MYMETICS - About us : Management team

Since 2005 Mymetics has pursued and furthered a mucosa approach that focuses on preventing early HIV entry into the organism during the first minutes or hours following exposure to the HIV virus. Its success is based on proprietary know how and key intellectual properties in matters of antigen engineering and vaccine design that has enabled Mymetics to engineer an effective vaccine candidate in the fight against HIV/AIDS.

Achievements
In October 2007 Mymetics and Pevion Biotech Ltd, a Switzerland- based biotechnology company, signed an agreement that allows the Company to use Pevion’s virosome technology as a carrier for vaccines that target malaria and HIV/AIDS as it helps boost the effect of antigens, the production of specific blood and mucosal antibodies, all without the use of additional adjuvants. Virosome technology has been safely used over the past decade with over 40 million vaccine doses sold around the world and approved in 43 countries.

AIDS : Summary of Our Technical Achievements
From 1997 to 2001, we documented the existence of an important three-dimensional molecular mimicry between the gp41 glycoprotein of HIV-1 and the human interleukin-2 (IL-2) cytokine, mimicry also found in lentiviruses causing AIDS in other animal species. Mymetics has explored this mimicry as the starting point for developing a safe HIV-1 candidate vaccine capable of eliciting protective antibodies, while preventing potential harmful cross-reactivities toward host proteins such as the human IL-2 (Mymetics US Patent 6,455,265). We believe that this innovative concept may render vaccines from the 21st century as efficacious as those from the 20th century, in addition to being safer.

In September 2003 we, together with Protein eXpert S.A., succeeded in engineering and producing in bacteria E.Coli the first gp41 generation which forms soluble and stable gp41 trimers that closely resemble the native gp41 found in HIV-1. This first generation of gp41 immunogen is devoid of the cluster I and 2F5/4E10 epitopes, in addition of being mutated in one important IL-2 mimicry area. The design of the first gp41 generation was intended to identify new important epitopes as well as to focus the immune response on possible neutralizing epitopes different from the 2F5/4E10 previously identified by other teams.

In 2004, we started a collaboration with Dr. Morgane Bomsel (Cochin Institute, Paris, France), a renowned scientist in the field of HIV transcytosis and mucosal immunity. Dr Bomsel had few monoclonal IgA antibodies obtained from phage display libraries issued from B cells of HIV resistant women. These monoclonal IgA antibodies were found later capable of preventing HIV transcytosis and HIV infection of primary isolates. Interestingly, these IgA have recognized epitopes on our gp41 first generation devoid of the 2F5/4E10 epitopes, meaning that other potential neutralizing epitopes exist and they are not limited to IgG isotopes.

From January to August 2004, we tested the first gp41 generation in rabbits for its capacity to elicit neutralizing antibodies toward HIV-1. Such antibodies were obtained in large quantities and their neutralizing potential was evaluated by our academic collaborators. Thus, Dr. Morgane Bomsel obtained 60% inhibition of HIV-1 transcytosis with primary strains. Sera were also tested in the laboratory of Dr. Christiane Moog (Institut Pasteur, Strasbourg, France), a recognized specialist in neutralizing antibodies in the HIV field. In the performed assay, primary T cells infection by primary HIV-1 strains from clade B (Bx-08 and SF-162) and clade C (TV1) were respectively neutralized at 70%, 80% and 90% by low sera dilutions. When total rabbit antibodies were purified from the serum, a neutralizing activity of 80% was obtained with an antibody concentration of 20ug/ml, using three primary HIV-1 strains. These results are similar to those obtained with the 2F5 monoclonal antibody (over 90% inhibition), one of the most potent neutralizing antibodies so far identified. Infection of primary human macrophages by primary HIV-1 strains was also strongly inhibited (over 90%) with a low antibody concentration (less than 2ug/ml). We found these preliminary results highly encouraging, considering that the first gp41 generation of immunogen did not include the 2F5/4E10 epitopes.

During winter 2004 and spring 2005 we engineered a third generation of recombinant gp41 proteins based on the experience we acquired over the first three years (2003-2005). In parallel to the protein approach, during winter 2004 and spring 2005 and in collaboration with Pevion Biotech Ltd. and Dr. Bomsel, we formulated the second vaccine prototype. This prototype consisted of using peptides derived from the conserved proximal membrane region of the gp41 ectodomain grafted in an oriented manner onto biosynthetic stable lipidic spheres called Virosomes. Rabbit immunizations in France were launched from May to November 2005 for targeting the mucosal immune response. Biological samples were analyzed and all rabbits have produced specific antibodies toward the gp41 peptides. More importantly, when these samples were tested into transcytosis assays, most of these vaginal and rectal secretions (diluted 10-fold for the assay) contained antibodies that were able to prevent translocation (transcytosis) of primary R5 clades B and C with an efficiency of 70-90%, which is close to what is observed with human secretions isolated from HIV-resistant women. From March to September 2006, based on this successful rabbit study, sixteen female macaques (non-human primates) in animal facilities in Beijing, China were immunized four times (40ug/100ul injected) over six months. We were hoping to reproduce the same results with Virosomes-gp41 peptides with as we did with the rabbit immunizations.

Achievements
Our vaccine based on Virosomes gp41 peptides elicited mucosal IgA and blood IgG antibodies in over 90% of vaccinated macaques.

These IgA and IgG antibodies were able to be redistributed into the genital and intestinal compartments, even in animals vaccinated by intra-muscular injection in the absence of mucosal adjuvant.
These antibodies were also capable of preventing at least 60% of HIV entry across a human mucosal epithelium in vitro and up to 98% in two out of sixteen animals. Significant inhibitions were obtained with primary HIV from clades B and C. Antibodies from secretions have been purified and their neutralizing capacity was as good as the 2F5/4E10 mAbs, when IC50% was compared.

We believe that such success in the macaque animal model, in the absence of a mucosal adjuvant, is a major breakthrough which is highly encouraging to us for future human clinical trials. From 2005 to 2007, we designed and produced a fourth generation of rgp41. Based on epitope studies we believe that such antigen will be a very good HIV vaccine candidate, especially when incorporated into Virosomes.

In October 2007 we launched a second non-human primate study at the Institute of Laboratory Animal Science & Chinese Academy of Medical Science (ILAS) in China, using macaques for evaluating the full vaccine. Animal vaccinations are scheduled over a six month period. We were expecting to reproduce the results from the first macaque study done in 2006-2007 and to have macaques either protected against the SHIV162p3 or having a viremia between 1-2 logs lower than the control group.

In early 2008, we successfully performed a viral challenge (vaginal route) on those animals having received our latest generation AIDS vaccine. We are preparing a clinical trial phase I to be launched in Q4 2008 for testing our second generation vaccine formulated with Virosomes.

The Mymetics/Pevion malaria vaccine approach features virosome technology. The vaccine’s design is based on optimized mimicry of the native parasite protein structures. Its focus is to elicit antibodies against both stages of the parasite, sporozoites and merozoites. Further, immunogenicity is greatly augmented when virosomes are used as an adjuvant.

Achievements
During 2007, we acquired from Pevion Biotech Ltd a malaria vaccine project which had successfully completed phase I and II human clinical trials with only two antigens in Switzerland and England. This prototype is currently undergoing a new round of phase I and II trials in Tanzania on children and young adults under "native" conditions. Upon successful completion of these tests, expected by the end of 2008, another round of phase I and II human clinical trial is planned, this time with four or possibly five antigens.

This gradual methodology is necessary for both scientific and ethical reasons since African countries, which have in the past been used as testing ground without their fully informed consent, now demand that any human test be first performed in developed countries.

In the HIV/AIDS vaccine field, most pharmaceutical companies have focused on the development of CTL based vaccines and, consequently, the recent failures and limited protection these vaccines have brought, the mucosal approach has been neglected and poorly investigated. Our vaccine approach however, shows promise through its uniqueness and innovative mucosal vaccine candidate.

Malaria is a complex pathogen with two parasite forms, each having different proteins. Most vaccine prototypes tested over the two past decades failed. They were designed to induce antibodies against only one protein and/or one form of the parasite. The ideal vaccine should elicit an immune response toward various proteins of the two parasite forms. The malaria vaccine proposed by Mymetics induces antibodies toward various proteins from the two parasite forms thus increasing the chance of protection. Recent pre-clinical and clinical results generated by Mymetics collaborators on HIV/AIDS and malaria vaccines have attracted the support of notable scientific partners. From this pool of significant luminaries, scientists and research laboratories, Mymetics has composed an impressive scientific network in its efforts in malaria and HIV/AIDS.

Mymetics’ collaboration with the NIH involved the testing of the virosome based AIDS vaccine including two gp41 peptides, one from clade B and one from clade C. This study conducted by the NIH has confirmed that Mymetics’ vaccine could elicit specific mucosal antibodies in both genital and intestinal compartments, confirming the previous study performed in 2006 in China, testing the HIV clade B.

Phase I & II on adults in Switzerland and the United Kingdom, respectively	(completed 2007)
100% of seroconversion after 3 vaccine injections producing 12 months of protection
Antibodies against the two malaria parasite forms were present
Superior results over the best prototype vaccine known to date with a long-lasting antibody response, which represents at least 3 times longer protection potential against Malaria -- 18 months versus 6 months
Phase Ib in Africa to validate the vaccine on children and teenagers under native conditions in pandemic areas with two antigens	(launched Q1 2008)
New round of Phase I and II in Europe involving four or more antigens will be conducted with financing expected by Malaria vaccine grants presently under discussion	(launched Q3 2008)

R&D on recombinant gp41 protein - unique, stable, soluble and trimeric protein is a world premier	(2002 - 2007)
Preliminary pre-clinical study on rabbits	(2004)
First macaques pre-clinical studies in China	(2006)

Results confirm the presence of protective IgA antibodies in various mucosal tissues	(2006 - 2007)
Fourth generation of rgp41 were engineered, the last one tested in non-human primates	(2007 - 2008)
Preliminary Phase I human clinical trial: production of GMP grade vaccine, toxicology tests, regulatory procedures, etc...	(Q1 2007- Q3 2008)
Macaques pre-clinical studies follow-up with vaccine efficacy in China	(Q2 2007 - Q4 2008)
Macaques Challenge in China at ILAS	(Q2 2008 - Q4 2008)
Toxicology study BSL Bioservice (Germany)	(Q2 2008 - Q3 2008)
First Phase I human clinical trial: 33 healthy volunteers, in Belgium -testing gp41 peptides for testing first generation vaccine for clade B in the US and Europe	(Q4 2008 - Q4 2009)

Objective: elicit mucosal IgA antibodies in the genital and intestinal compartments following vaccination with virosomes-gp41 peptides
Second Phase I human clinical trial: 40 healthy volunteers testing 2 components in addition to first vaccine formula (all clade B)	(Q2 2010 - Q2 2011)
Phase II human clinical trials (clade B): efficacy and dosage tests on 300 healthy volunteers	(2012 - 2013)
Phase III of human clinical trials Efficacy and protection on 15,000 volunteers	(2014 - 2018)

The company has identified certain other proven vaccine companies where Mymetic’s technology would be beneficial in safely and rapidly deploying their vaccine products. The company is firmly committed to the HIV/AIDS milestones as previously described in this document with contingency plans for each phase of the process. While different in scope, the company is also firmly committed to the Malaria Milestones with corresponding contingency plans equivalent to those for HIV/AIDS.