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的L2蛋白的氨基酸（AA）108-120包含针对生殖器HPV的交叉中和表位。我们在健康成年人中设计了一项安慰剂对照试验，以评估由HPV 16 L2（L2-108/120）区域的AA 108-120组成的合成肽的安全性和免疫原性。总共为0.1（n = 5）或0.5mg（n = 5）的肽或安慰剂（n = 3）提供了13名志愿者，在接种之前，在第0、4和12周时，在接种之前和6、16和36周时收集血清时，在第0、4和12周时，肽或安慰剂（n = 3）。接种产生了与0.5mg组的五个受体中的四名结合HPV16和52 L1/L2-capsids结合的抗L2抗体。四个接受者的血清表现出针对HPV16和52的中和活性。这项研究表明，L2-108/120肽在人类中是可以忍受的，并且具有针对生殖器HPV2的广泛预测性疫苗的潜力变异及其与HLA II类等位基因的关系。与局部对照（n = 138）和已发布的对照（n = 916）相比，HPV 16 E6原型的患者（n = 11）的患者中，DRB1*1501和DQB1*0602频率显着增加。此外，尽管我们找不到HLA II类等位基因与L83V变体之间的显着关联（n = 16），但DRB1*1502与特定的E6变体呈正相关（n = 25）。我们的放置表明E6Variant蛋白与HLA类型之间的特定匹配可能有助于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)。

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)。

Furuta R, Yoshikawa H, et al.: "Ectopic chromosome around centrosome in metaphase cells as a marker of high-risk human papillomavirus-associated cervical intraepithelial neoplasias."Int J Cancer.. 106(2). 167-171 (2003)

Furuta R、Yoshikawa H 等人：“中期细胞中心体周围的异位染色体作为高危人乳头瘤病毒相关宫颈上皮内瘤变的标志。”Int J Cancer.. 106(2)。

Yokoyama M, Yoshikawa H, et al.: "Prognostic factors associated with the clinical outcome of cervical 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)。