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Mymetics proposes an innovative AIDS vaccine that could prevent or reduce HIV entry at the mucosal level (primary entry: early event) as well as preventing cell infection by HIV (late event). To achieve this goal, Mymetics has combined three important concepts in the vaccine design for eliciting different sets of antibodies:
1- Preferential induction of mucosal antibodies for protecting various anatomical compartments. Mymetics postulates that the induction of protective mucosal antibodies such as IgA and secretory IgA might block the early event of HIV entry across the genito-reproductive and intestinal tracts. These mucosal antibodies could also contribute to prevent the HIV infection of target cells located just under the mucosal epithelium, thus preventing HIV entry and spreading in the body. Neutralizing blood antibodies (systemic) such as IgG will also be elicited by Mymetics' vaccine candidate. These blood antibodies will likely act on later events that may take place into secondary lymphoid organs, which consist to prevent the infection of target cells in the periphery, outside of the mucosal system. These mucosal (mostly IgA) and blood (mostly IgG) antibodies should act synergistically for optimal protection against HIV transmission and they may circulate from one compartment to another one, specially blood antibodies migrating to the mucosa levels.
2- Focused antibody response against relevant conserved gp41 regions, as observed in HIV resistant subjects. To achieve this objective, Mymetics' HIV vaccine candidate is constituted of gp41 peptides and recombinant proteins that are devoid of immunodistractive and useless areas. Generally, the immune system develops immune responses toward all possible regions of the foreign antigens (peptides, proteins, etc.). However, antigens are often harbouring several immunodominant regions, each eliciting an immune response of different magnitude (low, intermediate or strong recognition/affinity by the immune system) and frequency (region rarely, sometimes or often recognized by the immune system). Therefore, it's frequent to observe an immune response that preferentially recognizes some protein areas (immunodominant), while others are neglected. Furthermore, viruses have developed antigens that contain often immunodominant regions for distracting the immune system. These immunodistractive regions may have little or no function for the pathogen protein but may blind the immune system. Consequently, immune responses against the pathogen might be sometimes useless. Mymetics is developing vaccines that contain different antigens expressing limited and useful immunodominant regions, while useless immunodistractive regions have been removed or altered with minimal effect on the immunogenicity of the viral antigen. Using this approach, it forces the antibody response to focus on relevant viral protein regions.
3- Minimal mimicry. This concept consists to remove in part or entirely the human protein homologies naturally present in many HIV proteins that serve as vaccine component. To achieve that objective, Mymetics intends to use as candidate vaccine the smallest engineered viral antigen sequence for two main reasons. First, the smaller is the protein, the more limited are the homologies with human proteins. Second, it's easier to remove human homologies into a small viral protein or peptide because of their limited distribution. Using this approach, Mymetics believes that an HIV vaccine constituted of viral antigens or genes encoding viral antigens with minimal human homologies should reduce the risk of developing potential long-term autoimmunity side-effects after HIV vaccination.
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Figure 1. Mymetics' vaccine strategy
A better and optimal focused antibody response against the conserved regions of HIV proteins. |
How to trigger the protective immune reponse? Mymetics' vaccine uses the technology of Virosomes®, a lipid-like structure highly efficient for delivering the vaccine's active ingredients.
| The virosome-based vaccine is constituted of two types of virosomes, each with surface anchored gp41-derived conserved antigens, each eliciting different antibodies not mutually exclusive with a broad activity spectrum: |
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• Virosomes with peptides corresponding to the conserved Membrane Proximal Region (MPR) of gp41 for triggering protective mucosal anti-gp41 antibodies (mostly IgA) against a broad spectrum of HIV isolates.
• Virosomes with soluble/stable recombinant gp41 protein (rgp41) without the MPR for eliciting complementary neutralizing IgA and IgG anti-gp41 antibodies. |
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Figure 2. Virosomes as an efficient vaccine delivery system with major advantagesy
Virosomes are small synthetic spherical vesicles which essentially represent reconstituted empty influenza virus envelopes, devoid of nucleocapside and the genetic material. The HA & NA confer structural stability, homogeneity & immunological properties (adjuvant property). Grafting gp41 antigens on virosomes allows proper epitope orientation or presentation (not random) into a lipidic membrane that closely mimics the native viral membrane of HIV-1. |
This Virosomes® technology is already market approved in more than 40 countries with excellent safety profile and no mucosal adjuvant is required for triggering mucosal antibodies.
| By carefully modifying parts of the HIV gp41 molecule, Mymetics has obtained vaccine subunits such as gp41 peptides and engineered recombinant gp41 molecules that: |
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• May form stable dimers, trimers or tetramers and the protein folding is close to the native viral protein;
• Are soluble in the absence of detergent and can be incorporated into an artificial lipidic membrane, which is more suitable for in vivo work;
• Can be chemically synthesized or easily produced by recombinant bacteria like E. coli;
• Have been stripped of immunodominant areas that generate numerous non-neutralizing antibodies, which may fool the immune response.
• Have been stripped of its key IL-2-like sequence and other human homologies, minimizing the important potential cross-reaction with host proteins that may contribute to the destruction of the immune system seen in HIV patients;
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This type of new engineered gp41 molecules should be able to elicit antibodies with a broad spectrum of action (cross-clade neutralization likely possible): blocking virus translocation across the mucosal barrier and/or to inhibit cell infection, thus preventing HIV-1 infection.
Based on our recent research results, it is believed that Mymetics' HIV vaccine candidate and strategies definitely place us amongst the most advanced teams devoted to AIDS prophylactic vaccine research that aims to prevent HIV transmission across mucosal barrier.
Mymetics findings further apply to a range of additional diseases, including certain oncoviruses often associated with leukemia. |
