一种可诱发高滴度的针对人乳头瘤病毒HPV16,HPV52,HPV58中和抗体反应的HPV16嵌合病毒样颗粒疫苗的研究
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摘要
人乳头瘤病毒(Human papillomavirus,HPV)主要衣壳蛋白L1病毒样颗粒(VLP)主要诱发型别特异性中和抗体,增加L1VLP型别虽可扩大保护范围,但疫苗生产成本显著增加。HPV16,HPV52及HPV58是我国的主要高危型别。本文将HPV58次要衣壳蛋白L2aa.16~37多肽(与HPV52L2aa.16~37序列相同)插入HPV16L1的h4-βJ coil区,利用昆虫表达体系构建获得16L1h4-58dEVLP,协同人用佐剂氢氧化铝和单磷酰脂质A(Alum-MPL)免疫小鼠。活性检测结果显示16L1h4-58dE VLP免疫血清可中和17种HPV假病毒中的16种,其中针对HPV16的平均中和抗体滴度最高(滴度,76 800),与HPV16L1VLP对照组的相当(P>0.05);重要的是,针对HPV58及HPV52的平均中和抗体滴度均大于103(分别为4 050和1 725);另外,还可中等滴度中和HPV45(550),HPV18(506),HPV33(500),HPV39(463),HPV68(431),HPV6(300),HPV57(150),HPV11(125)及较低滴度的中和HPV2/HPV27(40),HPV35(38),HPV5(25),HPV31(13),但对HPV59没有中和活性。因此,以本研究构建16L1h4-58dE VLP进行广谱HPV疫苗的研究,可望降低疫苗成本,具有应用前景。
Current human papillomavirus(HPV)vaccines based on the major capsid protein L1 virus-like particle(VLP)mainly induce vaccine type-specific neutralizing antibodies.Continuing to add more type of VLPs in a vaccine will raise the complexity and cost of production.High-risk HPV16,HPV58 and HPV52 are highly prevalent in China.In this study,we constructed 16 L1 h4-58 dE chimeric VLP by displaying HPV58 L2 aa.16~37(100%identity with HPV52)on the h4 coil region of HPV16 L1,and assessed its immunogenicity in mice.We found that the 16 L1 h4-58 dE VLP adjuvanted with alum plus monophosphoryl lipid A could induce cross-neutralizing antibody responses against 16 out of 17 tested HPV pseudoviruses,and the titer against HPV16 was as high as that induced by HPV16 L1 VLP(titer>105,P>0.5).More importantly,titers over 103 were observed against two high-risk HPVs including HPV58(titer,4,050)and HPV52(titer,1,725),and medium or low titers of cross-neutralizing antibodies against other 13 tested HPV pseudoviruses,including HPV45, HPV18, HPV33, HPV39, HPV68, HPV6, HPV57,HPV11,HPV2/HPV27,HPV35,HPV5,HPV31,but not against HPV59.Our data demonstrate that the 16 L1 h4-58 dE VLP is a promising candidate for the formulation of broader-spectrum HPV vaccines.
Current human papillomavirus(HPV)vaccines based on the major capsid protein L1 virus-like particle(VLP)mainly induce vaccine type-specific neutralizing antibodies.Continuing to add more type of VLPs in a vaccine will raise the complexity and cost of production.High-risk HPV16,HPV58 and HPV52 are highly prevalent in China.In this study,we constructed 16 L1 h4-58 dE chimeric VLP by displaying HPV58 L2 aa.16~37(100%identity with HPV52)on the h4 coil region of HPV16 L1,and assessed its immunogenicity in mice.We found that the 16 L1 h4-58 dE VLP adjuvanted with alum plus monophosphoryl lipid A could induce cross-neutralizing antibody responses against 16 out of 17 tested HPV pseudoviruses,and the titer against HPV16 was as high as that induced by HPV16 L1 VLP(titer>105,P>0.5).More importantly,titers over 103 were observed against two high-risk HPVs including HPV58(titer,4,050)and HPV52(titer,1,725),and medium or low titers of cross-neutralizing antibodies against other 13 tested HPV pseudoviruses,including HPV45, HPV18, HPV33, HPV39, HPV68, HPV6, HPV57,HPV11,HPV2/HPV27,HPV35,HPV5,HPV31,but not against HPV59.Our data demonstrate that the 16 L1 h4-58 dE VLP is a promising candidate for the formulation of broader-spectrum HPV vaccines.
引文
[1]Bruni L,Barrionuevo-Rosas L,Albero G,Serrano B,Mena M,Gómez D,Mu1oz J,Bosch F X,de SanjoséS.ICO/IARC Information Centre on HPV and Cancer(HPV Information Centre).Human papillomavirus and related diseases in the world[M].Summary Report 27July 2017.
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[20]Nieto K,Weghofer M,Sehr P,Ritter M,Sedlmeier S,Kellner M,Horer M,Michaelis U,Roden RB,Gissmann L,Kleinschmidt J.Development of AAVLP(HPV16/31L2)particles as broadly protective HPV vaccine candidate[J/OL].PLoS One,2012,7:1-12.
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[22]Schellenbacher C,Roden R,Kirnbauer R.Chimeric L1-L2virus-like particles as potential broad-spectrum human papillomavirus vaccines[J].J Virol,2009,83:10085-10095.
[23]Huber B,Schellenbacher C,Jindra C,Fink D,ShaftiS,Kirnbauer R.A chimeric 18L1-45RG1 virus-like particle vaccine cross-protects against oncogenic alpha-7human papillomavirus types[J/OL].PLoS One,2015:1-18.
[24]Kondo K,Ochi H,Matsumoto T,Yoshikawa H,Kanda T.Modification of human papillomavirus-like particle vaccine by insertion of the cross-reactive L2-Epitopes[J].J Med Virol,2008,80:841-846.
[25]Schellenbacher C,Kwak K,Fink D,Shafti-keramat S,Huber B,Jindra C,Faust H,Dillner J,Roden R B and Kirnbauer R.Efficacy of RG1-VLP vaccination against infections with genital and cutaneous human papillomaviruses[J].J Invest Dermatol,2013,133:2706-2713.
[26]Bruni L,Barrionuevo-Rosas L,Albero G,Serrano B,Mena M,Gómez D,Bosch F X,de SanjoséS.ICO/IARC Information Centre on HPV and Cancer(HPV Information Centre).Human papillomavirus and related diseases in China[M].Summary Report 27July 2017.
[27]Zhang T,Xu Y,Qiao L,Wang Y,Wu X,Fan D,Peng Q,Xu X.Trivalent human papillomavirus(HPV)VLP vaccine covering HPV type 58can elicit high level of humoral immunity but also induce immune interference among component types[J].Vaccine,2010,28:3479-3487.
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