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Aids vaccination strategies - the feline model

Objective

The aim of the Concerted Action is to provide a rational basis for the design of HIV vaccines using the feline immunodeficiency virus (FIV) model. There are two major objectives. The first is the definition of the immunogen(s) required for protection against FIV infection. The second is the definition of the immunological correlates of protection
by vaccination.
2.1 Immunogens required for protection
2.1.1 Development from the inactivated virus and cell vaccines Inactivated FIV vaccines consistently provide protection from challenge. The nature of the immunogens required for protective immunity will be determined by vaccination with the purified products of disrupted virus. Non-infectious particles for use as immunogens will be generated by transfection of appropriate FIV genes in vitro.
2.1.2 Modulation of immune responses with 'conventional' adjuvants and cytokines Several recombinant subunits, particularly of the env gene products, which have not been protective in previous experiments will be used again with appropriate adjuvants to induce Th1 immune responses. Feline cytokines which are being generated at present will also be used as adjuvants.
2.1.3 Live recombinant viruses as vaccines FIV env and gag genes in a herpesvirus vector have been made and will be tested as vaccines. The Ankara strain of vaccinia virus will also be used as a vector.
2.1.4 DNA vaccination Two types of constructs will be used: first, individual cloned genes, particularly env genes, and secondly, full length molecular clones attenuated or rendered replication defective by targeted mutations. Co-transfection with cytokine genes will also be used. Antibody and cytotoxic T cell responses induced by DNA will be determined.
2.2 Correlates of protection
2.2.1 Virus neutralising antibodies (VNA) The role in vaccinal protection of VNA is controversial. Assays for the quantification of VNA in fibroblast and T cell systems will be refined to determine the viral targets for VNA. The antigenic spectrum of FIV isolates will be defined by virus neutralisation.
2.2.2 Facilitating or enhancing antibodies Certain immunogens induce enhancing antibodies. The regions of the Env proteins that induce enhancing antibodies and the mechanism of their action will be determined.
2.2.3 Cytotoxic T cells (CTL) CTL are induced by vaccination with inactivated
FIV vaccines. Response to the Env proteins predominate in vaccinated, protected cats,
in contrast to infected cats. Means to enhance the generation of Env-specific CTL responses
will be investigated.

The aim of the Concerted Action is to use the feline immunodeficiency virus (FIV) model to contribute to the development of a vaccine against human immunodeficiency virus (HIV) infection in man. FIV is a unique, naturally occurring analogue of HIV in which vaccine efficiency can be tested simply and rapidly. The major contribution will be the provision of a rational basis for the selection and presentation of immunogens for effective vaccines.

The two major objectives of the programme are, first, to define the immunogen(s) required for protection against FIV infection and secondly, to define the immunological correlates of protection by vaccination:
1. Immunogens required for protection;
1.1 Development from inactivated virus and cell vaccines. FIV vaccines consistently provide protection from challenge. The nature of the immunogens required for protective immunity will be determined by vaccination with the purified products of disrupted virus. Non-infectious particles for use as immunogens will be generated by transfection and expression of appropriate FIV genes in vitro;
1.2 Modulation of immune responses with "conventional" adjuvants and cytokines. Several recombinant subunits, particularly of the environment gene products, which have not been protective in previous experiments will be used with appropriate adjuvants to induce the immune responses. Feline cytokines which are being generated at present will also be used as adjuvants;
1.3 Live recombinant viruses as vaccines. FIV env and gag genes in a herpesvirus vector have been made and will be tested as a vaccine. The Ankara strain of vaccinia virus will also be used as a vector;
1.4 DNA vaccination. Two types of constructs will be used: first, individual cloned genes, particularly env genes, and secondly, full-length molecular clones attenuated or rendered replication defective by targeted mutations. Co-transfection with cytokine genes will also be used. Antibody and cytotoxic T cell responses induced by DNA will be determined;

2 Correlates of protection;
2.1 Virus neutralising antibodies (VNA). The role in vaccinal protection of VNA is controversial. Assays for the quantification of VNA in fibroblast and T cell systems will be refined to determine the viral targets for VNA. The antigenic spectrum of FIV isolates will be defined by virus neutralisation;
2.2 Facilitating or enhancing antibodies. Certain immunogens induce enhancing antibodies. The regions of the Env proteins that induce enhancing antibodies and the mechanism of their action will be determined;
2.3 Cytotoxic T cells (CTL) CTL are induced by vaccination with inactivated FIV vaccines. Response to the Env proteins predominate in vaccinated, protected cats, in contrast to infected cats. Means to enhance the generation of Env-specific CTL responses will be investigated;
2.4 Other mechanisms Chemokines are associated with resistance of cells in vivo to infection with HIV.

Their contribution to FIV infection and vaccination will be investigated. We have already established an extremely effective network for European research on FIV vaccination. Each of the ten partners will follow a complementary approach within the general framework of the work plan of the Concerted Action.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

UNIVERSITY OF GLASGOW
Address
Bearsden
G61 1QH Glasgow
United Kingdom