Authors: Martha Powell, Future Science Group
In line with our focus this month on all aspects of influenza, we spoke to Ed Schmidt, project manager of the Universal Influenza Vaccines Secured (UNISEC) consortium. Ed studied biology and completed his Ph.D. on endocrinology in 1992 in Amsterdam (Netherlands) before investigating the activity of signal transduction during cellular immunity as a senior scientist. He became Assistant Professor in epigenetics, and later co-founded a biotech company on the genetics of cellular immunity.
More and more he focused on the management of large international consortia with academic and industrial partners and over the last 10 years this has concentrated on the development and testing of new generation of influenza vaccines. You can find out more about the UNISEC consortium and its work towards developing a universal influenza vaccine below.
First, could you introduce UNISEC and the aims of this project?
Influenza is one of the major person-to-person transmittable respiratory viral infections. In the European Union (EU), seasonal influenza epidemics cause 4–50 million symptomatic cases and 15,000–70, 000 deaths during a normal flu season (further reading 1). The yearly economic burden associated with seasonal influenza in the EU is €6–14 billion 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 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.
UNISEC www.unisecconsortium.eu is a European consortium consisting of 3 academic partners, 5 National Health Institutes and 3 small biotech companies, 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 started its activities in October 2013 and will complete its current activities in March 2018.
Within the clinical trial network we already performed comparative Phase IIB clinical studies with two of our candidate vaccines. All the results of these trial studies, including the in-depth analyses of the cell-mediated immune responses in the vaccinated subjects, will be presented and published, in order to allow maximum transparency.
The UNISEC consortium is unique in being devoted to comparative evaluation of a panel of six universal influenza vaccine candidates. Thus, rather than focusing on a single vaccine UNISEC has a variety of vaccine concepts and these are tested in head-to-head comparison or in standardized animal or clinical tests. This approach allows for the transparent comparison of the pros and cons of the different vaccine candidates and facilitates selection of the most promising vaccine candidates for further development.
In comparison with large pharmaceutical companies, we perform our development at highly reduced costs. Even more important is the fact that, as a public-funded organization, we publish and present all our results. The pipeline for vaccine development can be applied to any other influenza candidate vaccine and even to other types of vaccines. Our strategy allows the public-funded development and testing of various candidate vaccines without the need for collaborating companies to apply for venture capital or be taken over by large vaccine manufacturers.
“The UNISEC consortium is unique in being devoted to comparative evaluation of a panel of six universal influenza vaccine candidates.“
The aim of UNISEC is to identify, develop and clinically test the most promising concepts for a universal influenza vaccine that can be demonstrated to offer adequate (universal) protection, and that are technically suitable for further development to a marketable product.
What are the issues with current influenza vaccines?
Globally, every year 250, 000–500,000 people die of influenza and another 3–5 million suffer severe illness. Vaccination is by far the best instrument to reduce this impact of influenza – so what is the current situation?
The existing seasonal trivalent or quadrivalent influenza vaccines provide protection against three or four strains, which are defined every 6 months by the WHO for the northern and the southern hemispheres, respectively. These vaccines normally have an efficacy of 30–50% in the target population (elderly and immune-compromised individuals). Unfortunately, they hardly protect against strains other than those selected, since protection afforded by current vaccines relies on antibodies against the highly variable surface proteins of influenza virus. Furthermore, the protection is short-lasting.
During the last flu season 128,000 influenza-related deaths were reported in Europe (further reading 2). The year before this it was even worse, with an estimated 228,000 excess deaths. An important issue in the limited protection provided by the influenza vaccines during these years was the fact that the seasonal vaccines did not sufficiently protect against the rapidly evolving influenza H3N2 virus.
“In the case of pandemics, the situation is worrying.”
In the case of pandemics, the situation is worrying. Firstly, it will take a couple of weeks until a suitable vaccine strain is available. Secondly, there is a limited production capacity with the current egg-based production platform that cannot be expanded, and might even be compromised in the case of avian influenza pandemics. A clear pattern emerges when we look at pandemic vaccines during the last pandemics: the H2N2 Asian influenza from 1957, the Hong Kong influenza from 1968 and the H1N1 influenza from 2009. In all cases the pandemic vaccines became available to the public ‘too little too late’. There was never enough pandemic vaccine available, and most of it arrived only after the first global wave of the pandemic was already over. Administration of the 2009 vaccines to vulnerable target groups, such as children, has been correlated with narcolepsy (GSK pandemic 2009 vaccine and fever in children (Novartis pandemic 2009 vaccine) (further reading 2)). These side-effects had not been registered within the mock-up dossiers of these vaccines prior to the pandemic.
“We can conclude that the available influenza vaccines leave something to be desired.”
We can conclude that the available influenza vaccines leave something to be desired. But we have to be pragmatic – even limited protection by sub-optimal vaccines is better than no pro”tection for the public. Influenza viruses do pose a serious challenge to vaccination efforts and developing highly efficient influenza vaccines is not a simple task.
What are the challenges facing development of influenza vaccines?
Influenza virus evolves rapidly by accumulation of point mutations as seen with circulating seasonal strains (genetic drift) and by exchange of genetic material between virus strains when they simultaneously infect the same cell (genetic shift). This results in novel virus strains to which populations have not been exposed to previously and therefore have no immunity, as occurs with a pandemic strain e.g., the 2009 pandemic.
This rapid influenza evolution means that the selection of virus strains for the seasonal vaccines is an ongoing process involving surveillance of current circulating strains isolated from patients, which are tested to confirm whether genetic drift from the strain in the vaccine has occurred or not. Seasonal strain-selection occurs twice yearly – once for the Northern hemisphere and once for the Southern hemisphere – to cover the upcoming influenza season. Which strains will be in the vaccine will obviously have to be decided to allow time for vaccine production and provision for the coming influenza season. This means that if the virus undergoes genetic drift after production and distribution, there may be a mismatch, leading to an increase in influenza cases during the following season. There is also an extensive reservoir of influenza strains in many mammalian and avian host species, giving rise to many new influenza strains which may be able to cross the species barrier and infect humans.
“This means that if the virus undergoes genetic drift after production and distribution, there may be a mismatch, leading to an increase in influenza cases during the following season.”
In order to overcome the shortcomings of the current vaccines new generation influenza vaccines need to fulfill the following characteristics: 1) They should be broadly protective against circulating subtypes and counter the effects of genetic drift; 2) They should induce long-lasting protection over several years; 3) They should be produced using a robust and up-scalable production platform; and 4) if possible they should be highly stable, allowing easy distribution and storage without a cold chain, and be suitable for simple needle-free application.
There are other challenges for the development of such ‘universal influenza vaccines’. It will be very important to characterize how these new vaccines function i.e., their mechanisms of action. New surrogates of immunity need to be identified during their development to measure the efficacy. The regulatory viewpoint will have to evolve together with the developed technologies, which make it very important to have a transparent communication with regulators throughout the whole developmental phase of universal vaccines. I feel it is important to note that in Europe there is already an established and rather conservative flu vaccine industry that is dominated by a few large vaccine manufacturers.
Could you outline the work on assessing candidates using comparable and standardized tests?
It will not be possible to establish one universal immunoassay for universal flu vaccine(s) because the approaches of these vaccines differ significantly in their nature and the vaccines induce different types of immune responses. Some of the universal influenza vaccines under development do not stimulate a humoral response, and therefore require new tests to be applied. In a recent international workshop an extensive overview of the potential assays for influenza vaccines was discussed. (further reading 3).
“It will not be possible to establish one universal immunoassay for universal flu vaccine(s) because the approaches of these vaccines differ significantly in their nature and the vaccines induce different types of immune responses.”
The three main serological assays, hemagglutination inhibition (HI), virus neutralization (VN) and single radial haemolysis (SRH) detect different populations of antibodies; therefore, different degrees of correlation between these assays can be seen. Inter-laboratory variability of VN and HI assays is quite large, and depends on technical standardization and variety in assay components like erythrocytes. The SRH assay has a much better reproducibility and has been defined as a correlate of protection.
Both T and B cells play a role in the generation of protective immune responses to influenza vaccines. Cellular immune assays have already been developed but are not used routinely for influenza vaccines yet. Examples include the Enzyme-linked immunosorbent spot (ELISpot) assay and the intracellular cytokine staining (ICS) assay. These assays are currently being standardized and validated through the UNISEC project. A number of variables need to be taken into consideration in order for the ELISpot and ICS assays to be standardized both within and between different labs, for example, PBMC preparation protocols, reagents, incubation periods and the stimulating antigen used in the assays. It is also necessary to use clinical trial data and human subjects in order to ascertain true as relevant correlates of protection.
A step towards standardization of the immunoassays between the laboratories is unification of assay protocols, use of common standards and regular proficiency assessment of the laboratories. Harmonization of methods does not always lead to improved agreement between laboratories and there are several examples known in the history, particularly the HI assay (further reading 4). While the harmonization of T-cell assay procedures is feasible, it is important to realize that the necessary standardization of critical reagents for any assay will require an internationally accepted toolbox of reagents, antigens and standard operating procedures. UNISEC has developed such a toolbox, and we are establishing communications with international stakeholders to make this toolbox widely available to industry, academia, and other interested organizations.
“UNISEC has developed such a toolbox, and we are establishing communications with international stakeholders…”
Could you give us a brief overview of some of the vaccine candidates in ongoing trials?
Two of the most developed candidate vaccines within UNISEC are Flu-V and M-001. For both Phase IIb trials have been performed in the context of UNISEC.
Flu-V is from the company partner SEEK (London, UK). Flu-V is composed of an equimolar mix of four peptides (FLU-5, FLU-7, FLU-8N, FLU-10) that covers conserved T-cell reactive regions in M1, M2 and NP influenza proteins.
The M-001 vaccine candidate was developed by the UNISEC company partner BiondVax (Israel). In this vaccine nine common epitopes of flu strains are connected to make one recombinant protein called M-001 produced in Escherichia coli.
UNISEC (and four other European consortia EDUFLUVAC, UNIVAX, FLUNIVAC and FLUTCORE) have another seven universal influenza candidate vaccines under development up to Phase I. In addition, several other candidate vaccines are under development in other parts of the world.
Have you seen any particularly surprising/promising results so far?
At this moment UNISEC has completed a comparative Phase IIb clinical trial study with the M-001 and the Flu-V candidate vaccines. Cell-mediated immunity (CMI) is the primary endpoint, with protection against flu a secondary endpoint for the Flu-V vaccine study.
“Our validated CMI assays are now completed for the M-001 vaccine and CMI and ELISpot are currently being performed for the Flu-V vaccine.”
Our validated CMI assays are now completed for the M-001 vaccine and CMI and ELISpot are currently being performed for the Flu-V vaccine. While our preliminary data show a robust cell-mediated immune response with the M-001 vaccine, it is unfortunately still too early to present a complete overview of the results from this comparative vaccine evaluation study.
Do you think the UNISEC project has wider implications on the field of vaccine development?
The global development of vaccines by industry is a rapidly expanding market. While the value of this industry was worth US$5 billion in 2000, it grew to US$24 billion in 2013 and is estimated to be US$100 billion by 2015 (WHO). This shows that vaccines are becoming a major engine for the pharmaceutical industry. Costs for the development for a new vaccine by these pharmaceutical companies are estimated to be approximately US$1 billion. Ultimately, this investment will have to be paid back with interest when it comes to assigning the price to be paid for such new vaccines.
“…small public funded consortia like UNISEC also provide a complete pipeline for vaccine development.”
In contrast to this, small public funded consortia like UNISEC also provide a complete pipeline for vaccine development. The difference is that the price for the development of a new vaccine, from the drawing board to completion of a Phase III clinical study is estimated to be US$50 million. This reduction in developmental cost will ultimately result in a reduced price for these developed vaccines and therefore will benefit the consumers, also making the vaccines more accessible to low-income countries.
Comparative evaluation of vaccines during their development will never be performed by large vaccine manufacturers as it is not in their interest to do so. Public-funded consortia on the other hand have to work in a completely transparent manner and will publish all results from their studies, even if they are not in line with expectations or may be negative for the candidate vaccines itself. The UNISEC approach to comparative influenza vaccine development can easily be applied to other products under development, for example tuberculosis, Zika or Ebola candidate vaccines. Public funding is important, but this investment can easily be earned back by the public at a later stage by reduced pricing of newly developed vaccines, increased availability and the fact that these vaccines have been developed and tested in a highly transparent method.
“The UNISEC approach to comparative influenza vaccine development can easily be applied to other products under development…”
Finally, what research do you think needs to be done in the next 5–10 years to achieve a universal influenza vaccine?
A number of candidate vaccines are already there for a long-lasting and broad protection against influenza virus. It will be very important now to test these new products in comparative Phase IIb and Phase III clinical efficacy studies. Comparative evaluation is important because on this way a proper selection can be made on the best product for specific target populations. It is unlikely that the established influenza vaccine manufacturers will sponsor trials with new vaccines because they directly compete with their existing current influenza vaccines. Furthermore, comparative evaluation poses a significant risk for vaccine manufacturers, and are therefore not be considered by this industry.
The Phase IIb trials performed within the public consortium UNISEC prove that with limited budgets comparative and independent trials can be performed in collaboration with small vaccine manufacturers. Public funding for trial studies will be an essential factor in the trial study phase. When the clinical trial phase has been completed for a variety of universal influenza vaccine candidates and one or more products are successful, the marketing of these products can start. In the most positive scenario, this could be before 2020.
“In the coming years I foresee that different new broadly protective and long-lasting influenza vaccines will reach the market and will slowly but steadily replace the current seasonal influenza vaccines.”
Important during the trial study phase are not only the determination of the level of protection and broadness of protection against different influenza strains, but also a detailed characterization of the cell-mediated immunity evoked by these candidate vaccines and its relation with protection against influenza. Intensive communication with the regulatory authorities and other international stakeholders will be essential at this stage for the definition of new criteria for such new vaccines.
In the coming years I foresee that different new broadly protective and long-lasting influenza vaccines will reach the market and will slowly but steadily replace the current seasonal influenza vaccines.
UNISEC. “The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement n°602012.” The author acknowledges Anke Huckriede and Kate Guilfoyle for helpful discussions.
- Proposal for a council recommendation on seasonal influenza vaccine. Comission of the European communities. http://ec.europa.eu/health/ph_threats/com/Influenza/docs/seasonflu_rec2009_en.pdf
- Seasonal Influenza/European Centre for Disease Prevention and Control. https://ecdc.europa.eu/en/seasonal-influenza (ECDC website and pers. comm)
- EDUFLUVAC. www.edufluvac.eu/news-events/events/edufluvac-workshop-immunoassay-standardisation-universal-flu-vaccines (report immunoassay standardization for universal influenza vaccines)
- Wood JM, Majr D, Heath A, Newman RW, Hoschler K, Stephenson I, Clark T, Katz J & Zambon MC Reproducibility of serology assays for pandemic influenza H1N1: collaborative study to evaluate a candidate WHO International Standard.. Vaccine. 30(2), 210–7 (2012).