文獻報道顯示目前的流感疫苗所提供的保護效力較為有限，而且對具有大流行威脅的病毒幾乎沒有保護作用。流感疫苗采用血凝素（HA）頭部結構域的免疫顯性表位，驅動免疫應答，但頭部區域易受抗原漂移影響。新一代疫苗旨在通過采用HA亞顯性表位，產生針對多種流感病毒亞型的、更為持久和廣譜的免疫應答。

近日，來自美國芝加哥大學的Patrick C. Wilson研究組在Immunity上發表題為Long-lasting B cell convergence to distinct broadly reactive epitopes following vaccination with chimeric influenza virus hemagglutinins的文章，就上述問題進行了深入研究，并發現嵌合血凝素壓顯性表位疫苗（cHA疫苗）可以誘導產生急性漿母細胞（PB），持久啟動記憶B細胞（MBC）響應。

為了研究B細胞特異性，以及比較不同疫苗接種之后B細胞的變化情況，作者首先設計了cH8/1 （H8頭部結構域，H1柄結構域）和cH5/1 （H5頭，H1柄）兩組疫苗，并通過LAIV和IIV AS03兩種方式進行接種。隨后，在不同時間點提取B細胞，進行單細胞RNA測序和B細胞受體測序。作者的接種思路是先接種cH8/1進行預刺激，漿母細胞產生單克隆抗體之后，再進行cH5/1 增強型刺激。

在一項I期臨床試驗中，嵌合血凝素 (cHA) 免疫原誘導了針對保守血凝素 (HA) 莖結構域的抗體應答，正如設計的那樣。本研究通過結合單細胞RNA測序和B細胞受體組測序，確定了cHA疫苗誘導的B細胞的特異性、功能和亞群。使用角鯊烯類佐劑（AS03）的cHA滅活疫苗可誘導針對莖結構域中兩個廣譜中和表位的強效活化B細胞和記憶B細胞 (MBC) 表型。急性漿母細胞 (PB) 和MBC應答的總體特異性克隆重疊，表明B細胞向這些廣譜保護表位趨同。免疫接種一年后，我們發現cHA疫苗重塑了HA特異性MBC池，從而富集了莖結合B細胞。總之，這些數據表明，cHA 疫苗針對 HA 莖結構域的廣泛保護性表位誘導了強大而持久的 B 細胞反應，這與血清學數據一致。

附文獻信息：

Title：Long-lasting B cell convergence to distinct broadly reactive epitopes following vaccination with chimeric influenza virus hemagglutinins

PMID:40132593 PMCID: PMC11981830

DOI:10.1016/j.immuni.2025.02.025

Highlights：（1）Recall of B cells specific for broadly protective HA epitopes with a shared Ig repertoire；（2）Discrete B cell populations and specificities linked to vaccine formulation；（3）Boosting of existing MBCs and priming of new MBCs against conserved HA stalk epitopes；（4）Greater proportion of stalk-binding MBCs in cHA vaccinees relative to seasonal vaccinees

Summary：In a phase 1 clinical trial, a chimeric hemagglutinin (cHA) immunogen induced antibody responses against the conserved hemagglutinin (HA) stalk domain as designed. Here, we determined the specificity, function, and subsets of B cells induced by cHA vaccination by pairing single-cell RNA sequencing and B cell receptor repertoire sequencing. We have shown that the cHA-inactivated vaccine with a squalene-based adjuvant induced a robust activated B cell and memory B cell (MBC) phenotype against two broadly neutralizing epitopes in the stalk domain. The overall specificities of the acute plasmablast (PB) and MBC responses clonally overlapped, suggesting B cell convergence to these broadly protective epitopes. At 1 year post immunization, we identified that cHA vaccination reshaped the HA-specific MBC pool to enrich for stalk-binding B cells. Altogether, these data indicate the cHA vaccine induced robust and durable B cell responses against broadly protective epitopes of the HA stalk domain, in line with serological data.