Current Projects and Pipeline
Rationale and Impact of MACIVIVA
With few exceptions, commercialized vaccines are generally delivered by injection through the intramuscular or subcutaneous route.
Vaccines contain immunogens classically found within a large variety of biological compounds such as peptides, proteins, glycoproteins and sometimes carbohydrates and lipids.
These immunogens may trigger the immune system for producing antibodies and/or cytotoxic T cells for preventing the pathogen transmission or blocking and/or slowing down the disease progression.
However, these vaccines generally exist as liquid formulation that are inherently prone to physical and/or chemical modifications. The cold chain storage is still fundamental for preserving the
bioactivity of most liquid and freeze-dried vaccines. For reconstituted freeze dried vaccines, they harbor important instability and must be used within hours and kept refrigerated. Vaccine degradation generally takes place
during shipment and/or storage of liquid or lyophilized products, which may affect the immunological properties of the immunogens, with unwanted immune responses or insufficient immune protection.
There is growing evidence that solid dosage formats (e.g. powder form) for vaccines may offer several advantages over the liquid formulations, such as the prevention of molecular motion and shear-induced degradation,
and slowing down modifications and degradation reactions involving water and oxygen radicals, resulting in improved stability, enhanced shelf-life of vaccines and greatly simplified logistics.
Today, no commercial vaccine has been developed yet under thermostable solid form (cold chain independent)
for direct nasal or oral delivery (ex. intranasal powder delivery or sublingual pills) without the need of reconstitution with a liquid.
Expertise: R&D on virosome formulations
Project responsability: Investigating and compiling the results about the physical and biochemical properties of the virosome-based vaccines obtained by spray-drying and lyophilization.
Expertise : Non-GMP and GMP virosome production, clinical development
Project responsability: Excipient selection for liquid virosomes, supervising the non-GMP and GMP manufacturing of the liquid virosomes and development of analytical methods.
Expertise: Non-GMP and GMP Spray drying
Project responsability: Identification of excipients and experimental conditions suitable for virosome spray drying, production of non-GMP and GMP powder forms for nasal and oral delivery.
CATALENT U.K. SWINDON ZYDIS LIMITED
Expertise: Zydis technology for fast-dissolving tablet, world leader in drug formulation and distribution
Project responsability: Identification of excipients and experimental conditions suitable for virosome lyophylization, according to the Zydis technology, non-GMP and GMP tablets for sublingual delivery.
CHIMERA BIOTEC GMBH
Expertise: Ultra sensitive immunoassays development and bioanalysis based on Imperacer® (Immuno-PCR) technology.
Project responsability: Immunogenicity study in animals with spray-dried and lyophilized virosomes. Imperacer® immunoassay development and evaluation of the vaccine-induced antibody response.
Expertise: R&D, non-GMP and GMP manufacturing of API, world supplier
Project responsability: Process Development and manufacture of peptide P1, GMP-grade, including development and validation of analytical methods.
PX’THERAPEUTICS announces the successful completion of RGP41 GMP manufacturing for Mymetics
Grenoble, France, and Epalinges, Switzerland, December 12th, 2017 – PX’Therapeutics, a CDMO specializing in the development of recombinant proteins for human and animal health, is proud to announce the end of the rgp41 manufacturing campaign and batch certification for clinical application. This drug substance will be used by Mymetics to develop a new vaccine formulation, within the framework of the MACIVIVA project, sustained by the European Union’s Horizon 2020 research and innovation program and the Swiss State Secretariat for Education, Research and Innovation (SERI) for the Swiss based consortium partners.
Rgp41 protein is one of the HIV-1 gp41 derived antigens constituting Mymetics’ HIV-1 vaccine that is anchored to the membrane surface of the virosome particle, which acts as vaccine delivery vehicle for soliciting the immune system for inducing the production of protective serum and mucosal antibodies.
PX’Therapeutics and Mymetics joined forces several years ago to work on rgp41 protein design and development of the production and purification processes of the molecule. PX teams managed to develop an efficient, scalable and GMP-compliant process. A clinical batch was produced from a scale fermentation volume of 120 L to deliver a sufficient quantity for formulation studies and clinical trials.
Claire Untereiner, Chief Operating Officer of PX’Therapeutics, commented as follows: “We are so happy to see the progress made with this molecule and to be part of this fantastic project. MACIVIVA’s objective, the development of cold-chain independent and virosome-based vaccines, responds to a real medical need, particularly in emerging countries, and is in line with PX’Therapeutics’ mission, to support and accelerate the development of innovative medicines”.
Sylvain Fleury, Chief Scientific Officer of Mymetics SA commented: “we are pleased that PX’Therapeutics could address many technical challenges related to the GMP development of the recombinant rgp41 protein and achieve a production yield superior to our expectations. With this rgp41, Mymetics will further pursue the development of its HIV-1 candidate vaccine, which could be administered through various immunization routes, as a standalone product or combined with viral vectors in a prime-boost approach”.
Vaccines are poorly accessible in developing countries
Vaccines require cold-chain storage and are often delivered by injection, which is undesirable, less safe and more expensive to administer.
Developing thermostable solid form vaccines through non-invasive routes may represent a long-term global solution to the vaccination challenge (Amorij, 2008).
Virosomes are an efficient vaccine delivery system
Virosomes are spherical, unilamellar lipid-based carriers, intercalated with functional glycoproteins to reflect the natural virus, however the lack of viral RNA means there is no risk of infection
(Figure 1). Virosomes can be tagged with different antigens and adjuvants, meaning they can be tailored to target different viruses, and offer increased immunogenicity over inactivated viruses.
Currently, virosomal influenza vaccines are only available in liquid form (Amorij, 2008).
Spray drying can produce dry powders for a range of dosage forms, including inhaled or nasal drug delivery.
A dry powder is formed when a liquid feed solution or suspension is atomised using a spray nozzle, and rapidly dried using hot air. However, while the drying process is gentle due to evaporative cooling,
there is still the potential to stress and inactivate vaccine components. It has been found that subunit and live-attenuated vaccines (and other delicate molecules such as proteins)
can be protected during processing b by incorporating them in an amorphous sugar matrix, which also offers longer term stability during storage (Kanojia, 2016).
A method has been developed to produce a powder form of virosome based influenza vaccine using spray-drying.
Formulations have been optimised for oral and nasal delivery.
Advantages of Virosomal Drug Delivery
Virosomal technology is approved by the FDA for use in humans, and has a high safety profile
Virosomes are biodegradable, biocompatible, and non-toxic12
No disease-transmission risk
No autoimmunogenity or anaphylaxis10
Broadly applicable with almost all important drugs (anticancer drugs, proteins, peptides, nucleic acids, antibiotics, fungicides)
Enables drug delivery into the cytoplasm of target cell
Promotes fusion activity in the endolysosomal pathway
Protects drugs against degradation
Virosomal Structure and Modifications
Figure 1: Virosomes are reconstituted influenza virus envelopes devoid of inner core and genetic information
Virosomes are spherical unilamellar vesicles with a mean diameter of around 150 nm. Influenza virus is most commonly used for virosome production. Virosomes cannot replicate but are pure fusion-active vesicles. In contrast to liposomes, vorosomes contain functional viral envelope glycoproteins: influenza virus hemagglutinin (HA) and neuraminidase (NA) are intercalated within the phospholipid bilayer membrane (Figure 1). Further characteristics of virosomes depend on the choice of bilayer components. Virosomes can be optimized for maximal incorporation of the drug, or for the best physiological effect by modifying the content or type of membrane lipids used. It is even possible to generate carriers for antisense-oligonucleotides or other genetic molecules, depending on whether positively or negatively loaded phospholipids are incorporated into the membrane. Various ligands, such as cytokines, peptides, and monoclonal antibodies (MAbs) can be incorporated into the virosome and displayed on the virosomal surface. Even tumor-specific monoclonal antibody fragments (Fab) can be linked to virosomes to direct the carrier to selected tumor cells.1,11
WO/1999/025377 (GP41 mutee) Method for obtaining vaccines for preventing the pathogenic effects related to a retroviral infection Mymetics Corp. Expiration date: November 16, 2018
WO/2005/010033 (GP41 ter) New soluble and stabilized trimeric form of GP 41 polypeptide Mymetics Corp. Expiration date: July 28, 2024
WO/2007/099446 (Virosome-P1) Virosome-like vesicles comprising gp41 - derived antigens Mymetics Corp. + INSERM + Pevion Expiration date: January 3, 2027
US/61/202 215 (GP41 4th gen) Mymetics Corp. Expiration date: February 5, 2029
US/61/202 219 (Splitting GP41) Mymetics Corp. Expiration date: February 5, 2029
WO/2004/106366 (UK39) Methods for synthetizing conformationally constrained peptides, peptidomimetics and use of such peptidomimetics as synthetic vaccines Mymetics Corp. Expiration date: June 1, 2024
WO/2004/078099 (AMA49) Compositions and methods for the generation of immune response against Malaria Mymetics Corp. Expiration date: March 2, 2023
WO/2004/045641 (APRECS) Antigen-complexes Bestewil BV Expiration date: November 19, 2023
WO/2004/110486 (Lipopeptide) Functionally reconstituted viral membranes containing adjuvant Bestewil BV Expiration date: June 17, 2024
WO/2004071492 (DCPC) Virosome-like particles Bestewil BV Expiration date: December 2, 2023
[Viruses that can be applied and used in the formation of the virosome-like-particles according to the invention can be derived from all sorts of viruses, non-limiting examples of such viruses being: Retroviridae such as Human Immunodeficiency virus (HIV); rubellavirus; paramyxoviridae such as parainfluenza viruses, measles, mumps, respiratory syncytial virus, human metapneumovirus; flaviviridae such as yellow fever virus, dengue virus, Hepatitis C Virus (HCV), Japanese Encephalitis Virus (JEV), tick-borne encephalitis, St. Louis encephalitis or West Nile virus; Herpesviridae such as Herpes Simplex virus, cytomegalovirus, Epstein-Barr virus; Bunyaviridae; Arenaviridae; Hantaviridae such as Hantaan; Coronaviridae; Papovaviridae such as human Papillomavirus; Rhabdoviridae such as rabies virus. Coronaviridae such as human coronavirus; Alphaviridae, Arteriviridae, filoviridae such as Ebolavirus, Arenaviridae, poxyiridae such as smallpox virus, and African Swine Fever virus.]