More than 40 million people are currently infected with HIV1, mostly coming
from developing countries resulting in an urgent need for effective and
affordable treatment of HIV1 infections. The main objective of the project is to
develop an efficient genetic vaccine candidate for therapeutic and
preventative use against HIV/AIDS.
The vaccine planned, should be capable of inducing cell-mediated and
humoral immunity against the virus and virally infected cells in different phases
of the viral life-cycle.
DNA vaccines could fulfil these requirements if rendered more efficient. To this
aim, a combination of complementary technologies by four SMEs will be used.
The novel DNA vaccination technology will combine:
- The restricted expression of the multi-epitope/multivalent HIV antigens
in specific cells of the epidermis
- A micro-needle array-based injection device for reproducible and
efficient delivery into the epidermis
- The EPI-GTU® technology that allows strong and long-term expression
using segregation/partitioning function of the Bovine papillomavirus
- The plasmo-VLP® technology that allows an expression of the
immunogens within and onto virus-like-particles
- The adjuvant effect of different cytokines.
The step-by-step combination of these technologies will be evaluated at the
laboratories of the three academic partners by using state of the art methods.
The initial evaluation of vaccine efficacy will be performed on mice and pigs
and will be ultimately validated in Cynomolgus monkeys.
EPIVAC aims to conduct its preclinical development up to the GMP production
phase. Testing of numerous vector batches will be aimed towards having
enough suitable material ready for evaluation in clinical trials.
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
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.
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.
- New devices and modalities for DNA delivery to the epidermis
- 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
- Generation of new proprietary HIV antigens based on the EPIVAC
- Epidermal genetic vaccinations; Improved treatment of HIV infection
and AIDS by using nanotechnology
- 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
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