Pub Date : 2025-01-01Epub Date: 2024-09-05DOI: 10.1016/S1473-3099(24)00458-4
Vera Buerger, Sandra Hadl, Martina Schneider, Michaela Schaden, Romana Hochreiter, Annegret Bitzer, Karin Kosulin, Robert Mader, Oliver Zoihsl, Andrea Pfeiffer, Ana Paula Loch, Eolo Morandi, Mauricio Lacerda Nogueira, Carlos Alexandre Antunes de Brito, Julio Croda, Mauro Martins Teixeira, Ivo Castelo-Branco Coelho, Ricardo Gurgel, Allex Jardim da Fonseca, Marcus Vinícius Guimarães de Lacerda, Edson Duarte Moreira, Ana Paula Rocha Veiga, Katrin Dubischar, Nina Wressnigg, Susanne Eder-Lingelbach, Juan Carlos Jaramillo
<p><strong>Background: </strong>Chikungunya outbreaks have been reported in Brazil since 2014. Adolescents are a sensitive population who would benefit from a prophylactic vaccine. This study assessed the immunogenicity and safety of the vaccine VLA1553 in adolescents in Brazil. With an overall trial duration of 12 months, we now report data on safety and immunogenicity over a period of 28 days after vaccination.</p><p><strong>Methods: </strong>In this double-blind, randomised, placebo-controlled phase 3 trial, adolescents aged 12 to <18 years were recruited. The trial was performed at ten trial sites across Brazil. Eligible participants were generally healthy. The main exclusion criteria comprised immune-mediated or chronic arthritis or arthralgia, a known or suspected defect of the immune system, or any live vaccine received within the 4 weeks before trial vaccination. Randomisation was stratified by baseline serostatus in a 2:1 ratio to receive VLA1553 (at a dose of 1 × 10<sup>4</sup> TCID<sub>50</sub> per 0·5 mL [ie, 50% tissue culture infectious dose]) or placebo. VLA1553 or placebo was administered intramuscularly as a single-dose immunisation on day 1. The primary endpoint was the proportion of baseline seronegative participants with chikungunya virus neutralising antibody levels of 150 or more in μPRNT<sub>50</sub> (a micro plaque reduction neutralisation test), which was considered a surrogate of protection. The safety analysis included all participants receiving a trial vaccination. Immunogenicity analyses were performed in a subset. The trial is registered with ClinicalTrials.gov, NCT04650399.</p><p><strong>Findings: </strong>Between Feb 14, 2022, and March 14, 2023, 754 participants received a trial vaccination (502 received VLA1553 and 252 received placebo) with a per-protocol population of 351 participants for immunogenicity analyses (303 in the VLA1553 group and 48 in the placebo group). In participants who were seronegative at baseline, VLA1553 induced seroprotective chikungunya virus neutralising antibody levels in 247 of 250 (98·8%, 95% CI 96·5-99·8) participants 28 days after vaccination. In seropositive participants, the baseline seroprotection rate of 96·2% increased to 100% after vaccination with VLA1553. Most (365 [93%] of 393) adverse events were of mild or moderate intensity, VLA1553 was generally well tolerated. When compared with placebo, participants exposed to VLA1553 had a significantly higher frequency of related adverse events (351 [69·9%] of 502 vs 121 [48·0%] of 252; p<0·0001), mostly headache, myalgia, fatigue, and fever. Among four reported serious adverse events (three in the VLA1553 group and one in the placebo group), one was classified as possibly related to VLA1553: a high-grade fever. Among 20 adverse events of special interest (ie, symptoms suggesting chikungunya-like disease), 16 were classified as related to trial vaccination (15 in the VLA1553 group and one in the placebo group), with severe symptoms
背景：自 2014 年以来，巴西一直有基孔肯雅疫情爆发的报道。青少年是一个敏感人群，他们将从预防性疫苗中获益。这项研究评估了 VLA1553 疫苗在巴西青少年中的免疫原性和安全性。整个试验持续时间为 12 个月，现在我们报告接种后 28 天内的安全性和免疫原性数据：在这项双盲、随机、安慰剂对照的 3 期试验中，12 至 4 TCID50 per 0-5 mL [即 50%组织培养感染剂量]）或安慰剂的青少年接种了 VLA1553 或安慰剂。VLA1553或安慰剂在第1天作为单剂量免疫注射进行肌肉注射。主要终点是基线血清阴性参与者中基孔肯雅病毒中和抗体水平达到或超过 150 μPRNT50（微斑块还原中和试验）的比例，这被认为是保护作用的替代指标。安全性分析包括所有接受试验疫苗接种的参与者。免疫原性分析在一个子集中进行。该试验已在ClinicalTrials.gov注册，编号为NCT04650399：2022年2月14日至2023年3月14日期间，754名参与者接种了试验疫苗（502人接种了VLA1553，252人接种了安慰剂），351名参与者按协议进行了免疫原性分析（VLA1553组303人，安慰剂组48人）。在基线血清阴性的参与者中，250人中有247人（98-8%，95% CI 96-5-99-8）在接种疫苗28天后获得了VLA1553诱导的血清保护性基孔肯雅病毒中和抗体水平。在血清反应呈阳性的参与者中，基线血清保护率为 96-2%，而接种 VLA1553 后则增至 100%。大多数不良反应（393例中的365例[93%]）为轻度或中度，VLA1553的耐受性普遍良好。与安慰剂相比，接种了VLA1553的参与者发生相关不良事件的频率明显更高（502人中有351人[69-9%]，252人中有121人[48-0%]；P解释：VLA1553总体上是安全的，几乎对所有接种过疫苗的青少年都有血清保护滴度，对基线血清反应阳性的青少年的安全性数据良好。这些数据支持将VLA1553用于预防基孔肯雅病毒在青少年和流行地区引起的疾病：资助：流行病防备创新联盟和欧盟地平线2020：摘要的葡萄牙语译文见补充材料部分。
{"title":"Safety and immunogenicity of a live-attenuated chikungunya virus vaccine in endemic areas of Brazil: interim results of a double-blind, randomised, placebo-controlled phase 3 trial in adolescents.","authors":"Vera Buerger, Sandra Hadl, Martina Schneider, Michaela Schaden, Romana Hochreiter, Annegret Bitzer, Karin Kosulin, Robert Mader, Oliver Zoihsl, Andrea Pfeiffer, Ana Paula Loch, Eolo Morandi, Mauricio Lacerda Nogueira, Carlos Alexandre Antunes de Brito, Julio Croda, Mauro Martins Teixeira, Ivo Castelo-Branco Coelho, Ricardo Gurgel, Allex Jardim da Fonseca, Marcus Vinícius Guimarães de Lacerda, Edson Duarte Moreira, Ana Paula Rocha Veiga, Katrin Dubischar, Nina Wressnigg, Susanne Eder-Lingelbach, Juan Carlos Jaramillo","doi":"10.1016/S1473-3099(24)00458-4","DOIUrl":"10.1016/S1473-3099(24)00458-4","url":null,"abstract":"<p><strong>Background: </strong>Chikungunya outbreaks have been reported in Brazil since 2014. Adolescents are a sensitive population who would benefit from a prophylactic vaccine. This study assessed the immunogenicity and safety of the vaccine VLA1553 in adolescents in Brazil. With an overall trial duration of 12 months, we now report data on safety and immunogenicity over a period of 28 days after vaccination.</p><p><strong>Methods: </strong>In this double-blind, randomised, placebo-controlled phase 3 trial, adolescents aged 12 to <18 years were recruited. The trial was performed at ten trial sites across Brazil. Eligible participants were generally healthy. The main exclusion criteria comprised immune-mediated or chronic arthritis or arthralgia, a known or suspected defect of the immune system, or any live vaccine received within the 4 weeks before trial vaccination. Randomisation was stratified by baseline serostatus in a 2:1 ratio to receive VLA1553 (at a dose of 1 × 10<sup>4</sup> TCID<sub>50</sub> per 0·5 mL [ie, 50% tissue culture infectious dose]) or placebo. VLA1553 or placebo was administered intramuscularly as a single-dose immunisation on day 1. The primary endpoint was the proportion of baseline seronegative participants with chikungunya virus neutralising antibody levels of 150 or more in μPRNT<sub>50</sub> (a micro plaque reduction neutralisation test), which was considered a surrogate of protection. The safety analysis included all participants receiving a trial vaccination. Immunogenicity analyses were performed in a subset. The trial is registered with ClinicalTrials.gov, NCT04650399.</p><p><strong>Findings: </strong>Between Feb 14, 2022, and March 14, 2023, 754 participants received a trial vaccination (502 received VLA1553 and 252 received placebo) with a per-protocol population of 351 participants for immunogenicity analyses (303 in the VLA1553 group and 48 in the placebo group). In participants who were seronegative at baseline, VLA1553 induced seroprotective chikungunya virus neutralising antibody levels in 247 of 250 (98·8%, 95% CI 96·5-99·8) participants 28 days after vaccination. In seropositive participants, the baseline seroprotection rate of 96·2% increased to 100% after vaccination with VLA1553. Most (365 [93%] of 393) adverse events were of mild or moderate intensity, VLA1553 was generally well tolerated. When compared with placebo, participants exposed to VLA1553 had a significantly higher frequency of related adverse events (351 [69·9%] of 502 vs 121 [48·0%] of 252; p<0·0001), mostly headache, myalgia, fatigue, and fever. Among four reported serious adverse events (three in the VLA1553 group and one in the placebo group), one was classified as possibly related to VLA1553: a high-grade fever. Among 20 adverse events of special interest (ie, symptoms suggesting chikungunya-like disease), 16 were classified as related to trial vaccination (15 in the VLA1553 group and one in the placebo group), with severe symptoms ","PeriodicalId":49923,"journal":{"name":"Lancet Infectious Diseases","volume":" ","pages":"114-125"},"PeriodicalIF":36.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-09-02DOI: 10.1016/S1473-3099(24)00559-0
David L V Bauer
{"title":"Weighing up monoclonals and vaccination against COVID-19.","authors":"David L V Bauer","doi":"10.1016/S1473-3099(24)00559-0","DOIUrl":"10.1016/S1473-3099(24)00559-0","url":null,"abstract":"","PeriodicalId":49923,"journal":{"name":"Lancet Infectious Diseases","volume":" ","pages":"5-6"},"PeriodicalIF":36.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142141625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-09-26DOI: 10.1016/S1473-3099(24)00512-7
Sean Wasserman, Joseph Donovan, Evelyne Kestelyn, James A Watson, Robert E Aarnoutse, James R Barnacle, David R Boulware, Felicia C Chow, Fiona V Cresswell, Angharad G Davis, Kelly E Dooley, Anthony A Figaji, Diana M Gibb, Julie Huynh, Darma Imran, Suzaan Marais, David B Meya, Usha K Misra, Manish Modi, Mihaja Raberahona, Ahmad Rizal Ganiem, Ursula K Rohlwink, Rovina Ruslami, James A Seddon, Keira H Skolimowska, Regan S Solomons, Cari J Stek, Nguyen Thuy Thuong Thuong, Reinout van Crevel, Claire Whitaker, Guy E Thwaites, Robert J Wilkinson
Tuberculous meningitis causes death or disability in approximately 50% of affected individuals and kills approximately 78 200 adults every year. Antimicrobial treatment is based on regimens used for pulmonary tuberculosis, which overlooks important differences between lung and brain drug distributions. Tuberculous meningitis has a profound inflammatory component, yet only adjunctive corticosteroids have shown clear benefit. There is an active pipeline of new antitubercular drugs, and the advent of biological agents targeted at specific inflammatory pathways promises a new era of improved tuberculous meningitis treatment and outcomes. Yet, to date, tuberculous meningitis trials have been small, underpowered, heterogeneous, poorly generalisable, and have had little effect on policy and practice. Progress is slow, and a new approach is required. In this Personal View, a global consortium of tuberculous meningitis researchers articulate a coordinated, definitive way ahead via globally conducted clinical trials of novel drugs and regimens to advance treatment and improve outcomes for this life-threatening infection.
{"title":"Advancing the chemotherapy of tuberculous meningitis: a consensus view.","authors":"Sean Wasserman, Joseph Donovan, Evelyne Kestelyn, James A Watson, Robert E Aarnoutse, James R Barnacle, David R Boulware, Felicia C Chow, Fiona V Cresswell, Angharad G Davis, Kelly E Dooley, Anthony A Figaji, Diana M Gibb, Julie Huynh, Darma Imran, Suzaan Marais, David B Meya, Usha K Misra, Manish Modi, Mihaja Raberahona, Ahmad Rizal Ganiem, Ursula K Rohlwink, Rovina Ruslami, James A Seddon, Keira H Skolimowska, Regan S Solomons, Cari J Stek, Nguyen Thuy Thuong Thuong, Reinout van Crevel, Claire Whitaker, Guy E Thwaites, Robert J Wilkinson","doi":"10.1016/S1473-3099(24)00512-7","DOIUrl":"10.1016/S1473-3099(24)00512-7","url":null,"abstract":"<p><p>Tuberculous meningitis causes death or disability in approximately 50% of affected individuals and kills approximately 78 200 adults every year. Antimicrobial treatment is based on regimens used for pulmonary tuberculosis, which overlooks important differences between lung and brain drug distributions. Tuberculous meningitis has a profound inflammatory component, yet only adjunctive corticosteroids have shown clear benefit. There is an active pipeline of new antitubercular drugs, and the advent of biological agents targeted at specific inflammatory pathways promises a new era of improved tuberculous meningitis treatment and outcomes. Yet, to date, tuberculous meningitis trials have been small, underpowered, heterogeneous, poorly generalisable, and have had little effect on policy and practice. Progress is slow, and a new approach is required. In this Personal View, a global consortium of tuberculous meningitis researchers articulate a coordinated, definitive way ahead via globally conducted clinical trials of novel drugs and regimens to advance treatment and improve outcomes for this life-threatening infection.</p>","PeriodicalId":49923,"journal":{"name":"Lancet Infectious Diseases","volume":" ","pages":"e47-e58"},"PeriodicalIF":36.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7616680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-09-05DOI: 10.1016/S1473-3099(24)00510-3
David O Freedman, Annika Beate Wilder-Smith, Annelies Wilder-Smith
{"title":"First immunogenicity and safety data on live chikungunya vaccine in an endemic area.","authors":"David O Freedman, Annika Beate Wilder-Smith, Annelies Wilder-Smith","doi":"10.1016/S1473-3099(24)00510-3","DOIUrl":"10.1016/S1473-3099(24)00510-3","url":null,"abstract":"","PeriodicalId":49923,"journal":{"name":"Lancet Infectious Diseases","volume":" ","pages":"11-13"},"PeriodicalIF":36.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-09-05DOI: 10.1016/S1473-3099(24)00493-6
Denise Hsu, Akila Jayaraman, Alicia Pucci, Riya Joshi, Kevin Mancini, Hui Ling Chen, Kindra Koslovsky, Xuezhou Mao, Angela Choi, Carole Henry, Jignesh Vakil, Daniel Stadlbauer, Patricia Jorquera, Guha Asthagiri Arunkumar, Nelia E Sanchez-Crespo, L Tyler Wadsworth, Vellore Bhupathy, Evelyn Du, Andrei Avanesov, Jintanat Ananworanich, Raffael Nachbagauer
<p><strong>Background: </strong>Inclusion of additional influenza A/H3N2 strains in seasonal influenza vaccines could expand coverage against multiple, antigenically distinct, cocirculating A/H3N2 clades and potentially replace the no longer circulating B/Yamagata strain. We aimed to evaluate the safety and immunogenicity of three next-generation seasonal influenza mRNA vaccines with different compositions that encode for haemagglutinins of multiple A/H3N2 strains, with or without the B/Yamagata strain, in adults.</p><p><strong>Methods: </strong>This randomised, open-label, phase 1/2 trial enrolled healthy adults aged 50-75 years across 22 sites in the USA. Participants were randomly assigned (1:1:1:1:1:1:1) via interactive response technology to receive a single dose of mRNA-1011.1 (pentavalent; containing one additional A/H3N2 strain [Newcastle]), mRNA-1011.2 (quadrivalent; B/Yamagata replaced with one additional A/H3N2 strain [Newcastle]), mRNA-1012 at one of two dose levels (pentavalent; B/Yamagata replaced with two additional A/H3N2 strains [Newcastle and Hong Kong]), or one of three quadrivalent mRNA-1010 controls each encoding one of the A/H3N2 study strains. The primary outcomes were safety, evaluated in all randomly assigned participants who received a study vaccination (safety population), and reactogenicity, evaluated in all participants from the safety population who contributed any solicited adverse reaction data (solicited safety population). The secondary outcome was humoral immunogenicity of investigational mRNA vaccines at day 29 versus mRNA-1010 control vaccines based on haemagglutination inhibition antibody (HAI) assay in the per-protocol population. Here, we summarise findings from the planned interim analysis after participants had completed day 29. The study is registered with ClinicalTrials.gov, NCT05827068, and is ongoing.</p><p><strong>Findings: </strong>Between March 27 and May 9, 2023, 1183 participants were screened for eligibility, 699 (59·1%) were randomly assigned, and 696 (58·8%) received vaccination (safety population, n=696; solicited safety population, n=694; per-protocol population, n=646). 382 (55%) of the 696 participants in the safety population self-reported as female and 314 (45%) as male. Frequencies of solicited adverse reactions were similar across vaccine groups; 551 (79%) of 694 participants reported at least one solicited adverse reaction within 7 days after vaccination and 83 (12%) of 696 participants reported at least one unsolicited adverse event within 28 days after vaccination. No vaccine-related serious adverse events or deaths were reported. All three next-generation influenza vaccines elicited robust antibody responses against vaccine-matched influenza A and B strains at day 29 that were generally similar to mRNA-1010 controls, and higher responses against additional A/H3N2 strains that were not included within respective mRNA-1010 controls. Day 29 geometric mean fold rises in HAI titres from
{"title":"Safety and immunogenicity of mRNA-based seasonal influenza vaccines formulated to include multiple A/H3N2 strains with or without the B/Yamagata strain in US adults aged 50-75 years: a phase 1/2, open-label, randomised trial.","authors":"Denise Hsu, Akila Jayaraman, Alicia Pucci, Riya Joshi, Kevin Mancini, Hui Ling Chen, Kindra Koslovsky, Xuezhou Mao, Angela Choi, Carole Henry, Jignesh Vakil, Daniel Stadlbauer, Patricia Jorquera, Guha Asthagiri Arunkumar, Nelia E Sanchez-Crespo, L Tyler Wadsworth, Vellore Bhupathy, Evelyn Du, Andrei Avanesov, Jintanat Ananworanich, Raffael Nachbagauer","doi":"10.1016/S1473-3099(24)00493-6","DOIUrl":"10.1016/S1473-3099(24)00493-6","url":null,"abstract":"<p><strong>Background: </strong>Inclusion of additional influenza A/H3N2 strains in seasonal influenza vaccines could expand coverage against multiple, antigenically distinct, cocirculating A/H3N2 clades and potentially replace the no longer circulating B/Yamagata strain. We aimed to evaluate the safety and immunogenicity of three next-generation seasonal influenza mRNA vaccines with different compositions that encode for haemagglutinins of multiple A/H3N2 strains, with or without the B/Yamagata strain, in adults.</p><p><strong>Methods: </strong>This randomised, open-label, phase 1/2 trial enrolled healthy adults aged 50-75 years across 22 sites in the USA. Participants were randomly assigned (1:1:1:1:1:1:1) via interactive response technology to receive a single dose of mRNA-1011.1 (pentavalent; containing one additional A/H3N2 strain [Newcastle]), mRNA-1011.2 (quadrivalent; B/Yamagata replaced with one additional A/H3N2 strain [Newcastle]), mRNA-1012 at one of two dose levels (pentavalent; B/Yamagata replaced with two additional A/H3N2 strains [Newcastle and Hong Kong]), or one of three quadrivalent mRNA-1010 controls each encoding one of the A/H3N2 study strains. The primary outcomes were safety, evaluated in all randomly assigned participants who received a study vaccination (safety population), and reactogenicity, evaluated in all participants from the safety population who contributed any solicited adverse reaction data (solicited safety population). The secondary outcome was humoral immunogenicity of investigational mRNA vaccines at day 29 versus mRNA-1010 control vaccines based on haemagglutination inhibition antibody (HAI) assay in the per-protocol population. Here, we summarise findings from the planned interim analysis after participants had completed day 29. The study is registered with ClinicalTrials.gov, NCT05827068, and is ongoing.</p><p><strong>Findings: </strong>Between March 27 and May 9, 2023, 1183 participants were screened for eligibility, 699 (59·1%) were randomly assigned, and 696 (58·8%) received vaccination (safety population, n=696; solicited safety population, n=694; per-protocol population, n=646). 382 (55%) of the 696 participants in the safety population self-reported as female and 314 (45%) as male. Frequencies of solicited adverse reactions were similar across vaccine groups; 551 (79%) of 694 participants reported at least one solicited adverse reaction within 7 days after vaccination and 83 (12%) of 696 participants reported at least one unsolicited adverse event within 28 days after vaccination. No vaccine-related serious adverse events or deaths were reported. All three next-generation influenza vaccines elicited robust antibody responses against vaccine-matched influenza A and B strains at day 29 that were generally similar to mRNA-1010 controls, and higher responses against additional A/H3N2 strains that were not included within respective mRNA-1010 controls. Day 29 geometric mean fold rises in HAI titres from","PeriodicalId":49923,"journal":{"name":"Lancet Infectious Diseases","volume":" ","pages":"25-35"},"PeriodicalIF":36.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142156488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-09-09DOI: 10.1016/S1473-3099(24)00431-6
Victoria Harris, Jane Holmes, Oghenekome Gbinigie-Thompson, Najib M Rahman, Duncan B Richards, Gail Hayward, Jienchi Dorward, David M Lowe, Joseph F Standing, Judith Breuer, Saye Khoo, Stavros Petrou, Kerenza Hood, Haroon Ahmed, Andrew Carson-Stevens, Jonathan S Nguyen-Van-Tam, Mahendra G Patel, Benjamin R Saville, Nick Francis, Nicholas P B Thomas, Philip Evans, Melissa Dobson, May Ee Png, Mark Lown, Oliver van Hecke, Bhautesh D Jani, Nigel D Hart, Daniel Butler, Lucy Cureton, Meena Patil, Monique Andersson, Maria Coates, Clare Bateman, Jennifer C Davies, Ivy Raymundo-Wood, Andrew Ustianowski, Ly-Mee Yu, F D Richard Hobbs, Paul Little, Christopher C Butler
<p><strong>Background: </strong>No randomised controlled trials have yet reported on the effectiveness of molnupiravir on longer term outcomes for COVID-19. The PANORAMIC trial found molnupiravir reduced time to recovery in acute COVID-19 over 28 days. We aimed to report the effect of molnupiravir treatment for COVID-19 on wellbeing, severe and persistent symptoms, new infections, health care and social service use, medication use, and time off work at 3 months and 6 months post-randomisation.</p><p><strong>Methods: </strong>This study is a follow-up to the main analysis, which was based on the first 28 days of follow-up and has been previously reported. For this multicentre, primary care, open-label, multi-arm, prospective randomised controlled trial conducted in the UK, participants were eligible if aged at least 50 years, or at least 18 years with a comorbidity, and unwell 5 days or less with confirmed COVID-19 in the community. Participants were randomly assigned to the usual care group or molnupiravir group plus usual care (800 mg twice a day for 5 days), which was stratified by age (<50 years or ≥50 years) and vaccination status (at least one dose: yes or no). The primary outcome was hospitalisation or death (or both) at 28 days; all longer term outcomes were considered to be secondary outcomes and included self-reported ratings of wellness (on a scale of 0-10), experiencing any symptom (fever, cough, shortness of breath, fatigue, muscle ache, nausea and vomiting, diarrhoea, loss of smell or taste, headache, dizziness, abdominal pain, and generally feeling unwell) rated as severe (moderately bad or major problem) or persistent, any health and social care use, health-related quality of life (measured by the EQ-5D-5L), time off work or school, new infections, and hospitalisation.</p><p><strong>Findings: </strong>Between Dec 8, 2021, and April 27, 2022, 25 783 participants were randomly assigned to the molnupiravir plus usual care group (n=12 821) or usual care group (n=12 962). Long-term follow-up data were available for 23 008 (89·2%) of 25 784 participants with 11 778 (91·9%) of 12 821 participants in the molnupiravir plus usual care group and 11 230 (86·6%) of 12 963 in the usual care group. 22 806 (99·1%) of 23 008 had at least one previous dose of a SARS-CoV-2 vaccine. Any severe (3 months: adjusted risk difference -1·6% [-2·6% to -0·6%]; probability superiority [p(sup)]>0·99; number needed to treat [NNT] 62·5; 6 months: -1·9% [-2·9% to -0·9%]; p(sup)>0·99, NNT 52·6) or persistent symptoms (3 months: adjusted risk difference -2·1% [-2·9% to -1·5%]; p(sup)>0·99; NNT 47·6; 6 months: -2·5% [-3·3% to -1·6%]; p(sup)>0·99; NNT 40) were reduced in severity, and health-related quality of life (measured by the EQ-5D-5L) improved in the molnupiravir plus usual care group at 3 months and 6 months (3 months: adjusted mean difference 1·08 [0·65 to 1·53]; p(sup)>0·99; 6 months: 1·09 [0·63 to 1·55]; p(sup)>0·99). Ratings of wellness (3 months: adjusted
{"title":"Health outcomes 3 months and 6 months after molnupiravir treatment for COVID-19 for people at higher risk in the community (PANORAMIC): a randomised controlled trial.","authors":"Victoria Harris, Jane Holmes, Oghenekome Gbinigie-Thompson, Najib M Rahman, Duncan B Richards, Gail Hayward, Jienchi Dorward, David M Lowe, Joseph F Standing, Judith Breuer, Saye Khoo, Stavros Petrou, Kerenza Hood, Haroon Ahmed, Andrew Carson-Stevens, Jonathan S Nguyen-Van-Tam, Mahendra G Patel, Benjamin R Saville, Nick Francis, Nicholas P B Thomas, Philip Evans, Melissa Dobson, May Ee Png, Mark Lown, Oliver van Hecke, Bhautesh D Jani, Nigel D Hart, Daniel Butler, Lucy Cureton, Meena Patil, Monique Andersson, Maria Coates, Clare Bateman, Jennifer C Davies, Ivy Raymundo-Wood, Andrew Ustianowski, Ly-Mee Yu, F D Richard Hobbs, Paul Little, Christopher C Butler","doi":"10.1016/S1473-3099(24)00431-6","DOIUrl":"10.1016/S1473-3099(24)00431-6","url":null,"abstract":"<p><strong>Background: </strong>No randomised controlled trials have yet reported on the effectiveness of molnupiravir on longer term outcomes for COVID-19. The PANORAMIC trial found molnupiravir reduced time to recovery in acute COVID-19 over 28 days. We aimed to report the effect of molnupiravir treatment for COVID-19 on wellbeing, severe and persistent symptoms, new infections, health care and social service use, medication use, and time off work at 3 months and 6 months post-randomisation.</p><p><strong>Methods: </strong>This study is a follow-up to the main analysis, which was based on the first 28 days of follow-up and has been previously reported. For this multicentre, primary care, open-label, multi-arm, prospective randomised controlled trial conducted in the UK, participants were eligible if aged at least 50 years, or at least 18 years with a comorbidity, and unwell 5 days or less with confirmed COVID-19 in the community. Participants were randomly assigned to the usual care group or molnupiravir group plus usual care (800 mg twice a day for 5 days), which was stratified by age (<50 years or ≥50 years) and vaccination status (at least one dose: yes or no). The primary outcome was hospitalisation or death (or both) at 28 days; all longer term outcomes were considered to be secondary outcomes and included self-reported ratings of wellness (on a scale of 0-10), experiencing any symptom (fever, cough, shortness of breath, fatigue, muscle ache, nausea and vomiting, diarrhoea, loss of smell or taste, headache, dizziness, abdominal pain, and generally feeling unwell) rated as severe (moderately bad or major problem) or persistent, any health and social care use, health-related quality of life (measured by the EQ-5D-5L), time off work or school, new infections, and hospitalisation.</p><p><strong>Findings: </strong>Between Dec 8, 2021, and April 27, 2022, 25 783 participants were randomly assigned to the molnupiravir plus usual care group (n=12 821) or usual care group (n=12 962). Long-term follow-up data were available for 23 008 (89·2%) of 25 784 participants with 11 778 (91·9%) of 12 821 participants in the molnupiravir plus usual care group and 11 230 (86·6%) of 12 963 in the usual care group. 22 806 (99·1%) of 23 008 had at least one previous dose of a SARS-CoV-2 vaccine. Any severe (3 months: adjusted risk difference -1·6% [-2·6% to -0·6%]; probability superiority [p(sup)]>0·99; number needed to treat [NNT] 62·5; 6 months: -1·9% [-2·9% to -0·9%]; p(sup)>0·99, NNT 52·6) or persistent symptoms (3 months: adjusted risk difference -2·1% [-2·9% to -1·5%]; p(sup)>0·99; NNT 47·6; 6 months: -2·5% [-3·3% to -1·6%]; p(sup)>0·99; NNT 40) were reduced in severity, and health-related quality of life (measured by the EQ-5D-5L) improved in the molnupiravir plus usual care group at 3 months and 6 months (3 months: adjusted mean difference 1·08 [0·65 to 1·53]; p(sup)>0·99; 6 months: 1·09 [0·63 to 1·55]; p(sup)>0·99). Ratings of wellness (3 months: adjusted","PeriodicalId":49923,"journal":{"name":"Lancet Infectious Diseases","volume":" ","pages":"68-79"},"PeriodicalIF":36.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142299642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-09-05DOI: 10.1016/S1473-3099(24)00456-0
Suzanne M E Kuijpers, David T P Buis, Kirsten A Ziesemer, Reinier M van Hest, Rogier P Schade, Kim C E Sigaloff, Jan M Prins
Background: Many trials, reviews, and meta-analyses have been performed on the comparison of short versus long antibiotic treatment in respiratory tract infections, generally supporting shorter treatment. The aim of this umbrella review is to assess the soundness of the current evidence base for optimal antibiotic treatment duration.
Methods: A search in Ovid MEDLINE, Embase, and Clarivate Analytics Web of Science Core Collection was performed on May 1, 2024, without date and language restrictions. Systematic reviews addressing treatment durations in community-acquired pneumonia (CAP), acute exacerbation of chronic obstructive pulmonary disease (AECOPD), hospital-acquired pneumonia (HAP), acute sinusitis, and streptococcal pharyngitis, tonsillitis, or pharyngotonsillitis were included. Studies from inpatient and outpatient settings were included; reviews in paediatric populations were excluded. Outcomes of interest were clinical and bacteriological cure, microbiological eradication, mortality, relapse rate, and adverse events. The quality of the reviews was assessed using the AMSTAR 2 tool, risk of bias of all included randomised controlled trials (RCTs) using the Cochrane risk-of-bias tool (version 1), and overall quality of evidence according to GRADE.
Findings: We identified 30 systematic reviews meeting the criteria; they were generally of a low to critically low quality. 21 reviews conducted a meta-analysis. For CAP outside the intensive care unit (ICU; 14 reviews, of which eight did a meta-analysis) and AECOPD (eight reviews, of which five did a meta-analysis), there was sufficient evidence supporting a treatment duration of 5 days; evidence for shorter durations is scarce. Evidence on non-ventilator-associated HAP is absent, despite identifying three reviews (of which one did a meta-analysis), since no trials were conducted exclusively in this population. For sinusitis the evidence appears to support a shorter regimen, but more evidence is needed in the population who actually require antibiotic treatment. For pharyngotonsillitis (eight reviews, of which six did a meta-analysis), sufficient evidence exists to support short-course cephalosporin but not short-course penicillin when dosed three times a day.
Interpretation: The available evidence for non-ICU CAP and AECOPD supports a short-course treatment duration of 5 days in patients who have clinically improved. Efforts of the scientific community should be directed at implementing this evidence in daily practice. High-quality RCTs are needed to underpin even shorter treatment durations for CAP and AECOPD, to establish the optimal treatment duration of HAP and acute sinusitis, and to evaluate shorter duration using an optimal penicillin dosing schedule in patients with pharyngotonsillitis.
{"title":"The evidence base for the optimal antibiotic treatment duration of upper and lower respiratory tract infections: an umbrella review.","authors":"Suzanne M E Kuijpers, David T P Buis, Kirsten A Ziesemer, Reinier M van Hest, Rogier P Schade, Kim C E Sigaloff, Jan M Prins","doi":"10.1016/S1473-3099(24)00456-0","DOIUrl":"10.1016/S1473-3099(24)00456-0","url":null,"abstract":"<p><strong>Background: </strong>Many trials, reviews, and meta-analyses have been performed on the comparison of short versus long antibiotic treatment in respiratory tract infections, generally supporting shorter treatment. The aim of this umbrella review is to assess the soundness of the current evidence base for optimal antibiotic treatment duration.</p><p><strong>Methods: </strong>A search in Ovid MEDLINE, Embase, and Clarivate Analytics Web of Science Core Collection was performed on May 1, 2024, without date and language restrictions. Systematic reviews addressing treatment durations in community-acquired pneumonia (CAP), acute exacerbation of chronic obstructive pulmonary disease (AECOPD), hospital-acquired pneumonia (HAP), acute sinusitis, and streptococcal pharyngitis, tonsillitis, or pharyngotonsillitis were included. Studies from inpatient and outpatient settings were included; reviews in paediatric populations were excluded. Outcomes of interest were clinical and bacteriological cure, microbiological eradication, mortality, relapse rate, and adverse events. The quality of the reviews was assessed using the AMSTAR 2 tool, risk of bias of all included randomised controlled trials (RCTs) using the Cochrane risk-of-bias tool (version 1), and overall quality of evidence according to GRADE.</p><p><strong>Findings: </strong>We identified 30 systematic reviews meeting the criteria; they were generally of a low to critically low quality. 21 reviews conducted a meta-analysis. For CAP outside the intensive care unit (ICU; 14 reviews, of which eight did a meta-analysis) and AECOPD (eight reviews, of which five did a meta-analysis), there was sufficient evidence supporting a treatment duration of 5 days; evidence for shorter durations is scarce. Evidence on non-ventilator-associated HAP is absent, despite identifying three reviews (of which one did a meta-analysis), since no trials were conducted exclusively in this population. For sinusitis the evidence appears to support a shorter regimen, but more evidence is needed in the population who actually require antibiotic treatment. For pharyngotonsillitis (eight reviews, of which six did a meta-analysis), sufficient evidence exists to support short-course cephalosporin but not short-course penicillin when dosed three times a day.</p><p><strong>Interpretation: </strong>The available evidence for non-ICU CAP and AECOPD supports a short-course treatment duration of 5 days in patients who have clinically improved. Efforts of the scientific community should be directed at implementing this evidence in daily practice. High-quality RCTs are needed to underpin even shorter treatment durations for CAP and AECOPD, to establish the optimal treatment duration of HAP and acute sinusitis, and to evaluate shorter duration using an optimal penicillin dosing schedule in patients with pharyngotonsillitis.</p><p><strong>Funding: </strong>None.</p>","PeriodicalId":49923,"journal":{"name":"Lancet Infectious Diseases","volume":" ","pages":"94-113"},"PeriodicalIF":36.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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