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Quantitative and qualitative analyses of the immune responses induced by a multivalent minigene DNA vaccine

Academic Article
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Overview

authors

  • An, L. L.
  • Rodriguez, F.
  • Harkins, S.
  • Zhang, J.
  • Whitton, J. Lindsay

publication date

  • April 2000

journal

  • Vaccine  Journal

abstract

  • Vaccines containing minigenes - isolated antigenic epitopes encoded by short open reading frames - can, under certain circumstances, confer protective immunity upon the vaccinee. Here we evaluate the efficacy of the minigene vaccine approach using DNA immunization and find that, to be immunogenic, a minigene-encoded epitope requires a perfect "Kozak" translational initiation region. In addition, using intracellular cytokine staining, we show that immunization with a plasmid encoding a full-length protein induces epitope-specific CD8(+) T cells which are detectable directly ex vivo, and constitute approximately 2% of the vaccinee's splenic CD8(+) T cells. In contrast, such cells are undetectable directly ex vivo in recipients of a minigene vaccine. Nevertheless, the minigene plasmid does induce a low number of epitope-specific CD8(+) T cells, which can be amplified to detectable levels by in vivo stimulation. Indeed, 4 days after in vivo stimulation (by virus infection), all vaccinated mice - regardless of whether they had been vaccinated with the minigene or with the full-length gene - had similar numbers of epitope-specific CD8(+) T cells. However, despite these strong responses at 4 days post-infection, recipients of the minigene vaccine showed no enhanced ability to limit virus replication and dissemination. We therefore observe a dichotomy; minigene vaccinees are not protected, despite the presence of strong virus-specific immune responses at 4 days post-challenge. We suggest that the protective benefits of vaccination exert themselves very soon - perhaps within minutes or hours - after virus challenge. If the vaccine-induced immune response is too low to achieve this early protective effect, virus-specific T cells will expand rapidly, but ineffectually, leading to the strong but non-protective response measured at 4 days post-infection. Thus, vaccine-induced immunity should be monitored very early in infection, since the extent to which these responses may later be amplified is largely irrelevant to the protection observed.

subject areas

  • Amino Acid Sequence
  • Animals
  • Antibodies, Viral
  • Antigens, Viral
  • Base Sequence
  • CD8-Positive T-Lymphocytes
  • Codon
  • Cytokines
  • Epitopes
  • Genes, Synthetic
  • Immunity, Cellular
  • Lymphocyte Count
  • Lymphocytic choriomeningitis virus
  • Mengovirus
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Open Reading Frames
  • Plasmids
  • Regulatory Sequences, Nucleic Acid
  • Respiratory Syncytial Viruses
  • Respirovirus
  • Spleen
  • Time Factors
  • Vaccination
  • Vaccines, DNA
  • Vesicular stomatitis Indiana virus
  • Viral Vaccines
  • Virus Replication
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Research

keywords

  • CTL
  • DNA immunization
  • minigene
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Identity

International Standard Serial Number (ISSN)

  • 0264-410X

Digital Object Identifier (DOI)

  • 10.1016/s0264-410x(99)00546-0

PubMed ID

  • 10715528
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Additional Document Info

start page

  • 2132

end page

  • 2141

volume

  • 18

issue

  • 20

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