ENHANCED EFFICACY AND SAFETY OF RECOMBINANT VACCINES

Project: Research project

Description

The long-term objective of this proposal is to increase the safety and
efficacy of live recombinant vaccines, for use on control of human
diseases. The immediate objective of this proposal is to enhance the
safety and efficacy of vaccinia virus (VV) recombinant vaccines for humans
and other animals. The principals that we address in this proposal using
VV as a model would have application for other live recombinant vaccines.
We propose improving the safety and enhancing the immunogenicity by co-
expressing cytokines and immunogenic antigens in a modified VV vector that
has had specific immune-modulating genes inactivated or deleted. The
efficacy of these alterations in the VV vector will be tested using a
vesicular stomatitis (VSV) model. This will enable us to evaluate our
vaccines for both systemic and localized disease conditions, using mice
and cattle, respectively, as hosts. We have demonstrated the adjuvant
effects of interferon-gamma (IFN-gamma) in cattle and mice immunized with
a mixture of the cytokine and the glycoprotein of vesicular stomatitis
virus. Accordingly, we co-expressed cytokine genes with other immunogenic
foreign genes in VV in an effort to increase efficacy of these vaccines.
Although dramatic attenuation of VV was demonstrated, no immune
enhancement to VV or co-expressed foreign proteins was detected. Our
hypothesis is that safety and immunogenicity of recombinant VV (rVV)
vaccines can be improved by co-expressing the lymphokine, interferon-gamma
(IFN-gamma) with an immunogenic protein, and inactivating one or more VV
immune-modulating genes. Such a vaccine will combine the effectiveness of
live attenuated vaccines with the safety of subunit vaccines and will have
several distinct advantages: 1) Antigens expressed by rVV are effective
in inducing both cytotoxic T-lymphocyte (CTL) and humoral immune
responses; 2) IFN-gamma attenuates VV virulence; 3) IFN-gamma will favor
a Type 1 immune response, an important component of the immune response to
virus infection to antigens; and 4) the inactivation of immune-modulating
genes will increase the safety of rVVs.
StatusFinished
Effective start/end date9/30/946/30/99

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

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Synthetic Vaccines
Vaccinia virus
Safety
Interferon-gamma
Vaccines
Genes
Cytokines
Antigens
Vesicular Stomatitis
Attenuated Vaccines
Subunit Vaccines
Lymphokines
Cytotoxic T-Lymphocytes
Virulence
Glycoproteins
Proteins
Virus Diseases
Humoral Immunity
Stomatitis

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)