Ragonnaud Emeline, Andersson Anne-Marie C, Mariya Silmi, Pedersen Anders G, Burk Robert D, Folgori Antonella, Colloca Stefano, Cortese Riccardo, Nicosia Alfredo, Pamungkas Joko, Iskandriati Diah, Holst Peter J
*Department of International Health, Immunology and Microbiology, Centre for Medical Parasitology, Copenhagen ‡Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark †Primate Research Center, Bogor Agricultural University, PSSP-IPB, Bogor, Indonesia Departments of §Pediatrics ∥Obstetrics, Gynecology and Women's Health ¶Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY #ReiThera, viale Citta' d'Europa, Rome, Italy **KEIRES, Bäumleingasse, Basel, Switzerland ††CEINGE, Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
J Immunother. 2017 Feb/Mar;40(2):51-61. doi: 10.1097/CJI.0000000000000153.
Currently available prophylactic vaccines have no therapeutic efficacy for preexisting human papillomavirus (HPVs) infections, do not target all oncogenic HPVs and are insufficient to eliminate the burden of HPV induced cancer. We aim to develop an alternative HPV vaccine which is broadly effective and capable of clearing preexisting infection. In an initial attempt to develop a broadly reactive therapeutic vaccine, we designed a putative papillomavirus (PV) ancestor antigen (circulating sequence derived antigenic sequences E1E2-CDSE1E2) based on the conserved E1 and E2 protein sequences from existing oncogenic HPV strains. This antigen was found to be as related to circulating oncogenic Macaca fascicularis papillomaviruses (MfPVs) as to oncogenic HPVs. The CDSE1E2 antigen was fused to a T-cell adjuvant and encoded in chimpanzee 3 and 63 adenoviral vectors. We first showed that the combination of these 2 vaccines induced long-lasting potent CDSE1E2 specific T cell responses in outbred mice. This prime-boost regimen was then tested in female macaques naturally infected with MfPVs. All immunized animals (16/16) responded to the vaccine antigen but with reduced cross-reactivity against existing PVs. Preexisting MfPV infections did not prime vaccine inducible immune responses. Importantly, immunized oncogenic MfPV type 3 (MfPV3) infected animals that responded toward MfPV3 were able to diminish cervical MfPV3 DNA content. Although insufficient breadth was achieved, our results suggest that a relevant level of E1E2 specific T cell immunity is achievable and might be sufficient for the elimination of PV infection. Importantly, naturally infected macaques, offer a relevant model for testing vaccines aimed at eliminating mucosal PV infections.
目前可用的预防性疫苗对已存在的人乳头瘤病毒（HPV）感染没有治疗效果，不能针对所有致癌性HPV，也不足以消除HPV引发癌症的负担。我们旨在开发一种具有广泛效力且能够清除已存在感染的替代性HPV疫苗。在初步尝试开发一种具有广泛反应性的治疗性疫苗时，我们基于现有致癌性HPV毒株保守的E1和E2蛋白序列，设计了一种假定的乳头瘤病毒（PV）祖先抗原（循环序列衍生抗原序列E1E2-CDSE1E2）。发现该抗原与循环致癌食蟹猴乳头瘤病毒（MfPVs）以及致癌性HPV的相关性相同。CDSE1E2抗原与一种T细胞佐剂融合，并编码于黑猩猩3型和63型腺病毒载体中。我们首先证明，这两种疫苗的组合在远交系小鼠中诱导了持久而强效的CDSE1E2特异性T细胞反应。然后在自然感染MfPVs的雌性猕猴中测试了这种初免-加强方案。所有免疫动物（16/16）都对疫苗抗原产生了反应，但对现有PV的交叉反应性降低。已存在的MfPV感染并未引发疫苗可诱导的免疫反应。重要的是，对致癌性MfPV 3型（MfPV3）感染且对MfPV3有反应的动物进行免疫后，能够降低宫颈MfPV3 DNA含量。尽管广度不够，但我们的结果表明，可以实现相关水平的E1E2特异性T细胞免疫，这可能足以消除PV感染。重要的是，自然感染的猕猴为测试旨在消除黏膜PV感染的疫苗提供了一个相关模型。
