EPIVAC

Background:

The Human Immunodeficiency Virus (HIV) induces chronic infection in patients, eventually leading to deterioration of the immune system and the onset of immune deficiency. HIV induces significant cell-mediated and humoral immune responses, which considerably reduce viral titre after initial burst of the HIV1 replication and spread in the body. These naturally induced immune responses only partially control HIV spread and in fact there are no clearly documented cases of true clearance of the viral infection.

Nevertheless, it is possible that the triggering of additional immune responses, notably through the presentation of modified HIV antigens, could generate different types of immune responses that could contribute towards better control of the infection and thus improve clinical evolution and reduce viral transmissibility.

The quality and intensity of the humoral or cellular immune responses required for efficacious preventative or therapeutic vaccinations vary, depending on the target infectious agents. Preventative vaccines against acute viral infections often rely on strong neutralising antibody responses, while therapeutic vaccines against chronic infectious diseases often rely on cytotoxic responses capable of eliminating infected cells.

Most antiviral vaccines in current use are based on homologous inactivated or attenuated viral particles, i.e. attenuated measles virus for measles vaccination. This establishes that packaging antigens in/onto particles is one of the most efficient ways of triggering efficient antiviral immune responses. Some of the most promising new vaccines have been designed and developed in the field of DNA vaccination. DNA vaccines are low in cost, stable and easy to produce whist offering the possibility to combine several antigens when required. However, it appears that DNA vaccination, typically induces cellular immunity, but rarely or inefficiently neutralising antibodies that often play a major role in protection against viruses (Tuteja et al., 1999).

Based on this knowledge, the EPIVAC Project proposes the concept of combining the advantages of various vaccines by engineering them into single vectors, i.e. by designing plasmids that harbour the genetic code necessary for the production of recombinant viral particles, which further target the skin as a preferential site for genetic immunisation.

Aim:

EPIVAC aims to generate a multi-step, improved, efficient and affordable DNAbased preventative and therapeutic vaccine against HIV. The first goal of EPIVAC is the development of a reliable, reproducible and robust delivery system. This will include micro-needle arrays and an injection device for the controlled delivery of the GTU®-based vector system and for celltype- specific epidermal expression of the genes of interest in epidermal differentiating keratinocytes, Langerhans cells and melanocytes. The plasmids and genes of interest used in these studies will allow for the quantitative evaluation of the efficiency and kinetics of delivery of plasmid DNA into the epidermis and epidermal cells. Further, to follow the process of diffusion, degradation and intracellular up-take and onset of biological activity of the delivered expression system in specific cells of the epidermis will be assessed. The plasmids used will carry the site-specific fluorescent labels for the monitoring of DNA delivery into the epidermis as well as the diffusion and degradation of the plasmid.

The second goal of the EPIVAC project will be to analyse the effect of different HIV1 antigen expression in different cells of the epidermis on the nature and breadth of the induced immune response.

One major problem in developing an AIDS vaccine is the lack of knowledge regarding immune mechanisms for protection against HIV1 infection and for removing the virus from the body. Another goal of this project is to contribute towards the identification of some immune correlates of protection during the evaluation of vaccine efficacy in non-human primates.

The induced immune response triggered by the vaccination will be characterised qualitatively and quantitatively towards every viral target protein. The immunised animals will be challenged after immunisations with the hybrid SHIV, and analysed for control, clearance and protection.

Expected results:

1. New devices and modalities for DNA delivery to the epidermis
2. Generate improved DNA-based vaccines combining the advantages of GTU vectors for long-term expression and plasmo-VLP vectors for the presentation of antigens onto VLPs
3. Generation of new proprietary HIV antigens based on the EPIVAC optimised vector.

Potential applications:

1. Epidermal genetic vaccinations; Improved treatment of HIV infection and AIDS by using nanotechnology
2. Improved standards for vaccination in large animals, notably by using swines that are not often used in vaccine development and which could become interesting alternatives to the use of non-human primates for challenge experiments.

Coordinator:

Ioana Stanescu
FIT Biotech Plc
Biokatu 8, 33520
Tampere,
Finland
Tel: + 358 3 3138 7020
Fax: + 358 3 3138 7050
E-mail: ioana.stanescu@fitbiotech.com
Website: www.fitbiotech.com

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