Safety and immunogenicity of the tetravalent, live-attenuated dengue vaccine Butantan-DV in adults in Brazil: a two-step, double-blind, randomised placebo-controlled phase 2 trial
The Butantan Institute has manufactured a lyophilised tetravalent live-attenuated dengue vaccine Butantan-DV, which is analogous to the US National Institutes of Health (NIH) TV003 admixture. We aimed to assess the safety and immunogenicity of Butantan-DV. We did a two-step, double-blind, randomised...
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| Veröffentlicht in: | The Lancet infectious diseases 2020-07, Vol.20 (7), p.839-850 |
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| creator | Kallas, Esper G Precioso, Alexander Roberto Palacios, Ricardo Thomé, Beatriz Braga, Patrícia Emília Vanni, Tazio Campos, Lúcia M A Ferrari, Lilian Mondini, Gabriella da Graça Salomão, Maria da Silva, Anderson Espinola, Heloisa M do Prado Santos, Joane Santos, Cecilia L S Timenetsky, Maria do Carmo S T Miraglia, João Luiz Gallina, Neuza M F Weiskopf, Daniela Sette, Alessandro Goulart, Raphaella Salles, Rafael Tavares Maestri, Alvino Sallum, Adriana Maluf Elias Farhat, Sylvia Costa Lima Sakita, Neusa K Ferreira, Juliana C O A Silveira, Cassia G T Costa, Priscilla R Raw, Isaias Whitehead, Stephen S Durbin, Anna P Kalil, Jorge |
| description | The Butantan Institute has manufactured a lyophilised tetravalent live-attenuated dengue vaccine Butantan-DV, which is analogous to the US National Institutes of Health (NIH) TV003 admixture. We aimed to assess the safety and immunogenicity of Butantan-DV.
We did a two-step, double-blind, randomised placebo-controlled phase 2 trial at two clinical sites in São Paulo, Brazil. We recruited healthy volunteers aged 18–59 years; pregnant women, individuals with a history of neurological, heart, lung, liver or kidney disease, diabetes, cancer, or autoimmune diseases, and individuals with HIV or hepatitis C were excluded. Step A was designed as a small bridge-study between Butantan-DV and TV003 in DENV-naive participants. In step A, we planned to randomly assign 50 dengue virus (DENV)-naive individuals to receive two doses of Butantan-DV, TV003, or placebo, given 6 months apart. In step B, we planned to randomly assign 250 participants (DENV-naive and DENV-exposed) to receive one dose of Butantan-DV or placebo. Participants were randomly assigned, by computer-generated block randomisation (block sizes of five); participants in step A were randomly assigned (2:2:1) to receive Butantan-DV, TV003, or placebo and participants in step B were randomly assigned (4:1) to receive Butantan-DV or placebo. Participants and study staff were unaware of treatment allocation. The primary safety outcome was the frequency of solicited and unsolicited local and systemic adverse reactions within 21 days of the first vaccination, analysed by intention to treat. The primary immunogenicity outcome was seroconversion rates of the DENV-1-4 serotypes measured 91 days after the first vaccination, analysed in the per-protocol population, which included all participants in step A, and all participants included in step B who completed all study visits with serology sample collection. This trial is registered with ClinicalTrials.gov, NCT01696422.
Between Nov 5, 2013, and Sept 21, 2015, 300 individuals were enrolled and randomly assigned: 155 (52%) DENV-naive participants and 145 (48%) DENV-exposed participants. Of the 155 DENV-naive participants, 97 (63%) received Butantan-DV, 17 (11%) received TV003, and 41 (27%) received placebo. Of the 145 DENV-exposed participants, 113 (78%) received Butantan-DV, three (2%) received TV003, and 29 (20%) received placebo. Butantan-DV and TV003 were both immunogenic, well-tolerated, and no serious adverse reactions were observed. In step A, rash was the most |
| doi_str_mv | 10.1016/S1473-3099(20)30023-2 |
| format | Article |
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We did a two-step, double-blind, randomised placebo-controlled phase 2 trial at two clinical sites in São Paulo, Brazil. We recruited healthy volunteers aged 18–59 years; pregnant women, individuals with a history of neurological, heart, lung, liver or kidney disease, diabetes, cancer, or autoimmune diseases, and individuals with HIV or hepatitis C were excluded. Step A was designed as a small bridge-study between Butantan-DV and TV003 in DENV-naive participants. In step A, we planned to randomly assign 50 dengue virus (DENV)-naive individuals to receive two doses of Butantan-DV, TV003, or placebo, given 6 months apart. In step B, we planned to randomly assign 250 participants (DENV-naive and DENV-exposed) to receive one dose of Butantan-DV or placebo. Participants were randomly assigned, by computer-generated block randomisation (block sizes of five); participants in step A were randomly assigned (2:2:1) to receive Butantan-DV, TV003, or placebo and participants in step B were randomly assigned (4:1) to receive Butantan-DV or placebo. Participants and study staff were unaware of treatment allocation. The primary safety outcome was the frequency of solicited and unsolicited local and systemic adverse reactions within 21 days of the first vaccination, analysed by intention to treat. The primary immunogenicity outcome was seroconversion rates of the DENV-1-4 serotypes measured 91 days after the first vaccination, analysed in the per-protocol population, which included all participants in step A, and all participants included in step B who completed all study visits with serology sample collection. This trial is registered with ClinicalTrials.gov, NCT01696422.
Between Nov 5, 2013, and Sept 21, 2015, 300 individuals were enrolled and randomly assigned: 155 (52%) DENV-naive participants and 145 (48%) DENV-exposed participants. Of the 155 DENV-naive participants, 97 (63%) received Butantan-DV, 17 (11%) received TV003, and 41 (27%) received placebo. Of the 145 DENV-exposed participants, 113 (78%) received Butantan-DV, three (2%) received TV003, and 29 (20%) received placebo. Butantan-DV and TV003 were both immunogenic, well-tolerated, and no serious adverse reactions were observed. In step A, rash was the most frequent adverse event (16 [845] of 19 participants in the Butantan-DV group and 13 [76%] of 17 participants in the TV003 group). Viraemia was similar between the Butantan-DV and TV003 groups. Of the 85 DENV-naive participants in the Butantan-DV group who attended all visits for sample collection for seroconversion analysis and thus were included in the per-protocol analysis population, 74 (87%) achieved seroconversion to DENV-1, 78 (92%) to DENV-2, 65 (76%) to DENV-3, and 76 (89%) to DENV-4. Of the 101 DENV-exposed participants in the Butantan-DV group who attended all visits for sample collection for seroconversion analysis, 82 (81%) achieved seroconversion to DENV-1, 79 (78%) to DENV-2, 83 (82%) to DENV-3, and 78 (77%) to DENV-4.
Butantan-DV and TV003 were safe and induced robust, balanced neutralising antibody responses against the four DENV serotypes. Efficacy evaluation of the Butantan-DV vaccine is ongoing.
Intramural Research Program US NIH National Institute of Allergy and Infectious Diseases, Brazilian National Bank for Economic and Social Development, Fundação de Amparo à Pesquisa do Estado de São Paulo, and Fundação Butantan.</description><identifier>ISSN: 1473-3099</identifier><identifier>EISSN: 1474-4457</identifier><identifier>DOI: 10.1016/S1473-3099(20)30023-2</identifier><identifier>PMID: 32220283</identifier><language>eng</language><publisher>United States: Elsevier Ltd</publisher><subject>Allergies ; Analysis ; Antibodies ; Autoimmune diseases ; Clinical trials ; Collection ; Dengue ; Dengue fever ; Diabetes mellitus ; Double-blind studies ; Exposure ; Hepatitis C ; HIV ; Human immunodeficiency virus ; Immunogenicity ; Infections ; Infectious diseases ; Kidney diseases ; Laboratories ; Licenses ; Liver diseases ; Lung diseases ; Pregnancy ; Public health ; Randomization ; Safety ; Seroconversion ; Serology ; Serotypes ; Side effects ; Studies ; Vaccination ; Vaccines ; Vector-borne diseases ; Viremia ; Viruses</subject><ispartof>The Lancet infectious diseases, 2020-07, Vol.20 (7), p.839-850</ispartof><rights>2020 Elsevier Ltd</rights><rights>Copyright © 2020 Elsevier Ltd. All rights reserved.</rights><rights>2020. Elsevier Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c476t-5578a1db4762e6a8baadebe654e242598d50ff2137c96d0d70ee8b1f96b8ad203</citedby><cites>FETCH-LOGICAL-c476t-5578a1db4762e6a8baadebe654e242598d50ff2137c96d0d70ee8b1f96b8ad203</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/2424137715?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>315,781,785,3551,27926,27927,45997,64387,64389,64391,72471</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32220283$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kallas, Esper G</creatorcontrib><creatorcontrib>Precioso, Alexander Roberto</creatorcontrib><creatorcontrib>Palacios, Ricardo</creatorcontrib><creatorcontrib>Thomé, Beatriz</creatorcontrib><creatorcontrib>Braga, Patrícia Emília</creatorcontrib><creatorcontrib>Vanni, Tazio</creatorcontrib><creatorcontrib>Campos, Lúcia M A</creatorcontrib><creatorcontrib>Ferrari, Lilian</creatorcontrib><creatorcontrib>Mondini, Gabriella</creatorcontrib><creatorcontrib>da Graça Salomão, Maria</creatorcontrib><creatorcontrib>da Silva, Anderson</creatorcontrib><creatorcontrib>Espinola, Heloisa M</creatorcontrib><creatorcontrib>do Prado Santos, Joane</creatorcontrib><creatorcontrib>Santos, Cecilia L S</creatorcontrib><creatorcontrib>Timenetsky, Maria do Carmo S T</creatorcontrib><creatorcontrib>Miraglia, João Luiz</creatorcontrib><creatorcontrib>Gallina, Neuza M F</creatorcontrib><creatorcontrib>Weiskopf, Daniela</creatorcontrib><creatorcontrib>Sette, Alessandro</creatorcontrib><creatorcontrib>Goulart, Raphaella</creatorcontrib><creatorcontrib>Salles, Rafael Tavares</creatorcontrib><creatorcontrib>Maestri, Alvino</creatorcontrib><creatorcontrib>Sallum, Adriana Maluf Elias</creatorcontrib><creatorcontrib>Farhat, Sylvia Costa Lima</creatorcontrib><creatorcontrib>Sakita, Neusa K</creatorcontrib><creatorcontrib>Ferreira, Juliana C O A</creatorcontrib><creatorcontrib>Silveira, Cassia G T</creatorcontrib><creatorcontrib>Costa, Priscilla R</creatorcontrib><creatorcontrib>Raw, Isaias</creatorcontrib><creatorcontrib>Whitehead, Stephen S</creatorcontrib><creatorcontrib>Durbin, Anna P</creatorcontrib><creatorcontrib>Kalil, Jorge</creatorcontrib><title>Safety and immunogenicity of the tetravalent, live-attenuated dengue vaccine Butantan-DV in adults in Brazil: a two-step, double-blind, randomised placebo-controlled phase 2 trial</title><title>The Lancet infectious diseases</title><addtitle>Lancet Infect Dis</addtitle><description>The Butantan Institute has manufactured a lyophilised tetravalent live-attenuated dengue vaccine Butantan-DV, which is analogous to the US National Institutes of Health (NIH) TV003 admixture. We aimed to assess the safety and immunogenicity of Butantan-DV.
We did a two-step, double-blind, randomised placebo-controlled phase 2 trial at two clinical sites in São Paulo, Brazil. We recruited healthy volunteers aged 18–59 years; pregnant women, individuals with a history of neurological, heart, lung, liver or kidney disease, diabetes, cancer, or autoimmune diseases, and individuals with HIV or hepatitis C were excluded. Step A was designed as a small bridge-study between Butantan-DV and TV003 in DENV-naive participants. In step A, we planned to randomly assign 50 dengue virus (DENV)-naive individuals to receive two doses of Butantan-DV, TV003, or placebo, given 6 months apart. In step B, we planned to randomly assign 250 participants (DENV-naive and DENV-exposed) to receive one dose of Butantan-DV or placebo. Participants were randomly assigned, by computer-generated block randomisation (block sizes of five); participants in step A were randomly assigned (2:2:1) to receive Butantan-DV, TV003, or placebo and participants in step B were randomly assigned (4:1) to receive Butantan-DV or placebo. Participants and study staff were unaware of treatment allocation. The primary safety outcome was the frequency of solicited and unsolicited local and systemic adverse reactions within 21 days of the first vaccination, analysed by intention to treat. The primary immunogenicity outcome was seroconversion rates of the DENV-1-4 serotypes measured 91 days after the first vaccination, analysed in the per-protocol population, which included all participants in step A, and all participants included in step B who completed all study visits with serology sample collection. This trial is registered with ClinicalTrials.gov, NCT01696422.
Between Nov 5, 2013, and Sept 21, 2015, 300 individuals were enrolled and randomly assigned: 155 (52%) DENV-naive participants and 145 (48%) DENV-exposed participants. Of the 155 DENV-naive participants, 97 (63%) received Butantan-DV, 17 (11%) received TV003, and 41 (27%) received placebo. Of the 145 DENV-exposed participants, 113 (78%) received Butantan-DV, three (2%) received TV003, and 29 (20%) received placebo. Butantan-DV and TV003 were both immunogenic, well-tolerated, and no serious adverse reactions were observed. In step A, rash was the most frequent adverse event (16 [845] of 19 participants in the Butantan-DV group and 13 [76%] of 17 participants in the TV003 group). Viraemia was similar between the Butantan-DV and TV003 groups. Of the 85 DENV-naive participants in the Butantan-DV group who attended all visits for sample collection for seroconversion analysis and thus were included in the per-protocol analysis population, 74 (87%) achieved seroconversion to DENV-1, 78 (92%) to DENV-2, 65 (76%) to DENV-3, and 76 (89%) to DENV-4. Of the 101 DENV-exposed participants in the Butantan-DV group who attended all visits for sample collection for seroconversion analysis, 82 (81%) achieved seroconversion to DENV-1, 79 (78%) to DENV-2, 83 (82%) to DENV-3, and 78 (77%) to DENV-4.
Butantan-DV and TV003 were safe and induced robust, balanced neutralising antibody responses against the four DENV serotypes. Efficacy evaluation of the Butantan-DV vaccine is ongoing.
Intramural Research Program US NIH National Institute of Allergy and Infectious Diseases, Brazilian National Bank for Economic and Social Development, Fundação de Amparo à Pesquisa do Estado de São Paulo, and Fundação Butantan.</description><subject>Allergies</subject><subject>Analysis</subject><subject>Antibodies</subject><subject>Autoimmune diseases</subject><subject>Clinical trials</subject><subject>Collection</subject><subject>Dengue</subject><subject>Dengue fever</subject><subject>Diabetes mellitus</subject><subject>Double-blind studies</subject><subject>Exposure</subject><subject>Hepatitis C</subject><subject>HIV</subject><subject>Human immunodeficiency virus</subject><subject>Immunogenicity</subject><subject>Infections</subject><subject>Infectious diseases</subject><subject>Kidney diseases</subject><subject>Laboratories</subject><subject>Licenses</subject><subject>Liver diseases</subject><subject>Lung diseases</subject><subject>Pregnancy</subject><subject>Public health</subject><subject>Randomization</subject><subject>Safety</subject><subject>Seroconversion</subject><subject>Serology</subject><subject>Serotypes</subject><subject>Side effects</subject><subject>Studies</subject><subject>Vaccination</subject><subject>Vaccines</subject><subject>Vector-borne 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Thomé, Beatriz ; Braga, Patrícia Emília ; Vanni, Tazio ; Campos, Lúcia M A ; Ferrari, Lilian ; Mondini, Gabriella ; da Graça Salomão, Maria ; da Silva, Anderson ; Espinola, Heloisa M ; do Prado Santos, Joane ; Santos, Cecilia L S ; Timenetsky, Maria do Carmo S T ; Miraglia, João Luiz ; Gallina, Neuza M F ; Weiskopf, Daniela ; Sette, Alessandro ; Goulart, Raphaella ; Salles, Rafael Tavares ; Maestri, Alvino ; Sallum, Adriana Maluf Elias ; Farhat, Sylvia Costa Lima ; Sakita, Neusa K ; Ferreira, Juliana C O A ; Silveira, Cassia G T ; Costa, Priscilla R ; Raw, Isaias ; Whitehead, Stephen S ; Durbin, Anna P ; Kalil, Jorge</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c476t-5578a1db4762e6a8baadebe654e242598d50ff2137c96d0d70ee8b1f96b8ad203</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Allergies</topic><topic>Analysis</topic><topic>Antibodies</topic><topic>Autoimmune diseases</topic><topic>Clinical trials</topic><topic>Collection</topic><topic>Dengue</topic><topic>Dengue fever</topic><topic>Diabetes mellitus</topic><topic>Double-blind studies</topic><topic>Exposure</topic><topic>Hepatitis C</topic><topic>HIV</topic><topic>Human immunodeficiency virus</topic><topic>Immunogenicity</topic><topic>Infections</topic><topic>Infectious diseases</topic><topic>Kidney diseases</topic><topic>Laboratories</topic><topic>Licenses</topic><topic>Liver diseases</topic><topic>Lung diseases</topic><topic>Pregnancy</topic><topic>Public health</topic><topic>Randomization</topic><topic>Safety</topic><topic>Seroconversion</topic><topic>Serology</topic><topic>Serotypes</topic><topic>Side effects</topic><topic>Studies</topic><topic>Vaccination</topic><topic>Vaccines</topic><topic>Vector-borne diseases</topic><topic>Viremia</topic><topic>Viruses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kallas, Esper G</creatorcontrib><creatorcontrib>Precioso, Alexander Roberto</creatorcontrib><creatorcontrib>Palacios, Ricardo</creatorcontrib><creatorcontrib>Thomé, Beatriz</creatorcontrib><creatorcontrib>Braga, Patrícia Emília</creatorcontrib><creatorcontrib>Vanni, Tazio</creatorcontrib><creatorcontrib>Campos, Lúcia M A</creatorcontrib><creatorcontrib>Ferrari, Lilian</creatorcontrib><creatorcontrib>Mondini, Gabriella</creatorcontrib><creatorcontrib>da Graça Salomão, Maria</creatorcontrib><creatorcontrib>da Silva, Anderson</creatorcontrib><creatorcontrib>Espinola, Heloisa M</creatorcontrib><creatorcontrib>do Prado Santos, Joane</creatorcontrib><creatorcontrib>Santos, Cecilia L S</creatorcontrib><creatorcontrib>Timenetsky, Maria do Carmo S T</creatorcontrib><creatorcontrib>Miraglia, João Luiz</creatorcontrib><creatorcontrib>Gallina, Neuza M F</creatorcontrib><creatorcontrib>Weiskopf, Daniela</creatorcontrib><creatorcontrib>Sette, Alessandro</creatorcontrib><creatorcontrib>Goulart, Raphaella</creatorcontrib><creatorcontrib>Salles, Rafael Tavares</creatorcontrib><creatorcontrib>Maestri, Alvino</creatorcontrib><creatorcontrib>Sallum, Adriana Maluf Elias</creatorcontrib><creatorcontrib>Farhat, Sylvia Costa Lima</creatorcontrib><creatorcontrib>Sakita, Neusa K</creatorcontrib><creatorcontrib>Ferreira, Juliana C O A</creatorcontrib><creatorcontrib>Silveira, Cassia G T</creatorcontrib><creatorcontrib>Costa, Priscilla R</creatorcontrib><creatorcontrib>Raw, Isaias</creatorcontrib><creatorcontrib>Whitehead, Stephen S</creatorcontrib><creatorcontrib>Durbin, Anna P</creatorcontrib><creatorcontrib>Kalil, Jorge</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Pharma and Biotech Premium PRO</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Nursing & Allied Health Database</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Lancet Titles</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>MEDLINE - Academic</collection><jtitle>The Lancet infectious diseases</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kallas, Esper G</au><au>Precioso, Alexander Roberto</au><au>Palacios, Ricardo</au><au>Thomé, Beatriz</au><au>Braga, Patrícia Emília</au><au>Vanni, Tazio</au><au>Campos, Lúcia M A</au><au>Ferrari, Lilian</au><au>Mondini, Gabriella</au><au>da Graça Salomão, Maria</au><au>da Silva, Anderson</au><au>Espinola, Heloisa M</au><au>do Prado Santos, Joane</au><au>Santos, Cecilia L S</au><au>Timenetsky, Maria do Carmo S T</au><au>Miraglia, João Luiz</au><au>Gallina, Neuza M F</au><au>Weiskopf, Daniela</au><au>Sette, Alessandro</au><au>Goulart, Raphaella</au><au>Salles, Rafael Tavares</au><au>Maestri, Alvino</au><au>Sallum, Adriana Maluf Elias</au><au>Farhat, Sylvia Costa Lima</au><au>Sakita, Neusa K</au><au>Ferreira, Juliana C O A</au><au>Silveira, Cassia G T</au><au>Costa, Priscilla R</au><au>Raw, Isaias</au><au>Whitehead, Stephen S</au><au>Durbin, Anna P</au><au>Kalil, Jorge</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Safety and immunogenicity of the tetravalent, live-attenuated dengue vaccine Butantan-DV in adults in Brazil: a two-step, double-blind, randomised placebo-controlled phase 2 trial</atitle><jtitle>The Lancet infectious diseases</jtitle><addtitle>Lancet Infect Dis</addtitle><date>2020-07-01</date><risdate>2020</risdate><volume>20</volume><issue>7</issue><spage>839</spage><epage>850</epage><pages>839-850</pages><issn>1473-3099</issn><eissn>1474-4457</eissn><abstract>The Butantan Institute has manufactured a lyophilised tetravalent live-attenuated dengue vaccine Butantan-DV, which is analogous to the US National Institutes of Health (NIH) TV003 admixture. We aimed to assess the safety and immunogenicity of Butantan-DV.
We did a two-step, double-blind, randomised placebo-controlled phase 2 trial at two clinical sites in São Paulo, Brazil. We recruited healthy volunteers aged 18–59 years; pregnant women, individuals with a history of neurological, heart, lung, liver or kidney disease, diabetes, cancer, or autoimmune diseases, and individuals with HIV or hepatitis C were excluded. Step A was designed as a small bridge-study between Butantan-DV and TV003 in DENV-naive participants. In step A, we planned to randomly assign 50 dengue virus (DENV)-naive individuals to receive two doses of Butantan-DV, TV003, or placebo, given 6 months apart. In step B, we planned to randomly assign 250 participants (DENV-naive and DENV-exposed) to receive one dose of Butantan-DV or placebo. Participants were randomly assigned, by computer-generated block randomisation (block sizes of five); participants in step A were randomly assigned (2:2:1) to receive Butantan-DV, TV003, or placebo and participants in step B were randomly assigned (4:1) to receive Butantan-DV or placebo. Participants and study staff were unaware of treatment allocation. The primary safety outcome was the frequency of solicited and unsolicited local and systemic adverse reactions within 21 days of the first vaccination, analysed by intention to treat. The primary immunogenicity outcome was seroconversion rates of the DENV-1-4 serotypes measured 91 days after the first vaccination, analysed in the per-protocol population, which included all participants in step A, and all participants included in step B who completed all study visits with serology sample collection. This trial is registered with ClinicalTrials.gov, NCT01696422.
Between Nov 5, 2013, and Sept 21, 2015, 300 individuals were enrolled and randomly assigned: 155 (52%) DENV-naive participants and 145 (48%) DENV-exposed participants. Of the 155 DENV-naive participants, 97 (63%) received Butantan-DV, 17 (11%) received TV003, and 41 (27%) received placebo. Of the 145 DENV-exposed participants, 113 (78%) received Butantan-DV, three (2%) received TV003, and 29 (20%) received placebo. Butantan-DV and TV003 were both immunogenic, well-tolerated, and no serious adverse reactions were observed. In step A, rash was the most frequent adverse event (16 [845] of 19 participants in the Butantan-DV group and 13 [76%] of 17 participants in the TV003 group). Viraemia was similar between the Butantan-DV and TV003 groups. Of the 85 DENV-naive participants in the Butantan-DV group who attended all visits for sample collection for seroconversion analysis and thus were included in the per-protocol analysis population, 74 (87%) achieved seroconversion to DENV-1, 78 (92%) to DENV-2, 65 (76%) to DENV-3, and 76 (89%) to DENV-4. Of the 101 DENV-exposed participants in the Butantan-DV group who attended all visits for sample collection for seroconversion analysis, 82 (81%) achieved seroconversion to DENV-1, 79 (78%) to DENV-2, 83 (82%) to DENV-3, and 78 (77%) to DENV-4.
Butantan-DV and TV003 were safe and induced robust, balanced neutralising antibody responses against the four DENV serotypes. Efficacy evaluation of the Butantan-DV vaccine is ongoing.
Intramural Research Program US NIH National Institute of Allergy and Infectious Diseases, Brazilian National Bank for Economic and Social Development, Fundação de Amparo à Pesquisa do Estado de São Paulo, and Fundação Butantan.</abstract><cop>United States</cop><pub>Elsevier Ltd</pub><pmid>32220283</pmid><doi>10.1016/S1473-3099(20)30023-2</doi><tpages>12</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1473-3099 |
| ispartof | The Lancet infectious diseases, 2020-07, Vol.20 (7), p.839-850 |
| issn | 1473-3099 1474-4457 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2384216177 |
| source | Access via ScienceDirect (Elsevier); ProQuest Central UK/Ireland |
| subjects | Allergies Analysis Antibodies Autoimmune diseases Clinical trials Collection Dengue Dengue fever Diabetes mellitus Double-blind studies Exposure Hepatitis C HIV Human immunodeficiency virus Immunogenicity Infections Infectious diseases Kidney diseases Laboratories Licenses Liver diseases Lung diseases Pregnancy Public health Randomization Safety Seroconversion Serology Serotypes Side effects Studies Vaccination Vaccines Vector-borne diseases Viremia Viruses |
| title | Safety and immunogenicity of the tetravalent, live-attenuated dengue vaccine Butantan-DV in adults in Brazil: a two-step, double-blind, randomised placebo-controlled phase 2 trial |
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