Explaining and Improving Efficacy of targeted
Immunodeficiency Virus-like Particle Vaccines against AIDS (
Objectives
With support
from two successive, framework V, EU sponsored consortia, we have developed a
targeted immunodeficiency virus-like particle vaccine (VLP) which has the
G-protein of vesicular stomatitis
virus incorporated in the membrane of the particle. Incorporation of VSV-G increases
uptake and presentation of VLPs by dendritic cells. A pilot vaccination experiment in the
SIV/macaque model provided strong protection against challenge with a
pathogenic SIV. Given the urgent need for an HIV vaccine, the potential of this
innovative vaccine approach should be evaluated as quickly as possible.
Therefore, the aims of the current STREP application of the consortium are 1)
to determine the efficacy of the VLPs in a larger
number of animals, 2) to better understand the requirements for and the
mechanisms of protection, and 3) to further improve the targeted VLPs.
Partners
Coordinator Ruhr-University
Partner 2 Bernhard-Nocht-Institute for Tropical Medicine (Prof. Dr. P. Racz)
Partner 3 The Rockefeller-University (Prof. Dr. R. Steinman)
Partner 4
Partner 5 Charité, University Medicine of
Partner 6 Institute
for Research in Biomedicine (Dr. M.Uguccioni)
Partner 7
Link to Partner´s
Web site: http://134.100.62.15/bni/others/koerber/partner/index.html
Background
With HIV
spreading worldwide, the need for a preventive or therapeutic vaccine is more
urgent than ever before. According to the United Nations Program on HIV/AIDS
approximately 40 million people worldwide are infected with HIV. No HIV vaccine
is yet available. Efficacy studies in humans require large cohorts, and only a
single trial using recombinant gp120 surface protein has been performed with no
evidence of protection. Therefore, most of our knowledge on HIV vaccines comes
from animal models, particularly the infection of macaques with simian
immunodeficiency viruses (SIV).
Work on
live-attenuated immunodeficiency viruses in non-human primate models has shown
that a vaccine can provide protection from progression to AIDS even in the
absence of a sterilising immunity. Thus, vaccine-induced antiviral immune
responses can control immunodeficiency virus replication. A number of effector mechanisms, including neutralizing antibodies and
CD8+ cytotoxic T-cells are likely to contribute to protection. In addition to
the live-attenuated vaccines, which for safety reasons are unlikely to be
applicable in humans, a number of vaccine approaches have been studied in the
SIV model. Vaccination with recombinant env proteins
does not provide sufficient protection against pathogenic SIV, which is
consistent with results from the human phase-III trial. Similarly,
whole inactivated SIV vaccines and virus-like particles do not provide
significant protection. A common feature of vaccination with recombinant
viral proteins and whole inactivated viruses is injection of exogenous
antigens, which predominantly leads to MHC-II-restricted cellular immune
responses and production of antibodies. Expression of antigens by cells of the vaccinees should lead to presentation of antigens to MHC-I
and MHC-II molecules. Therefore, DNA and viral vector vaccines have been
extensively studied and depending on the stringency of the challenge system
various degrees of protection have been observed.
Instead of
using viral vector systems to induce MHC-I and MHC-II-restricted immune
responses, a heterologous fusion protein was
incorporated into immunodeficiency virus-like particles, which
should increase uptake and presentation of exogenous antigens on MHC-I and
MHC-II molecules. This might explain the initial evidence of protection from
disease progression in monkeys immunized with these targeted virus-like
particles.
Consortium
To achieve
the objectives, we have endeavoured to put together a consortium of excellence
in