Development of vaccine platforms for membrane display of surface antigens using HIV-1 Env as model immunogen

Abstract

The HIV-1 pandemic remains a major public health concern worldwide with over 1.5 million new infections every year. Despite the many effective prevention tools now available, access to treatment and implementations of these tools are proving difficult. Thus, developing an effective vaccine to prevent HIV-1 transmission remains of upmost importance. To date, HIV-1 vaccines failed to induce robust protective immunity and prophylactic vaccines that will elicit long-lasting protective immune responses still remain to be developed. The HIV-1 Envelope glycoprotein (Env) has been the main target of immunogen design with the aim of inducing neutralizing antibodies. In order to cover Env diversity, prophylactic vaccines are expected to induce broadly neutralizing antibodies (bNAbs). This will likely require Env trimers that limit exposure of non-neutralizing antibody (nNAb) epitopes within stabilized closed pre-fusion Envs that exhibit bNAb epitopes. In this thesis, an iterative design process generated membrane-bound Env immunogens that present stabilized native-like trimers. This ultimately resulted in the ConSOSL.UFO.750 trimer that preferentially binds quaternary-specific bNAbs relative to nNAbs. Further characterization of the soluble ConSOSL.UFO.664 confirmed presentation of a closed pre-fusion native-like structure. Immunogenicity studies demonstrated that ConSOSL.UFO.664 can induce autologous Tier 2 neutralization in rabbits and showed that ConSOSL.UFO.750 can modulate the T helper response in a mouse model. To improve the potential of the membrane-bound designs to induce relevant immune responses, virus-like particles (VLPs) based on Mumps and PIV5 pseudotyping were developed. These VLPs displayed Env immunogens and were able to modulate the immune response by intrastructural help in mice. Work presented in this thesis shows the successful design of immunogens that preserve the pre-fusion native-like structure of Env, amenable to various vaccination platforms. The ConSOSL.UFO design has now been moved into phase I clinical trial within the EAVI2020 consortium which will provide critical information for the development of an effective vaccine.