Influenza is one of the major person-to-person transmittable respiratory viral infections in humans. In the EU http://ec.europa.eu/health/ph_threats/com/Influenza/docs/seasonflu_rec2009_en.pdf, seasonal influenza epidemics cause 4-50 million symptomatic cases and 15.000-70.000 deaths yearly. The yearly economic burden associated with seasonal influenza in the EU is €6-14billion while the impact of a very moderate pandemic is estimated to be around €50 billion. The current strategy to prevent influenza-associated health risks is annual immunization of risk populations. Yet, current vaccines need to be adjusted each year and even then it is not guaranteed that they will match the circulating epidemic virus. Moreover, current vaccines are not effective against newly emerging influenza virus strains as demonstrated during the Mexican Flu pandemic in 2009. Universal influenza vaccines capable of providing protection against a broad spectrum of influenza virus strains are thus urgently needed. These vaccines need to be based on conserved constituents of the virus and should raise humoral as well as cellular immunity that effectively protect against influenza-associated disease symptoms.
The UNISEC objective is to bring together a number of vaccine concepts into a single study in order to identify, develop and clinically test the most promising leads for a universal influenza vaccine, which must (1) demonstrate adequate (universal) protection, and (2) be technically suitable for development to a marketable product.
To achieve this overall aim, UNISEC has defined six sub-objectives:
UNISEC is a European consortium consisting of 3 academic partners, 5 National Health Institutes and SMEs, all with leading expertise in influenza vaccine research and development. In addition, UNISEC has access to a network of clinical trial centers. The expertise present in the consortium spans the entire range from vaccine design via vaccine formulation to vaccine production, pre-clinical and clinical testing and regulatory issues.
The consortium is supported by an advisory board consisting of representatives from the influenza vaccine industry, public health institutions, the World Health Organization (WHO), the European Center for Disease Control (ECDC), and the Biomedical Advanced Research and Development Authority (BARDA). UNISEC is coordinated by Prof. Dr. Henderik W. Frijlink, Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, The Netherlands, and started its activities in October 2013.
The UNISEC consortium is unique in being devoted to comparative evaluation of a panel of universal influenza vaccine candidates. Thus, rather than focusing on a single vaccine UNISEC harbours a variety of vaccine concepts and these are tested in head-to-head comparison or in standardized animal or clinical tests. This approach allows comparison of the pros and cons of the different vaccine candidates and facilitates selection of the most promising vaccine candidates for further development.
In order to allow for comparative vaccine assessment UNISEC has identified and (internally) published a set of criteria to be fulfilled by a ‘universal’ or better ‘broad spectrum’ influenza vaccine (D2.1). Moreover, after discussion with the Innovative Task Force of the European Medicine Agency UNISEC has drafted a white paper in which these criteria are further specified next to issues concerning manufacturing, storage, efficacy, safety, and regulatory approval of a broad spectrum influenza vaccine (D2.5).
As comparison of results across different preclinical and clinical studies is a key objective of UNISEC much effort has been put into study standardization. Partner 6 (NIBSC) has provided for the UNISEC partners standardized and well characterized material including different influenza virus strains, inactivated vaccines as well as antigens for immune response evaluation. In numerous discussions the UNISEC partners agreed upon standardized experimental conditions for the preclinical as well as for the clinical studies (D2.3 and D4.1). The UNISEC partners identified T cell immunity as a primary read-out in preclinical and clinical studies. Under the lead of Partner 10 (RKI) UNISEC partners have developed, optimized and validated standardized protocols for collection, processing and storage of peripheral blood mononuclear cells. Moreover, standard operating procedures for multi-parametric FACS analysis (allowing simultaneous assessment of various cytokines and cytotoxicity markers in CD4 and CD8 T cells) as well as methods for reliable statistical analysis of the obtained T cell data have been worked out in detail and are now ready for use (D5.1).
A major activity of the UNISEC program is the execution of clinical Phase IIb trials with two universal influenza vaccine candidates, Flu-v developed by Partner 3 (SEEK) and Multimeric-001 (M-001) developed by Partner 4 (Biondvax). For this purpose Partner 1 (RUG) established a study trial centre network and Partner 2 (UMCG) audited the sites involved and provided on-site training in trial excecution (D6.1, D6.8). Detailed study protocols were developed, submitted to the relevant ethical committees for approval, and registered in EudraCT (D6.2 – D6.7). A data management plan was drawn up and an internet-based secured data management tool was installed.
The M-001 clinical trial has taken place at the St. Istvan and St Laszlo hospital in Budapest, Hungary and four additional satellite trial sites. From October 2015 245 subjects were screened of which 225 entered randomization and 219 completed the study in October 2016. All samples were collected according to schedule and have been shipped to Partner 10 for further analysis. Analysis is ongoing and final data are expected to be available by mid 2017.
The Flu-v clinical trial started at the Isala Clinics, Zwolle, The Netherlands, in May 2016. Recruitment is still ongoing but more than 40 participants have already received the planned two vaccinations. It is expected that by the end of 2016 all vaccinations will be completed. Blood sampling will go on in 2017 and data are expected at the end of the year.
UNISEC partners have developed and tested in head-to-head or standardized experiments several new vaccine candidates including peptide-based vaccines, DNA-based vaccines, vector-based vaccines and vaccines combined with different adjuvants (D4.3). Experiments were performed in mice, ferrets and cotton rats (D4.4). Several vaccines have been successfully formulated as dry powders (D3.1 –D3.4) thus allowing extended storage, independence from cold chain and new administration routes (eg. pulmonary).
UNISEC governance activities comprised a.o. the establishment of a UNISEC website (www.unisecconsortium.eu), holding regular teleconferences with the general assembly, and the organisation of three face-to-face meetings (October 2013 Groningen, March 2014 Copenhagen, May 2015 Berlin). These latter meetings proved an excellent opportunity for the young researchers to present their data and get engaged together with the senior scientists in discussions about results obtained and further planning of activities.
In addition to UNISEC internal meetings get-togethers and workshops with other EU consortia active in the field of universal influenza vaccine development were organized in order to exchange about correlates of protection, animal models, use of resources etc. Meetings with other international stakeholders like DG-Health, EMA, WHO and BARDA were also organized, and these communications are expected to be intensified in the subsequent stage of the UNISEC project.
The UNISEC consortium expects that by the end of the project period at least one promising universal influenza vaccine candidate will have been identified and will be ready to enter phase III clinical studies. If successful in further clinical testing the candidate vaccine will be made available to European manufacturers thereby strengthening their market position. The lead user of the UNISEC final product will be the European population which will be better protected from seasonal epidemics as well as pandemics caused by newly emerging virus strains.
In addition to these direct, yet long-term, impacts UNISEC will also enhance future vaccine development in indirect ways: (i) The UNISEC work program will contribute to the resolution of current problems of non-uniformity in the (pre-)clinical development and evaluation of universal influenza vaccines in Europe by a unified approach using a sustainable vaccine expertise network.(ii) The UNISEC project will deliver a portfolio of validated methods and standardized reagents and viral stocks (toolbox) for evaluation of immune responses for influenza vaccines. (iii) UNISEC can serve as an example for coordinated development of vaccines as it is a unique initiative in which the partners have set aside competition issues and have rather committed themselves to provide candidate vaccines and expertise for head-to-head comparisons with the aim to focus further investments on the most promising vaccine candidate(s). Comparative evaluation of the new generation of influenza vaccines will become essential in the coming years to define the best vaccine candidate for each task and target populations. After 70 years, the technology of influenza vaccines is finally being upgraded. Replacing the existent flu jab with improved broadly protective, long lasting influenza vaccines with new application technologies is already creating the need for new regulations, safety standards, production criteria, and distribution logistics. Through intense contact with regulatory authorities UNISEC is paving the way towards registration of new influenza vaccine modalities. Europe is now at the forefront of technological break-throughs in the field of influenza vaccination, and with coordinated efforts we can finally minimize the burden of influenza infection for the European population.
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10/16/2015 1:36:32 PM