Development and Evaluation of a Vaccine Platform Based on Human Papillomavirus-Like Particles Presenting the HIV-1 Envelope Glycoprotein

Human immunodeficiency virus (HIV) remains one of the most significant global health challenges, with tens of millions of people infected worldwide. Despite over three decades of intensive research and numerous clinical trials, an effective HIV vaccine has yet to be developed. Conventional vaccine approaches have largely failed to induce the protective immunity needed against HIV’s extraordinary diversity and immune evasion strategies. This has prompted a search for novel vaccine platforms and immunogen designs. In this context, nanotechnology-based vaccine strategies, particularly those utilizing nanoparticles and virus-like particles (VLPs), offer promising advantages. VLP-based vaccines can mimic the size and repetitive antigen display of real viruses, leading to enhanced immune recognition and stronger immunogenicity compared to traditional soluble antigens. Such nanoparticles inherently present multivalent arrays of antigens, which greatly enhances B-cell receptor crosslinking and antigen uptake by antigen-presenting cells, resulting in robust B-cell and T-cell responses. Indeed, VLPs have an excellent safety profile and have proven their efficacy in licensed vaccines. Prominent examples are VLP-based vaccines formed by the L1 protein of human papillomavirus (HPV), which induce strong neutralizing antibody responses and long-lasting protection. Leveraging the self-assembling properties of HPV VLPs for HIV vaccine design is therefore a logical and innovative strategy. In this study, we developed a HPV-based nanoparticle platform designed to present the HIV-1 envelope glycoprotein (Env) as a heterologous vaccine antigen. The HPV16 L1 capsid protein was expressed in a bacterial system, purified, and assembled into VLPs. HIV-1 Env trimers were then site-specifically conjugated to the nanoparticle surface via their C-termini using dibenzylcyclooctyne (DBCO) terminated linkers through copper-free click chemistry, generating L1-Env nanoparticles. These nanoparticles stimulated Env-specific B cells more efficiently than unconjugated Env in a B cell receptor–dependent manner. Immunization of mice with L1-Env nanoparticles elicited Env-specific antibody responses without the use of adjuvants. Notably, the Env-specific antibody response was significantly higher than that induced by a mixture of Env trimers and unconjugated L1-VLPs. Although self-assembled L1 nanoparticles are attractive scaffolds for vaccine development due to their structural stability and functionality, widespread prior exposure to HPV vaccines has resulted in pre-existing anti-L1 immunity, which may lead to rapid clearance of L1-based nanoparticles and reduced antigen presentation. To overcome this limitation, we also developed a silica-coated L1-VLP (L1-SiO₂) formulation. This strategy should confer two key advantages: (a) shielding L1 epitopes to minimize recognition by pre-existing antibodies, thereby prolonging nanoparticle circulation and enhancing antigen exposure (shielding effect); and (b) improving surface chemistry for more efficient and flexible antigen conjugation. Together, these features enhance the immunogenic potential of the platform, directing immune responses more effectively toward the target antigen.