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

The outmost challenge in vaccinology is "the moving target". How to make vaccines against pathogens that change over time, such as influenza virus, HIV and COVID-19. The problem is that the changes primarily affect the sites against which antibodies are directed; such sites are called immunodominant sites. Thus, when a virus changes, it can escape destruction by antibodies. The problem might be solved if vaccines induced antibodies that bind conserved sites that do not change between the viruses. Regrettably, such sites elicit only poor immune responses, and are for that reason called immunorecessive sites. To solve this problem, this proposal aims at developing a vaccine technology that turns immunorecessive sites into immunodominant ones. The basis for the project is as follows: vaccine molecules that express two identical virus proteins induce strong immune responses while vaccine molecules that only express a single virus protein only induce weak responses. Thus, if vaccine molecules could be made that have two copies of immunorecessive sites but only a single copy of immunodominant sites, the objective would be obtained. Production of such vaccines can be achieved by using a novel vaccine format that the project leader and colleagues have developed. The proof-of-concept experiments will be performed with an influenza protein, hemagglutinin (HA), as antigen. The hope is that the novel strategy will result in strong antibody responses against conserved sites on HA, thus making it difficult for influenza virus to escape immunity. We will explore a novel DNA vaccine platform that target the vaccine against antigen presenting cells (APC) in a focused way. The initial DNA vaccines are prepared and in vitro and in vivo experiments are performed to ensure functional DNA vaccines. Preliminary experiments in mice against seasonal flu are encouraging. Experiments will be extended to avian and pandemic flu. Next, experiments will be translated to ferrets and non-human primates to prepare the ground for human clinical trials. The project will hopefully result in a general vaccine technology that can turn immunorecessive sites into dominant ones, not only for influenza, but also for other viral diseases such as HIV and COVID-19.

It has been problematic to generate vaccines against viruses that change frequently, such as influenza virus and HIV. The problem is that the changes (mutations) primarily affect the sites against which antibodies are typically directed; these sites are called immunodominant sites. The problem would be solved if vaccines could induce antibodies that bind conserved sites that do not mutate very much. Regrettably, such sites elicit only poor immune responses and are thus called immunorecessive sites. To solve this problem, this proposal aims at developing a vaccine technology that turns immunorecessive sites into immunodominant sites, and vice versa. This objective may be accomplished the following way: since bivalency of a site in vaccine molecules induces strong immune responses while monovalency induces only weak responses, vaccine molecules can be constructed where immunorecessive sites are made bivalent while immunodominant sites are made monovalent. Such manipulation of valency can easily be done in a heterodimeric vaccine format that PI and colleagues have developed. The proof-of-concept experiments will be done in influenza with use of hemagglutinin (HA) profusely expressed in the viral membrane, as antigen. The hope is that this strategy will result in strong immune responses against conserved epitopes on HA, thus making it difficult for influenza virus to escape immunity. Preliminary experiments in mice are encouraging. Experiments will be extended to avian and pandemic flu in addition to seasonal flu. Experiments will be translated to ferrets and non-human primates and finally to humans. The project will hopefully result in a novel vaccine technology that can turn recessive epitopes into dominant ones. This would be a ground-breaking result that would surpass the forefront of international research in this field. The results are not only relevant for influenza but also other viral diseases such as HIV.