Project: Development of an enhanced vaccine production and delivery platform

Vaccines are used for preventing a variety of serious diseases such as pandemic flu, malaria or HPV, and represent a multi-billion dollar market. However, modern antigen based vaccines often face barriers of cost and efficacy. The project aim is to develop a protein expression and delivery system designed to produce highly efficacious vaccines more cost effectively. _x000D__x000D_We have established a consortium of two SMEs and a University group that is ideally suited to successfully complete the project. The project builds on Mucosis' Bacterium-Like Particle (BLP) adjuvant, ExpreS2ion's S2 insect cell protein expression system, and combines the development with University of Copenhagen's (UCPH) promising pre-clinical placental malaria(PM) vaccine planned to enter clinical trials within the next 3 years._x000D__x000D_A vaccine against placental malaria, also called pregnancy associated malaria, is sorely needed. PM has been estimated to be responsible for 20,000 maternal and 200,000 infant deaths annually. In 2003, UCPH identified a lead PM vaccine antigen, which is currently in late pre-clinical development . Today, more than 100 papers have confirmed their findings. However, natural variation of the antigen requires a vaccine with high cross-reactivity, while the nature of the target population requires the vaccine to induce long term memory to be effective. Furthermore, the economy of endemic areas place financial restrains on the cost of the vaccine. The problems faced by a PM vaccine are broadly shared by vaccines in general, e.g. product cost, efficacy, and cross-protection. Technologies developed to address PM would therefore be widely applicable to the entire vaccine industry._x000D__x000D_These obstacles will be addressed by developing a novel, immunogenicity-enhancing S2 insect cell protein expression system and combining it with a multivalent BLP adjuvant based delivery system. ExpreS2ion has developed the Drosophila S2 expression system, ExpreS2, over the last 12 years, which has a number of key advantages over other systems. ExpreS2ion has applied S2 technology in clinical vaccine trials up to phase 2. The immunogenicity-enhancing S2 protein expression system will be established by glyco-engineering the Drosophila S2 cells to produce vaccine antigens with more immunogenic glycosylation patterns. The immunogenicity of non-human glycoforms offers a unique opportunity to modulate immune response through targeted cell line glyco-engineering. _x000D__x000D_Enhanced antigens produced in the new S2 cell line will then be conjugated to a BLP adjuvant, establishing a multivalent, cross-protecting vaccine. The BLP technology is based on the food-grade Gram-positive bacterium Lactococcus lactis. The non-recombinant L. lactis bacterium is used to produce BLPs. These bacterial particles are efficiently taken up by antigen presenting cells and stimulate the innate immunity through the TLR2 pathway. Multiple antigens are conjugated to the surface of BLPs using Mucosis’ proprietary Protan linker technology. _x000D_The role of the BLPs will be: _x000D_- Enhance the immune response through its adjuvant effects_x000D_- Significantly improve memory response_x000D_- Exploit the unique ability of the BLPs to be loaded with multiple antigens to enable a highly cross-protective vaccine. _x000D__x000D_For Mucosis and ExpreS2ion, the market is not only malaria vaccination (US$400M public market by 2025), but also other vaccine segments, where the technology platforms of the two companies fulfill key unmet needs. Frost and Sullivan estimates that the World vaccines market will cross the mark of US$ 40 Billion by 2015, growing from over US$ 25 billion in 2011. Industry analysts point to a number of growing segments with potential opportunities, e.g. the Influenza vaccine market is expected to cross US$ 7 Billion market by 2015, and Bio-protection and Travel & Endemic vaccines market is expected to double by 2015 from their market in 2009._x000D__x000D_Thus, the three principle goals of the project are: _x000D_1. A novel production and vaccine delivery system combination that will lead to an optimum immune response for vaccine antigens _x000D_2. An improved S2 expression system for the cost-effective production of highly immunogenic vaccine antigens_x000D_3. A multivalent placental malaria vaccine with improved population coverage and efficacy_x000D__x000D_In summary, the requirements for an effective low-cost vaccine production and delivery system are well defined and the S2 system and the BLP adjuvant technology has inherent qualities that make them attractive platforms to fulfill these requirements. The objectives and work plans for this project are designed specifically to meet the needs of the industry for a new cost-effective and efficacious vaccine production system. Furthermore, a successful project will result in a low-cost placental malaria vaccine with enhanced cross-protection and immunogenicity, which will address a critical medical need and clearly demonstrate the advantages of the new production and delivery platform.

Acronym Improved Vaccines (Reference Number: 7245)
Duration 15/09/2012 - 14/09/2015
Project Topic The project aim is to develop protein expression and delivery systems designed to produce high efficacy vaccines more cost effectively. The project builds on successful adjuvant and S2 expression technologies, and combines the development with a promising pre-clinical placental malaria vaccine.
Project Results
(after finalisation)
The project was successful in its CO goal of developing an improved malaria vaccine. Furthermore, the technologies developed in the project can be used to produce improved vaccines in general. Also, technologies developed for the glyco-modification of S2 cells resulted in several improvements to the service and product offerings of ExpreS2ion, and significant progress was made towards a potentially commercial glyco-optimized cell line._x000D__x000D_Specifically the following results were achieved:_x000D_- Two new Virus-like-particle (VLP) approaches were developed during the course of project and IP was filed on both_x000D_- One of the VLP approaches significantly improves the placental malaria vaccine and will be employed in further development of the vaccine, as well as potential future clinical trials. _x000D_ - These VLP approach shows promise not only for traditional vaccines, but also for cancer immunotherapy against self-antigens (and resulted in one paper so far)_x000D__x000D_- Progress towards a glyco-engineered Drosophila S2 cell line was made, and during this work the following tools, products and service offerings were developed as well:_x000D_ - Methods for the co-expression of up to six different proteins, including a ribosomal skipping method, an IRES based method, and the creation of a set of vectors with alternative and compatible selection markers. _x000D_ - One of the new selection marker vectors have been included in the ExpreS2ion kit, strengthening our offer. The expanded kit is currently sold to customers._x000D_ - One of the new vectors has enabled ExpreS2ion to offer a new Fast-Select cell line method, which halves the time from gene to protein production compared to our standard method._x000D_ - The new selection vector also appears to be able to allow us to do selection without the use of fetal bovine serum (FBS), which would have significant regulatory and safety advantages for future vaccines produced from our system._x000D_ - Implementation of the CRISPR method for deletion of specific glycosyltransferases has been implemented and can now be used to further optimize the cell line for production_x000D_ - Advanced cloning methods using FACS sorting to support cloning and CRISPR projects have been developed and will soon be offered to clients_x000D_ _x000D_- Although there was no Vaccine outcome for the BLP approach, additional data was generated showing the binding of the antigen to the Bacteria-like-Particle (BLP), and increased immunogenicity, which Mucosis can use to support the BLP technology in the future._x000D_
Network Eurostars
Call Eurostars Cut-Off 8

Project partner

Number Name Role Country
3 Mucosis B.V. Partner Netherlands
3 ExpreS2ion Biotechnologies ApS Coordinator Denmark
3 University of Copenhagen Partner Denmark