Safety and immunogenicity of a modified-vaccinia-virus-Ankara-based influenza A H5N1 vaccine: a randomised, double-blind phase 1/2a clinical trial
Identifieur interne : 001E17 ( PascalFrancis/Curation ); précédent : 001E16; suivant : 001E18Safety and immunogenicity of a modified-vaccinia-virus-Ankara-based influenza A H5N1 vaccine: a randomised, double-blind phase 1/2a clinical trial
Auteurs : Joost H. C. M. Kreijtz [Pays-Bas] ; Marco Goeijenbier [Pays-Bas] ; Fleur M. Moesker [Pays-Bas] ; Lennert Van Den Dries [Pays-Bas] ; Simone Goeijenbier [Pays-Bas] ; Heidi L. M. De Gruyter [Pays-Bas] ; Michael H. Lehmann [Allemagne] ; Gerrie De Mutsert [Pays-Bas] ; David A. M. C. Van De Vijver [Pays-Bas] ; Asisa Volz [Allemagne] ; Ron A. M. Fouchier [Pays-Bas] ; Eric C. M. Van Gorp [Pays-Bas] ; Guus F. Rimmelzwaan [Pays-Bas] ; Gerd Sutter [Allemagne] ; Albert D. M. E. Osterhaus [Pays-Bas, Allemagne]Source :
- Lancet. Infectious diseases : (print) [ 1473-3099 ] ; 2014.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Vaccin.
English descriptors
- KwdEn :
Abstract
Background Modified vaccinia virus Ankara (MVA) is a promising viral vector platform for the development of an H5N1 influenza vaccine. Preclinical assessment of MVA-based H5N1 vaccines showed their immunogenicity and safety in different animal models. We aimed to assess the safety and immunogenicity of the MVA-haemagglutinin-based H5N1 vaccine MVA-H5-sfMR in healthy individuals. Methods In a single-centre, double-blind phase 1/2a study, young volunteers (aged 18-28 years) were randomly assigned with a computer-generated list in equal numbers to one of eight groups and were given one injection or two injections intramuscularly at an interval of 4 weeks of a standard dose (108 plaque forming units [pfu]) or a ten times lower dose (107 pfu) of the MVA-H5-sfMR (vector encoding the haemagglutinin gene of influenza A/Vietnam/1194/2004 virus [H5N1 subtype]) or MVA-F6-sfMR (empty vector) vaccine. Volunteers and physicians who examined and administered the vaccine were masked to vaccine assignment. Individuals who received the MVA-H5-sfMR vaccine were eligible for a booster immunisation 1 year after the first immunisation. Primary endpoint was safety. Secondary outcome was immunogenicity. The trial is registered with the Dutch Trial Register, number NTR3401. Findings 79 of 80 individuals who were enrolled completed the study. No serious adverse events were identified. 11 individuals reported severe headache and lightheadedness, erythema nodosum, respiratory illness (accompanied by influenza-like symptoms), sore throat, or injection-site reaction. Most of the volunteers had one or more local (itch, pain, redness, and swelling) and systemic reactions (rise in body temperature, headache, myalgia, arthralgia, chills, malaise, and fatigue) after the first, second, and booster immunisations. Individuals who received the 107 dose had fewer systemic reactions. The MVA-H5-sfMR vaccine at 108 pfu induced significantly higher antibody responses after one and two immunisations than did 107 pfu when assessed with haemagglutination inhibition geometric mean titre at 8 weeks against H5N1 A/Vietnam/1194/2004 (30.2 [SD 3.8] vs 9.2 [2.3] and 108.1 [2.4] vs 15.8 [3.2]). 27 of 39 eligible individuals were enrolled in the booster immunisation study. A single shot of MVA-H5-sfMR 108 pfu prime immunisation resulted in higher antibody responses after the booster immunisation than did two shots of MVA-H5-sfMR at the ten times lower dose. Interpretation The MVA-based H5N1 vaccine was well tolerated and immunogenic and therefore the vaccine candidates arising from the MVA platform hold great promise for rapid development in response to a future influenza pandemic threat. However, the immunogenicity of this vaccine needs to be compared with conventional H5N1 inactivated non-adjuvanted vaccine candidates in head-to-head clinical trials.
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Rimmelzwaan</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Viroscience Lab, Erasmus Medical Center</s1><s2>Rotterdam</s2><s3>NLD</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>15 aut.</sZ></inist:fA14><country>Pays-Bas</country></affiliation></author><author><name sortKey="Sutter, Gerd" sort="Sutter, Gerd" uniqKey="Sutter G" first="Gerd" last="Sutter">Gerd Sutter</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Institute for Infectious Diseases and Zoonoses, Ludwig Maximilian University of Munich</s1><s2>Munich</s2><s3>DEU</s3><sZ>7 aut.</sZ><sZ>10 aut.</sZ><sZ>14 aut.</sZ></inist:fA14><country>Allemagne</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>German Centre for Infection Research</s1><s2>Munich</s2><s3>DEU</s3><sZ>7 aut.</sZ><sZ>10 aut.</sZ><sZ>14 aut.</sZ></inist:fA14><country>Allemagne</country></affiliation></author><author><name sortKey="Osterhaus, Albert D M E" sort="Osterhaus, Albert D M E" uniqKey="Osterhaus A" first="Albert D. M. E." last="Osterhaus">Albert D. M. E. Osterhaus</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Viroscience Lab, Erasmus Medical Center</s1><s2>Rotterdam</s2><s3>NLD</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>15 aut.</sZ></inist:fA14><country>Pays-Bas</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Centerfor Infection Medicine and Zoonoses Research, University of Veterinary Medicine</s1><s2>Hannover</s2><s3>DEU</s3><sZ>15 aut.</sZ></inist:fA14><country>Allemagne</country></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">15-0022824</idno><date when="2014">2014</date><idno type="stanalyst">PASCAL 15-0022824 INIST</idno><idno type="RBID">Pascal:15-0022824</idno><idno type="wicri:Area/PascalFrancis/Corpus">000002</idno><idno type="wicri:Area/PascalFrancis/Curation">001E17</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Safety and immunogenicity of a modified-vaccinia-virus-Ankara-based influenza A H5N1 vaccine: a randomised, double-blind phase 1/2a clinical trial</title><author><name sortKey="Kreijtz, Joost H C M" sort="Kreijtz, Joost H C M" uniqKey="Kreijtz J" first="Joost H. C. M." last="Kreijtz">Joost H. C. M. Kreijtz</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Viroscience Lab, Erasmus Medical Center</s1><s2>Rotterdam</s2><s3>NLD</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>15 aut.</sZ></inist:fA14><country>Pays-Bas</country></affiliation></author><author><name sortKey="Goeijenbier, Marco" sort="Goeijenbier, Marco" uniqKey="Goeijenbier M" first="Marco" last="Goeijenbier">Marco Goeijenbier</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Viroscience Lab, Erasmus Medical Center</s1><s2>Rotterdam</s2><s3>NLD</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>15 aut.</sZ></inist:fA14><country>Pays-Bas</country></affiliation></author><author><name sortKey="Moesker, Fleur M" sort="Moesker, Fleur M" uniqKey="Moesker F" first="Fleur M." last="Moesker">Fleur M. Moesker</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Viroscience Lab, Erasmus Medical Center</s1><s2>Rotterdam</s2><s3>NLD</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>15 aut.</sZ></inist:fA14><country>Pays-Bas</country></affiliation></author><author><name sortKey="Van Den Dries, Lennert" sort="Van Den Dries, Lennert" uniqKey="Van Den Dries L" first="Lennert" last="Van Den Dries">Lennert Van Den Dries</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Viroscience Lab, Erasmus Medical Center</s1><s2>Rotterdam</s2><s3>NLD</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>15 aut.</sZ></inist:fA14><country>Pays-Bas</country></affiliation></author><author><name sortKey="Goeijenbier, Simone" sort="Goeijenbier, Simone" uniqKey="Goeijenbier S" first="Simone" last="Goeijenbier">Simone Goeijenbier</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Viroscience Lab, Erasmus Medical Center</s1><s2>Rotterdam</s2><s3>NLD</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>15 aut.</sZ></inist:fA14><country>Pays-Bas</country></affiliation></author><author><name sortKey="De Gruyter, Heidi L M" sort="De Gruyter, Heidi L M" uniqKey="De Gruyter H" first="Heidi L. M." last="De Gruyter">Heidi L. M. De Gruyter</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Viroscience Lab, Erasmus Medical Center</s1><s2>Rotterdam</s2><s3>NLD</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>15 aut.</sZ></inist:fA14><country>Pays-Bas</country></affiliation></author><author><name sortKey="Lehmann, Michael H" sort="Lehmann, Michael H" uniqKey="Lehmann M" first="Michael H." last="Lehmann">Michael H. Lehmann</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Institute for Infectious Diseases and Zoonoses, Ludwig Maximilian University of Munich</s1><s2>Munich</s2><s3>DEU</s3><sZ>7 aut.</sZ><sZ>10 aut.</sZ><sZ>14 aut.</sZ></inist:fA14><country>Allemagne</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>German Centre for Infection Research</s1><s2>Munich</s2><s3>DEU</s3><sZ>7 aut.</sZ><sZ>10 aut.</sZ><sZ>14 aut.</sZ></inist:fA14><country>Allemagne</country></affiliation></author><author><name sortKey="De Mutsert, Gerrie" sort="De Mutsert, Gerrie" uniqKey="De Mutsert G" first="Gerrie" last="De Mutsert">Gerrie De Mutsert</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Viroscience Lab, Erasmus Medical Center</s1><s2>Rotterdam</s2><s3>NLD</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>15 aut.</sZ></inist:fA14><country>Pays-Bas</country></affiliation></author><author><name sortKey="Van De Vijver, David A M C" sort="Van De Vijver, David A M C" uniqKey="Van De Vijver D" first="David A. M. C." last="Van De Vijver">David A. M. C. Van De Vijver</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Viroscience Lab, Erasmus Medical Center</s1><s2>Rotterdam</s2><s3>NLD</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>15 aut.</sZ></inist:fA14><country>Pays-Bas</country></affiliation></author><author><name sortKey="Volz, Asisa" sort="Volz, Asisa" uniqKey="Volz A" first="Asisa" last="Volz">Asisa Volz</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Institute for Infectious Diseases and Zoonoses, Ludwig Maximilian University of Munich</s1><s2>Munich</s2><s3>DEU</s3><sZ>7 aut.</sZ><sZ>10 aut.</sZ><sZ>14 aut.</sZ></inist:fA14><country>Allemagne</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>German Centre for Infection Research</s1><s2>Munich</s2><s3>DEU</s3><sZ>7 aut.</sZ><sZ>10 aut.</sZ><sZ>14 aut.</sZ></inist:fA14><country>Allemagne</country></affiliation></author><author><name sortKey="Fouchier, Ron A M" sort="Fouchier, Ron A M" uniqKey="Fouchier R" first="Ron A. M." last="Fouchier">Ron A. M. Fouchier</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Viroscience Lab, Erasmus Medical Center</s1><s2>Rotterdam</s2><s3>NLD</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>15 aut.</sZ></inist:fA14><country>Pays-Bas</country></affiliation></author><author><name sortKey="Van Gorp, Eric C M" sort="Van Gorp, Eric C M" uniqKey="Van Gorp E" first="Eric C. M." last="Van Gorp">Eric C. M. Van Gorp</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Viroscience Lab, Erasmus Medical Center</s1><s2>Rotterdam</s2><s3>NLD</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>15 aut.</sZ></inist:fA14><country>Pays-Bas</country></affiliation></author><author><name sortKey="Rimmelzwaan, Guus F" sort="Rimmelzwaan, Guus F" uniqKey="Rimmelzwaan G" first="Guus F." last="Rimmelzwaan">Guus F. Rimmelzwaan</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Viroscience Lab, Erasmus Medical Center</s1><s2>Rotterdam</s2><s3>NLD</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>15 aut.</sZ></inist:fA14><country>Pays-Bas</country></affiliation></author><author><name sortKey="Sutter, Gerd" sort="Sutter, Gerd" uniqKey="Sutter G" first="Gerd" last="Sutter">Gerd Sutter</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Institute for Infectious Diseases and Zoonoses, Ludwig Maximilian University of Munich</s1><s2>Munich</s2><s3>DEU</s3><sZ>7 aut.</sZ><sZ>10 aut.</sZ><sZ>14 aut.</sZ></inist:fA14><country>Allemagne</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>German Centre for Infection Research</s1><s2>Munich</s2><s3>DEU</s3><sZ>7 aut.</sZ><sZ>10 aut.</sZ><sZ>14 aut.</sZ></inist:fA14><country>Allemagne</country></affiliation></author><author><name sortKey="Osterhaus, Albert D M E" sort="Osterhaus, Albert D M E" uniqKey="Osterhaus A" first="Albert D. M. E." last="Osterhaus">Albert D. M. E. Osterhaus</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Viroscience Lab, Erasmus Medical Center</s1><s2>Rotterdam</s2><s3>NLD</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>15 aut.</sZ></inist:fA14><country>Pays-Bas</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Centerfor Infection Medicine and Zoonoses Research, University of Veterinary Medicine</s1><s2>Hannover</s2><s3>DEU</s3><sZ>15 aut.</sZ></inist:fA14><country>Allemagne</country></affiliation></author></analytic><series><title level="j" type="main">Lancet. Infectious diseases : (print)</title><title level="j" type="abbreviated">Lancet. Infect. dis. : (print)</title><idno type="ISSN">1473-3099</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Lancet. Infectious diseases : (print)</title><title level="j" type="abbreviated">Lancet. Infect. dis. : (print)</title><idno type="ISSN">1473-3099</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Clinical trial</term><term>Immunogenicity</term><term>Immunoprophylaxis</term><term>Influenza</term><term>Influenzavirus A(H5N1)</term><term>Phase I trial</term><term>Phase II trial</term><term>Prevention</term><term>Vaccine</term><term>Vaccinia virus</term><term>Vector</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Grippe</term><term>Immunoprophylaxie</term><term>Immunogénicité</term><term>Vaccin</term><term>Prévention</term><term>Virus vaccine</term><term>Essai clinique</term><term>Essai clinique phase I</term><term>Essai clinique phase II</term><term>Vecteur</term><term>Influenzavirus A(H5N1)</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Vaccin</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Background Modified vaccinia virus Ankara (MVA) is a promising viral vector platform for the development of an H5N1 influenza vaccine. Preclinical assessment of MVA-based H5N1 vaccines showed their immunogenicity and safety in different animal models. We aimed to assess the safety and immunogenicity of the MVA-haemagglutinin-based H5N1 vaccine MVA-H5-sfMR in healthy individuals. Methods In a single-centre, double-blind phase 1/2a study, young volunteers (aged 18-28 years) were randomly assigned with a computer-generated list in equal numbers to one of eight groups and were given one injection or two injections intramuscularly at an interval of 4 weeks of a standard dose (10<sup>8</sup> plaque forming units [pfu]) or a ten times lower dose (10<sup>7</sup> pfu) of the MVA-H5-sfMR (vector encoding the haemagglutinin gene of influenza A/Vietnam/1194/2004 virus [H5N1 subtype]) or MVA-F6-sfMR (empty vector) vaccine. Volunteers and physicians who examined and administered the vaccine were masked to vaccine assignment. Individuals who received the MVA-H5-sfMR vaccine were eligible for a booster immunisation 1 year after the first immunisation. Primary endpoint was safety. Secondary outcome was immunogenicity. The trial is registered with the Dutch Trial Register, number NTR3401. Findings 79 of 80 individuals who were enrolled completed the study. No serious adverse events were identified. 11 individuals reported severe headache and lightheadedness, erythema nodosum, respiratory illness (accompanied by influenza-like symptoms), sore throat, or injection-site reaction. Most of the volunteers had one or more local (itch, pain, redness, and swelling) and systemic reactions (rise in body temperature, headache, myalgia, arthralgia, chills, malaise, and fatigue) after the first, second, and booster immunisations. Individuals who received the 10<sup>7</sup> dose had fewer systemic reactions. The MVA-H5-sfMR vaccine at 10<sup>8</sup> pfu induced significantly higher antibody responses after one and two immunisations than did 10<sup>7</sup> pfu when assessed with haemagglutination inhibition geometric mean titre at 8 weeks against H5N1 A/Vietnam/1194/2004 (30.2 [SD 3.8] vs 9.2 [2.3] and 108.1 [2.4] vs 15.8 [3.2]). 27 of 39 eligible individuals were enrolled in the booster immunisation study. A single shot of MVA-H5-sfMR 10<sup>8</sup> pfu prime immunisation resulted in higher antibody responses after the booster immunisation than did two shots of MVA-H5-sfMR at the ten times lower dose. Interpretation The MVA-based H5N1 vaccine was well tolerated and immunogenic and therefore the vaccine candidates arising from the MVA platform hold great promise for rapid development in response to a future influenza pandemic threat. However, the immunogenicity of this vaccine needs to be compared with conventional H5N1 inactivated non-adjuvanted vaccine candidates in head-to-head clinical trials.</div></front></TEI><inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>1473-3099</s0></fA01><fA03 i2="1"><s0>Lancet. Infect. dis. : (print)</s0></fA03><fA05><s2>14</s2></fA05><fA06><s2>12</s2></fA06><fA08 i1="01" i2="1" l="ENG"><s1>Safety and immunogenicity of a modified-vaccinia-virus-Ankara-based influenza A H5N1 vaccine: a randomised, double-blind phase 1/2a clinical trial</s1></fA08><fA11 i1="01" i2="1"><s1>KREIJTZ (Joost H. C. M.)</s1></fA11><fA11 i1="02" i2="1"><s1>GOEIJENBIER (Marco)</s1></fA11><fA11 i1="03" i2="1"><s1>MOESKER (Fleur M.)</s1></fA11><fA11 i1="04" i2="1"><s1>VAN DEN DRIES (Lennert)</s1></fA11><fA11 i1="05" i2="1"><s1>GOEIJENBIER (Simone)</s1></fA11><fA11 i1="06" i2="1"><s1>DE GRUYTER (Heidi L. M.)</s1></fA11><fA11 i1="07" i2="1"><s1>LEHMANN (Michael H.)</s1></fA11><fA11 i1="08" i2="1"><s1>DE MUTSERT (Gerrie)</s1></fA11><fA11 i1="09" i2="1"><s1>VAN DE VIJVER (David A. M. C.)</s1></fA11><fA11 i1="10" i2="1"><s1>VOLZ (Asisa)</s1></fA11><fA11 i1="11" i2="1"><s1>FOUCHIER (Ron A. M.)</s1></fA11><fA11 i1="12" i2="1"><s1>VAN GORP (Eric C. M.)</s1></fA11><fA11 i1="13" i2="1"><s1>RIMMELZWAAN (Guus F.)</s1></fA11><fA11 i1="14" i2="1"><s1>SUTTER (Gerd)</s1></fA11><fA11 i1="15" i2="1"><s1>OSTERHAUS (Albert D. M. E.)</s1></fA11><fA14 i1="01"><s1>Viroscience Lab, Erasmus Medical Center</s1><s2>Rotterdam</s2><s3>NLD</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>15 aut.</sZ></fA14><fA14 i1="02"><s1>Institute for Infectious Diseases and Zoonoses, Ludwig Maximilian University of Munich</s1><s2>Munich</s2><s3>DEU</s3><sZ>7 aut.</sZ><sZ>10 aut.</sZ><sZ>14 aut.</sZ></fA14><fA14 i1="03"><s1>German Centre for Infection Research</s1><s2>Munich</s2><s3>DEU</s3><sZ>7 aut.</sZ><sZ>10 aut.</sZ><sZ>14 aut.</sZ></fA14><fA14 i1="04"><s1>Centerfor Infection Medicine and Zoonoses Research, University of Veterinary Medicine</s1><s2>Hannover</s2><s3>DEU</s3><sZ>15 aut.</sZ></fA14><fA20><s1>1196-1207</s1></fA20><fA21><s1>2014</s1></fA21><fA23 i1="01"><s0>ENG</s0></fA23><fA43 i1="01"><s1>INIST</s1><s2>27478</s2><s5>354000508296480160</s5></fA43><fA44><s0>0000</s0><s1>© 2015 INIST-CNRS. All rights reserved.</s1></fA44><fA45><s0>35 ref.</s0></fA45><fA47 i1="01" i2="1"><s0>15-0022824</s0></fA47><fA60><s1>P</s1></fA60><fA61><s0>A</s0></fA61><fA64 i1="01" i2="1"><s0>Lancet. Infectious diseases : (print)</s0></fA64><fA66 i1="01"><s0>GBR</s0></fA66><fC01 i1="01" l="ENG"><s0>Background Modified vaccinia virus Ankara (MVA) is a promising viral vector platform for the development of an H5N1 influenza vaccine. Preclinical assessment of MVA-based H5N1 vaccines showed their immunogenicity and safety in different animal models. We aimed to assess the safety and immunogenicity of the MVA-haemagglutinin-based H5N1 vaccine MVA-H5-sfMR in healthy individuals. Methods In a single-centre, double-blind phase 1/2a study, young volunteers (aged 18-28 years) were randomly assigned with a computer-generated list in equal numbers to one of eight groups and were given one injection or two injections intramuscularly at an interval of 4 weeks of a standard dose (10<sup>8</sup> plaque forming units [pfu]) or a ten times lower dose (10<sup>7</sup> pfu) of the MVA-H5-sfMR (vector encoding the haemagglutinin gene of influenza A/Vietnam/1194/2004 virus [H5N1 subtype]) or MVA-F6-sfMR (empty vector) vaccine. Volunteers and physicians who examined and administered the vaccine were masked to vaccine assignment. Individuals who received the MVA-H5-sfMR vaccine were eligible for a booster immunisation 1 year after the first immunisation. Primary endpoint was safety. Secondary outcome was immunogenicity. The trial is registered with the Dutch Trial Register, number NTR3401. Findings 79 of 80 individuals who were enrolled completed the study. No serious adverse events were identified. 11 individuals reported severe headache and lightheadedness, erythema nodosum, respiratory illness (accompanied by influenza-like symptoms), sore throat, or injection-site reaction. Most of the volunteers had one or more local (itch, pain, redness, and swelling) and systemic reactions (rise in body temperature, headache, myalgia, arthralgia, chills, malaise, and fatigue) after the first, second, and booster immunisations. Individuals who received the 10<sup>7</sup> dose had fewer systemic reactions. The MVA-H5-sfMR vaccine at 10<sup>8</sup> pfu induced significantly higher antibody responses after one and two immunisations than did 10<sup>7</sup> pfu when assessed with haemagglutination inhibition geometric mean titre at 8 weeks against H5N1 A/Vietnam/1194/2004 (30.2 [SD 3.8] vs 9.2 [2.3] and 108.1 [2.4] vs 15.8 [3.2]). 27 of 39 eligible individuals were enrolled in the booster immunisation study. A single shot of MVA-H5-sfMR 10<sup>8</sup> pfu prime immunisation resulted in higher antibody responses after the booster immunisation than did two shots of MVA-H5-sfMR at the ten times lower dose. Interpretation The MVA-based H5N1 vaccine was well tolerated and immunogenic and therefore the vaccine candidates arising from the MVA platform hold great promise for rapid development in response to a future influenza pandemic threat. However, the immunogenicity of this vaccine needs to be compared with conventional H5N1 inactivated non-adjuvanted vaccine candidates in head-to-head clinical trials.</s0></fC01><fC02 i1="01" i2="X"><s0>002B05C02C</s0></fC02><fC03 i1="01" i2="X" l="FRE"><s0>Grippe</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="ENG"><s0>Influenza</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="SPA"><s0>Gripe</s0><s5>01</s5></fC03><fC03 i1="02" i2="X" l="FRE"><s0>Immunoprophylaxie</s0><s5>04</s5></fC03><fC03 i1="02" i2="X" l="ENG"><s0>Immunoprophylaxis</s0><s5>04</s5></fC03><fC03 i1="02" i2="X" l="SPA"><s0>Inmunoprofilaxia</s0><s5>04</s5></fC03><fC03 i1="03" i2="X" l="FRE"><s0>Immunogénicité</s0><s5>07</s5></fC03><fC03 i1="03" i2="X" l="ENG"><s0>Immunogenicity</s0><s5>07</s5></fC03><fC03 i1="03" i2="X" l="SPA"><s0>Inmunogenicidad</s0><s5>07</s5></fC03><fC03 i1="04" i2="X" l="FRE"><s0>Vaccin</s0><s5>08</s5></fC03><fC03 i1="04" i2="X" l="ENG"><s0>Vaccine</s0><s5>08</s5></fC03><fC03 i1="04" i2="X" l="SPA"><s0>Vacuna</s0><s5>08</s5></fC03><fC03 i1="05" i2="X" l="FRE"><s0>Prévention</s0><s5>09</s5></fC03><fC03 i1="05" i2="X" l="ENG"><s0>Prevention</s0><s5>09</s5></fC03><fC03 i1="05" i2="X" l="SPA"><s0>Prevención</s0><s5>09</s5></fC03><fC03 i1="06" i2="X" l="FRE"><s0>Virus vaccine</s0><s2>NW</s2><s5>10</s5></fC03><fC03 i1="06" i2="X" l="ENG"><s0>Vaccinia virus</s0><s2>NW</s2><s5>10</s5></fC03><fC03 i1="06" i2="X" l="SPA"><s0>Vaccinia virus</s0><s2>NW</s2><s5>10</s5></fC03><fC03 i1="07" i2="X" l="FRE"><s0>Essai clinique</s0><s5>13</s5></fC03><fC03 i1="07" i2="X" l="ENG"><s0>Clinical trial</s0><s5>13</s5></fC03><fC03 i1="07" i2="X" l="SPA"><s0>Ensayo clínico</s0><s5>13</s5></fC03><fC03 i1="08" i2="X" l="FRE"><s0>Essai clinique phase I</s0><s5>14</s5></fC03><fC03 i1="08" i2="X" l="ENG"><s0>Phase I trial</s0><s5>14</s5></fC03><fC03 i1="08" i2="X" l="SPA"><s0>Ensayo clínico fase I</s0><s5>14</s5></fC03><fC03 i1="09" i2="X" l="FRE"><s0>Essai clinique phase II</s0><s5>15</s5></fC03><fC03 i1="09" i2="X" l="ENG"><s0>Phase II trial</s0><s5>15</s5></fC03><fC03 i1="09" i2="X" l="SPA"><s0>Ensayo clínico fase II</s0><s5>15</s5></fC03><fC03 i1="10" i2="X" l="FRE"><s0>Vecteur</s0><s5>16</s5></fC03><fC03 i1="10" i2="X" l="ENG"><s0>Vector</s0><s5>16</s5></fC03><fC03 i1="10" i2="X" l="SPA"><s0>Vector</s0><s5>16</s5></fC03><fC03 i1="11" i2="X" l="FRE"><s0>Influenzavirus A(H5N1)</s0><s4>CD</s4><s5>96</s5></fC03><fC03 i1="11" i2="X" l="ENG"><s0>Influenzavirus A(H5N1)</s0><s4>CD</s4><s5>96</s5></fC03><fC07 i1="01" i2="X" l="FRE"><s0>Virose</s0></fC07><fC07 i1="01" i2="X" l="ENG"><s0>Viral disease</s0></fC07><fC07 i1="01" i2="X" l="SPA"><s0>Virosis</s0></fC07><fC07 i1="02" i2="X" l="FRE"><s0>Infection</s0></fC07><fC07 i1="02" i2="X" l="ENG"><s0>Infection</s0></fC07><fC07 i1="02" i2="X" l="SPA"><s0>Infección</s0></fC07><fC07 i1="03" i2="X" l="FRE"><s0>Orthopoxvirus</s0><s2>NW</s2></fC07><fC07 i1="03" i2="X" l="ENG"><s0>Orthopoxvirus</s0><s2>NW</s2></fC07><fC07 i1="03" i2="X" l="SPA"><s0>Orthopoxvirus</s0><s2>NW</s2></fC07><fC07 i1="04" i2="X" l="FRE"><s0>Chordopoxvirinae</s0><s2>NW</s2></fC07><fC07 i1="04" i2="X" l="ENG"><s0>Chordopoxvirinae</s0><s2>NW</s2></fC07><fC07 i1="04" i2="X" l="SPA"><s0>Chordopoxvirinae</s0><s2>NW</s2></fC07><fC07 i1="05" i2="X" l="FRE"><s0>Poxviridae</s0><s2>NW</s2></fC07><fC07 i1="05" i2="X" l="ENG"><s0>Poxviridae</s0><s2>NW</s2></fC07><fC07 i1="05" i2="X" l="SPA"><s0>Poxviridae</s0><s2>NW</s2></fC07><fC07 i1="06" i2="X" l="FRE"><s0>Virus</s0><s2>NW</s2></fC07><fC07 i1="06" i2="X" l="ENG"><s0>Virus</s0><s2>NW</s2></fC07><fC07 i1="06" i2="X" l="SPA"><s0>Virus</s0><s2>NW</s2></fC07><fN21><s1>033</s1></fN21></pA></standard></inist></record>Pour manipuler ce document sous Unix (Dilib)
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