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Vector-Mediated Antibody Expression

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  • Authors: Bruce C. Schnepp1, Philip R. Johnson2
  • Editors: James E. Crowe Jr.3, Diana Boraschi4, Rino Rappuoli5
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: The Children's Hospital of Philadelphia, Abramson Research Center, Philadelphia, PA 19104; 2: The Children's Hospital of Philadelphia, Abramson Research Center, Philadelphia, PA 19104; 3: Vanderbilt University School of Medicine, Nashville, TN; 4: National Research Council, Pisa, Italy; 5: Novartis Vaccines, Siena, Italy
  • Source: microbiolspec August 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.AID-0016-2014
  • Received 08 April 2014 Accepted 11 April 2014 Published 15 August 2014
  • : Philip R. Johnson, johnsonphi@email.chop.edu
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  • Abstract:

    This article focuses on a novel vaccine strategy known as vector-mediated antibody gene transfer, with a particular focus on human immunodeficiency virus (HIV). This strategy provides a solution to the problem of current vaccines that fail to generate neutralizing antibodies to prevent HIV-1 infection and AIDS. Antibody gene transfer allows for predetermination of antibody affinity and specificity prior to “immunization” and avoids the need for an active humoral immune response against the HIV envelope protein. This approach uses recombinant adeno-associated viral (rAAV) vectors, which have been shown to transduce muscle with high efficiency and direct the long-term expression of a variety of transgenes, to deliver the encoding a broadly neutralizing antibody into the muscle. Following rAAV vector gene delivery, the broadly neutralizing antibodies are endogenously synthesized in myofibers and passively distributed to the circulatory system. This is an improvement over classical passive immunization strategies that administer antibody to the host to provide protection from infection. Vector-mediated gene transfer studies in mice and monkeys with anti-HIV and simian immunodeficiency virus (SIV)-neutralizing antibodies demonstrated long-lasting neutralizing activity in serum with complete protection against intravenous challenge with virulent HIV and SIV. These results indicate that existing potent anti-HIV antibodies can be rapidly moved into the clinic. However, this methodology need not be confined to HIV. The general strategy of vector-mediated antibody gene transfer can be applied to other difficult vaccine targets such as hepatitis C virus, malaria, respiratory syncytial virus, and tuberculosis.

  • Citation: Schnepp B, Johnson P. 2014. Vector-Mediated Antibody Expression. Microbiol Spectrum 2(4):AID-0016-2014. doi:10.1128/microbiolspec.AID-0016-2014.

Key Concept Ranking

Simian immunodeficiency virus
0.49756992
Hepatitis C virus
0.4886517
Humoral Immune Response
0.4543719
0.49756992

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/content/journal/microbiolspec/10.1128/microbiolspec.AID-0016-2014
2014-08-15
2017-11-20

Abstract:

This article focuses on a novel vaccine strategy known as vector-mediated antibody gene transfer, with a particular focus on human immunodeficiency virus (HIV). This strategy provides a solution to the problem of current vaccines that fail to generate neutralizing antibodies to prevent HIV-1 infection and AIDS. Antibody gene transfer allows for predetermination of antibody affinity and specificity prior to “immunization” and avoids the need for an active humoral immune response against the HIV envelope protein. This approach uses recombinant adeno-associated viral (rAAV) vectors, which have been shown to transduce muscle with high efficiency and direct the long-term expression of a variety of transgenes, to deliver the encoding a broadly neutralizing antibody into the muscle. Following rAAV vector gene delivery, the broadly neutralizing antibodies are endogenously synthesized in myofibers and passively distributed to the circulatory system. This is an improvement over classical passive immunization strategies that administer antibody to the host to provide protection from infection. Vector-mediated gene transfer studies in mice and monkeys with anti-HIV and simian immunodeficiency virus (SIV)-neutralizing antibodies demonstrated long-lasting neutralizing activity in serum with complete protection against intravenous challenge with virulent HIV and SIV. These results indicate that existing potent anti-HIV antibodies can be rapidly moved into the clinic. However, this methodology need not be confined to HIV. The general strategy of vector-mediated antibody gene transfer can be applied to other difficult vaccine targets such as hepatitis C virus, malaria, respiratory syncytial virus, and tuberculosis.

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FIGURE 1

Immunoprophylaxis by antibody gene transfer. Passive immunization involves intravenous delivery of purified antibodies to engender the host with short-lived immunity in serum and mucosa. In contrast, vector-mediated antibody gene transfer uses a viral vector to deliver the antibody to the host via intramuscular injection. The antibody is produced endogenously in the muscle and secreted into the circulatory system and mucosa providing long-term protection from infection. (Reprinted from reference 72 [Schnepp BC, Johnson PR. 2014. Adeno-associated virus delivery of broadly neutralizing antibodies. 205–256] with permission.) doi:10.1128/microbiolspec.AID-0016-2014.f1

Source: microbiolspec August 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.AID-0016-2014
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FIGURE 2

rAAV vectors for antibody gene transfer. The wild-type AAV (wtAAV) genome consists of the and genes flanked by inverted terminal repeats (ITRs). For rAAV vectors, the and genes are removed and replaced by an antibody expression cassette flanked by ITRs, which are necessary for rAAV vector genome replication and packaging. Immunoadhesins contain the antibody variable domains (VL, variable light; VH, variable heavy) usually joined by a flexible protein linker. The variable domains are connected to the hinge and constant heavy-chain domains (CH2 and CH3). The immunoadhesins can form dimers through disulfide bonding in the hinge region. Full antibodies can be expressed by using either a dual promoter or single-promoter system. For dual promoter expression, the antibody heavy and light chains are each expressed separately from their own promoter. For the single promoter system, the heavy and light chains are expressed as a single polypeptide separated by the foot-and-mouth-disease virus 2A peptide (FMDV-2A). The FMDV-2A peptide can undergo self-cleavage to give rise to separate heavy and light chains. doi:10.1128/microbiolspec.AID-0016-2014.f2

Source: microbiolspec August 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.AID-0016-2014
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TABLE 1

Vector-mediated antibody gene transfer studies

Source: microbiolspec August 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.AID-0016-2014

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