Resumen de Una nova plataforma de virus-like particles (vlp) embolcallada amb elevada immunogenicitat i versatibilitat
Vaccines are one of the most successful achievements in the history of medicine. However, for some infectious agents, there still is a lack of an effective protective vaccine. Such is the case of the Human Immunodeficiency Virus (HIV-1), which is the causative agent of the acquired immunodeficiency syndrome (AIDS). HIV-1 has eluded nearly 40 years of vaccine research owing to its enhanced immune evasion mechanisms and the poor incorporation of the envelope glycoprotein (Env) at the viral surface, which is the main target for neutralising antibodies. HIV-1 vaccine candidates are based on nucleic acid strategies, subunit proteins or multivalent platforms that try to elicit potent and balanced humoral and cellular adaptive immune responses. The presentation of antigens within a multivalent platform induces a superior immune response compared to subunit proteins, and the combination of different vaccine strategies has been demonstrated to elicit more robust responses. One of these promising multivalent vaccine platforms are virus-like particles (VLPs), which mimic the structure of the virus. VLPs are non-infectious, non-replicative and highly immunogenic platforms that can be safely used as vaccines. HIV-1 based VLPs are produced by the cellular expression of the HIV-1 structural protein Gag, leading to the budding of lipid-enveloped VLPs that are structurally similar to HIV-1. The antigens can be easily expressed on the lipid membrane of the VLPs, but with poorly efficient incorporation. To bypass this limitation, our group designed a novel VLP-based platform yielding a high density of antigens at the VLP surface. This novel strategy consisted in fusing a small Env-derived immunogen (Min), which had a transmembrane domain, to Gag. This process resulted in high-density antigen-expressing MinGag-VLPs.
The hypothesis of this work was that the expression of a high density of antigens at the surface of VLPs would induce a robust immune response that could be beneficial for an HIV-1 vaccine candidate. To test that, we developed efficient production and purification protocols for our fusion-protein MinGag- VLPs. Additionally, antigen exposition on MinGag-VLPs was improved by the introduction of mutations at the transmembrane domain, resulting in an optimised Min(RA)Gag-VLP candidate. Furthermore, the fusion-protein VLP vaccine platform could easily be formulated into nucleic acid-based vaccine strategies that were successfully delivered by in vivo DNA electroporation, favouring the development of combination heterologous DNA/VLP strategies that could lead to more potent responses. In vivo immunogenicity studies in mice demonstrated the superiority of heterologous DNA/VLP vaccination compared to homologous VLP regimens in most of the immune parameters assessed. Immune profiling of immunised mice showed how antibody titres in plasma were approximately 10-times higher with the heterologous regimen. Fusion-protein VLPs induced modest cellular responses and non-neutralising antibodies against HIV-1 pseudoviruses. However, these mouse anti-Min antibodies mainly displayed an IgG2c profile that could mediate antibody-dependent effector functions. This finding was relevant since these types of responses have been associated with modest correlates of protection against HIV-1 in human clinical trials. The absence of a relevant mouse model to study vaccine-mediated protection by vaccination led us to develop a mouse model where a Min-expressing tumour cell line acted as a surrogate of HIV-1 infected cells. Vaccination with Min(RA)Gag-VLPs efficiently impaired the progression of the Min-expressing tumour, hence demonstrating that fusion-protein-VLPs induced a full-fledged protective immune response. Finally, fusion-protein VLPs confirmed their versatility as a platform since they could present a wide diversity of immunogens on their surface, including a full HIV-1 Env trimer with preserved antigenicity.
Overall, our novel VLP platform demonstrated its potential and that merits further studies as potential HIV-1 vaccine candidates.
