 5 (7) The pneumococcus produces a polysaccharide capsule, encoded by the cps locus, that provides protection against phagocytosis and determines serotype. Nearly 100 serotypes have been identified with new serotypes still being discovered, especially in previously understudied regions. Here we present an analysis of the cps loci of more than 18 000 genomes from the Global Pneumococcal Sequencing (GPS) project with the aim of identifying novel cps loci with the potential to produce previously unrecognized capsule structures. Serotypes were assigned using whole genome sequence data and 66 of the approximately 100 known serotypes were included in the final dataset. Closer examination of each serotype's sequences identified nine putative novel cps loci (9X, 11X, 16X, 18X1, 18X2, 18X3, 29X, 33X and 36X) found in ~2.6 % of the genomes. The large number and global distribution of GPS genomes provided an unprecedented opportunity to identify novel cps loci and consider their phylogenetic and geographical distribution. Nine putative novel cps loci were identified and examples of each will undergo subsequent structural and immunological analysis. |
Pneumococcal lineages associated with serotype replacement and antibiotic resistance in childhood invasive pneumococcal disease in the post-PCV13 era: an international whole-genome sequencing study.
Lo SW , Gladstone RA , van Tonder AJ , Lees JA , du Plessis M , Benisty R , Givon-Lavi N , Hawkins PA , Cornick JE , Kwambana-Adams B , Law PY , Ho PL , Antonio M , Everett DB , Dagan R , von Gottberg A , Klugman KP , McGee L , Breiman RF , Bentley SD . Lancet Infect Dis 2019 19 (7) 759-769 BACKGROUND: Invasive pneumococcal disease remains an important health priority owing to increasing disease incidence caused by pneumococci expressing non-vaccine serotypes. We previously defined 621 Global Pneumococcal Sequence Clusters (GPSCs) by analysing 20 027 pneumococcal isolates collected worldwide and from previously published genomic data. In this study, we aimed to investigate the pneumococcal lineages behind the predominant serotypes, the mechanism of serotype replacement in disease, as well as the major pneumococcal lineages contributing to invasive pneumococcal disease in the post-vaccine era and their antibiotic resistant traits. METHODS: We whole-genome sequenced 3233 invasive pneumococcal disease isolates from laboratory-based surveillance programmes in Hong Kong (n=78), Israel (n=701), Malawi (n=226), South Africa (n=1351), The Gambia (n=203), and the USA (n=674). The genomes represented pneumococci from before and after pneumococcal conjugate vaccine (PCV) introductions and were from children younger than 3 years. We identified predominant serotypes by prevalence and their major contributing lineages in each country, and assessed any serotype replacement by comparing the incidence rate between the pre-PCV and PCV periods for Israel, South Africa, and the USA. We defined the status of a lineage as vaccine-type GPSC (>/=50% 13-valent PCV [PCV13] serotypes) or non-vaccine-type GPSC (>50% non-PCV13 serotypes) on the basis of its initial serotype composition detected in the earliest vaccine period to measure their individual contribution toward serotype replacement in each country. Major pneumococcal lineages in the PCV period were identified by pooled incidence rate using a random effects model. FINDINGS: The five most prevalent serotypes in the PCV13 period varied between countries, with only serotypes 5, 12F, 15B/C, 19A, 33F, and 35B/D common to two or more countries. The five most prevalent serotypes in the PCV13 period varied between countries, with only serotypes 5, 12F, 15B/C, 19A, 33F, and 35B/D common to two or more countries. These serotypes were associated with more than one lineage, except for serotype 5 (GPSC8). Serotype replacement was mainly mediated by expansion of non-vaccine serotypes within vaccine-type GPSCs and, to a lesser extent, by increases in non-vaccine-type GPSCs. A globally spreading lineage, GPSC3, expressing invasive serotypes 8 in South Africa and 33F in the USA and Israel, was the most common lineage causing non-vaccine serotype invasive pneumococcal disease in the PCV13 period. We observed that same prevalent non-vaccine serotypes could be associated with distinctive lineages in different countries, which exhibited dissimilar antibiotic resistance profiles. In non-vaccine serotype isolates, we detected significant increases in the prevalence of resistance to penicillin (52 [21%] of 249 vs 169 [29%] of 575, p=0.0016) and erythromycin (three [1%] of 249 vs 65 [11%] of 575, p=0.0031) in the PCV13 period compared with the pre-PCV period. INTERPRETATION: Globally spreading lineages expressing invasive serotypes have an important role in serotype replacement, and emerging non-vaccine serotypes associated with different pneumococcal lineages in different countries might be explained by local antibiotic-selective pressures. Continued genomic surveillance of the dynamics of the pneumococcal population with increased geographical representation in the post-vaccine period will generate further knowledge for optimising future vaccine design. FUNDING: Bill & Melinda Gates Foundation, Wellcome Sanger Institute, and the US Centers for Disease Control. |
International genomic definition of pneumococcal lineages, to contextualise disease, antibiotic resistance and vaccine impact.
Gladstone RA , Lo SW , Lees JA , Croucher NJ , van Tonder AJ , Corander J , Page AJ , Marttinen P , Bentley LJ , Ochoa TJ , Ho PL , du Plessis M , Cornick JE , Kwambana-Adams B , Benisty R , Nzenze SA , Madhi SA , Hawkins PA , Everett DB , Antonio M , Dagan R , Klugman KP , von Gottberg A , McGee L , Breiman RF , Bentley SD . EBioMedicine 2019 43 338-346 BACKGROUND: Pneumococcal conjugate vaccines have reduced the incidence of invasive pneumococcal disease, caused by vaccine serotypes, but non-vaccine-serotypes remain a concern. We used whole genome sequencing to study pneumococcal serotype, antibiotic resistance and invasiveness, in the context of genetic background. METHODS: Our dataset of 13,454 genomes, combined with four published genomic datasets, represented Africa (40%), Asia (25%), Europe (19%), North America (12%), and South America (5%). These 20,027 pneumococcal genomes were clustered into lineages using PopPUNK, and named Global Pneumococcal Sequence Clusters (GPSCs). From our dataset, we additionally derived serotype and sequence type, and predicted antibiotic sensitivity. We then measured invasiveness using odds ratios that relating prevalence in invasive pneumococcal disease to carriage. FINDINGS: The combined collections (n=20,027) were clustered into 621 GPSCs. Thirty-five GPSCs observed in our dataset were represented by >100 isolates, and subsequently classed as dominant-GPSCs. In 22/35 (63%) of dominant-GPSCs both non-vaccine serotypes and vaccine serotypes were observed in the years up until, and including, the first year of pneumococcal conjugate vaccine introduction. Penicillin and multidrug resistance were higher (p<.05) in a subset dominant-GPSCs (14/35, 9/35 respectively), and resistance to an increasing number of antibiotic classes was associated with increased recombination (R(2)=0.27 p<.0001). In 28/35 dominant-GPSCs, the country of isolation was a significant predictor (p<.05) of its antibiogram (mean misclassification error 0.28, SD+/-0.13). We detected increased invasiveness of six genetic backgrounds, when compared to other genetic backgrounds expressing the same serotype. Up to 1.6-fold changes in invasiveness odds ratio were observed. INTERPRETATION: We define GPSCs that can be assigned to any pneumococcal genomic dataset, to aid international comparisons. Existing non-vaccine-serotypes in most GPSCs preclude the removal of these lineages by pneumococcal conjugate vaccines; leaving potential for serotype replacement. A subset of GPSCs have increased resistance, and/or serotype-independent invasiveness. |
Global funders consortium for universal influenza vaccine development
Bresee JS , McKinlay MA , Abramson J , Klugman KP , Wairagkar N . Vaccine 2018 37 (2) 211-213 A century after the great influenza pandemic of 1918, influenza remains a major public health threat. Annual epidemics are associated with significant mortality and morbidity globally, leading to an estimated 290,000–650,000 deaths each year [1]. In addition, the ongoing threat of the next pandemic requires significant resources and attention to ensure that communities and governments are prepared to mitigate the health and societal impact that would likely be much larger than the seasonal toll from influenza [2]. Vaccines against influenza have long been used to reduce seasonal disease risk and to reduce illness and spread of pandemic influenza [3], [4], [5], [6]. However, the variable and moderate effectiveness, the limited ability to prevent influenza caused by antigenically dissimilar challenge viruses, and the complex and lengthy process for semiannual vaccine production, highlight the limitations of current vaccines to optimally address both seasonal and pandemic threats [7], [8], [9], [10]. As a result, growing interest in developing improved influenza vaccines has been voiced by public health authorities and other global stakeholders. |
Global distribution of invasive serotype 35D Streptococcus pneumoniae post-PCV13 introduction.
Lo SW , Gladstone RA , van Tonder AJ , Hawkins PA , Kwambana-Adams B , Cornick JE , Madhi SA , Nzenze SA , du Plessis M , Kandasamy R , Carter PE , Koseoglu Eser O , Ho PL , Elmdaghri N , Shakoor S , Clarke SC , Antonio M , Everett DB , von Gottberg A , Klugman KP , McGee L , Breiman RF , Bentley SD . J Clin Microbiol 2018 56 (7) A newly recognized pneumococcal serotype 35D, which differs from the 35B polysaccharide in structure and serology by not binding to factor serum 35a, was recently reported. The genetic basis for this distinctive serology is due to the presence of an inactivating mutation in wciG, which encodes an O-acetyltransferase responsible for O-acetylation of a galactofuranose. Here, we assessed the genomic data of a worldwide pneumococcal collection to identify serotype 35D isolates and understand their geographical distribution, genetic background and invasiveness potential. Of 21,980 pneumococcal isolates, 444 were originally typed as serotype 35B by PneumoCaT. Analysis of wciG revealed 23 isolates from carriage (n=4) and disease (n=19) with partial or complete loss-of-funtion mutations, including mutations resulting in pre-mature stop codons (n=22) and an in-frame mutation (n=1). These were selected for further analysis. The putative 35D isolates were geographically widespread and 65.2% (15/23) of them was recovered after PCV13 introduction. Compared with serotype 35B, putative serotype 35D isolates have higher invasive disease potentials based on odds ratio (OR) (11.58; 95% CI, 1.42-94.19 vs 0.61; 95% CI, 0.40-0.92) and a higher prevalence of macrolide resistance mediated by mefA (26.1% vs 7.6%, p=0.009). Using Quellung, 50% (10/20) of viable isolates were serotype 35D, 25% (5/20) serotype 35B, and 25% (5/20) a mixture of 35B/35D. The discrepancy between phenotype and genotype requires further investigation. These findings illustrated a global distribution of an invasive serotype 35D among young children post-PCV13 introduction and underlined the invasive potential conferred by the loss of O-acetylation in the pneumococcal capsule. |
Imputing the direct and indirect effectiveness of childhood pneumococcal conjugate vaccine against invasive pneumococcal disease by surveying temporal changes in nasopharyngeal pneumococcal colonization
Nzenze SA , Madhi SA , Shiri T , Klugman KP , De Gouveia L , Moore DP , Karstaedt AS , Tempia S , Nunes MC , Von Gottberg A . Am J Epidemiol 2017 186 (4) 435-444 The limited capability in most low- to middle-income countries to study the benefit of pneumococcal conjugate vaccine (PCV) in protecting against invasive pneumococcal disease (IPD) calls for alternate strategies to assess this. We used a mathematical model to predict the direct and indirect effectiveness of PCV by analyzing serotypespecific colonization prevalence and IPD incidence prior to and following childhood PCV immunization in South Africa. We analyzed IPD incidence from 2005 to 2012 and colonization studies undertaken in human immunodeficiency virus (HIV)-uninfected and HIV-infected child-mother dyads from 2007 to 2009 (pre-PCV era), in 2010 (7-valent PCV era), and in 2012 (13-valent PCV era). We compared the model-predicted changes in IPD incidence with observed changes in IPD incidence, according to HIV status, in children aged 3 months-5 years and in women aged 18-45 years. We observed reductions in vaccine-serotype colonization and IPD due to vaccine serotypes among children and women after PCV introduction. Using the changes in vaccine-serotype colonization data, the model-predicted changes in vaccine-serotype IPD incidence rates were similar to the observed changes in PCVunvaccinated children and adults, but not among children under age 24 months. Surveillance of colonization prior to and following PCV use can be used to impute the indirect protection afforded by PCV in unvaccinated age groups, including those in high-HIV-prevalence settings. Copyright © The Author(s) 2017. |
Estimated severe pneumococcal disease cases and deaths before and after pneumococcal conjugate vaccine introduction in children younger than 5 years of age in South Africa
von Mollendorf C , Tempia S , von Gottberg A , Meiring S , Quan V , Feldman C , Cloete J , Madhi SA , O'Brien KL , Klugman KP , Whitney CG , Cohen C . PLoS One 2017 12 (7) e0179905 INTRODUCTION: Streptococcus pneumoniae is a leading cause of severe bacterial infections globally. A full understanding of the impact of pneumococcal conjugate vaccine (PCV) on pneumococcal disease burden, following its introduction in 2009 in South Africa, can support national policy on PCV use and assist with policy decisions elsewhere. METHODS: We developed a model to estimate the national burden of severe pneumococcal disease, i.e. disease requiring hospitalisation, pre- (2005-2008) and post-PCV introduction (2012-2013) in children aged 0-59 months in South Africa. We estimated case numbers for invasive pneumococcal disease using data from the national laboratory-based surveillance, adjusted for specimen-taking practices. We estimated non-bacteraemic pneumococcal pneumonia case numbers using vaccine probe study data. To estimate pneumococcal deaths, we applied observed case fatality ratios to estimated case numbers. Estimates were stratified by HIV status to account for the impact of PCV and HIV-related interventions. We assessed how different assumptions affected estimates using a sensitivity analysis. Bootstrapping created confidence intervals. RESULTS: In the pre-vaccine era, a total of approximately 107,600 (95% confidence interval [CI] 83,000-140,000) cases of severe hospitalised pneumococcal disease were estimated to have occurred annually. Following PCV introduction and the improvement in HIV interventions, 41,800 (95% CI 28,000-50,000) severe pneumococcal disease cases were estimated in 2012-2013, a rate reduction of 1,277 cases per 100,000 child-years. Approximately 5000 (95% CI 3000-6000) pneumococcal-related annual deaths were estimated in the pre-vaccine period and 1,900 (95% CI 1000-2500) in 2012-2013, a mortality rate difference of 61 per 100,000 child-years. CONCLUSIONS: While a large number of hospitalisations and deaths due to pneumococcal disease still occur among children 0-59 months in South Africa, we found a large reduction in this estimate that is temporally associated with PCV introduction. In HIV-infected individuals the scale-up of other interventions, such as improvements in HIV care, may have also contributed to the declines in pneumococcal burden. |
Clinical and microbiological features of invasive nontyphoidal Salmonella associated with HIV-infected patients, Gauteng Province, South Africa
Keddy KH , Musekiwa A , Sooka A , Karstaedt A , Nana T , Seetharam S , Nchabaleng M , Lekalakala R , Angulo FJ , Klugman KP . Medicine (Baltimore) 2017 96 (13) e6448 The aim of this study was to define factors associated with HIV-infected versus uninfected patients with invasive nontyphoidal Salmonella (iNTS) and factors associated with mortality, which are inadequately described in Africa.Laboratory-based surveillance for iNTS was undertaken. At selected sentinel sites, clinical data (age, sex, HIV status, severity of illness, and outcome) were collected.Surveillance was conducted in Gauteng, South Africa, from 2003 to 2013. Clinical and microbiological differences between HIV-infected and uninfected patients were defined and risk factors for mortality established.Of 4886 iNTS infections in Gauteng from 2003 to 2013, 3106 (63.5%) were diagnosed at sentinel sites. Among persons with iNTS infections, more HIV-infected persons were aged ≥5 years (chi = 417.6; P < 0.001) and more HIV-infected children were malnourished (chi = 5.8; P = 0.02). Although 760 (30.6%) patients died, mortality decreased between 2003 [97/263 (36.9%)] and 2013 [926/120 (21.7%)]. On univariate analysis, mortality was associated with patients aged 25 to 49 years [odds ratio (OR) = 2.2; 95% confidence interval (CI) = 1.7-2.7; P < 0.001 and ≥50 years (OR = 3.0; 95% CI = 2.2-4.1; P < 0.001) compared with children < 5 years, HIV-infected patients (OR = 2.4; 95% CI = 1.7-3.4; P < 0.001), and severe illness (OR = 5.4; 95% CI = 3.6-8.1; P < 0.001). On multivariate analysis, mortality was associated with patients aged ≥50 years [adjusted OR (AOR) = 3.6, 95% CI = 2.1-6.1, P < 0.001] and severe illness (AOR = 6.3; 95% CI = 3.8-10.5; P < 0.001).Mortality due to iNTS in Gauteng remains high primarily due to disease severity. Interventions must be aimed at predisposing conditions, including HIV, other immune-suppressive conditions, and malignancy. |
An association between decreasing incidence of invasive non-typhoidal salmonellosis and increased use of antiretroviral therapy, Gauteng Province, South Africa, 2003-2013
Keddy KH , Takuva S , Musekiwa A , Puren AJ , Sooka A , Karstaedt A , Klugman KP , Angulo FJ . PLoS One 2017 12 (3) e0173091 BACKGROUND: HIV-infected persons are at increased risk of opportunistic infections, including invasive nontyphoidal Salmonella (iNTS) infections; antiretroviral therapy (ART) reduces this risk. We explored changing iNTS incidence associated with increasing ART availability in South Africa. METHODS: Laboratory-based surveillance for iNTS was conducted in Gauteng Province, South Africa, with verification using the National Health Laboratory Service's Central Data Warehouse (CDW), between 2003 and 2013. Isolates were serotyped at the Centre for Enteric Diseases. CDW data on patient numbers obtaining HIV viral load measurements provided estimates of numbers of HIV-infected patients receiving ART. A Poisson regression model was used to measure the changing incidence of iNTS infection from 2003 to 2013. The correlation between the incidence of iNTS and ART use from 2004 to 2013 was determined using Pearson's correlation coefficient. RESULTS: From 2003-2013, the incidence of iNTS per 100,000 population per year decreased from 5.0 to 2.2 (p < .001). From 2004 to 2013, the incidence per 100,000 population of HIV viral load testing increased from 75.2 to 3,620.3 (p < .001). The most common serotypes causing invasive disease were Salmonella enterica serovar Typhimurium (Salmonella Typhimurium), and Salmonella Enteritidis: 2,469 (55.4%) and 1,156 (25.9%) of 4,459 isolates serotyped, respectively. A strong negative correlation was observed between decreasing iNTS incidence and increasing ART use from 2004 to 2013 (r = -0.94, p < .001). Similarly, decreasing incidence of invasive Salmonella Typhimurium infection correlated with increasing ART use (r = -0.93, p < .001). Incidence of invasive Salmonella Enteritidis infection increased, however (r = 0.95, p < .001). Between 2003 and 2004, fewer adult men than women presented with iNTS (male-to-female rate ratio 0.73 and 0.89, respectively). This was reversed from 2005 through 2013 (ranging from 1.07 in 2005 to 1.44 in 2013). Adult men accessed ART less (male-to-female rate ratio ranging from 0.61 [2004] to 0.67 [2013]). CONCLUSIONS: The incidence of iNTS infections including Salmonella Typhimurium decreased significantly in Gauteng Province in association with increased ART utilization. Adult men accessed ART programs less than women, translating into increasing iNTS incidence in this group. Monitoring iNTS incidence may assist in monitoring the ART program. Increasing incidence of invasive Salmonella Enteritidis infections needs further elucidation. |
Effectiveness of the 13-valent pneumococcal conjugate vaccine against invasive pneumococcal disease in South African children: a case-control study
Cohen C , von Mollendorf C , de Gouveia L , Lengana S , Meiring S , Quan V , Nguweneza A , Moore DP , Reubenson G , Moshe M , Madhi SA , Eley B , Hallbauer U , Finlayson H , Varughese S , O'Brien KL , Zell ER , Klugman KP , Whitney CG , von Gottberg A . Lancet Glob Health 2017 5 (3) e359-e369 BACKGROUND: The 13-valent pneumococcal conjugate vaccine (PCV13) was designed to include disease-causing serotypes that are important in low-income and middle-income countries. Vaccine effectiveness estimates are scarce in these settings. South Africa replaced PCV7 with PCV13 in 2011 using a 2 + 1 schedule. We aimed to assess the effectiveness of two or more doses of PCV13 against invasive pneumococcal disease in children with HIV infection and in those not infected with HIV. METHODS: Cases of invasive pneumococcal disease in children aged 5 years or younger were identified through national laboratory-based surveillance. Isolates were serotyped with the Quellung reaction or PCR. We sought in-hospital controls for every case, matched for age, HIV status, and study site. We aimed to enrol four controls for every case not infected with HIV and six controls for every case with HIV infection (case-control sets). With conditional logistic regression, we calculated vaccine effectiveness as a percentage, with the equation 1 - [adjusted odds ratio for vaccination] x 100. We included data from an earlier investigation of PCV7 to assess vaccine effectiveness in children exposed to but not infected with HIV and in malnourished children not infected with HIV. FINDINGS: Between January, 2012, and December, 2014, we enrolled children aged 16 weeks or older to our study: 240 were cases not infected with HIV, 75 were cases with HIV infection, 1118 were controls not infected with HIV, and 283 were controls with HIV infection. The effectiveness of two or more doses of PCV13 against PCV13-serotype invasive pneumococcal disease was 85% (95% CI 37 to 96) among 11 case-control sets of children not infected with HIV and 91% (-35 to 100) among three case-control sets of children with HIV infection. PCV13 effectiveness among 26 case-control sets of children not infected with HIV was 52% (95% CI -12 to 79) against all-serotype invasive pneumococcal disease and 94% (44 to 100) for serotype 19A. Vaccine effectiveness against PCV7-serotype invasive pneumococcal disease was 87% (95% CI 38 to 97) in children exposed to HIV but uninfected and 90% (53 to 98) in malnourished children not infected with HIV. INTERPRETATION: Our results indicate that PCV13 in a 2 + 1 schedule is effective for preventing vaccine-type pneumococcal infections in young children not infected with HIV, including those who are malnourished or who have been exposed to HIV. Although the point estimate for PCV13 vaccine effectiveness in children infected with HIV was high, it did not reach significance, possibly because of the small sample size. These findings support recommendations for widespread use of pneumococcal conjugate vaccine in low-income and middle-income countries. FUNDING: Gavi, The Vaccine Alliance. |
The global distribution and diversity of protein vaccine candidate antigens in the highly virulent Streptococcus pnuemoniae serotype 1.
Cornick JE , Tastan Bishop O , Yalcin F , Kiran AM , Kumwenda B , Chaguza C , Govindpershad S , Ousmane S , Senghore M , du Plessis M , Pluschke G , Ebruke C , McGee L , Sigauque B , Collard JM , Bentley SD , Kadioglu A , Antonio M , von Gottberg A , French N , Klugman KP , Heyderman RS , Alderson M , Everett DB . Vaccine 2017 35 (6) 972-980 Serotype 1 is one of the most common causes of pneumococcal disease worldwide. Pneumococcal protein vaccines are currently being developed as an alternate intervention strategy to pneumococcal conjugate vaccines. Pre-requisites for an efficacious pneumococcal protein vaccine are universal presence and minimal variation of the target antigen in the pneumococcal population, and the capability to induce a robust human immune response. We used in silico analysis to assess the prevalence of seven protein vaccine candidates (CbpA, PcpA, PhtD, PspA, SP0148, SP1912, SP2108) among 445 serotype 1 pneumococci from 26 different countries, across four continents. CbpA (76%), PspA (68%), PhtD (28%), PcpA (11%) were not universally encoded in the study population, and would not provide full coverage against serotype 1. PcpA was widely present in the European (82%), but not in the African (2%) population. A multi-valent vaccine incorporating CbpA, PcpA, PhtD and PspA was predicted to provide coverage against 86% of the global population. SP0148, SP1912 and SP2108 were universally encoded and we further assessed their predicted amino acid, antigenic and structural variation. Multiple allelic variants of these proteins were identified, different allelic variants dominated in different continents; the observed variation was predicted to impact the antigenicity and structure of two SP0148 variants, one SP1912 variant and four SP2108 variants, however these variants were each only present in a small fraction of the global population (<2%). The vast majority of the observed variation was predicted to have no impact on the efficaciousness of a protein vaccine incorporating a single variant of SP0148, SP1912 and/or SP2108 from S. pneumoniae TIGR4. Our findings emphasise the importance of taking geographic differences into account when designing global vaccine interventions and support the continued development of SP0148, SP1912 and SP2108 as protein vaccine candidates against this important pneumococcal serotype. |
Understanding pneumococcal serotype 1 biology through population genomic analysis.
Chaguza C , Cornick JE , Harris SR , Andam CP , Bricio-Moreno L , Yang M , Yalcin F , Ousmane S , Govindpersad S , Senghore M , Ebruke C , Du Plessis M , Kiran AM , Pluschke G , Sigauque B , McGee L , Klugman KP , Turner P , Corander J , Parkhill J , Collard JM , Antonio M , von Gottberg A , Heyderman RS , French N , Kadioglu A , Hanage WP , Everett DB , Bentley SD . BMC Infect Dis 2016 16 (1) 649 BACKGROUND: Pneumococcus kills over one million children annually and over 90 % of these deaths occur in low-income countries especially in Sub-Saharan Africa (SSA) where HIV exacerbates the disease burden. In SSA, serotype 1 pneumococci particularly the endemic ST217 clone, causes majority of the pneumococcal disease burden. To understand the evolution of the virulent ST217 clone, we analysed ST217 whole genomes from isolates sampled from African and Asian countries. METHODS: We analysed 226 whole genome sequences from the ST217 lineage sampled from 9 African and 4 Asian countries. We constructed a whole genome alignment and used it for phylogenetic and coalescent analyses. We also screened the genomes to determine presence of antibiotic resistance conferring genes. RESULTS: Population structure analysis grouped the ST217 isolates into five sequence clusters (SCs), which were highly associated with different geographical regions and showed limited intracontinental and intercontinental spread. The SCs showed lower than expected genomic sequence, which suggested strong purifying selection and small population sizes caused by bottlenecks. Recombination rates varied between the SCs but were lower than in other successful clones such as PMEN1. African isolates showed higher prevalence of antibiotic resistance genes than Asian isolates. Interestingly, certain West African isolates harbored a defective chloramphenicol and tetracycline resistance-conferring element (Tn5253) with a deletion in the loci encoding the chloramphenicol resistance gene (cat pC194), which caused lower chloramphenicol than tetracycline resistance. Furthermore, certain genes that promote colonisation were absent in the isolates, which may contribute to serotype 1's rarity in carriage and consequently its lower recombination rates. CONCLUSIONS: The high phylogeographic diversity of the ST217 clone shows that this clone has been in circulation globally for a long time, which allowed its diversification and adaptation in different geographical regions. Such geographic adaptation reflects local variations in selection pressures in different locales. Further studies will be required to fully understand the biological mechanisms which makes the ST217 clone highly invasive but unable to successfully colonise the human nasopharynx for long durations which results in lower recombination rates. |
Typhoid fever in South Africa in an endemic HIV setting
Keddy KH , Sooka A , Smith AM , Musekiwa A , Tau NP , Klugman KP , Angulo FJ . PLoS One 2016 11 (10) e0164939 BACKGROUND: Typhoid fever remains an important disease in Africa, associated with outbreaks and the emerging multidrug resistant Salmonella enterica serotype Typhi (Salmonella Typhi) haplotype, H58. This study describes the incidence of, and factors associated with mortality due to, typhoid fever in South Africa, where HIV prevalence is high. METHODS AND FINDINGS: Nationwide active laboratory-based surveillance for culture-confirmed typhoid fever was undertaken from 2003-2013. At selected institutions, additional clinical data from patients were collected including age, sex, HIV status, disease severity and outcome. HIV prevalence among typhoid fever patients was compared to national HIV seroprevalence estimates. The national reference laboratory tested Salmonella Typhi isolates for antimicrobial susceptibility and haplotype. Unadjusted and adjusted logistic regression analyses were conducted determining factors associated with typhoid fever mortality. We identified 855 typhoid fever cases: annual incidence ranged from 0.11 to 0.39 per 100,000 population. Additional clinical data were available for 369 (46.8%) cases presenting to the selected sites. Among typhoid fever patients with known HIV status, 19.3% (29/150) were HIV-infected. In adult females, HIV prevalence in typhoid fever patients was 43.2% (19/44) versus 15.7% national HIV seroprevalence (P < .001); in adult males, 16.3% (7/43) versus 12.3% national HIV seroprevalence (P = .2). H58 represented 11.9% (22/185) of Salmonella Typhi isolates tested. Increased mortality was associated with HIV infection (AOR 10.7; 95% CI 2.3-50.3) and disease severity (AOR 9.8; 95% CI 1.6-60.0) on multivariate analysis. CONCLUSIONS: Typhoid fever incidence in South Africa was largely unchanged from 2003-2013. Typhoid fever mortality was associated disease severity. HIV infection may be a contributing factor. Interventions mandate improved health care access, including to HIV management programmes as well as patient education. Further studies are necessary to clarify relationships between HIV infection and typhoid fever in adults. |
Nasopharyngeal pneumococcal serotypes before and after mass azithromycin distributions for trachoma
Keenan JD , Sahlu I , McGee L , Cevallos V , Vidal JE , Chochua S , Hawkins P , Gebre T , Tadesse Z , Emerson PM , Gaynor BD , Lietman TM , Klugman KP . J Pediatric Infect Dis Soc 2016 5 (2) 222-6 Twenty-four Ethiopian communities were randomized to receive either (1) quarterly mass azithromycin distributions for trachoma for 1 year or (2) delayed treatment. Nasopharyngeal swabs collected from separate cross-sectional population-based samples of children were processed for Streptococcus pneumoniae Mass azithromycin did not significantly alter the pneumococcal serotype distribution, and hence it would not be expected to alter vaccine coverage. |
Phylogenetic Analysis of Invasive Serotype 1 Pneumococcus in South Africa, 1989-2013.
du Plessis M , Allam M , Tempia S , Wolter N , de Gouveia L , Mollendorf CV , Jolley KA , Mbelle N , Wadula J , Cornick JE , Everett DB , McGee L , Breiman RF , Gladstone RA , Bentley SD , Klugman KP , von Gottberg A . J Clin Microbiol 2016 54 (5) 1326-34 BACKGROUND: Serotype 1 is an important cause of invasive pneumococcal disease in South Africa and has declined following introduction of the 13-valent pneumococcal conjugate vaccine in 2011. METHODS: We genetically characterized 912 invasive serotype 1 isolates from 1989-2013. Simpson's diversity index and recombination ratios were calculated. Factors associated with sequence types (ST) were assessed. RESULTS: Clonal complex 217 represented 96% (872/912) of sampled isolates. Post PCV13, ST diversity increased in children <5 years (0.39 to 0.63, p=0.002) and individuals >14 years (0.35 to 0.54, p<0.001): ST-217 declined proportionately in children <5 years [153/203 (75%) vs. 21/37 (57%), p=0.027], and individuals >14 years [242/305 (79%) vs. 96/148 (65%), p=0.001], whereas ST-9067 increased [4/684 (0.6%) vs. 24/228 (11%), p<0.001]. Three sub-clades were identified within ST-217: ST-217C1 (353/382, 92%), ST-217C2 (15/382, 4%) and ST-217C3 (14/382, 4%). ST-217C2, ST-217C3 and single-locus variant (SLV) ST-8314 (20/912, 2%) were associated with non-susceptibility to chloramphenicol, tetracycline and co-trimoxazole. ST-8314 (20/912, 2%) was also associated with increased non-susceptibility to penicillin (p<0.001). ST-217C3 and newly reported ST-9067 had higher recombination ratios compared to ST-217C1 (4.344 vs. 0.091, p<0.001 and 0.086 vs. 0.013, p<0.001, respectively). CONCLUSIONS: Increases in genetic diversity were noted post PCV13, and lineages associated with antimicrobial non-susceptibility were identified. |
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