Protection of rabbits against challenge with rabbit papillomaviruses by immunization with the N terminus of human papillomavirus type 16 minor capsid antigen L2
Protection of rabbits against challenge with rabbit papillomaviruses by immunization with the N terminus of human papillomavirus type 16 minor capsid antigen L2
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DOI：
10.1128/jvi.01577-07
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发表时间：
2007-11-01
影响因子：
5.4
通讯作者：
Roden, Richard B. S.
中科院分区：
文献类型：
--
作者：
Gambhira, Ratish;Jagu, Subhashini;Roden, Richard B. S.
目前的L1病毒样颗粒(VLP)疫苗针对与宫颈癌相关的一小部分人乳头瘤病毒(HPV)基因型提供了类型限制性保护，需要对接种者进行持续的细胞学筛查。在缺乏筛查或高价HPV VLP疫苗资源的国家，宫颈癌问题最严重，这表明需要一种低成本、广泛保护的疫苗原。这里，在细菌中产生含有来自HPV16、牛乳头瘤病毒1型(BPV1)或棉尾兔乳头瘤病毒(CRPV)的残基1~88或11~200的N-末端L2多肽。用这些N端L2多肽免疫兔，同时用CRPV和兔口腔乳头瘤病毒(ROPV)攻击。用CRPV N端L2多肽免疫兔有效地保护了CRPV攻击，但对CRPV基因组DNA皮肤攻击所致的乳头状瘤无明显保护作用。此外，L2表达缺陷的CRPV基因组DNA诱导的乳头状瘤的生长速度与野生型CRPV基因组DNA诱导的乳头状瘤的生长速度相同，进一步表明L2多肽疫苗缺乏治疗活性。>；15的中和血清抗体效价与保护相关(P<；0.001)，这一发现与中和抗体介导的保护一致。令人惊讶的是，在接种N-末端L2多肽后，观察到对异源乳头瘤病毒类型的显著保护程度。值得注意的是，接种HPV16L2 11-200疫苗可分别保护皮肤和粘膜免受CRPV和ROPV的攻击，这两种病毒在进化上与HPV16不同。此外，接种HPV16L211-200可产生广泛的交叉中和血清抗体，提示L2有可能成为第二代预防性HPV疫苗抗原。
Current L1 virus-like particle (VLP) vaccines provide type-restricted protection against a small subset of the human papillomavirus (HPV) genotypes associated with cervical cancer, necessitating continued cytologic screening of vaccinees. Cervical cancer is most problematic in countries that lack the resources for screening or highly multivalent HPV VLP vaccines, suggesting the need for a low-cost, broadly protective vaccinogen. Here, N-terminal L2 polypeptides comprising residues 1 to 88 or 11 to 200 derived from HPV16, bovine papillomavirus type 1 (BPV1), or cottontail rabbit papillomavirus (CRPV) were produced in bacteria. Rabbits were immunized with these N-terminal L2 polypeptides and concurrently challenged with CRPV and rabbit oral papillomavirus (ROPV). Vaccination with either N-terminal L2 polypeptides of CRPV effectively protected rabbits from CRPV challenge but not from papillomas induced by cutaneous challenge with CRPV genomic DNA. Furthermore, papillomas induced by CRPV genomic DNA deficient for L2 expression grew at the same rate as those induced by wild-type CRPV genomic DNA, further suggesting that the L2 polypeptide vaccines lack therapeutic activity. Neutralizing serum antibody titers of >15 correlated with protection (P < 0.001), a finding consistent with neutralizing antibody-mediated protection. Surprisingly, a remarkable degree of protection against heterologous papillomavirus types was observed after vaccination with N-terminal L2 polypeptides. Notably, vaccination with HPV16 L2 11-200 protected against cutaneous and mucosal challenge with CRPV and ROPV, respectively, papillomaviruses that are evolutionarily divergent from HPV16. Further, vaccination with HPV16 L2 11-200 generates broadly cross -neutralizing serum antibody, suggesting the potential of L2 as a second-generation preventive HPV vaccine antigen.