RESUMEN
Highly-active antiretroviral therapy (HAART) suppresses HIV viral replication and restores immune function in HIV-infected individuals, but HIV-1 can still persist in circulating, resting CD4+ T-cells. Recent studies demonstrate that adjunct immunotherapeutic strategies that enhance T-cell responses during HAART can, in certain cases, promote continued immune control of the AIDS virus after drugs are discontinued. However, development of immunotherapeutic strategies that target and eliminate the reservoir of HIV-1 infected, quiescent T-cells will likely be needed to achieve long-term control and eradication of the AIDS virus.
Asunto(s)
Terapia Antirretroviral Altamente Activa , Infecciones por VIH/terapia , VIH-1 , Inmunoterapia , Animales , Terapia Combinada , Infecciones por VIH/tratamiento farmacológico , Humanos , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Replicación ViralRESUMEN
A DNA vaccine against the hepatitis B virus (HBV) was evaluated for safety and induction of immune responses in 12 healthy, hepatitis-naïve human volunteers using the needle-free PowderJect system to deliver gold particles coated with DNA directly into cells of the skin. Three groups of four volunteers received three administrations of DNA encoding the surface antigen of HBV at one of the three dose levels (1, 2, or 4 microg). The vaccine was safe and well tolerated, causing only transient and mild to moderate responses at the site of administration. HBV-specific antibody and both CD4+ and CD8+ T cell responses were measured before and after each immunization. All the volunteers developed protective antibody responses of at least 10 mIU/ml. In volunteers who were positive for the HLA class I A2 allele, the vaccine also induced antigen-specific CD8+ T cells that bound HLA-A2/HBsAg(335-343) tetramers, secreted IFN-gamma, and lysed target cells presenting a hepatitis B surface antigen (HBsAg) CTL epitope. Enumeration of HBsAg-specific T cells producing cytokine indicated preferential induction of a Type 1 T helper cell response. These results provide the first demonstration of a DNA vaccine inducing protective antibody titers and both humoral and cell-mediated immune responses in humans.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Anticuerpos contra la Hepatitis B/biosíntesis , Vacunas contra Hepatitis B/administración & dosificación , Linfocitos T Colaboradores-Inductores/inmunología , Vacunas de ADN/administración & dosificación , Adulto , Biolística , Femenino , Oro , Hepatitis B/inmunología , Hepatitis B/prevención & control , Antígenos de Superficie de la Hepatitis B/inmunología , Vacunas contra Hepatitis B/efectos adversos , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/inmunología , Humanos , Masculino , Persona de Mediana Edad , Tamaño de la Partícula , Plásmidos/genética , Seguridad , Vacunas de ADN/efectos adversosRESUMEN
We are developing a DNA vaccine toward hepatitis-B virus (HBV) using PowderJect's proprietary needle-free technology to deliver DNA-coated gold particles directly into cells of the skin. Preclinical studies in animals showed that (i) microgram doses of the DNA vaccine were sufficient to immunize pigs and non-human primates to antibody levels comparable to those obtained with a commercial recombinant subunit vaccine; (ii) the DNA vaccine was effective in mouse strains that respond poorly to protein subunit vaccines; (iii) the vaccine induces robust cytotoxic T-cell responses, and (iv) the vaccine is non-toxic and well tolerated. Based on these findings, this DNA vaccine was evaluated for safety, tolerability, and the induction of immune responses in phase 1 clinical studies in healthy, hepatitis-naïve human volunteers. Preliminary results indicate that the vaccine is safe and well tolerated, and elicits both humoral and cellular immune responses in man.