The majority of HIV vaccine strategies have so far focused
on the structural antigens of HIV-1, in particular Env. These
Env-based vaccines have induced a protection that was limited
to homologous virus challenge or closely related HIV-1 strains,
while protection from heterologous virus challenge has proven
to be much more difficult to achieve. It has been postulated
that past failures to elicit broad neutralizing antibodies
with the viral glycoproteins may be due in part to the use
of recombinant monomeric gp41, gp120 or gp160 molecules that
were improperly folded and did not expose the neutralization
epitopes, in addition to having monomeric structures that may
differ significantly from the native trimeric glycoproteins
found on HIV surface. So far, only five broadly neutralizing
HIV-1 reactive mAb have been isolated; two are directed against
the gp120 (2G12 and b12), and the other three are directed
against the gp41 (2F5, 4E10 and Z13). the 2F5 being the most
potent, 4E10 the most broad and Z13 the least efficient.
Of primary concern in recent efforts to develop an efficient HIV-1 vaccine has been the design of immunogens capable of eliciting neutralizing antibodies (2F5-like) against a wide spectrum of HIV-1 strains. New candidate vaccines based on trimeric glycoproteins gp160, gp140 and gp41 that are closer to the native viral proteins have been designed. However, these artificially produced trimeric forms are usually unstable in solution without detergent or when mixed with adjuvants, and usually contain several immunodominant regions on the same antigens, which may hamper efforts to produce an effective preventive vaccine.
Mymetics Corp's primary goal is to engineer modified gp41-derived immunogens capable of eliciting a broad antibody response to various HIV-1 clades. To achieve this goal, Mymetics Corp. and its key partners, Dr. Morgane Bomsel (Cochin Institute, Paris, France) and, Protein'eXpert
S.A. (Grenoble, France), a company highly specialized in protein production, have developed engineered gp41 HIV peptides and glycoproteins. We have found a way of making stable peptide associations and gp41 trimers, all properly oriented and presented. We propose to develop gp41 immunogens with impaired immunodominant cluster I area that distract the immune system. This loop generates numerous non-neutralizing antibodies that may distract the immune system, in addition to being an important mimicry area for the IL-2 and other human proteins. Therefore, our HIV-1 vaccine approach is based on the use of an engineered stable dimeric and trimeric forms of gp41-derived antigens that closely resembles the native gp41 and capable of focusing the immune response on epitopes that may induce protective antibodies with minimal cross-reactivity toward self-proteins like IL-2 (Mymetics US Patent 6,455,265). Therefore, our candidate vaccine may be considered safer because of the removal of human homologies in the viral antigen. Mymetics has developed four generations of gp41 trimers and the latest one is promising.
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