使用稳定的天然样HIV-1包膜免疫原进行的实验性医学研究可引发长期抗体反应，但缺乏中和广度。

Experimental medicine study with stabilised native-like HIV-1 Env immunogens drives long-term antibody responses, but lacks neutralising breadth.

作者信息

Pollock Katrina M, Cheeseman Hannah M, McFarlane Leon R, Day Suzanne, Tolazzi Monica, Turner Hannah L, Joypooranachandran Jennifer, Shramko Katsiaryna, Dispinseri Stefania, Mundsperger Philipp, Bontjer Ilja, Lemm Nana-Marie, Coelho Sofia, Tanaka Maniola, Cole Tom, Korber Bette, Katinger Dietmar, Sattentau Quentin J, Ward Andrew B, Scarlatti Gabriella, Sanders Rogier W, Shattock Robin J

机构信息

Imperial College London, Department of Infectious Disease, UK; NIHR Imperial Clinical Research Facility and NIHR Imperial Biomedical Research Centre, London, UK.

Imperial College London, Department of Infectious Disease, UK.

出版信息

EBioMedicine. 2025 Feb;112:105544. doi: 10.1016/j.ebiom.2024.105544. Epub 2025 Jan 2.

DOI:10.1016/j.ebiom.2024.105544

PMID:39753033

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11753977/

Abstract

BACKGROUND

We report findings from an experimental medicine study of rationally designed prefusion stabilised native-like HIV envelope glycoprotein (Env) immunogens, representative of global circulating strains, delivered by sequential intramuscular injection.

METHODS

Healthy adult volunteers were enrolled into one of five groups (A to E) each receiving a different schedule of one of two consensus Env immunogens (ConM SOSIP, ConS UFO, either unmodified or stabilised by chemical cross-linking, followed by a boost with two mosaic Env immunogens (Mos3.1 and Mos3.2). All immunogens were co-formulated with liposomal Monophosphoryl-Lipid A (MPLA) adjuvant, and volunteers were followed up for 28 days post final Mosaic booster injection. Participants gave written informed consent to join the study. The study is registered on ClinicalTrials.gov ID NCT03816137.

FINDINGS

Fifty-one participants (men n = 23 and women n = 28) aged 18-55 were enrolled. The seroconversion rate against Env was 100% with all participants having measurable anti-Env IgG antibodies after their second injection and throughout the study. Neutralisation was detected against the ConM pseudovirus in sera of those who had received both ConM and ConS immunogens. However, this activity was limited in breadth and was neither boosted nor broadened in those receiving the Mos3.1 and Mos3.2 immunogens. Neutralising antibody function correlated with binding to V1/V3 and V5 epitopes and peaked after the third injection.

INTERPRETATION

Rationally designed prefusion-stabilised native-like Env trimers are robustly immunogenic in a prime-boost schedule. When given alone they are insufficient to induce neutralising antibody titres of significant breadth, but they represent potentially valuable polishing immunogens after germline-targeting.

FUNDING

European Aids Vaccine initiative (EAVI2020) received funding from EU Horizon 2020, grant number 681137. Structural studies were supported by the Bill and Melinda Gates Foundation (INV-002916).

摘要

背景

我们报告了一项实验性医学研究的结果，该研究涉及通过连续肌肉注射递送的、合理设计的预融合稳定化天然样HIV包膜糖蛋白（Env）免疫原，这些免疫原代表全球流行毒株。

方法

健康成年志愿者被纳入五个组（A至E）之一，每组接受两种共有Env免疫原（ConM SOSIP、ConS UFO，未修饰或通过化学交联稳定化）之一的不同接种方案，随后用两种嵌合Env免疫原（Mos3.1和Mos3.2）进行加强免疫。所有免疫原均与脂质体单磷酰脂质A（MPLA）佐剂共同配制，志愿者在最后一次嵌合加强注射后随访28天。参与者签署了书面知情同意书以加入该研究。该研究已在ClinicalTrials.gov上注册，编号为NCT03816137。

结果

招募了51名年龄在18至55岁之间的参与者（男性n = 23，女性n = 28）。针对Env的血清转化率为100%，所有参与者在第二次注射后及整个研究过程中均具有可测量的抗Env IgG抗体。在同时接受ConM和ConS免疫原的参与者血清中检测到针对ConM假病毒的中和作用。然而，这种活性的广度有限，在接受Mos3.1和Mos3.2免疫原的参与者中既未增强也未拓宽。中和抗体功能与结合V1/V3和V5表位相关，并在第三次注射后达到峰值。