Influenza pandemics are dangerous and can claim many lives. Children and the elderly in particular run a high risk of developing influenza-related complications, because their immune system is often weakened by the virus. In Germany, annual vaccination against seasonal influenza has therefore been recommended for these target groups for quite a few years now. However, producing vaccines is costly and time-consuming. Researchers at the University of Konstanz are developing a new vaccine that is easy to use and protects people against a wide range of strains.
A distinctive feature of the winter months is the prevalence of influenza outbreaks, which can sometimes assume epidemic proportions. It is therefore important to protect vulnerable population groups such as children and the elderly who run a particularly high risk of infection with the influenza virus by vaccinating them before the cold season begins. Influenza vaccines usually contain either three inactivated or attenuated influenza strains. The vaccine's viral components trigger the production of antibodies directed against the surface glycoproteins (antigens) of the viruses. However, these surface glycoproteins are highly variable and the effect of the vaccines depends on the virus strains chosen for the seasonal influenza vaccine. It is therefore important to anticipate well in advance (in spring) the influenza virus strains that are likely to be circulating in the upcoming winter season. If the wrong viruses are chosen, the influenza vaccine has very little effect. Other influenza virus strains are then able to spread in the population. In terms of production methods, influenza vaccines are mostly made using an egg-based process, which is both time-consuming and rather costly.
Valerie Herrmann, a biologist at the University of Konstanz, has made a decisive contribution to the development of a new vaccine against influenza A viruses. During her doctoral studies, she was involved in a project to facilitate the production of influenza A vaccines. The idea was to produce vaccines that, unlike standard vaccines, did not depend on anticipating which influenza virus strains are likely to be around in a given winter. This would therefore preclude selection of the wrong viruses, making the new vaccines more effective than current ones.
Standard influenza vaccines contain a mixture of three or four viral strains and subtypes. These vaccines activate B cells that only produce antibodies against the antigens on the surface of the targeted virus strains. As a result, the vaccines only protect against specific strains and subtypes and new vaccines have to be produced every year.
"Our new vaccine uses highly conserved antigens that occur inside the virus. These antigens activate cytotoxic T cells," says Valerie Herrmann who gained her PhD in August 2015. Cytotoxic T cells exhibit immunity against most influenza viruses. In their study, the researchers encapsulated two highly conserved influenza A virus peptide antigens together with immunostimulatory substances in biodegradable polylactide co-glycolide (PLGA) microspheres. The microspheres are made from lactic and glycolic acids and can be readily biodegraded by the human body, which is why they have been approved for use in humans. PLGA microspheres are taken up in the cells by specific antigen-presenting cells. The encapsulated immunostimulatory substances are recognised by cells as dangerous, putting them in a state of high alert, and reinforcing their ability to activate cytotoxic T cells which then kill the virus-infected cells. "The antigens that we use in our study are peptides of defined length and amino acid sequence. The peptides are synthesised chemically and are non-infectious. They can be produced relatively quickly and stored for a long time," says the young scientist highlighting the advantages of the new vaccine.
"The two core aspects of our immunisation are the antigens and the way the vaccine is administered. Influenza vaccines, which may be administered as subcutaneous injection or nasal spray, are unable to generate a sufficient number of cytotoxic T cells in the lung," says Valerie Herrmann. However, cytotoxic T cells are required at the site of infection, i.e. lungs, in order to mount an effective immune response against the influenza viruses. This is achievable in two immunisation rounds, the first in the form of a subcutaneous injection, which induces T cell responses in immunological organs, and the second as an intranasal application, which induces a local immune response against the influenza virus. "Nasal sprays are a very gentle way of administering vaccines and can easily be applied by people with no medical education. The microspheres are resuspended in a saline solution and inhaled," says the biologist explaining how the new vaccine works.
Scientists from the University of Konstanz have been working on a vaccine involving PLGA microspheres for quite some time. The effect of this vaccine in cancer prevention has already been tested in preclinical models. In a cooperative project with Prof. Oliver Planz from the University of Tübingen, the researchers from Konstanz realised that the method might also be suitable for developing a more efficient influenza vaccine.
Together with her mentor, biologist Prof. Marcus Groettrup, Valerie Herrmann developed the idea, designed the experiments and produced the PLGA microspheres. Prof. Planz and his team from Tübingen were in charge of the work with influenza A. The project partners have been working together on the project for two years now. Two-tier immunisation with the vaccine, i.e. subcutaneous priming followed by intranasal boosting, triggers strong and systemic T cell responses in lymphatic organs and the lungs. Experiments with mice have already shown that the strong T-cell response interferes with viral replication, weight loss and infection-related death. However, the vaccine's effectiveness has yet to be proven before it can be used on a larger scale to attenuate pandemic outbreaks of influenza viruses. "I am pleased that my work has contributed to the development of a new vaccine that has the potential to limit the spread of influenza A in humans," concludes Valerie Herrmann.