Development of heterodimeric DNA vaccines for broad protection against influenza
Worldwide, seasonal influenza epidemics cause around 3-5 million cases of severe illness and 290.000 to 650.000 deaths each year. These numbers could be much higher in unexpected pandemics. Because the influenza virus mutates rapidly, current influenza vaccines have to be updated and administered every year to keep up with these changes. Drastic changes could lead do a new pandemic, to which existing vaccines do not protect. A new type of vaccine with high protection against several or all different influenza strains that can rapidly be produced would improve our preparedness for a pandemic and improve seasonal protection.
One major outer protein on the influenza virus surface is hemagglutinin (HA). Our group created DNA vaccines that target HA to specific immune cells (antigen presenting cells). This vaccine induces good immune responses in mice and protected them from influenza infection. However, different strains of the influenza virus contain different types of HA, and immune responses against one type usually don't protect against other types of HA. In recent experiments we mixed many different HA types from different viruses in one vaccine. This vaccine induced immune responses against multiple types of HA in mice, and partially protected them from influenza infection. We now want to improve the protective effect of our vaccine.
All vaccines are characterized in vitro, but to study the immunogenicity of new vaccines, animal experiments are the only alternative available. The immune system is complex, and it will be impossible to fully predict the effect of a vaccine in physiological conditions without experiments in mice. We therefore apply for 2180 mice. These mice will be vaccinated and the resulting immune response will be studied with different methods. The experiments were designed to minimize the number of mice by including enough animals in each experiment to gain significantly relevant results. These numbers were based on power calculations and experience with previous experiments in our group. To minimize discomfort, mice are anesthesized before vaccination. Little adverse effects are expected after vaccination. To study the protective effect of a vaccine, it is important to infect vaccinated mice with influenza virus. Affected mice are expected to lose weight, and experience flu symptoms for 1-3 days and will experience moderate discomfort. Mice that lose too much weight, determined by a defined human endpoint, will be euthanized to prevent further pain and discomfort.
With the proposed experiment we want to better understand what immune response is necessary for a broad protection towards different influenza viruses, and use that knowledge to optimize our vaccine to induce stronger immune responses and better protection. The knowledge we hope to gain will bring us closer to a universally protective influenza vaccine.
We want also to expand the knowledge for human targeting units within influenza, and include HLA DQ2 tg mice for further translation to human vaccines. These mice contains human HLA on DCs and allow for targeting of vaccine with similar targeting units that can be used in human clinical trials.
One major outer protein on the influenza virus surface is hemagglutinin (HA). Our group created DNA vaccines that target HA to specific immune cells (antigen presenting cells). This vaccine induces good immune responses in mice and protected them from influenza infection. However, different strains of the influenza virus contain different types of HA, and immune responses against one type usually don't protect against other types of HA. In recent experiments we mixed many different HA types from different viruses in one vaccine. This vaccine induced immune responses against multiple types of HA in mice, and partially protected them from influenza infection. We now want to improve the protective effect of our vaccine.
All vaccines are characterized in vitro, but to study the immunogenicity of new vaccines, animal experiments are the only alternative available. The immune system is complex, and it will be impossible to fully predict the effect of a vaccine in physiological conditions without experiments in mice. We therefore apply for 2180 mice. These mice will be vaccinated and the resulting immune response will be studied with different methods. The experiments were designed to minimize the number of mice by including enough animals in each experiment to gain significantly relevant results. These numbers were based on power calculations and experience with previous experiments in our group. To minimize discomfort, mice are anesthesized before vaccination. Little adverse effects are expected after vaccination. To study the protective effect of a vaccine, it is important to infect vaccinated mice with influenza virus. Affected mice are expected to lose weight, and experience flu symptoms for 1-3 days and will experience moderate discomfort. Mice that lose too much weight, determined by a defined human endpoint, will be euthanized to prevent further pain and discomfort.
With the proposed experiment we want to better understand what immune response is necessary for a broad protection towards different influenza viruses, and use that knowledge to optimize our vaccine to induce stronger immune responses and better protection. The knowledge we hope to gain will bring us closer to a universally protective influenza vaccine.
We want also to expand the knowledge for human targeting units within influenza, and include HLA DQ2 tg mice for further translation to human vaccines. These mice contains human HLA on DCs and allow for targeting of vaccine with similar targeting units that can be used in human clinical trials.