EBioMedicine · 2026
Antibody-mediated targeting of SOSIP HIV-1 Env to skin Langerhans cells potentiates humoral responses.
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Hammoudi Adele, Surenaud Mathieu, Legros Jade, Picard Florence, Hypolite Guillaume, Manso Justine, Agyar Tugba, Kembou Anaïs, Esposito Michela, Sicherre Emma, Flor Guillaume, Pedenko Borys, Guilligay Delphine, Bouceba Tahar, Fenwick Craig, Moog Christiane, Zurawski Sandra, Zurawski Gerard, Pantaleo Giuseppe, Weissenhorn Winfried, Centlivre Mireille, Godot Véronique, Lévy Yves, Cardinaud Sylvain
Аннотация
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).
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).