Antibody-mediated targeting of SOSIP HIV-1 Env to skin Langerhans cells potentiates humoral responses.

BACKGROUND

Despite decades of research and multiple phase 2b/3 trials, an effective HIV vaccine remains out of reach. A key obstacle is the need for innovative delivery strategies that can induce potent and durable protective immune responses. Targeting antigen-presenting cells in the skin, specifically Langerhans cells (LCs), offers a promising approach to enhance vaccine efficacy by promoting early and efficient activation of the humoral immune system.

METHODS

We developed an Antibody-Mediated targeting Vaccine (AMV) platform that delivers HIV-1 Env trimeric antigens directly to LCs via an anti-Langerin scFv domain. Two constructs were tested: LC3.Env3, carrying a trimeric gp140z Env fusion protein, and LC3.SOSIP, carrying the well-characterised BG505 SOSIP.664 trimer. Immunogenicity of these constructs was evaluated in mice and rabbits without adjuvant, assessing the germinal centre (GC)/Tfh reaction in draining lymph nodes (dLN), Env-IgG production and HIV-1 neutralisation.

FINDINGS: We show that, as compared to an anti-Langerin mAb fused with Env monochains, LC-targeted delivery of Env3 through LC3.Env3 significantly enhanced Tfh and GC B cells (BGC) formation (p < 0.0001), with an expansion of Env-specific BGC cells in mice (p < 0.05). Env IgG responses was enhanced with LC3.Env3 as compared to non-targeted trimeric Env (p < 0.05). Results were extended using LC3.SOSIP constructs which maintained the structural integrity of trimeric Env, but also markedly promoted as compared to Env3 and LC3Env3 the presentation of the native-like, prefusion-closed structure that displays all major quaternary-dependent broadly neutralising antibodies (bNAbs) regions. LC3.SOSIP elicited in rabbits robust, Env-specific antibody responses with cross-clade reactivity, including neutralising antibodies (NeutAbs), without the use of adjuvants. Finally, as compared to non-targeted SOSIP, LC3.SOSIP elicited stronger Env IgG responses (p < 0.01), even at low antigen doses, and neutralising activity against to Tier-1A but also autologous BG505 Tier-2 viruses (2 rabbits out of 8).

INTERPRETATION: These results validate LC-targeting as an efficient, adjuvant-free, strategy for inducing potent humoral responses against HIV-1. The AMV platform enables precise delivery of structurally intact Env trimers to skin-resident LCs facilitating early B cell activation and maturation. This approach offers distinct advantages over conventional adjuvanted sub-unit protein vaccines supporting its potential for clinical translation.

FUNDING: This work was supported by Inserm, the Vaccine Research Institute (VRI), the French National Research Agency (ANR-10-LABX-77, ANR-10-INBS-05-02, ANR-10-EURE-0003), and the European Union's Horizon 2020 (grant 681032).