Turning recessive epitopes into dominant epitopes: Application to a universal influenza vaccine

The biggest challenge in vaccine development is to create vaccines against viruses that change frequently, such as the influenza virus, HIV and COVID-19. The problem is that the changes often change the structures that antibodies are directed against. Therefore, when the virus mutates, it will escape destruction mediated by antibodies. The problem would be solved if vaccines could induce antibodies that bind conserved structures that do not change between viruses. Unfortunately, conserved structures are poor at inducing antibodies. Such structures are therefore called immunorecessive (submissive) structures. In order to solve this problem, in this project we will develop a vaccine strategy that makes recessive structures dominant. The basis for the project is as follows: Vaccine molecules that express two copies of a structure induce strong antibody responses, while vaccine molecules that only have one copy induce weak antibody responses. Therefore, if one could make vaccine molecules that express two copies of immunorecessive structures, and only one copy of an immunodominant structure, then the goal might be achieved. Such vaccine molecules can be made with a technology that the project leader and employees have developed. The experiments will be carried out with an influenza protein, hemagglutinin, as antigen. The hope is that the new strategy will induce strong antibody responses against conserved structures on hemagglutinin (HA), and therefore make it difficult for viruses to escape the antibodies. The project will use a newly developed vaccine platform that guides the antigen to the immune cells that start the adaptive immune response, i.e. the antigen presenting cells (APC), in a focused way. The first DNA vaccines have been made and preliminary trials in vitro and in vivo to confirm the quality of the DNA vaccines are underway. Initial trials in mice are promising. These trials are aimed at seasonal influenza. The trials will be extended to bird flu and pandemic flu. The experiments will then be extended to ferrets and monkeys in order to create the right conditions for clinical trials in humans. Hopefully, the project will result in a general vaccine technology that can turn immunorecessive structures into dominant ones. This vaccine technology will be important not only for influenza, but also for other types of diseases such as HIV and COVID-19.