PO.IM03.01 · 免疫学
二价纳米颗粒疫苗诱导针对致癌疱疹病毒的交叉保护性抗体
Bivalent nanoparticle vaccine elicits cross-protective antibody against oncogenic herpesviruses
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摘要 Abstract
中文摘要
背景：Epstein-Barr病毒（EBV）和卡波西肉瘤相关疱疹病毒（KSHV）是致癌性gamma疱疹病毒，与多种恶性肿瘤存在因果关联，但缺乏获批疫苗。由于病毒相关癌症构成了相当大的全球肿瘤负担，预防性疫苗接种为癌症预防提供了一种合理途径。这两种病毒都依赖于保守的gHgL异二聚体来进行受体结合和入侵，提示gHgL可作为广泛gamma疱疹病毒保护的共同疫苗靶点。
方法：我们开发了一种二价纳米颗粒疫苗（bi-NP），其在自组装的I53-50支架上共同展示EBV和KSHV的gHgL，并将其免疫原性和保护效力与单抗原及可溶性对照进行比较。免疫原的结构和抗原完整性通过尺寸排阻色谱、负染电子显微镜以及与特异性单克隆抗体的结合来验证。在小鼠、家兔和非人灵长类动物（NHP）中评估了免疫原性，同时使用异源（鼠gamma疱疹病毒68，MHV-68）和同源（人源化小鼠中EBV/KSHV共感染）攻毒模型评估了体内保护作用。
结果：二价gHgL纳米颗粒在各物种中持续诱导出更高且更均衡的针对EBV和KSHV的抗体应答，有效阻断病毒对其各自易感细胞类型的感染。Bi-NP免疫诱导出识别保守gHgL表位的交叉反应性抗体，增加了家兔中交叉结合EBV和KSHV gHgL的B细胞频率，诱导出交叉中和MHV-68的抗体，并在体内赋予对MHV-68小鼠攻毒的交叉保护。此外，从bi-NP免疫的猕猴中纯化的IgG被动转移保护了人源化小鼠免受EBV/KSHV共感染，显著减少病毒DNA拷贝数，防止体重减轻，并减轻EBER+和LANA+病理改变。
结论：本研究确立gHgL作为一个合理的二价疫苗靶点，并证明EBV和KSHV抗原的纳米颗粒共展示能够诱导出跨越不同gamma疱疹病毒的交叉反应性、广泛保护性抗体。这些发现凸显了一个用于预防gamma疱疹病毒相关癌症及潜在人畜共患感染的有前景的平台。
查看英文原文 English abstract
Background: Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are oncogenic gamma-herpesviruses causally linked to multiple malignancies but lack approved vaccines. As virus-associated cancers represent a substantial global tumor burden, preventive vaccination offers a rational approach to cancer prevention. Both viruses depend on the conserved gHgL heterodimer for receptor engagement and entry, suggesting gHgL as a shared vaccine target for broad gamma-herpesvirus protection.
Methods: We developed a bivalent nanoparticle vaccine (bi-NP) that co-displays EBV and KSHV gHgL on the self-assembling I53-50 scaffold and compared its immunogenicity and protecting efficacy with single-antigen and soluble counterparts. Structural and antigenic integrity of immunogens were validated by size-exclusion chromatography, negative-stain electron microscopy and binding to specific monoclonal antibodies. Immunogenicity was evaluated in mice, rabbits, and non-human primates (NHPs), while in vivo protection was evaluated using heterologous (murine gamma-herpesvirus 68, MHV-68) and homologous (EBV/KSHV co-infection in humanized mice) challenge models.
Results: The bivalent gHgL nanoparticle elicited consistently higher and more balanced antibody responses against both EBV and KSHV across species, effectively blocking viral infection of their respective susceptible cell types. Bi-NP immunization induced cross-reactive antibodies recognizing conserved gHgL epitopes, increasing the frequency of B cells cross-binding both EBV and KSHV gHgL in rabbits, eliciting antibodies cross-neutralizing MHV-68, and conferring in vivo cross-protection against MHV-68 mice challenge. Moreover, passive transfer of IgG purified from bi-NP-immunized macaques protected humanized mice from EBV/KSHV co-infection, markedly reducing viral DNA copies, preventing weight loss, and diminishing EBER + and LANA + pathology.
Conclusions: This study establishes gHgL as a rational bivalent vaccine target and demonstrates that nanoparticle co-display of EBV and KSHV antigens elicits cross-reactive, broadly protective antibodies across divergent gamma-herpesviruses. The findings highlight a promising platform for preventive strategies against gamma-herpesvirus-associated cancers and potential zoonotic infections.
利益披露 Disclosure
M. Zeng, None..
C. Xie, None..
C. Sun, None..
P. Wu, None..
P. Li, None..
B. Cheng, None..
G. Zhao, None..
G. Bu, None..
W. Du, None..
Z. Jiang, None..
H. Zhou, None..
X. Fang, None..
X. Tian, None..
Y. Yang, None..
S. Sui, None..
Z. Liu, None.