title: Phase I clinical trial in healthy adults of a nasal vaccine candidate containing recombinant hepatitis B surface and core antigens.
abstract: BACKGROUND
  The nasal vaccine candidate (NASVAC), comprising hepatitis B virus (HBV) surface (HBsAg) and core antigens (HBcAg), has been shown to be highly immunogenic in animal models.
  
  
  METHODS
  A phase I double-blinded, placebo-controlled randomized clinical trial was carried out in 19 healthy male adults with no serologic markers of immunity/infection to HBV. This study was aimed at exploring the safety and immunogenic profile of nasal co-administration of both HBV recombinant antigens. The trial was performed according to Good Clinical Practice guidelines. Participants ranged in age from 18 to 45 years and were randomly allocated to receive a mixture of 50 microg HBsAg and 50 microg HBcAg or 0.9% physiologic saline solution, as a placebo, via nasal spray in a five-dose schedule at 0, 7, 15, 30, and 60 days. A total volume of 0.5 ml was administered in two dosages of 125 microl per nostril. Adverse events were actively recorded 1 h, 6 h, 12 h, 24 h, 48 h, 72 h, 7 days and 30 days after each dose. Anti-HBs and anti-HBc titers were evaluated using corresponding ELISA kits at days 30 and 90.
  
  
  RESULTS
  The vaccine candidate was safe and well tolerated. Adverse reactions included sneezing (34.1%), rhinorrhea (12.2%), nasal stuffiness (9.8%), palate itching (9.8%), headache (9.8%), and general malaise (7.3%). These reactions were all self-limiting and mild in intensity. No severe or unexpected events were recorded during the trial. The vaccine elicited anti-HBc seroconversion in 100% of subjects as early as day 30 of the immunization schedule, while a seroprotective anti-HBs titer (>or=10 IU/l) was at a maximum at day 90 (75%). All subjects in the placebo group remained seronegative during the trial.
  
  
  CONCLUSIONS
  The HBsAg-HBcAg vaccine candidate was safe, well tolerated and immunogenic in this phase I study in healthy adults. To our knowledge, this is the first demonstration of safety and immunogenicity for a nasal vaccine candidate comprising HBV antigens.
authors.affiliation: Vaccine Division, Vaccine Clinical Trials Department, Center for Genetic Engineering and Biotechnology, PO Box 6162, Cubanacán, Playa, Havana City, Cuba. aristides.aguilar@cigb.edu.cu
authors.forename: Arístides Aguilar
authors.initials: AA
authors.lastname: Betancourt
authors.forename: C A González
authors.initials: CA
authors.lastname: Delgado
authors.forename: Z Cinza
authors.initials: ZC
authors.lastname: Estévez
authors.forename: J Cabrera
authors.initials: JC
authors.lastname: Martínez
authors.forename: G Véliz
authors.initials: GV
authors.lastname: Ríos
authors.forename: S R Moreno
authors.initials: SR
authors.lastname: Aureoles-Roselló
authors.forename: R Alemán
authors.initials: RA
authors.lastname: Zaldívar
authors.forename: M Alonso
authors.initials: MA
authors.lastname: Guzmán
authors.forename: N Figueroa
authors.initials: NF
authors.lastname: Baile
authors.forename: P A Días
authors.initials: PA
authors.lastname: Reyes
authors.forename: L Olivera
authors.initials: LO
authors.lastname: Ruano
authors.forename: A Correa
authors.initials: AC
authors.lastname: Fernández
authors.forename: Y
authors.initials: Y
authors.lastname: Lobaina-Matos
authors.forename: A Delahanty
authors.initials: AD
authors.lastname: Fernández
authors.forename: A I Juvier
authors.initials: AI
authors.lastname: Madrazo
authors.forename: M I Alonso
authors.initials: MI
authors.lastname: Martínez
authors.forename: M Lago
authors.initials: ML
authors.lastname: Baños
authors.forename: N Puble
authors.initials: NP
authors.lastname: Alvarez
authors.forename: M David
authors.initials: MD
authors.lastname: Baldo
authors.forename: R E Soto
authors.initials: RE
authors.lastname: Mestre
authors.forename: M V Pérez
authors.initials: MV
authors.lastname: Pérez
authors.forename: M E Peña
authors.initials: ME
authors.lastname: Martínez
authors.forename: D Acosta
authors.initials: DA
authors.lastname: Escobar
authors.forename: M J Cerna
authors.initials: MJ
authors.lastname: Guanche
authors.forename: L Mila
authors.initials: LM
authors.lastname: Cáceres
authors.forename: R Sánchez
authors.initials: RS
authors.lastname: Betancourt
authors.forename: E Hardy
authors.initials: EH
authors.lastname: Rando
authors.forename: G E Guillén
authors.initials: GE
authors.lastname: Nieto
authors.forename: V L Muzio
authors.initials: VL
authors.lastname: González
authors.forename: J C Aguilar
authors.initials: JC
authors.lastname: Rubido
mesh_terms: D000281:Administration, Intranasal; D000293:Adolescent; D000328:Adult; D004311:Double-Blind Method; D006509:Hepatitis B / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D006510:Hepatitis B Antibodies / Q000276:immunology; D006512:Hepatitis B Core Antigens / Q000235:genetics / Q000276:immunology*; D006514:Hepatitis B Surface Antigens / Q000235:genetics / Q000276:immunology*; D017325:Hepatitis B Vaccines / Q000008:administration & dosage* / Q000009:adverse effects; D006515:Hepatitis B virus / Q000235:genetics / Q000276:immunology*; D006801:Humans; D018928:Immunity, Mucosal / Q000276:immunology; D008297:Male; D008875:Middle Aged; D017778:Vaccines, Combined / Q000008:administration & dosage / Q000009:adverse effects; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D006510:Hepatitis B Antibodies; D006512:Hepatitis B Core Antigens; D006514:Hepatitis B Surface Antigens; D017325:Hepatitis B Vaccines; D017778:Vaccines, Combined; D014614:Vaccines, Synthetic