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具有乱序免疫优势表位的 H3 血凝素流感疫苗诱导针对免疫亚优势头部表位的抗体。

Influenza H3 hemagglutinin vaccine with scrambled immunodominant epitopes elicits antibodies directed toward immunosubdominant head epitopes.

机构信息

Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison , Madison, Wisconsin, USA.

Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo , Tokyo, Japan.

出版信息

mBio. 2023 Aug 31;14(4):e0062223. doi: 10.1128/mbio.00622-23. Epub 2023 Jul 19.

Abstract

Vaccination is the most effective countermeasure to reduce the severity of influenza. Current seasonal influenza vaccines mainly elicit humoral immunity targeting hemagglutinin (HA). In particular, the amino acid residues around the receptor-binding site in the HA head domain are predominantly targeted by humoral immunity as "immunodominant" epitopes. However, mutations readily accumulate in the head domain due to high plasticity, resulting in antigenic drift and vaccine mismatch, particularly with influenza A (H3N2) viruses. A vaccine strategy that targets more conserved immunosubdominant epitopes is required to attain a universal vaccine. Here, we designed an H3 HA vaccine antigen with various amino acids at immunodominant epitopes of the HA head domain, termed scrambled HA (scrHA). In ferrets, scrHA vaccination induced lower serum neutralizing antibody levels against homologous virus compared with wild-type (WT) HA vaccination; however, similar levels of moderately neutralizing titers against antigenically distinct H3N2 viruses were observed. Ferrets vaccinated with scrHA twice and then challenged with homologous or heterologous virus showed the same level of reduced virus shedding in nasal swabs as WT HA-vaccinated animals but reduced body temperature increase, whereas WT HA-vaccinated ferrets exhibited body temperature increases similar to those of mock-vaccinated animals. scrHA elicited antibodies against HA immunodominant and -subdominant epitopes at lower and higher levels, respectively, than WT HA vaccination, whereas antistalk antibodies were induced at the same level for both groups, suggesting scrHA-induced redirection from immunodominant to immunosubdominant head epitopes. scrHA vaccination thus induced broader coverage than WT HA vaccination by diluting out the immunodominancy of HA head epitopes. IMPORTANCE Current influenza vaccines mainly elicit antibodies that target the immunodominant head domain, where strain-specific mutations rapidly accumulate, resulting in frequent antigenic drift and vaccine mismatch. Targeting conserved immunosubdominant epitopes is essential to attain a universal vaccine. Our findings with the scrHA developed in this study suggest that designing vaccine antigens that "dilute out" the immunodominancy of the head epitopes may be an effective strategy to induce conserved immunosubdominant epitope-based immune responses.

摘要

接种疫苗是减轻流感严重程度的最有效对策。目前的季节性流感疫苗主要针对血凝素(HA)诱导体液免疫。特别是,HA 头部结构域中受体结合位点周围的氨基酸残基主要作为“免疫优势”表位被体液免疫靶向。然而,由于高度的可塑性,头部结构域中容易积累突变,导致抗原漂移和疫苗不匹配,特别是对于甲型流感(H3N2)病毒。需要针对更保守的免疫次优势表位的疫苗策略来实现通用疫苗。在这里,我们设计了一种具有 HA 头部结构域免疫优势表位各种氨基酸的 H3 HA 疫苗抗原,称为杂化 HA(scrHA)。在雪貂中,与野生型(WT)HA 疫苗接种相比,scrHA 疫苗接种诱导针对同源病毒的血清中和抗体水平较低;然而,观察到针对抗原不同的 H3N2 病毒的中和效价相似。两次接种 scrHA 然后用同源或异源病毒攻毒的雪貂在鼻拭子中病毒脱落量与 WT HA 疫苗接种动物相同,但体温升高减少,而 WT HA 疫苗接种的雪貂体温升高与模拟接种动物相似。与 WT HA 疫苗接种相比,scrHA 分别诱导针对 HA 免疫优势和次优势表位的抗体水平降低和升高,而抗 stalk 抗体在两组中的诱导水平相同,表明 scrHA 诱导的免疫优势向免疫次优势头部表位的重定向。因此,scrHA 疫苗接种通过稀释 HA 头部表位的免疫优势诱导了比 WT HA 疫苗接种更广泛的覆盖范围。

重要性 当前的流感疫苗主要诱导针对免疫优势头部结构域的抗体,其中快速积累了株特异性突变,导致频繁的抗原漂移和疫苗不匹配。针对保守的免疫次优势表位对于实现通用疫苗至关重要。本研究中开发的 scrHA 的研究结果表明,设计“稀释”头部表位免疫优势的疫苗抗原可能是诱导保守的免疫次优势表位为基础的免疫反应的有效策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0082/10470489/c611996b766a/mbio.00622-23.f001.jpg

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