A replication defective recombinant Ad5 vaccine expressing Ebola virus GP is safe and immunogenic in healthy adults
ABSTRACT 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.
- SourceAvailable from: Raj Kurupati
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- "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). "
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; DOI:10.1089/hum.2013.216 · 3.62 Impact Factor
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- "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   "
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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ABSTRACT: Recent case reports of viral hemorrhagic fever in Europe and the United States have raised concerns about the possibility for increased importation of filoviruses to non-endemic areas. This emerging threat is concerning because of the increase in global air travel and the rise of tourism in central and eastern Africa and the greater dispersion of military troops to areas of infectious disease outbreaks. Marburg viruses (MARV) and Ebola viruses (EBOV) have been associated with outbreaks of severe hemorrhagic fever involving high mortality (25-90% case fatality rates). First recognized in 1967 and 1976 respectively, subtypes of MARV and EBOV are the only known viruses of the Filoviridae family, and are among the world's most virulent pathogens. This article focuses on information relevant for health care practitioners in travel medicine to include, the epidemiology and clinical features of filovirus infection and efforts toward development of a filovirus vaccine.Travel Medicine and Infectious Disease 06/2010; 9(3):126-34. DOI:10.1016/j.tmaid.2010.05.003 · 1.54 Impact Factor