Phase I clinical trial in healthy adults of a nasal vaccine candidate containing recombinant hepatitis B surface and core antigens.
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.
Betancourt
Arístides Aguilar
AA
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
Delgado
C A González
CA
Estévez
Z Cinza
ZC
Martínez
J Cabrera
JC
Ríos
G Véliz
GV
Aureoles-Roselló
S R Moreno
SR
Zaldívar
R Alemán
RA
Guzmán
M Alonso
MA
Baile
N Figueroa
NF
Reyes
P A Días
PA
Ruano
L Olivera
LO
Fernández
A Correa
AC
Lobaina-Matos
Y
Y
Fernández
A Delahanty
AD
Madrazo
A I Juvier
AI
Martínez
M I Alonso
MI
Baños
M Lago
ML
Alvarez
N Puble
NP
Baldo
M David
MD
Mestre
R E Soto
RE
Pérez
M V Pérez
MV
Martínez
M E Peña
ME
Escobar
D Acosta
DA
Guanche
M J Cerna
MJ
Cáceres
L Mila
LM
Betancourt
R Sánchez
RS
Rando
E Hardy
EH
Nieto
G E Guillén
GE
González
V L Muzio
VL
Rubido
J C Aguilar
JC
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
D006510:Hepatitis B Antibodies; D006512:Hepatitis B Core Antigens; D006514:Hepatitis B Surface Antigens; D017325:Hepatitis B Vaccines; D017778:Vaccines, Combined; D014614:Vaccines, Synthetic