Human Papillomavirus Vaccine (Genetic Immunity)

我国目前上市的预防性接种HPV疫苗主要有五种：二价HPV疫苗(GSK)、四价HPV疫苗(默沙东)、九价HPV疫苗(默沙东)、国产大肠杆菌产HPV二价疫苗(万泰)、毕赤酵母产HPV二价疫苗(沃森/玉溪泽润)。Front. Immunol. 14:1112750.疫苗有效率(VE)/抗体阳性率：GSK：Cervarix®的3期临床(NCT00779766)包括6081个受试者。72个月时，HPV16和HPV18抗体阳性率>95%，几何平均滴度(GMT)分别为678.1 EU/mL和343.7 EU/mL。对HPV16/18相关的宫颈上皮内2级或更差瘤变(CIN2+)的疫苗有效率(VE)在ATP-E组为87.3%，在TVC-E组为88.7%，在TVC组为100%(指14种高危型HPVDNA均为阴性，HPV16和18在基线时血清阴性和细胞学阴性)。万泰：Cecolin®一项包含7372名受试者的临床(NCT01735006)中期分析显示，VE对HPV16/18相关的高度生殖器病变(HSIL)的有效率为100.0%(95%CI:55.6%~100.0%；疫苗组为0/3306，对照组为10/3296)。同时，对持续性感染(PI)的有效率为97.8%(95%CI:87.1%~99.9%，1/3240比45/3246)。另一个包含1455名受试者的3期双盲随机对照试验表明，经过66个月随访，万泰疫苗对HSIL的VE仍然保持100%(疫苗组0/3310，对照组13/3302)。沃森/玉溪泽润：Walrinvax®的3期临床显示，在PPS-I人群中，对应疗效为78.6%(95%CI:23.3~96.1；疫苗组3/5190，对照组14/5167)。默沙东：Gardasil的临床试验显示，随访78个月后，HPV16/18相关CIN2+的有效率为100%(95%CI:32.3~100；疫苗组0，对照组7)。HPV6/11/16/18相关CIN1+的有效率同样为100%(95%CI:70.9~100；疫苗组0，对照组14例)。30个月时对6个月PIs的有效率为91.6%，78个月时对12个月PIs的有效率为97.5%。最近发表的对368名参与者的8年随访显示，疫苗对HPV相关疾病的3剂持续保护持续时间中位数为94个月，最长达125月。clinicaltrials.gov在已感染接种者身上的抗感染能力：GSK的一项包含168 名参与者的2/3期试验(NCT00779766)评估了Cervarix在72个月的随访期内对871名年龄在18-25岁的中国女性抗hrHPV感染的疗效。在接种疫苗时已经感染了HPV的女性仍然可以从HPV疫苗中受益。结果显示，HPV16/18DNA阴性而其他HR-HPV型阳性的女性VE与6个月和12个月HPV16/18PI的相对符合率分别为100.0%(95%CI:79.8~100.0)和100.0%(95%CI:47.2~100.0)。基线为71.0%。接种后辅助清除感染：Cervarix对治疗后14 小时HPV 感染的VE为27%。治疗后感染14hrHPV的接种疫苗的VE为27%，治疗14hrHPV感染后新感染的VE估计为32.0%，HPV16/18感染的VE为41.2%(95%CI都范围较大)。因此认为其并无加速清除感染的作用。BMC Infect Dis 20, 846 (2020)2价vs4价 保护效力和持久性对比2023年3月，关于默沙东的4价疫苗Gardasil®和GSK的2价疫苗Cervarix®对HPV16型、18型的保护效力比较的一篇文章被发表在NPJ Vaccine上。数据来自一组24人、随访13个月的队列。其对比内容包括：中和抗体：Gardasil®和Cervarx®随时间推移可诱导相似的总体抗体Fc谱。不过随着时间的推移，Gardasil®和Cervarx®疫苗应答中的抗体同型和亚类分布出现细微的单变量差异。npj Vaccines与Cervarx®诱导的应答相比，Gardasil®诱导的抗体可能会更快地减弱。同时，尽管Gardasil®在防止疫苗中包含的HPV基因型向CIN2+进展方面有效，但Cevarix®对CIN2+提供了更好的保护，甚至对与系统发育相关的非疫苗基因型HPV病毒感染也是如此。FcR特异性体液免疫：除了中和作用外，抗体还通过Fc受体(FCR)引导所有先天免疫细胞的抗病毒活性，从而参与控制和清除其他几种病毒感染。HPV特异性免疫球蛋白单抗也可能以一种Fc依赖的方式提供对感染的保护。HPV16主衣壳蛋白(L1)和HPV18L1都能诱导出能够与所有4种低亲和力IgG Fc受体相互作用的抗体。与亚类和同型反应类似，两种疫苗的Fc受体结合在8个月时达到峰值。HPV16L1特异性FcγR2a、FcγR3a、Fcγr2b和FcγR3b结合抗体在Cervarx®免疫个体中出现得更早，在Cervarx®接受者中免疫原性峰值略高，这可能与疫苗制剂方案不同有关，但最终在两种疫苗中达到了相似的水平和相似的动力学。npj Vaccines相反的是，HPV18L1特异性的FcγR2a和FcγR3a在不同时间点的结合反应更相似，但Fcγr2b和FcγR3b结合抗体在这两种疫苗接种后8个月和13个月出现差异：与接种Gardasil®的个体相比，Cervarx®免疫个体的Fc受体结合持久性增强，暗示各疫苗之间可能有潜在的功能耐久性差异。HPV16和HPV18 L1特异性免疫之间的协调水平的差异npj Vaccines小结HPV疫苗拓宽适应年龄后，国内九价疫苗还是存在供给不充足的情况。最近也有很多科普宣传建议不必“死等”九价，二价疫苗就能覆盖大部分需求。将GSK2价和默沙东4价对比的这篇文献（参考资料1）得出，对于最高危的HPV16/18型，二价保护效力反而更持久，显然是为这类观点提供了数据支持。那在考虑2价的前提下，国内2价疫苗的选择有2-3种（小编处社区暂未提供Walrinvax），万泰疫苗和GSK疫苗的VE数据接近，就试验数据来看或许是性价比最高的。参考文献：Roy, V., Jung, W., Linde, C. et al. Differences in HPV-specific antibody Fc-effector functions following Gardasil® and Cervarix® vaccination. npj Vaccines 8, 39 (2023). https://doi.org/10.1038/s41541-023-00628-8Li M, Zhao C, Zhao Y, Li J and Wei L (2023) Immunogenicity, efficacy, and safety of human papillomavirus vaccine: Data from China. Front. Immunol. 14:1112750. doi: 10.3389/fimmu.2023.1112750Zhao, S., Hu, S., Xu, X. et al. Impact of HPV-16/18 AS04-adjuvanted vaccine on preventing subsequent infection and disease after excision treatment: post-hoc analysis from a randomized controlled trial. BMC Infect Dis 20, 846 (2020). https://doi.org/10.1186/s12879-020-05560-zChao Zhao, Yun Zhao, Jingran Li, Mingzhu Li, Yanyan Su, Xin Mi, Su Yi La Tu, Danhua Shen, Lihua Ren, Yanyan Li, Linhong Wang & Lihui Wei (2022) The eight-year long-term follow-up on the effectiveness of the quadrivalent human papillomavirus vaccine in Chinese women 20-45 years of age, Human Vaccines & Immunotherapeutics, 18:5, DOI: 10.1080/21645515.2022.2052700Shangying Hu, Xiaoqian Xu, Fengcai Zhu, Ying Hong, Yuemei Hu, Xun Zhang, Qinjing Pan, Wenhua Zhang, Chengfu Zhang, Xiaoping Yang, Jiaxi Yu, Jiahong Zhu, Yejiang Zhu, Feng Chen, Shuang Zhao, Naveen Karkada, Haiwen Tang, Dan Bi, Frank Struyf & Fanghui Zhao (2021) Efficacy of the AS04-adjuvanted HPV-16/18 vaccine in young Chinese women with oncogenic HPV infection at baseline: post-hoc analysis of a randomized controlled trial, Human Vaccines &Immunotherapeutics,17:4,955964,DOI:10.1080/21645515.2020.1829411近期热门视频更多精彩视频，尽在佰傲谷视频号，欢迎关注~本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处﹀ 点亮在看，传递信息♥

FDA approves RGVax's (HPV16 RG1-VLP) IND for Phase 1 clinical trials. BALTIMORE, March 29, 2023 /PRNewswire/ -- PathoVax LLC ("PathoVax"), a biotech company focused on developing a universally preventative Human Papillomavirus (HPV) vaccine - "RGVax", today announced that the U.S. Food and Drug Administration (FDA) has completed its review of the investigational new drug (IND) application for its licensed monovalent component- HPV16 RG1-VLP and concluded that a Phase 1 clinical trial in the United States and Austria is now given the go-ahead to proceed. This Phase 1, first-in-human, global multicenter clinical study seeks to demonstrate the safety and immunogenicity responses to HPV16 RG1-VLP in healthy volunteers. The underlying RGVax foundational technology was licensed from Johns Hopkins University and the subsequent GMP as well as Phase 1 development of this vaccine was supported by the NCI PREVENT cancer program. "The world needs more, and particularly broad-based, HPV vaccines. We are excited that our collaborators have been able to move forward with the clinical development of HPV16 RG1-VLP. This clinical proof of concept will demonstrate the potential it holds for positively impacting the lives of many individuals at risk of HPV infection and diseases. We look forward to globally supporting these efforts in parallel and beyond this Phase 1 especially in Asia-Pacific and other developing countries too where there is a high burden of HPV diseases," said Dr Kevin Koh, Chairman of PathoVax. PathoVax was co-founded to licensed and developed a game changing preventative universal HPV vaccine. The foundational technology (RGVax technology) is based off vaccine scientific research at the Johns Hopkins University and Medical University Vienna. Unlike existing HPV vaccines that do not target all HPV types, the RGVax technology and formulation has been shown to provide comprehensive protection against at least 18 high risk HPV types with immunogenicity lasting over a year without additional boosts in head-to-head studies with existing approved HPV vaccines. This leapfrogs current vaccines as multiple diseases are now linked to HPV infection. It is anticipated that such additional protection will eventually establish new standards of care for many patients. Dr Joshua Wang, a co-founder of PathoVax LLC said the following "Securing FDA clearance to start clinical trials is a significant achievement. This could not have been possible without the ongoing academic-industry collaborations that have occurred since day one between PathoVax LLC, Johns Hopkins and the National Cancer Institute's PREVENT program." About PathoVax LLC: PathoVax LLC, is a start-up company that is based on foundational technology developed at Johns Hopkins University to advance RGVaxTM, the world's first comprehensive HPV vaccine that aims to target all clinically relevant HPV. It is expected that such additional protection will eventually establish new standards in the $2B HPV market. PathoVax's collaborative partnerships include well-known institutions such as the U.S. National Cancer Institute to push forward an academic phase 1 study. For more information, visit: Forward-Looking Statements Any statements in this release that are not historical facts may be considered to be "forward-looking statements." Forward-looking statements are based on management's current expectations and are subject to risks and uncertainties which may cause results to differ materially and adversely from the statements contained herein. Such statements include, but are not limited to, statements regarding the market opportunity for PathoVax's product candidates; and the business strategies and development plans of PathoVax. Some of the potential risks and uncertainties that could cause actual results to differ from those expected include Pathovax's ability to: make commercially available its products and technologies in a timely manner or at all; enter into other strategic alliances, including arrangements for the development and distribution of its products; obtain intellectual property protection for its assets; accurately estimate its expenses and cash burn and raise additional funds when necessary. Undue reliance should not be placed on forward-looking statements, which speak only as of the date they are made. Except as required by law, Pathovax does not undertake any obligation to update any forward-looking statements to reflect new information, events or circumstances after the date they are made, or to reflect the occurrence of unanticipated events. CONTACT: info@pathovax.com