Vaccination with HPV16 L2E6E7 fusion protein in GPI-0100 adjuvant elicits protective humoral and cell-mediated immunity
Vaccination with HPV16 L2E6E7 fusion protein in GPI-0100 adjuvant elicits protective humoral and cell-mediated immunity
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DOI：
10.1016/j.vaccine.2008.11.099
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发表时间：
2009-02-11
期刊：
影响因子：
5.5
通讯作者：
Roden, Richard B. S.
中科院分区：
文献类型：
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作者：
Karanam, Balasubramanyam;Gambhira, Ratish;Roden, Richard B. S.
在单一串联融合蛋白（称为TA-CIN）中包含人乳头瘤病毒16型（HPV 16）L2、E6和E7的疫苗具有通过诱导能够交叉中和不同HPV类型的L2抗体而针对HPV传播的广泛交叉保护和通过刺激靶向HPV 16早期蛋白的T细胞应答而进行治疗的潜在优点。然而，单独接种TA-CIN的患者产生弱的HPV中和抗体和E6/E7特异性T细胞应答。在这里，我们测试了与佐剂GPI-0100一起沿着配制的TA-CIN，GPI-0100是一种半合成皂树皂苷类似物，其被开发用于促进体液和细胞免疫应答。对小鼠皮下给予TA-CIN（20 μ g）与50 μ g GPI-0100，每两周间隔三次，引起高滴度的HPV 16中和血清抗体，对其它HPV 16相关类型（包括HPV 31和HPV 58）的稳健中和滴度，并在较小程度上中和其它生殖器粘膜萎缩性乳头状瘤病毒，如HPV 18、HPV 45、HPV 6和HPV 11。值得注意的是，用GPI-0100中的TA-CIN疫苗接种与没有佐剂的HPV 16 L1 VLP一样有效地保护免受皮肤HPV 16攻击。TA-CIN与GPI-0100的制剂使E7特异性、产生干扰素γ的CD 8（+）T细胞前体的产生增加了20倍。用GPI-0100中的TA-CIN疫苗接种也完全防止了用5 × 101个HPV 16转化的TC-1肿瘤细胞攻击后的肿瘤生长，而单独用TA-CIN疫苗接种延迟了肿瘤生长。此外，猪尾猕猴对125 μ g TA-CIN和1000 μ g GPI-0100的三个月一次的疫苗接种耐受性良好，并诱导HPV 16 E6/E7特异性T细胞应答和中和所有测试的HPV类型的血清抗体。(C)2008年由Elsevier Ltd.出版
A vaccine comprising human papillomavirus type 16 (HPV16) L2, E6 and E7 in a single tandem fusion protein (termed TA-CIN) has the potential advantages of both broad cross-protection against HPV transmission through induction of L2 antibodies able to cross neutralize different HPV types and of therapy by stimulating T cell responses targeting HPV16 early proteins. However, patients vaccinated with TA-CIN alone develop weak HPV neutralizing antibody and E6/E7-specific T cell responses. Here we test TA-CIN formulated along with the adjuvant GPI-0100, a semi-synthetic quillaja saponin analog that was developed to promote both humoral and cellular immune responses. Subcutaneous administration to mice of TA-CIN (20 mu g) with 50 mu g GPI-0100, three times at biweekly intervals, elicited high titer HPV16 neutralizing serum antibody, robust neutralizing titers for other HPV16-related types, including HPV31 and HPV58, and neutralized to a lesser extent other genital mucosatropic papillomaviruses like HPV18, HPV45, HPV6 and HPV11. Notably, vaccination with TA-CIN in GPI-0100 protected truce from Cutaneous HPV16 challenge as effectively as HPV16 L1 VLP without adjuvant. Formulation of TA-CIN with GPI-0100 enhanced the production of E7-specific, interferon gamma producing CD8(+) T cell precursors by 20-fold. Vaccination with TA-CIN in GPI-0100 also completely prevented tumor growth after challenge with 5 x 101 HPV16-transformed TC-1 tumor cells, whereas vaccination with TA-CIN alone delayed tumor growth. Furthermore, three monthly vaccinations with 125 mu g of TA-CIN and 1000 mu g GPI-0100 were well tolerated by pigtail macaques and induced both HPV16 E6/E7-specific T cell responses and serum antibodies that neutralized all HPV types tested. (C) 2008 Published by Elsevier Ltd.