Ebola virus causes irregular outbreaks of severe hemorrhagic fever in equatorial Africa. Case mortality remains high; there is no effective treatment and outbreaks are sporadic and unpredictable. Studies of Ebola virus vaccine platforms in non-human primates have established that the induction of protective immunity is possible and safety and human immunogenicity has been demonstrated in a previous Phase I clinical trial of a 1st generation Ebola DNA vaccine. We now report the safety and immunogenicity of a recombinant adenovirus serotype 5 (rAd5) vaccine encoding the envelope glycoprotein (GP) from the Zaire and Sudan Ebola virus species, in a randomized, placebo-controlled, double-blinded, dose escalation, Phase I human study. Thirty-one healthy adults received vaccine at 2×10(9) (n=12), or 2×10(10) (n=11) viral particles or placebo (n=8) as an intramuscular injection. Antibody responses were assessed by ELISA and neutralizing assays; and T cell responses were assessed by ELISpot and intracellular cytokine staining assays. This recombinant Ebola virus vaccine was safe and subjects developed antigen specific humoral and cellular immune responses.
"Using Ad vectors derived from a variety of serotypes, families, or species showed consistently that they induced potent transgene productspecific B and CD8 + T cell responses. Several Ad vectors are in clinical trials as vaccine carriers for antigens of HIV-1 (Catanzaro et al., 2006; Baden et al., 2012), Mycobacterium tuberculosis (Hoft et al., 2012), hepatitis C virus (Barnes et al., 2012), Ebola virus (Ledgerwood et al., 2010), influenza virus (Gurwith et al., 2013), and Plasmodium falciparum (Sheehy et al., 2012). One Ad vaccine vector, based on a replication-competent E3-deleted Ad vector of human serotype 5 (HAdV-5) expressing the rabies virus glycoprotein for immunization of wildlife animals, has been licensed (Mainguy et al., 2013). "
[Show abstract][Hide abstract] ABSTRACT: Here we describe a series of replication-defective adenovirus vectors designed to express transgene products from two expression cassettes placed into the deleted E1- and E3-domains. Vectors that contained an E1-cassette with a CMV promoter in the forward orientation and an E3-cassette with the chicken β-actin promoter in the reverse orientation grew to acceptable yields and expressed both transgenes. Additionally, they elicited immune responses to both transgene products. Levels of expression and the vectors immunogenicity were influenced by the presence of regulatory elements shared between the two expression cassettes. Specifically, vectors that carried the same intron and enhancer in both expression cassettes could be rescued and expanded but they were poorly immunogenic. Deletion of the enhancer or both the enhancer and the intron from the E3 cassette increased T and B cell responses to both transgene products.
Human gene therapy 12/2013; 25(4). DOI:10.1089/hum.2013.216 · 3.76 Impact Factor
"Rates and types of adverse events are comparable to ongoing trials using human adenovirus 5 as a vector. In a recent phase 1 trial of a human adenovirus 5 expressing glycoprotein (GP) from the Ebola virus species where 11 subjects received 2 × 1010 vp of vaccine, 6 moderate or severe systemic adverse events were reported at this dose (6 of 29 total systemic adverse events) . In comparison, we report 1 moderate or severe systemic adverse event occurring post-ChAd63 ME-TRAP at 1 × 1010 vp (1 of 29 total systemic adverse events reported) making ChAd63 less reactogenic. "
[Show abstract][Hide abstract] ABSTRACT: Vaccine development in human Plasmodium falciparum malaria has been hampered by the exceptionally high levels of CD8(+) T cells required for efficacy. Use of potently immunogenic human adenoviruses as vaccine vectors could overcome this problem, but these are limited by preexisting immunity to human adenoviruses.
From 2007 to 2010, we undertook a phase I dose and route finding study of a new malaria vaccine, a replication-incompetent chimpanzee adenovirus 63 (ChAd63) encoding the preerythrocytic insert multiple epitope thrombospondin-related adhesion protein (ME-TRAP; n = 54 vaccinees) administered alone (n = 28) or with a modified vaccinia virus Ankara (MVA) ME-TRAP booster immunization 8 weeks later (n = 26). We observed an excellent safety profile. High levels of TRAP antigen-specific CD8(+) and CD4(+) T cells, as detected by interferon γ enzyme-linked immunospot assay and flow cytometry, were induced by intramuscular ChAd63 ME-TRAP immunization at doses of 5 × 10(10) viral particles and above. Subsequent administration of MVA ME-TRAP boosted responses to exceptionally high levels, and responses were maintained for up to 30 months postvaccination.
The ChAd63 chimpanzee adenovirus vector appears safe and highly immunogenic, providing a viable alternative to human adenoviruses as vaccine vectors for human use.
The Journal of Infectious Diseases 03/2012; 205(5):772-81. DOI:10.1093/infdis/jir850 · 6.00 Impact Factor
"Studies have also demonstrated a less important role for CD4 + T cells in protection by filovirus vaccines  and, unfortunately, the role of CD4 + T cells was not assessed in the aforementioned mechanistic studies in nonhuman primates by Sullivan et al.  Existing efforts are focused on the identification of CD4 + T cell responses and their role in EBOV and MARV infection, especially given their dominance in responses in vaccinated humans   "
[Show abstract][Hide abstract] ABSTRACT: Infection with many emerging viruses, such as the hemorrhagic fever disease caused by the filoviruses, Marburg (MARV), and Ebola virus (EBOV), leaves the host with a short timeframe in which to mouse a protective immune response. In lethal cases, uncontrolled viral replication and virus-induced immune dysregulation are too severe to overcome, and mortality is generally associated with a lack of notable immune responses. Vaccination studies in animals have demonstrated an association of IgG and neutralizing antibody responses against the protective glycoprotein antigen with survival from lethal challenge. More recently, studies in animal models of filovirus hemorrhagic fever have established that induction of a strong filovirus-specific cytotoxic T lymphocyte (CTL) response can facilitate complete viral clearance. In this review, we describe assays used to discover CTL responses after vaccination or live filovirus infection in both animal models and human clinical trials. Unfortunately, little data regarding CTL responses have been collected from infected human survivors, primarily due to the low frequency of disease and the inability to perform these studies in the field. Advancements in assays and technologies may allow these studies to occur during future outbreaks.
BioMed Research International 12/2011; 2011:984241. DOI:10.1155/2011/984241 · 2.71 Impact Factor
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