Development of improved DNA vaccines for broad protection against influenza
Influenza epidemics cause around 3-5 million cases of severe illness and 290.000 to 650.000 deaths worldwide each year.
Influenza is a rapidly mutating virus. Current influenza vaccines are updated every year to keep up with these changes. Drastic changes could lead to a new pandemic, to which existing vaccines do not protect. We want to address these problems by developing a new rapidly producible vaccine that provides protection against many influenza strains.
The influenza virus contains two major surface proteins; hemagglutinin (HA) and neuraminidase (NA). After vaccination or infection, our body forms immune responses against these proteins. Different influenza virus strains contain different variations of HA and NA. Mutations in the virus can lead to changes in HA an NA that enable evasion of existing immune responses.
Our group designed DNA vaccines that target HA to specific immune cells (antigen presenting cells). This vaccine induces potent protective immune responses in mice. However, these responses mainly protect against virus strains with the same HA as present in the vaccine, but usually do not protect against other strains. We recently tested a mix vaccine containing many different variations of HA. This mixed vaccine induced immune responses against multiple HA variations, and partially protected mice from influenza infection. In this project, we want to improve the protective efficacy of our vaccine. We also want to test the potential of NA in our vaccines to induce broad immunity, and test if combining different influenza antigens can improve our vaccine. Additionally, we want to test some vaccine strategies in the form of mRNA and viral vectors. We also we want to compare some of our new vaccines to conventional-type inactivated virus vaccines. Finally, to expand our vaccines for human use, we want to test the effectiveness of our vaccines with human targeting units using mice carrying human HLA on antigen presenting cells.
We characterize all our vaccines in vitro, but only animal experiments enable us to study the immunogenicity of vaccines. It is impossible to predict the effect of vaccines in the physiological conditions of the complex mammalian immune system without animal experiments. We therefore apply for 4963 mice. Mice will be vaccinated and immune response (antibodies, T cells, protection against infection) will be studied. We design experiments to include enough animals to gain significantly relevant results, thereby minimizing the number of repeat experiments and mice needed. We base these numbers on power calculations and experience with previous experiments. To minimize discomfort, mice are anesthetized before vaccination. We expect little adverse effects after vaccination or blood sampling. To study the protective effect of a vaccine, it is important to infect mice with influenza. Affected mice will lose weight, experience flu symptoms for 1-3 days and experience moderate discomfort. Mice that lose too much weight, determined by a defined humane endpoint, are euthanized.
With the proposed experiments, the knowledge we hope to gain will bring us closer to developing a universally protective influenza vaccine.
Influenza is a rapidly mutating virus. Current influenza vaccines are updated every year to keep up with these changes. Drastic changes could lead to a new pandemic, to which existing vaccines do not protect. We want to address these problems by developing a new rapidly producible vaccine that provides protection against many influenza strains.
The influenza virus contains two major surface proteins; hemagglutinin (HA) and neuraminidase (NA). After vaccination or infection, our body forms immune responses against these proteins. Different influenza virus strains contain different variations of HA and NA. Mutations in the virus can lead to changes in HA an NA that enable evasion of existing immune responses.
Our group designed DNA vaccines that target HA to specific immune cells (antigen presenting cells). This vaccine induces potent protective immune responses in mice. However, these responses mainly protect against virus strains with the same HA as present in the vaccine, but usually do not protect against other strains. We recently tested a mix vaccine containing many different variations of HA. This mixed vaccine induced immune responses against multiple HA variations, and partially protected mice from influenza infection. In this project, we want to improve the protective efficacy of our vaccine. We also want to test the potential of NA in our vaccines to induce broad immunity, and test if combining different influenza antigens can improve our vaccine. Additionally, we want to test some vaccine strategies in the form of mRNA and viral vectors. We also we want to compare some of our new vaccines to conventional-type inactivated virus vaccines. Finally, to expand our vaccines for human use, we want to test the effectiveness of our vaccines with human targeting units using mice carrying human HLA on antigen presenting cells.
We characterize all our vaccines in vitro, but only animal experiments enable us to study the immunogenicity of vaccines. It is impossible to predict the effect of vaccines in the physiological conditions of the complex mammalian immune system without animal experiments. We therefore apply for 4963 mice. Mice will be vaccinated and immune response (antibodies, T cells, protection against infection) will be studied. We design experiments to include enough animals to gain significantly relevant results, thereby minimizing the number of repeat experiments and mice needed. We base these numbers on power calculations and experience with previous experiments. To minimize discomfort, mice are anesthetized before vaccination. We expect little adverse effects after vaccination or blood sampling. To study the protective effect of a vaccine, it is important to infect mice with influenza. Affected mice will lose weight, experience flu symptoms for 1-3 days and experience moderate discomfort. Mice that lose too much weight, determined by a defined humane endpoint, are euthanized.
With the proposed experiments, the knowledge we hope to gain will bring us closer to developing a universally protective influenza vaccine.