Basic Research on development of HPV vaccine for prevention of cervical cancer

预防宫颈癌HPV疫苗研制的基础研究

• 批准号: 13470345
• 负责人: YOSHIKAWA Hiroyuki
• 金额: $ 9.79万
• 依托单位: UNIVERSITY OF TSUKUBA
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470345/
• 关键词: HPV; Cervical Cancer; Vaccine; VLP; HLA; Phase I; II trial; CIN; E6; 子宮頚がん; VLP抗体; 子宮頸癌; variants; L2

1.Amino acid (aa) 108-120 of L2 protein of HPV16 contains a cross-neutralization epitope against genital HPV. We designed a placebo-controlled trial in healthy adults to evaluate the safety and immunogenicity of a synthetic peptide consisting of the aa 108-120 of HPV 16 L2(L2-108/120) region. A total of 13 volunteers were given nasal inoculations with 0.1 (n=5) or 0.5mg (n=5) doses of the peptides or placebo (n=3) without adjuvant at weeks 0, 4, and 12. Sera were collected before inoculation and at 6, 16 and 36 weeks. The inoculation generated anti-L2 antibodies binding to both HPV16 and 52 L1/L2-capsids in four of the five recipients in the 0.5mg group. Sera of the four recipients showed neutralizing activities against HPV16 and 52. This study suggests the L2-108/120 peptide is tolerable in humans and has the potential as a broad-spectrum prophylactic vaccine against genital HPV2.To investigate the association between E6 variants and HLA polymorphism within a Japanese population, 55 women with HPV 16-positive cervical cancer were analyzed for E6 sequence variation and its relationship to HLA class II alleles. Compared with local controls (n=138) and published controls (n=916), DRB1*1501 and DQB1*0602 frequencies were significantly increased among patients with HPV 16 E6 prototype (n=11). Additionally, DRB1*1502 was positively associated with a particular E6 variant designated D25E (n=25), although we could not find a significant association between HLA class II alleles and L83V variant (n=16). Our doservations suggest that a specific match between E6variant proteins and HLA types may contribute to HPV16-related cervical carcinogenesis

1.HPV16 L2蛋白氨基酸（aa） 108-120含有一个抗生殖器HPV的交叉中和表位。我们在健康成人中设计了一项安慰剂对照试验，以评估由HPV 16 L2（L2-108/120）区aa 108-120组成的合成肽的安全性和免疫原性。在第0、4和12周，共有13名志愿者接受了0.1 （n=5）或0.5mg （n=5）剂量的多肽或安慰剂（n=3）鼻接种，不含佐剂。接种前、6周、16周、36周采集血清。接种0.5mg组的5名受者中有4名产生了结合HPV16和52个L1/ l2衣壳的抗l2抗体。4名受者血清对HPV16和hpv52表现出中和活性。这项研究表明L2-108/120肽在人体中是可耐受的，并且有潜力作为一种广谱预防生殖器hpv v2的疫苗。为了研究日本人群中E6变异与HLA多态性之间的关系，我们分析了55名HPV 16阳性宫颈癌妇女的E6序列变异及其与HLA II类等位基因的关系。与本地对照（n=138）和公开对照（n=916）相比，HPV 16 E6原型患者（n=11）的DRB1*1501和DQB1*0602频率显著升高。此外，DRB1*1502与特定的E6变体D25E呈正相关（n=25），尽管我们没有发现HLA II类等位基因与L83V变体之间的显著关联（n=16）。我们的研究表明，e6变异蛋白与HLA类型之间的特异性匹配可能有助于hpv16相关的宫颈癌发生

项目成果

Matsumoto K, Yoshikawa H.: "Human papillomavirus type 16 E6 variants and HLA class II alleles among Japanese women with cervical cancer"Int J Cancer. 106(2). 919-922 (2003)

Matsumoto K、Yoshikawa H.：“日本女性宫颈癌中的人乳头瘤病毒 16 型 E6 变体和 HLA II 类等位基因”Int J Cancer。

Yokoyama M, Yoshikawa H, et al.: "Prognostic factors associated with the clinical outcome of cervica intraepithelial neoplasia : a cohort study in Japan."Cancer Lett.. 192(2). 171-179 (2003)

Yokoyama M、Yoshikawa H 等人：“与宫颈上皮内瘤变临床结果相关的预后因素：日本的一项队列研究。”Cancer Lett.. 192(2)。

Matsumoto K, Yoshikawa H.: "Are smoking and chlamydial infection risk factors for CIN? : Different results after adjustment for HPV DNA and antibodies"Br J Cancer. 89(5). 831-833 (2003)

Matsumoto K、Yoshikawa H.：“吸烟和衣原体感染是 CIN 的危险因素吗？：调整 HPV DNA 和抗体后的不同结果”Br J Cancer。

Kawana K.: "Neutralizing antibodies against oncogenic human papillomavirus as a possible determinant of the fate of low-grade cervical intraepithelial neoplasia"BBRC. 296・1. 102-105 (2002)

Kawana K.：“中和致癌性人乳头瘤病毒抗体可能是低度宫颈上皮内瘤变命运的决定因素” BBRC 296·1 (2002)。

Kawana K.: "Human papillomavirus type 16 minor capsid protein L2 N-terminal region containing a common neutralization epitope binds to cell surface and enters the cytoplasm"J.Virology. 75・5. 2331-2336 (2001)

Kawana K.：“含有共同中和表位的人乳头瘤病毒 16 型小衣壳蛋白 L2 N 末端区域与细胞表面结合并进入细胞质”J. Virology 75·5 (2001)。