title: Safety and immunogenicity of a modified-vaccinia-virus-Ankara-based influenza A H5N1 vaccine: a randomised, double-blind phase 1/2a clinical trial.
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 (10(8) plaque forming units [pfu]) or a ten times lower dose (10(7) 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.
  
  
  RESULTS
  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(7) dose had fewer systemic reactions. The MVA-H5-sfMR vaccine at 10(8) pfu induced significantly higher antibody responses after one and two immunisations than did 10(7) 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(8) 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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  European Research Council.
authors.affiliation: Viroscience Lab, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: Joost H C M
authors.initials: JH
authors.lastname: Kreijtz
authors.affiliation: Viroscience Lab, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: Marco
authors.initials: M
authors.lastname: Goeijenbier
authors.affiliation: Viroscience Lab, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: Fleur M
authors.initials: FM
authors.lastname: Moesker
authors.affiliation: Viroscience Lab, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: Lennert
authors.initials: L
authors.lastname: van den Dries
authors.affiliation: Viroscience Lab, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: Simone
authors.initials: S
authors.lastname: Goeijenbier
authors.affiliation: Viroscience Lab, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: Heidi L M
authors.initials: HL
authors.lastname: De Gruyter
authors.affiliation: Institute for Infectious Diseases and Zoonoses, Ludwig Maximilian University of Munich, Munich, Germany; German Centre for Infection Research, Munich, Germany.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Lehmann
authors.affiliation: Viroscience Lab, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: Gerrie de
authors.initials: Gd
authors.lastname: Mutsert
authors.affiliation: Viroscience Lab, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: David A M C
authors.initials: DA
authors.lastname: van de Vijver
authors.affiliation: Institute for Infectious Diseases and Zoonoses, Ludwig Maximilian University of Munich, Munich, Germany; German Centre for Infection Research, Munich, Germany.
authors.forename: Asisa
authors.initials: A
authors.lastname: Volz
authors.affiliation: Viroscience Lab, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: Ron A M
authors.initials: RA
authors.lastname: Fouchier
authors.affiliation: Viroscience Lab, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: Eric C M
authors.initials: EC
authors.lastname: van Gorp
authors.affiliation: Viroscience Lab, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: Guus F
authors.initials: GF
authors.lastname: Rimmelzwaan
authors.affiliation: Institute for Infectious Diseases and Zoonoses, Ludwig Maximilian University of Munich, Munich, Germany; German Centre for Infection Research, Munich, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Sutter
authors.affiliation: Viroscience Lab, Erasmus Medical Center, Rotterdam, Netherlands; Artemis, Utrecht, Netherlands; Center for Infection Medicine and Zoonoses Research, University of Veterinary Medicine, Hannover, Germany. Electronic address: a.osterhaus@erasmusmc.nl.
authors.forename: Albert D M E
authors.initials: AD
authors.lastname: Osterhaus
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D004311:Double-Blind Method; D004337:Drug Carriers; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D005260:Female; D005822:Genetic Vectors; D064368:Healthy Volunteers; D006385:Hemagglutination Inhibition Tests; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000276:immunology*; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics / Q000276:immunology*; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000235:genetics / Q000276:immunology*; D007273:Injections, Intramuscular; D008297:Male; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics*; D055815:Young Adult
chemical_list: D000914:Antibodies, Viral; D004337:Drug Carriers; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; D014614:Vaccines, Synthetic; C109963:hemagglutinin, avian influenza A virus