HIV疫苗突破:创新研究中的抗体保护动物

诸平

Transmission electron micrograph of HIV-1 virus particles (red) budding and replicating from a segment of a chronically infected H9 cell (blue). Particles are in various stages of maturity; arc/semi-circles are immature particles that have started to form but are still part of the cell. Immature particles slowly change morphology into mature forms and exhibit the classic “conical or spherical-shaped core.” Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID

据美国国立卫生研究院（National Institutes Of Health简称NIH, Bethesda, MD, USA）2024年1月20日提供的消息，NIH与美国宾夕法尼亚大学（University of Pennsylvania, Philadelphia, PA , USA）的研究人员合作，在HIV疫苗创新研究中有所突破（HIV Vaccine Breakthrough: Antibodies Protect Animals in Innovative Study）。研究人员发现，针对融合肽（fusion peptide）的三种不同的HIV抗体可以保护猴子免受猿类HIV（simian-HIV简称SHIV）的感染，这为开发HIV疫苗提供了有希望的见解。

在一项安慰剂对照的概念验证研究中，三种不同的HIV抗体各自独立地保护猴子免受SHIV感染，该研究旨在为人类预防性HIV疫苗的开发提供信息。这些抗体是一种人类广泛中和抗体和两种从先前接种过疫苗的猴子中分离出来的抗体，其目标是融合肽，这是HIV表面蛋白上的一个位点，有助于病毒融合并进入细胞。这项研究于2024年1月17日已经在《科学转化医学》（Science Translational Medicine）杂志网站发表。，这项研究由NIH下属的美国国家过敏和传染病研究所(National Institute of Allergy and Infectious Diseases简称NIAID)的疫苗研究中心(Vaccine Research Center简称VRC)领导，美国宾夕法尼亚大学佩雷尔曼医学院医学系（Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA）参与完成。详见Amarendra Pegu, Sarah E. Lovelace, Megan E. Demouth, Michelle D. Cully, Daniel J. Morris, Yingying Li, Keyun Wang, Stephen D. Schmidt, Misook Choe, Cuiping Liu, Xuejun Chen, Elise Viox, Ariana Rowshan, Justin D. Taft, Baoshan Zhang, Kai Xu, Hongying Duan, Li Ou, John-Paul Todd, Rui Kong, Hui Li, George M. Shaw, Nicole A. Doria-Rose, Peter D. Kwong, Richard A. Koup, John R. Mascola. Antibodies targeting the fusion peptide on the HIV envelope provide protection to rhesus macaques against mucosal SHIV challenge. Science Translational Medicine, 17 January 2024, 16(730). DOI: 10.1126/scitranslmed.adh9039. https://www.science.org/doi/10.1126/scitranslmed.adh9039

融合肽导向抗体:新的希望（Fusion Peptide-Directed Antibodies: A New Hope）

针对融合肽的抗体可以在体外，即在试管或活生物体外的培养皿中，中和多种HIV毒株。NIAID VRC从一名为研究捐献血液样本的艾滋病毒感染者身上分离出一种融合肽导向的人类抗体，称为VRC34.01。他们还从恒河猴（rhesus macaques）身上分离出了两种抗体，恒河猴是一种免疫系统与人类相似的猴子，此前曾接受过一种旨在产生融合肽定向抗体的疫苗方案。

证明这些抗体保护动物将验证融合肽作为人类疫苗设计的靶标。SHIV挑战即向恒河猴注射感染剂量的SHIV是一种广泛使用的评估HIV抗体和疫苗性能的动物模型。

实验结果及启示（Experimental Findings and Implications）

在这项研究中，四组恒河猴均接受单次静脉输注一种抗体(2.5或10 mg/kg体重剂量的VRC34.01)，或两种疫苗引发的恒河猴抗体中的一种，其他恒河猴接受安慰剂输注。为了确定抗体的保护作用，每只猴子在注射一种已知对融合肽定向抗体敏感的SHIV菌株5天后受到攻击。

所有接受安慰剂输注的猴子在挑战之后都获得了SHIV。在接受VRC34.01注射的猴子中，接受10 mg/kg剂量的猴子中无感染SHIV病例，接受2.5 mg/kg剂量的猴子中有25%感染SHIV。在那些接受疫苗诱导的恒河猴抗体的猴子中，没有猴子接受名为DFPH-a.15抗体感染了SHIV，而接受了名为DF1W-a.01抗体的猴子中，有25%感染了SHIV。随着时间的推移，接受DFPH-a.15抗体的动物血液中的抗体浓度下降。30天后，这些动物再次激发，以观察抗体浓度降低是否会降低保护作用，其中一半感染了SHIV。

所研究的三种抗体都提供了统计上显著的SHIV保护，并且效果是剂量依赖性的，即在血液中抗体浓度较高的猴子中效果最高。

结论:向研制出一种有效的HIV疫苗迈进（Conclusion: Towards an Effective HIV Vaccine）

根据上述论文作者的说法，这些发现代表了融合肽定向抗体可以提供针对SHIV的保护的概念证明，并有助于确定疫苗需要产生保护的抗体浓度。他们认为，他们在一些动物中疫苗引发的抗体的发现，支持了进一步设计针对融合肽的预防性HIV疫苗概念的工作。

研究人员得出结论，一种针对HIV融合肽的有效HIV疫苗可能需要在本研究中使用的概念基础上进行扩展，通过产生多种融合肽定向抗体。这将增加疫苗在流通中的各种各样的艾滋病毒变体中保持预防作用的可能性。

本研究得到了美国国立卫生研究院（National Institutes of Health: R01 AI160607; OPP1145046）的资助。

上述介绍，仅供参考。欲了解更多信息，敬请注意浏览原文或者相关报道。

Editor’s summary

The fusion peptide (FP) on the HIV-1 envelope protein is a conserved site that can be targeted by neutralizing antibodies. However, the extent of protection conferred by FP-directed antibodies in the context of mucosal infection is unclear. Here, Pegu et al. tested three different anti-FP antibodies, including one human antibody and two rhesus macaque antibodies, for their ability to neutralize HIV-1 in vitro and confer protection against simian-HIV (SHIV) challenge of rhesus macaques in vivo. All three antibodies conferred protection against mucosal challenge with SHIV at clinically meaningful titers, supporting further development of both anti-FP antibody therapies and vaccines designed to elicit anti-FP humoral responses. —Courtney Malo

Abstract

The fusion peptide (FP) on the HIV-1 envelope (Env) trimer can be targeted by broadly neutralizing antibodies (bNAbs). Here, we evaluated the ability of a human FP-directed bNAb, VRC34.01, along with two vaccine-elicited anti-FP rhesus macaque mAbs, DFPH-a.15 and DF1W-a.01, to protect against simian-HIV (SHIV)BG505 challenge. VRC34.01 neutralized SHIVBG505 with a 50% inhibitory concentration (IC50) of 0.58 μg/ml, whereas DF1W-a.01 and DFPH-a.15 were 4- or 30-fold less potent, respectively. VRC34.01 was infused into four rhesus macaques at a dose of 10 mg/kg and four rhesus macaques at a dose of 2.5 mg/kg. The animals were intrarectally challenged 5 days later with SHIVBG505. In comparison with all 12 control animals that became infected, all four animals infused with VRC34.01 (10 mg/kg) and three out of four animals infused with VRC34.01 (2.5 mg/kg) remained uninfected. Because of the lower potency of DF1W-a.01 and DFPH-a.15 against SHIVBG505, we infused both Abs at a higher dose of 100 mg/kg into four rhesus macaques each, followed by SHIVBG505 challenge 5 days later. Three of four animals that received DF1W-a.01 were protected against infection, whereas all animals that received DFPH-a.15 were protected. Overall, the protective serum neutralization titers observed in these animals were similar to what has been observed for other bNAbs in similar SHIV infection models and in human clinical trials. In conclusion, FP-directed mAbs can thus provide dose-dependent in vivo protection against mucosal SHIV challenges, supporting the development of prophylactic vaccines targeting the HIV-1 Env FP.