Department of Pharmacology and Molecular Sciences, School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
PLoS One. 2010 Jan 18;5(1):e8754. doi: 10.1371/journal.pone.0008754.
The immune-related evolution of influenza viruses is exceedingly complex and current vaccines against influenza must be reformulated for each influenza season because of the high degree of antigenic drift among circulating influenza strains. Delay in vaccine production is a serious problem in responding to a pandemic situation, such as that of the current H1N1 strain. Immune escape is generally attributed to reduced antibody recognition of the viral hemagglutinin and neuraminidase proteins whose rate of mutation is much greater than that of the internal non-structural proteins. As a possible alternative, vaccines directed at T cell epitope domains of internal influenza proteins, that are less susceptible to antigenic variation, have been investigated.
METHODOLOGY/PRINCIPAL FINDINGS: HLA transgenic mouse strains expressing HLA class I A0201, A2402, and B0702, and class II DRB11501, DRB10301 and DRB10401 were immunized with 196 influenza H1N1 peptides that contained residues of highly conserved proteome sequences of the human H1N1, H3N2, H1N2, H5N1, and avian influenza A strains. Fifty-four (54) peptides that elicited 63 HLA-restricted peptide-specific T cell epitope responses were identified by IFN-gamma ELISpot assay. The 54 peptides were compared to the 2007-2009 human H1N1 sequences for selection of sequences in the design of a new candidate H1N1 vaccine, specifically targeted to highly-conserved HLA-restricted T cell epitopes.
CONCLUSIONS/SIGNIFICANCE: Seventeen (17) T cell epitopes in PB1, PB2, and M1 were selected as vaccine targets based on sequence conservation over the past 30 years, high functional avidity, non-identity to human peptides, clustered localization, and promiscuity to multiple HLA alleles. These candidate vaccine antigen sequences may be applicable to any avian or human influenza A virus.
流感病毒的免疫进化极其复杂，由于流行株之间存在高度的抗原漂移，目前的流感疫苗必须针对每个流感季节进行重新配方。疫苗生产的延迟是应对大流行情况（如当前的 H1N1 株）的一个严重问题。免疫逃逸通常归因于病毒血凝素和神经氨酸酶蛋白的抗体识别减少，其突变率远高于内部非结构蛋白。作为一种替代方法，已经研究了针对内部流感蛋白 T 细胞表位域的疫苗，这些表位域较少受到抗原变异的影响。
方法/主要发现：表达 HLA 类 I A0201、A2402 和 B0702 以及类 II DRB11501、DRB10301 和 DRB10401 的 HLA 转基因小鼠株用 196 种含有高度保守的人类 H1N1、H3N2、H1N2、H5N1 和禽流感 A 株的蛋白质组序列的流感 H1N1 肽进行免疫。通过 IFN-γ ELISpot 测定鉴定了 54 种（54 种）引发 63 种 HLA 限制性肽特异性 T 细胞表位反应的肽。将这 54 种肽与 2007-2009 年人类 H1N1 序列进行比较，以选择设计新型候选 H1N1 疫苗的序列，该疫苗专门针对高度保守的 HLA 限制性 T 细胞表位。
结论/意义：根据过去 30 年的序列保守性、高功能亲和力、与人肽无同源性、聚类定位和对多种 HLA 等位基因的混杂性，从 PB1、PB2 和 M1 中选择了 17 个 T 细胞表位作为疫苗靶标。这些候选疫苗抗原序列可能适用于任何禽流感或人类流感 A 病毒。
