Short-term antiviral therapy with the nucleoside analogue entecavir (ETV), given at an early stage of duck hepatitis B virus (DHBV) infection, restricts virus spread and leads to clearance of DHBV-infected hepatocytes in approximately 50% of ETV-treated ducks, whereas widespread and persistent DHBV infection develops in 100% of untreated ducks. To increase the treatment response rate, ETV treatment was combined in the current study with a post-exposure "prime-boost" vaccination protocol. Four groups of 14-day-old ducks were inoculated intravenously with a dose of DHBV previously shown to induce persistent DHBV infection. One hour post-infection (p.i.), ducks were primed with DNA vaccines that expressed DHBV core (DHBc) and surface (pre-S/S and S) antigens (Groups A, B) or the DNA vector alone (Groups C, D). ETV (Groups A, C) or water (Groups B, D) was simultaneously administered by gavage and continued for 14 days. Ducks were boosted 7 days p.i. with recombinant fowlpoxvirus (rFPV) strains also expressing DHBc and pre-S/S antigens (Groups A, B) or the FPV-M3 vector (Groups C, D). DHBV-infected hepatocytes were observed in the liver of all ducks at day 4 p.i. with reduced numbers in the ETV-treated ducks. Ducks treated with ETV plus the control vectors showed restricted spread of DHBV infection during ETV treatment...
Hepatitis B virus (HBV) is a life-threatening pathogen with major economic significance. Acute infection in adults is common, albeit usually self-limiting. Importantly, infection in infants typically results in chronic infection and increased incidence of hepatocellular carcinoma (HCC). Furthermore, the infectious carrier state is perpetuated in chronically infected individuals. Successful immuno-therapeutic vaccination would reduce the incidence of chronic infection and of HCC as well as reduce transmission of the disease.
Recovery from acute and chronic HBV infection typically occurs in the presence of robust antigen-specific humoral and cellular immune responses (CMI), whereas these responses are low or absent in chronically HBV-infected individuals. Therefore, it was hypothesised that effective stimulation of both humoral and CMI responses, in conjunction with currently available antiviral therapies, may contribute significantly to development of vaccines for treatment of chronic HBV infection.
The duck hepatitis B virus (DHBV) model of HBV infection was used to test novel vaccine strategies that could complement existing antiviral therapeutic approaches to treat chronically HBV-infected humans. To this end, three separate vaccine studies were conducted to investigate potential therapeutic regimes.
Methods to assess the efficacies of the vaccine strategies included immunoperoxidase detection of viral antigen and immune cell markers within the liver and development of sensitive assays to monitor levels of DHBV DNA...
We recently reported the development of a successful post-exposure combination antiviral and “prime-boost” vaccination strategy using the duck hepatitis B virus (DHBV) model of human hepatitis B virus infection. The current study aimed to simplify the vaccination strategy and to test the post-exposure efficacy of combination therapy with the Bristol-Myers Squibb antiviral drug, entecavir (ETV) and either a single dose of DHBV DNA vaccines on day 0 post-infection (p.i.) or a single dose of recombinant fowlpoxvirus (rFPV–DHBV) vaccines on day 7 p.i. Whilst untreated control ducks infected with an equal dose of DHBV all developed persistent and wide spread DHBV infection of the liver, ducks treated with ETV combined with either the DHBV DNA vaccines on day 0 p.i. or the rFPV–DHBV vaccines on day 7 p.i. had no detectable DHBV-infected hepatocytes by day 14 p.i. and were protected from the development of persistent DHBV infection.; Feng Feng, Chee Quin Teoh, Qiao Qiao, David Boyle and Allison R. Jilbert
Dale, C Jane; De Rose, Robert; Wilson, Kim M; Croom, H; Thomson, Scott; Coupar, Barbara E H; Ramsay, Alistair; Purcell, Damian F J; Ffrench, Rosemary A; Law, Matthew G; Emery, Sean; Cooper, Desmond Wishart; Ramshaw, Ian; Boyle, David B; Kent, Stephen J
Fonte: ElsevierPublicador: Elsevier
Tipo: Artigo de Revista Científica
Relevância na Pesquisa
Induction of HIV-specific T-cell responses by vaccines may facilitate efficient control of HIV. Plasmid DNA vaccines and recombinant fowlpoxvirus (rFPV) vaccines are promising HIV-1 vaccine candidates, although either vaccine alone may be insufficient to
Kent, Stephen J; Dale, C Jane; Ranasinghe, Charani; Stratov, Ivan; De Rose, Robert; Chea, Socheata; Montefiori, David C; Thomson, Scott; Ramshaw, Ian; Coupar, Barbara E H; Boyle, David B; Law, Matthew G; Wilson, Kim M; Ramsay, Alistair
Further advances are required in understanding protection from AIDS by T cell immunity across mucosal sites of virus transmission. We analysed a set of multigenic HIV and SHIV DNA and Fowlpoxvirus (FPV) prime and boost vaccines for immunogenicity and protective efficacy in outbred pigtail macaques when delivered via mucosal surfaces (intranasally or intrarectally). Intranasally delivered DNA, even when adjuvanted and given as a fine droplet spray, was neither immunogenic nor protective in macaques. Some protection from acute infection with a pathogenic vaginal SHIVSF162P3 challenge was, however, observed with a regimen involving intramuscular DNA vaccine priming followed by either intranasally or intrarectally delivered rFPV boosting. Interestingly, animals boosted with rFPV vaccine via either of these mucosal routes had poor circulating T cell responses prior to challenge with SHIV compared to those boosted via the intramuscular route. Nevertheless, the mucosally-vaccinated animals generated equivalent anamnestic mucosal and systemic SHIV-specific CD4 and CD8 T cell responses following SHIV administration, with significant reduction in acute plasma viremia against this vaginal challenge. Our data suggest strategies for effective priming of partial immunity to mucosal HIV-1 exposure utilizing systemic prime and mucosal boost vaccination strategies.
Preventive and/or therapeutic vaccines against Human Immunodeficiency Virus (HIV-1) are urgently required. Induction of cellular immunity is favoured since these responses correlate with control of HIV-1. Recombinant fowlpoxvirus (FPV) vaccines encoding both HIV-1 gag/pol and interferon-gamma (FPV gag/pol-IFNγ) were hypothesised to enhance HIV-specific cellular immunity and were further evaluated in macaques previously infected with HIV-1. A novel assay to detect IFNγ secretion following HIV antigen stimulation of whole blood was developed to further assess the safety and immunogenicity of the FPV gag/pol-IFNγ vaccine. Immunisation with FPV gag/pol-IFNγ safely enhanced HIV-specific IFNγ secretion following ex vivo stimulation of whole blood, greater than that observed following FPV gag/pol vaccination not co-expressing IFNγ. Both HIV-specific IFNγ-spot-forming cells by ELISPOT and CD69 expression by CD4+ lymphocytes were also enhanced following FPV gag/pol-IFNγ vaccination. Hence, the FPV-HIV vaccine co-expressing IFNγ stimulated HIV-specific T cell responses in macaques, and should be further evaluated as a therapeutic or preventive HIV vaccine. (C) Munksgaard, Copenhagen.
In this article, we describe several novel genetic vaccination strategies designed to facilitate the development of different types of immune responses. These include: i) the consecutive use of DNA and fowlpoxvirus vectors in 'prime-boost' strategies which induce greatly enhanced and sustained levels of both cell-mediated immunity and humoral immunity, including mucosal responses; ii) the co-expression of genes encoding cytokines and cell-surface receptors, and the use of immunogenic carrier molecules, for immune modulation and/or improved targeting of vector-expressed vaccine antigens; and iii) the expression of minimal immunogenic amino acid sequences, particularly cytotoxic CD8+ T-cell determinants, in 'polytope' vector vaccines. The capacity to modulate and enhance specific immune responses by the use of approaches such as these may underpin the development of vaccines against diseases for which no effective strategies are currently available.
De Rose, Robert; Chea, Socheata; Dale, C Jane; Reece, Jeanette; Fernandez, Caroline S; Wilson, Kim M; Thomson, Scott; Ramshaw, Ian; Coupar, Barbara E H; Boyle, David B; Sullivan, Mark T; Kent, Stephen J
To induce broad T cell immunity to HIV-1, we evaluated the safety, immunogenicity and dose-response relationship of DNA and recombinant Fowlpoxvirus (rFPV) vaccines encoding five shared HIV subtype AE genes (Gag, Pol, Env, Tat, Rev) in pigtail macaques. The DNA (three doses of either 1 mg or 4.5 mg) and rFPV (a single boost of either 5 × 107 or 2 × 108 plaque forming units) vaccines were administered intramuscularly without adjuvants. Broadly reactive HIV-specific T cell immunity was stimulated by all doses of the vaccines administered, without significant differences between the high and low doses studied. The vaccines induced both CD4 and CD8 T cell responses to Gag, Pol, Env and Tat/Rev proteins, with CD4 T cell responses being greater in magnitude than CD8 T cell responses. The vaccine-induced T cell responses had significant cross-recognition of heterologous HIV-1 proteins from non-AE HIV-1 subtypes. In conclusion, these subtype AE HIV-1 DNA and rFPV vaccines were safe, induced broad T-cell immunity in macaques, and are suitable for progression into clinical trials.