DeLuca Jenna M, Blasi Maria, McGee Taylor J, Jha Shalini, Shen Xiaoying, Gu Shuqin, Pollara Justin, Kerkau Melissa, Purwar Mansi, Carnathan Diane G, Negri Donatella, Cara Andrea, Wollenberg Kurt, Wiehe Kevin, Saunders Kevin O, Lu Shan, Silvestri Guido, Weiner David B, Klotman Mary E, Ferrari Guido, Anthony Moody M, Bonsignori Mattia
Translational Immunobiology Unit, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Duke Human Vaccine Institute, Duke University, Durham, NC, USA.
Commun Med (Lond). 2025 May 15;5(1):175. doi: 10.1038/s43856-025-00899-3.
Sequential multivalent immunizations are used to counter diversity in rapidly mutating viruses. Here, we evaluated the effect of HIV-1 immunogen formats on the binding profile of memory B-cells elicited in two independent Rhesus macaque trials.
In one trial, female Rhesus macaques were immunized with a multiclade HIV-1 gp120 envelope glycoprotein (Env) cocktail and bled two weeks post final immunization. In another trial, male and female Rhesus macaques were sequentially immunized with clonally-related Env glycoproteins: Four immunogens were administered as non-stabilized gp140 Envs and the fifth as a specially stabilized gp140 Env trimer (SOSIP); animals were bled before and after SOSIP immunization. Immunogen-binding peripheral memory B-cells were sorted and cultured at limiting dilution. Culture supernatants were assessed by ELISA for binding to individual immunogens.
In the first trial, 81% (591/734) of B-cells cross-react with multiple Envs and most bind to all immunogens. In the second trial, 81% (331/410) of B-cells isolated before SOSIP administration react with all non-stabilized gp140 Env immunogens and 27% also cross-react with the yet-to-be-administered SOSIP-stabilized Env. However, after SOSIP administration, SOSIP-stabilized trimer-reactive B-cells increase to 86% (219/256) but most (82%) do not cross-react with the preceding immunogens.
Multiclade and sequential regimens before SOSIP-stabilized Env immunization elicited B-cells that converge on shared epitopes. A change in immunogen format results in a divergent B-cell response that vastly fails to engage prior responses. Critically, B-cell priming with non-stabilized Env cannot modify the effect of the epitope immunodominance hierarchy in a SOSIP trimer. These results suggest that a change in immunogen format may cause off-target B-cell engagement, but also that B-cell repriming is possible despite pre-existing immunity.
序贯多价免疫用于应对快速变异病毒的多样性。在此，我们评估了HIV-1免疫原形式对两项独立的恒河猴试验中引发的记忆B细胞结合谱的影响。
在一项试验中，雌性恒河猴用多亚型HIV-1 gp120包膜糖蛋白（Env）鸡尾酒进行免疫，并在最后一次免疫后两周采血。在另一项试验中，雄性和雌性恒河猴序贯接种克隆相关的Env糖蛋白：四种免疫原作为非稳定化的gp140 Env给药，第五种作为特殊稳定化的gp140 Env三聚体（SOSIP）给药；在SOSIP免疫前后对动物进行采血。对免疫原结合外周记忆B细胞进行分选并以有限稀释度培养。通过ELISA评估培养上清液与单个免疫原的结合情况。
在第一项试验中，81%（591/734）的B细胞与多种Env发生交叉反应，且大多数与所有免疫原结合。在第二项试验中，在给予SOSIP之前分离的81%（331/410）的B细胞与所有非稳定化的gp140 Env免疫原发生反应，27%的B细胞也与尚未给药的SOSIP稳定化Env发生交叉反应。然而，在给予SOSIP后，SOSIP稳定化三聚体反应性B细胞增加到86%（219/256），但大多数（82%）不与先前的免疫原发生交叉反应。
在SOSIP稳定化Env免疫之前的多亚型和序贯方案引发了聚集在共享表位上的B细胞。免疫原形式的改变导致了不同的B细胞反应，且极大地未能与先前的反应结合。至关重要的是，用非稳定化Env进行的B细胞启动不能改变SOSIP三聚体中表位免疫优势等级的影响。这些结果表明，免疫原形式的改变可能导致脱靶B细胞结合，但也表明尽管存在预先存在的免疫力，B细胞重新启动也是可能的。
