Pub Date : 2024-07-01DOI: 10.1016/S2666-5247(24)00071-5
Miriam Massese , Marilena La Sorda , Flavio De Maio , Antonio Gatto , Roberto Rosato , Valeria Pansini , Anya Caroselli , Barbara Fiori , Maurizio Sanguinetti , Antonio Chiaretti , Brunella Posteraro
{"title":"Epidemiology of group A streptococcal infection: are we ready for a new scenario?","authors":"Miriam Massese , Marilena La Sorda , Flavio De Maio , Antonio Gatto , Roberto Rosato , Valeria Pansini , Anya Caroselli , Barbara Fiori , Maurizio Sanguinetti , Antonio Chiaretti , Brunella Posteraro","doi":"10.1016/S2666-5247(24)00071-5","DOIUrl":"10.1016/S2666-5247(24)00071-5","url":null,"abstract":"","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":null,"pages":null},"PeriodicalIF":20.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666524724000715/pdfft?md5=f05358ff2a6d164d26761d2abbb64143&pid=1-s2.0-S2666524724000715-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140768603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 10.1016/S2666-5247(24)00024-7
Thomas G Evans MD , Flora Castellino MD , Monika Kowalik Dobczyk MD , Gwen Tucker MA , Ana Marie Walley MD , Katrin Van Leuven MD , Jelle Klein MD , Kathryn Rutkowski MS , Chris Ellis RN , Elizabeth Eagling-Vose MBA , John Treanor MD , Carel van Baalen PhD , Ella Filkov MSc , Cyril Laurent PhD , Juilee Thacker PhD , Jason Asher PhD , Armen Donabedian MD
Background
Protection afforded by inactivated influenza vaccines can theoretically be improved by inducing T-cell responses to conserved internal influenza A antigens. We assessed whether, in an influenza controlled human infection challenge, susceptible individuals receiving a vaccine boosting T-cell responses would exhibit lower viral load and decreased symptoms compared with placebo recipients.
Methods
In this single centre, randomised, double-blind phase 2 study, healthy adult (aged 18–55 years) volunteers with microneutralisation titres of less than 20 to the influenza A(H3N2) challenge strain were enrolled at an SGS quarantine facility in Antwerp, Belgium. Participants were randomly assigned double-blind using a permuted-block list with a 3:2 allocation ratio to receive 0·5 mL intramuscular injections of modified vaccinia Ankara (MVA) expressing H3N2 nucleoprotein (NP) and matrix protein 1 (M1) at 1·5 × 108 plaque forming units (4·3 × 108 50% tissue culture infectious dose [TCID50]; MVA-NP+M1 group) or saline placebo (placebo group). At least 6 weeks later, participants were challenged intranasally with 0·5 mL of a 1 × 106 TCID50/mL dose of influenza A/Belgium/4217/2015 (H3N2). Nasal swabs were collected twice daily from day 2 until day 11 for viral PCR, and symptoms of influenza were recorded from day 2 until day 11. The primary outcome was to determine the efficacy of MVA-NP+M1 vaccine to reduce the degree of nasopharyngeal viral shedding as measured by the cumulative viral area under the curve using a log-transformed quantitative PCR. This study is registered with ClinicalTrials.gov, NCT03883113.
Findings
Between May 2 and Oct 24, 2019, 145 volunteers were enrolled and randomly assigned to the MVA-NP+M1 group (n=87) or the placebo group (n=58). Of these, 118 volunteers entered the challenge period (71 in the MVA-NP+M1 group and 47 in the placebo group) and 117 participants completed the study (71 in the MVA-NP+M1 group and 46 in the placebo group). 78 (54%) of the 145 volunteers were female and 67 (46%) were male. The primary outcome, overall viral load as determined by quantitative PCR, did not show a statistically significant difference between the MVA-NP+M1 (mean 649·7 [95% CI 552·7–746·7) and placebo groups (mean 726·1 [604·0–848·2]; p=0·17). All reported treatment emergent adverse events (TEAEs; 11 in the vaccination phase and 51 in the challenge phase) were grade 1 and 2, except for two grade 3 TEAEs in the placebo group in the challenge phase. A grade 4 second trimester fetal death, considered possibly related to the MVA-NP+M1 vaccination, and an acute psychosis reported in a placebo participant during the challenge phase were reported.
Interpretation
The use of an MVA vaccine to expand CD4+ or CD8+ T cells to conserved influenza
{"title":"Assessment of CD8+ T-cell mediated immunity in an influenza A(H3N2) human challenge model in Belgium: a single centre, randomised, double-blind phase 2 study","authors":"Thomas G Evans MD , Flora Castellino MD , Monika Kowalik Dobczyk MD , Gwen Tucker MA , Ana Marie Walley MD , Katrin Van Leuven MD , Jelle Klein MD , Kathryn Rutkowski MS , Chris Ellis RN , Elizabeth Eagling-Vose MBA , John Treanor MD , Carel van Baalen PhD , Ella Filkov MSc , Cyril Laurent PhD , Juilee Thacker PhD , Jason Asher PhD , Armen Donabedian MD","doi":"10.1016/S2666-5247(24)00024-7","DOIUrl":"10.1016/S2666-5247(24)00024-7","url":null,"abstract":"<div><h3>Background</h3><p>Protection afforded by inactivated influenza vaccines can theoretically be improved by inducing T-cell responses to conserved internal influenza A antigens. We assessed whether, in an influenza controlled human infection challenge, susceptible individuals receiving a vaccine boosting T-cell responses would exhibit lower viral load and decreased symptoms compared with placebo recipients.</p></div><div><h3>Methods</h3><p>In this single centre, randomised, double-blind phase 2 study, healthy adult (aged 18–55 years) volunteers with microneutralisation titres of less than 20 to the influenza A(H3N2) challenge strain were enrolled at an SGS quarantine facility in Antwerp, Belgium. Participants were randomly assigned double-blind using a permuted-block list with a 3:2 allocation ratio to receive 0·5 mL intramuscular injections of modified vaccinia Ankara (MVA) expressing H3N2 nucleoprotein (NP) and matrix protein 1 (M1) at 1·5 × 10<sup>8</sup> plaque forming units (4·3 × 10<sup>8</sup> 50% tissue culture infectious dose [TCID<sub>50</sub>]; MVA-NP+M1 group) or saline placebo (placebo group). At least 6 weeks later, participants were challenged intranasally with 0·5 mL of a 1 × 10<sup>6</sup> TCID<sub>50</sub>/mL dose of influenza A/Belgium/4217/2015 (H3N2). Nasal swabs were collected twice daily from day 2 until day 11 for viral PCR, and symptoms of influenza were recorded from day 2 until day 11. The primary outcome was to determine the efficacy of MVA-NP+M1 vaccine to reduce the degree of nasopharyngeal viral shedding as measured by the cumulative viral area under the curve using a log-transformed quantitative PCR. This study is registered with ClinicalTrials.gov, <span>NCT03883113</span><svg><path></path></svg>.</p></div><div><h3>Findings</h3><p>Between May 2 and Oct 24, 2019, 145 volunteers were enrolled and randomly assigned to the MVA-NP+M1 group (n=87) or the placebo group (n=58). Of these, 118 volunteers entered the challenge period (71 in the MVA-NP+M1 group and 47 in the placebo group) and 117 participants completed the study (71 in the MVA-NP+M1 group and 46 in the placebo group). 78 (54%) of the 145 volunteers were female and 67 (46%) were male. The primary outcome, overall viral load as determined by quantitative PCR, did not show a statistically significant difference between the MVA-NP+M1 (mean 649·7 [95% CI 552·7–746·7) and placebo groups (mean 726·1 [604·0–848·2]; p=0·17). All reported treatment emergent adverse events (TEAEs; 11 in the vaccination phase and 51 in the challenge phase) were grade 1 and 2, except for two grade 3 TEAEs in the placebo group in the challenge phase. A grade 4 second trimester fetal death, considered possibly related to the MVA-NP+M1 vaccination, and an acute psychosis reported in a placebo participant during the challenge phase were reported.</p></div><div><h3>Interpretation</h3><p>The use of an MVA vaccine to expand CD4<sup>+</sup> or CD8<sup>+</sup> T cells to conserved influenza","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":null,"pages":null},"PeriodicalIF":20.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666524724000247/pdfft?md5=8b03bfe70027156f51744386e69e3813&pid=1-s2.0-S2666524724000247-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140904902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 10.1016/S2666-5247(24)00127-7
Gavin J Churchyard, Rein M G J Houben, Katherine Fielding, Andrew L Fiore-Gartland, Hanif Esmail, Alison D Grant, Molebogeng X Rangaka, Marcel Behr, Alberto L Garcia-Basteiro, Emily B Wong, Mark Hatherill, Vidya Mave, Alemnew F Dagnew, Alexander C Schmidt, Willem A Hanekom, Frank Cobelens, Richard G White
Tuberculosis is a leading cause of death from an infectious agent globally. Infectious subclinical tuberculosis accounts for almost half of all tuberculosis cases in national tuberculosis prevalence surveys, and possibly contributes to transmission and might be associated with morbidity. Modelling studies suggest that new tuberculosis vaccines could have substantial health and economic effects, partly based on the assumptions made regarding subclinical tuberculosis. Evaluating the efficacy of prevention of disease tuberculosis vaccines intended for preventing both clinical and subclinical tuberculosis is a priority. Incorporation of subclinical tuberculosis as a composite endpoint in tuberculosis vaccine trials can help to reduce the sample size and duration of follow-up and to evaluate the efficacy of tuberculosis vaccines in preventing clinical and subclinical tuberculosis. Several design options with various benefits, limitations, and ethical considerations are possible in this regard, which would allow for the generation of the evidence needed to estimate the positive global effects of tuberculosis vaccine trials, in addition to informing policy and vaccination strategies.
{"title":"Implications of subclinical tuberculosis for vaccine trial design and global effect.","authors":"Gavin J Churchyard, Rein M G J Houben, Katherine Fielding, Andrew L Fiore-Gartland, Hanif Esmail, Alison D Grant, Molebogeng X Rangaka, Marcel Behr, Alberto L Garcia-Basteiro, Emily B Wong, Mark Hatherill, Vidya Mave, Alemnew F Dagnew, Alexander C Schmidt, Willem A Hanekom, Frank Cobelens, Richard G White","doi":"10.1016/S2666-5247(24)00127-7","DOIUrl":"https://doi.org/10.1016/S2666-5247(24)00127-7","url":null,"abstract":"<p><p>Tuberculosis is a leading cause of death from an infectious agent globally. Infectious subclinical tuberculosis accounts for almost half of all tuberculosis cases in national tuberculosis prevalence surveys, and possibly contributes to transmission and might be associated with morbidity. Modelling studies suggest that new tuberculosis vaccines could have substantial health and economic effects, partly based on the assumptions made regarding subclinical tuberculosis. Evaluating the efficacy of prevention of disease tuberculosis vaccines intended for preventing both clinical and subclinical tuberculosis is a priority. Incorporation of subclinical tuberculosis as a composite endpoint in tuberculosis vaccine trials can help to reduce the sample size and duration of follow-up and to evaluate the efficacy of tuberculosis vaccines in preventing clinical and subclinical tuberculosis. Several design options with various benefits, limitations, and ethical considerations are possible in this regard, which would allow for the generation of the evidence needed to estimate the positive global effects of tuberculosis vaccine trials, in addition to informing policy and vaccination strategies.</p>","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":null,"pages":null},"PeriodicalIF":20.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141535652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 10.1016/S2666-5247(24)00023-5
Almahamoudou Mahamar PhD , Merel J Smit MD , Koualy Sanogo MD , Youssouf Sinaba MD , Sidi M Niambele PharmD , Adama Sacko MS , Oumar M Dicko MD , Makonon Diallo MD , Seydina O Maguiraga MD , Yaya Sankaré MD , Sekouba Keita MS , Siaka Samake Pharm D , Adama Dembele MS , Kjerstin Lanke PhD , Rob ter Heine PhD , John Bradley PhD , Yahia Dicko MD , Sekou F Traore PhD , Prof Chris Drakeley PhD , Prof Alassane Dicko MD , Will Stone PhD
Background
Artemether–lumefantrine is widely used for uncomplicated Plasmodium falciparum malaria; sulfadoxine–pyrimethamine plus amodiaquine is used for seasonal malaria chemoprevention. We aimed to determine the efficacy of artemether–lumefantrine with and without primaquine and sulfadoxine–pyrimethamine plus amodiaquine with and without tafenoquine for reducing gametocyte carriage and transmission to mosquitoes.
Methods
In this phase 2, single-blind, randomised clinical trial conducted in Ouelessebougou, Mali, asymptomatic individuals aged 10–50 years with P falciparum gametocytaemia were recruited from the community and randomly assigned (1:1:1:1) to receive either artemether–lumefantrine, artemether–lumefantrine with a single dose of 0·25 mg/kg primaquine, sulfadoxine–pyrimethamine plus amodiaquine, or sulfadoxine–pyrimethamine plus amodiaquine with a single dose of 1·66 mg/kg tafenoquine. All trial staff other than the pharmacist were masked to group allocation. Participants were not masked to group allocation. Randomisation was done with a computer-generated randomisation list and concealed with sealed, opaque envelopes. The primary outcome was the median within-person percent change in mosquito infection rate in infectious individuals from baseline to day 2 (artemether–lumefantrine groups) or day 7 (sulfadoxine–pyrimethamine plus amodiaquine groups) after treatment, assessed by direct membrane feeding assay. All participants who received any trial drug were included in the safety analysis. This study is registered with ClinicalTrials.gov, NCT05081089.
Findings
Between Oct 13 and Dec 16, 2021, 1290 individuals were screened and 80 were enrolled and randomly assigned to one of the four treatment groups (20 per group). The median age of participants was 13 (IQR 11–20); 37 (46%) of 80 participants were female and 43 (54%) were male. In individuals who were infectious before treatment, the median percentage reduction in mosquito infection rate 2 days after treatment was 100·0% (IQR 100·0–100·0; n=19; p=0·0011) with artemether–lumefantrine and 100·0% (100·0–100·0; n=19; p=0·0001) with artemether–lumefantrine with primaquine. Only two individuals who were infectious at baseline infected mosquitoes on day 2 after artemether–lumefantrine and none at day 5. By contrast, the median percentage reduction in mosquito infection rate 7 days after treatment was 63·6% (IQR 0·0–100·0; n=20; p=0·013) with sulfadoxine–pyrimethamine plus amodiaquine and 100% (100·0–100·0; n=19; p<0·0001) with sulfadoxine–pyrimethamine plus amodiaquine with tafenoquine. No grade 3–4 or serious adverse events occurred.
Interpretation
These data support the effectiveness of artemether–lumefantrine alone for preventing nearly all mosquito infections. By contrast, there was considerable post-treatment transmission after sulfadoxine–pyr
{"title":"Artemether–lumefantrine with or without single-dose primaquine and sulfadoxine–pyrimethamine plus amodiaquine with or without single-dose tafenoquine to reduce Plasmodium falciparum transmission: a phase 2, single-blind, randomised clinical trial in Ouelessebougou, Mali","authors":"Almahamoudou Mahamar PhD , Merel J Smit MD , Koualy Sanogo MD , Youssouf Sinaba MD , Sidi M Niambele PharmD , Adama Sacko MS , Oumar M Dicko MD , Makonon Diallo MD , Seydina O Maguiraga MD , Yaya Sankaré MD , Sekouba Keita MS , Siaka Samake Pharm D , Adama Dembele MS , Kjerstin Lanke PhD , Rob ter Heine PhD , John Bradley PhD , Yahia Dicko MD , Sekou F Traore PhD , Prof Chris Drakeley PhD , Prof Alassane Dicko MD , Will Stone PhD","doi":"10.1016/S2666-5247(24)00023-5","DOIUrl":"10.1016/S2666-5247(24)00023-5","url":null,"abstract":"<div><h3>Background</h3><p>Artemether–lumefantrine is widely used for uncomplicated <em>Plasmodium falciparum</em> malaria; sulfadoxine–pyrimethamine plus amodiaquine is used for seasonal malaria chemoprevention. We aimed to determine the efficacy of artemether–lumefantrine with and without primaquine and sulfadoxine–pyrimethamine plus amodiaquine with and without tafenoquine for reducing gametocyte carriage and transmission to mosquitoes.</p></div><div><h3>Methods</h3><p>In this phase 2, single-blind, randomised clinical trial conducted in Ouelessebougou, Mali, asymptomatic individuals aged 10–50 years with <em>P falciparum</em> gametocytaemia were recruited from the community and randomly assigned (1:1:1:1) to receive either artemether–lumefantrine, artemether–lumefantrine with a single dose of 0·25 mg/kg primaquine, sulfadoxine–pyrimethamine plus amodiaquine, or sulfadoxine–pyrimethamine plus amodiaquine with a single dose of 1·66 mg/kg tafenoquine. All trial staff other than the pharmacist were masked to group allocation. Participants were not masked to group allocation. Randomisation was done with a computer-generated randomisation list and concealed with sealed, opaque envelopes. The primary outcome was the median within-person percent change in mosquito infection rate in infectious individuals from baseline to day 2 (artemether–lumefantrine groups) or day 7 (sulfadoxine–pyrimethamine plus amodiaquine groups) after treatment, assessed by direct membrane feeding assay. All participants who received any trial drug were included in the safety analysis. This study is registered with ClinicalTrials.gov, <span>NCT05081089</span><svg><path></path></svg>.</p></div><div><h3>Findings</h3><p>Between Oct 13 and Dec 16, 2021, 1290 individuals were screened and 80 were enrolled and randomly assigned to one of the four treatment groups (20 per group). The median age of participants was 13 (IQR 11–20); 37 (46%) of 80 participants were female and 43 (54%) were male. In individuals who were infectious before treatment, the median percentage reduction in mosquito infection rate 2 days after treatment was 100·0% (IQR 100·0–100·0; n=19; p=0·0011) with artemether–lumefantrine and 100·0% (100·0–100·0; n=19; p=0·0001) with artemether–lumefantrine with primaquine. Only two individuals who were infectious at baseline infected mosquitoes on day 2 after artemether–lumefantrine and none at day 5. By contrast, the median percentage reduction in mosquito infection rate 7 days after treatment was 63·6% (IQR 0·0–100·0; n=20; p=0·013) with sulfadoxine–pyrimethamine plus amodiaquine and 100% (100·0–100·0; n=19; p<0·0001) with sulfadoxine–pyrimethamine plus amodiaquine with tafenoquine. No grade 3–4 or serious adverse events occurred.</p></div><div><h3>Interpretation</h3><p>These data support the effectiveness of artemether–lumefantrine alone for preventing nearly all mosquito infections. By contrast, there was considerable post-treatment transmission after sulfadoxine–pyr","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":null,"pages":null},"PeriodicalIF":20.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666524724000235/pdfft?md5=d2becfd9b44d3eac932d539a6c48153f&pid=1-s2.0-S2666524724000235-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140868421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mutations in the Plasmodium falciparum dhfr gene confer resistance to pyrimethamine, which is widely used for malaria chemoprevention in Africa. We aimed to evaluate the frequency and evolution of dhfr mutations in Plasmodium ovale spp in Africa and their functional consequences, which are incompletely characterised.
Methods
We analysed dhfr mutations and their frequencies in P ovale spp isolates collected between Feb 1, 2004, and Aug 31, 2023, from the French National Malaria Reference Centre collection and from field studies in Benin, Gabon, and Kenya. Genetic patterns of positive selection were investigated. Full-length recombinant wild-type and mutant DHFR enzymes from both P ovale curtisi and P ovale wallikeri were expressed in bacteria to test whether the most common mutations reduced pyrimethamine susceptibility.
Findings
We included 518 P ovale spp samples (314 P ovale curtisi and 204 P ovale wallikeri). In P ovale curtisi, Ala15Ser-Ser58Arg was the most common dhfr mutation (39%; 124 of 314 samples). In P ovale wallikeri, dhfr mutations were less frequent, with Phe57Leu-Ser58Arg reaching 17% (34 of 204 samples). These two mutants were the most prevalent in central and east Africa and were fixed in Kenyan isolates. We detected six and four other non-synonymous mutations, representing 8% (24 isolates) and 2% (five isolates) of the P ovale curtisi and P ovale wallikeri isolates, respectively. Whole-genome sequencing and microsatellite analyses revealed reduced genetic diversity around the mutant pocdhfr and powdhfr genes. The mutant DHFR proteins showed structural changes at the pyrimethamine binding site in-silico, confirmed by a 4-times increase in pyrimethamine half-maximal inhibitory concentration in an Escherichia coli growth assay for the Phe57Leu-Ser58Arg mutant and 50-times increase for the Ala15Ser-Ser58Arg mutant, compared with the wild-type counterparts.
Interpretation
The widespread use of sulfadoxine–pyrimethamine for malaria chemoprevention might have exerted fortuitous selection pressure for dhfr mutations in P ovale spp. This calls for closer monitoring of dhfr and dhps mutations in P ovale spp.
Funding
French Ministry of Health, Agence Nationale de la Recherche, and Global Emerging Infections Surveillance branch of the Armed Forces Health Surveillance Division.
{"title":"Plasmodium ovale spp dhfr mutations associated with reduced susceptibility to pyrimethamine in sub-Saharan Africa: a retrospective genetic epidemiology and functional study","authors":"Valentin Joste PharmD , Romain Coppée PhD , Justine Bailly MSc , Yann Rakotoarivony BSc , Francine Ghislaine Toko Tchokoteu BSc , Shany Achache BSc , Bruno Pradines PhD , Gilles Cottrell PhD , Prof Frédéric Ariey PhD , Nimol Khim PhD , Jean Popovici PhD , Prof Toshihiro Mita PhD , Mirjam Groger PhD , Prof Michael Ramharter MD , Timothy Egbo PhD , Dennis W Juma MSc , Hoseah Akala PhD , Prof Sandrine Houzé PhD , Jérôme Clain PhD , Rella Zoleko-Manego","doi":"10.1016/S2666-5247(24)00054-5","DOIUrl":"10.1016/S2666-5247(24)00054-5","url":null,"abstract":"<div><h3>Background</h3><p>Mutations in the <em>Plasmodium falciparum dhfr</em> gene confer resistance to pyrimethamine, which is widely used for malaria chemoprevention in Africa. We aimed to evaluate the frequency and evolution of <em>dhfr</em> mutations in <em>Plasmodium ovale</em> spp in Africa and their functional consequences, which are incompletely characterised.</p></div><div><h3>Methods</h3><p>We analysed <em>dhfr</em> mutations and their frequencies in <em>P ovale</em> spp isolates collected between Feb 1, 2004, and Aug 31, 2023, from the French National Malaria Reference Centre collection and from field studies in Benin, Gabon, and Kenya. Genetic patterns of positive selection were investigated. Full-length recombinant wild-type and mutant DHFR enzymes from both <em>P ovale curtisi</em> and <em>P ovale wallikeri</em> were expressed in bacteria to test whether the most common mutations reduced pyrimethamine susceptibility.</p></div><div><h3>Findings</h3><p>We included 518 <em>P ovale</em> spp samples (314 <em>P ovale curtisi</em> and 204 <em>P ovale wallikeri</em>). In <em>P ovale curtisi</em>, Ala15Ser-Ser58Arg was the most common <em>dhfr</em> mutation (39%; 124 of 314 samples). In <em>P ovale wallikeri</em>, <em>dhfr</em> mutations were less frequent, with Phe57Leu-Ser58Arg reaching 17% (34 of 204 samples). These two mutants were the most prevalent in central and east Africa and were fixed in Kenyan isolates. We detected six and four other non-synonymous mutations, representing 8% (24 isolates) and 2% (five isolates) of the <em>P ovale curtisi</em> and <em>P ovale wallikeri</em> isolates, respectively. Whole-genome sequencing and microsatellite analyses revealed reduced genetic diversity around the mutant <em>pocdhfr</em> and <em>powdhfr</em> genes. The mutant DHFR proteins showed structural changes at the pyrimethamine binding site in-silico, confirmed by a 4-times increase in pyrimethamine half-maximal inhibitory concentration in an <em>Escherichia coli</em> growth assay for the Phe57Leu-Ser58Arg mutant and 50-times increase for the Ala15Ser-Ser58Arg mutant, compared with the wild-type counterparts.</p></div><div><h3>Interpretation</h3><p>The widespread use of sulfadoxine–pyrimethamine for malaria chemoprevention might have exerted fortuitous selection pressure for <em>dhfr</em> mutations in <em>P ovale</em> spp. This calls for closer monitoring of <em>dhfr</em> and <em>dhps</em> mutations in <em>P ovale</em> spp.</p></div><div><h3>Funding</h3><p>French Ministry of Health, Agence Nationale de la Recherche, and Global Emerging Infections Surveillance branch of the Armed Forces Health Surveillance Division.</p></div>","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":null,"pages":null},"PeriodicalIF":20.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666524724000545/pdfft?md5=bee63f41ce0b7fe861607d39af5dceb5&pid=1-s2.0-S2666524724000545-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140960020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 10.1016/S2666-5247(24)00051-X
Qiu E Yang , Shungui Zhou , Timothy R Walsh
{"title":"Distribution of IncX3 plasmids in bacteria – Authors’ reply","authors":"Qiu E Yang , Shungui Zhou , Timothy R Walsh","doi":"10.1016/S2666-5247(24)00051-X","DOIUrl":"10.1016/S2666-5247(24)00051-X","url":null,"abstract":"","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":null,"pages":null},"PeriodicalIF":20.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S266652472400051X/pdfft?md5=3f69da3ce1f18abbfbf5b9f9688d0eb8&pid=1-s2.0-S266652472400051X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140274551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 10.1016/S2666-5247(24)00072-7
Henrik Salje , Francis M Jiggins
{"title":"Risks of releasing imperfect Wolbachia strains for arbovirus control","authors":"Henrik Salje , Francis M Jiggins","doi":"10.1016/S2666-5247(24)00072-7","DOIUrl":"10.1016/S2666-5247(24)00072-7","url":null,"abstract":"","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":null,"pages":null},"PeriodicalIF":20.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666524724000727/pdfft?md5=fe4a3b547a173a85f8a251a4b52e9afc&pid=1-s2.0-S2666524724000727-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140761203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 10.1016/S2666-5247(24)00166-6
The Lancet Microbe
{"title":"Still time to contain artemisinin resistance in Africa","authors":"The Lancet Microbe","doi":"10.1016/S2666-5247(24)00166-6","DOIUrl":"https://doi.org/10.1016/S2666-5247(24)00166-6","url":null,"abstract":"","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":null,"pages":null},"PeriodicalIF":20.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666524724001666/pdfft?md5=8944b9b0aeeb87116bbb5840ebdb8913&pid=1-s2.0-S2666524724001666-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141482868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-25DOI: 10.1016/S2666-5247(24)00159-9
William Calero-Cáceres, José Luis Balcázar
{"title":"Leveraging genomic surveillance for public health: insights from Latin America.","authors":"William Calero-Cáceres, José Luis Balcázar","doi":"10.1016/S2666-5247(24)00159-9","DOIUrl":"https://doi.org/10.1016/S2666-5247(24)00159-9","url":null,"abstract":"","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":null,"pages":null},"PeriodicalIF":20.9,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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