Periodic Reporting for period 1 - RSVTriVax (Development of a trivalent epitope-focused RSV vaccine to boost pre-existing immunity)
Okres sprawozdawczy: 2019-10-01 do 2021-09-30
The development of an RSV vaccine is deemed a global health priority by the World Health Organization. Several decades of intensive research by both academic and private stakeholders are yet to deliver a clinically approved vaccine. Globally, RSV causes on the order of 33 million episodes of infection yearly and up to 120,000 deaths annually [1]. Besides children, RSV infection in adults is also a substantial health burden for the elderly population. The only available preventive measure is passive immunization with the monoclonal antibody Palivizumab (Synagis®) indicated for children at high risk. Due to its high costs (50,000 – 90,000 EUR to prevent a single RSV related hospitalization), a vaccine is urgently needed, but RSV has resisted all traditional vaccine development efforts for the last 60 years. This failure is mainly attributed to sophisticated mechanisms evolved by the pathogen to escape potent antibody responses focused on neutralization epitopes. The failure of traditional vaccine approaches is strikingly illustrated in a failed vaccine trial in the 1960’s, during which children were injected with a formalin-inactivated pathogen formulation. The outcome was disastrous, as the vaccine caused disease enhancement upon later infection, and one study participant died of severe RSV disease. This unfortunate event set a large safety constraint on pathogen-based RSV vaccine formulations, and instead requires the induction of a precisely controlled immune response targeting functional epitopes. A major challenge for vaccine development against RSV and other pathogens (e.g. influenza) is that humans encounter multiple infections throughout their life. These infections establish immunodominance hierarchies, in which potent neutralizing antibodies (nAbs) are subdominant (i.e. present in very low titers), and antibodies targeting variable or non-functional epitopes dominate. Thus, the fundamental challenge of next-generation vaccines is to boost these subdominant, nAbs under conditions of pre-existing immunity. To address this need we developed a new cocktail vaccine candidate – TriVax – that aims to elicit focused and precise antibody responses against bona fide neutralization epitopes. Within the cope of this project we performed several pre-clinical tests with the designed immunogens obtaining encouraging results in terms of immunogenicity and neutralization triggered by the antigens. However it has been challenging to scale the production of such immunogens and in the next development of the project we will further optimize this aspect of our vaccine approach.