title: Safety and tolerability of conserved region vaccines vectored by plasmid DNA, simian adenovirus and modified vaccinia virus ankara administered to human immunodeficiency virus type 1-uninfected adults in a randomized, single-blind phase I trial.
abstract: METHODS
  HIV-1 vaccine development has advanced slowly due to viral antigenic diversity, poor immunogenicity and recently, safety concerns associated with human adenovirus serotype-5 vectors. To tackle HIV-1 variation, we designed a unique T-cell immunogen HIVconsv from functionally conserved regions of the HIV-1 proteome, which were presented to the immune system using a heterologous prime-boost combination of plasmid DNA, a non-replicating simian (chimpanzee) adenovirus ChAdV-63 and a non-replicating poxvirus, modified vaccinia virus Ankara. A block-randomized, single-blind, placebo-controlled phase I trial HIV-CORE 002 administered for the first time candidate HIV-1- vaccines or placebo to 32 healthy HIV-1/2-uninfected adults in Oxford, UK and elicited high frequencies of HIV-1-specific T cells capable of inhibiting HIV-1 replication in vitro. Here, detail safety and tolerability of these vaccines are reported.
  
  
  METHODS
  Local and systemic reactogenicity data were collected using structured interviews and study-specific diary cards. Data on all other adverse events were collected using open questions. Serum neutralizing antibody titres to ChAdV-63 were determined before and after vaccination.
  
  
  RESULTS
  Two volunteers withdrew for vaccine-unrelated reasons. No vaccine-related serious adverse events or reactions occurred during 190 person-months of follow-up. Local and systemic events after vaccination occurred in 27/32 individuals and most were mild (severity grade 1) and predominantly transient (<48 hours). Myalgia and flu-like symptoms were more strongly associated with MVA than ChAdV63 or DNA vectors and more common in vaccine recipients than in placebo. There were no intercurrent HIV-1 infections during follow-up. 2/24 volunteers had low ChAdV-63-neutralizing titres at baseline and 7 increased their titres to over 200 with a median (range) of 633 (231-1533) post-vaccination, which is of no safety concern.
  
  
  CONCLUSIONS
  These data demonstrate safety and good tolerability of the pSG2.HIVconsv DNA, ChAdV63.HIVconsv and MVA.HIVconsv vaccines and together with their high immunogenicity support their further development towards efficacy studies.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01151319.
authors.affiliation: Centre for Clinical Vaccinology and Tropical Medicine, The Jenner Institute, University of Oxford, Churchill Hospital, Oxford, United Kingdom.
authors.forename: Emma-Jo
authors.initials: EJ
authors.lastname: Hayton
authors.affiliation: Centre for Clinical Vaccinology and Tropical Medicine, The Jenner Institute, University of Oxford, Churchill Hospital, Oxford, United Kingdom.
authors.forename: Annie
authors.initials: A
authors.lastname: Rose
authors.affiliation: Centre for Clinical Vaccinology and Tropical Medicine, The Jenner Institute, University of Oxford, Churchill Hospital, Oxford, United Kingdom.
authors.forename: Umar
authors.initials: U
authors.lastname: Ibrahimsa
authors.affiliation: Okairos, Rome, Italy.
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Del Sorbo
authors.affiliation: Okairos, Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Capone
authors.affiliation: Centre for Clinical Vaccinology and Tropical Medicine, The Jenner Institute, University of Oxford, Churchill Hospital, Oxford, United Kingdom.
authors.forename: Alison
authors.initials: A
authors.lastname: Crook
authors.affiliation: Centre for Clinical Vaccinology and Tropical Medicine, The Jenner Institute, University of Oxford, Churchill Hospital, Oxford, United Kingdom.
authors.forename: Antony P
authors.initials: AP
authors.lastname: Black
authors.affiliation: Centre for Clinical Vaccinology and Tropical Medicine, The Jenner Institute, University of Oxford, Churchill Hospital, Oxford, United Kingdom; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, The John Radcliffe, Oxford, United Kingdom; Nuffield Department of Medicine Research Building, University of Oxford, Oxford, United Kingdom; The Jenner Institute Laboratories, University of Oxford, Old Road Campus Research Building, Oxford, United Kingdom.
authors.forename: Lucy
authors.initials: L
authors.lastname: Dorrell
authors.affiliation: Centre for Clinical Vaccinology and Tropical Medicine, The Jenner Institute, University of Oxford, Churchill Hospital, Oxford, United Kingdom; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, The John Radcliffe, Oxford, United Kingdom; The Jenner Institute Laboratories, University of Oxford, Old Road Campus Research Building, Oxford, United Kingdom.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Hanke
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000261:Adenoviruses, Simian / Q000235:genetics / Q000276:immunology*; D000293:Adolescent; D000328:Adult; D057134:Antibodies, Neutralizing / Q000097:blood; D017124:Conserved Sequence; D005260:Female; D005822:Genetic Vectors; D057809:HEK293 Cells; D015483:HIV Antibodies / Q000097:blood; D015658:HIV Infections / Q000517:prevention & control*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010957:Plasmids / Q000235:genetics; D016037:Single-Blind Method; D014614:Vaccines, Synthetic / Q000235:genetics / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology*; D014779:Virus Replication; D055815:Young Adult
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D054298:Human Immunodeficiency Virus Proteins; D014614:Vaccines, Synthetic