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Strategies for the design of peptide vaccines for the control of major human infections

Objective


Studies on AIDS
The aim of these studies is to evaluate protein antigens of HIV with respect to their immunogenicity in the inducjtion CTL responses in non-infected and in HIV-infected human individuals. On the one hand, we have established an in vitro system to induce and monitor human CTL responses to HIV-Nef. Potent CTL responses could be induced in non-infected individuals. These CTL recognize and efficiently lyzed autologous human CD4 T cells infected with either HIV-1 or HIV-2, further supporting HIV-Nef as a promising vaccine constituent. On the other hand, we have analyzed the impact of sequencial changes in 5 epitopes of HIV-1 Nef on CTL recognition in 4 stable patients. A high rate of variation was found and we could detect CTL specific for 32 out of 36 autologous virus variants. Some virus variants were eliminated upon appearance of variant-specific CTL, other virus variants persisted in spite of specific CTL recognition. Furthermore, we monitored the dynamics of CTL responses to RT, Env, Gag and Pol in HIV infected patients over a 3 year period. A remarkable flexibility of the immune system allows constant adaptation of CTL to multiple HIV variants and thus elimination of HIV variant-producing cells in slow progresses.
Studies on Lyme disease
The aim of these studies is to evaluate the outer surface protein OspA as a human Lyme disease vaccine and to identify additional Borrelia antigens which may be useful as vaccine constituents. To this end, a phase I clinical trial with OspA vaccine has been conducted with very promising results. A phase II clinical trial has recently been concluded also with encouraging results. Presently, a phase III clinical trial involving several thousand human subjects is in progress in the US. We have found that European Borrelia strains show greater species variability in OspA sequence than US strains of Borrelia, calling for differences in vaccine design for European and US use. Recently, we have begun to evaluate DNA-based vaccination. Potent humoral immune responses were generated with various vectors containing the OspA gene, and we found that OspA gene expression in the mouse is independent of an eukaryotic promoter enhancer system. DNA vaccination against Borrelia antigens may thus be a promising avenue to be followed in the future.
Studies on malaria
The aim of these studies is to identify immunoprotective blood stage antigens of Plasmodium falciparum. To this end, we study human immune responses to P. falciparum blood stage antigens and compare them with results from a mouse model, P. chabaudi. Our approach is to analyze the naturally processed peptides of parasite proteins presented on MHC class II molecules, using MHC class II restricted T cell hybridomas specific for Plasmodium chabaudi erythrocytic stage proteins. These proteins are introduced into suitable antigen presenting cells which are then lyzed and solubilized MHC class II molecules with bound peptides are isolated. Several different procedures of identifying epitopes in the complex peptide mixtures are presently being evaluated. Peptide identification has recently been facilitated by the development of a new mass spectrometer, quadropole orthogonal acceleration time of flight, which shows a higher sensitivity, resolution and mass accuracy than previous instruments. Separations, biochemical characterizations and functional analyses of several identified candidate epitopes are in progress.

MAJOR SCIENTIFIC BREAKTHROUGHS:
1. HIV-Nef-specific CTL of normal human individuals destroy HIV-infected cells.
2. DNA vectors containing Borrelia burgdorferi antigens without eukaryotic enhancer/promoter sequences induce potent humoral immunity against Borrelia burgdorferi.
3. Proteasomal digestion of antigens was found to be a highly efficient general method for identifying CTL epitopes.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

Max-Planck-Gesellschaft zur Forderungder Wissenschaften e.V.
Address
Stübeweg 51
79108 Freiburg
Germany

Participants (2)

Centre National de la Recherche Scientifique (CNRS)
France
Address
91 Boulevard De L'hôpital
75634 Paris
SMITHKLINE BEECHAM BIOLOGICALS S.A
Belgium
Address
89,Rue De L'institut 89
1330 Rixensart