Brown Darron R, Garland Suzanne M, Ferris Daron G, Joura Elmar, Steben Marc, James Margaret, Radley David, Vuocolo Scott, Garner Elizabeth I O, Haupt Richard M, Bryan Janine T
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Hum Vaccin. 2011 Feb;7(2):230-8. doi: 10.4161/hv.7.2.13948. Epub 2011 Feb 1.
Safe and effective vaccines against anogenital human papillomaviruses (HPV) are now available. These vaccines, composed of virus-like particles (VLPs) made from the L1 major capsid protein of specific HPV types, induce a polyclonal antibody response directed against specific conformational and linear epitopes displayed on the VLP. Numerous studies indicated the importance of neutralizing antibodies in protection from infection. However, our understanding of the antibody responses to these vaccines is not complete, and there is no established immune correlate of protection nor antibody threshold that correlates with protection against HPV infection or disease. In the current study, antibody responses of young women to Gardasil®, the quadrivalent HPV 6, 11, 16 and 18 L1 VLP vaccine (qHPV), were assessed through 48 months (M) in total IgG and competitive Luminex immunoassays (total IgG LIA and cLIA). The total IgG LIA was developed as a research assay to evaluate preclinical multivalent HPV VLP vaccine formulations. The cLIA simultaneously evaluates the antibody response to a unique conformational, neutralizing epitope on each of the four HPV types present in the quadrivalent vaccine; HPV 6, 11, 16 and 18. The same sera from women vaccinated with the qHPV vaccine were tested in both the total IgG LIA and the cLIA assays. The proportion of vaccinated women achieving seropositivity and the anti-HPV VLP total IgG and cLIA geometric mean titers (GMTs) were summarized at M7, M24, M48 based on the serostatus cut-points defined for each immunoassay. Overall, greater than 99% of subjects seroconverted to all four vaccine types in both assays; GMTs peaked at M7. For all four HPV types, regardless of the immunoassay used, the most significant decline in GMTs was observed between M7 and M24. By M24, the antibody titers had reached a plateau and minimal declines in antibody titers were observed between M24 and M48 for all four HPV types in both immunoassays. Testing the same sera, seropositivity for M48 HPV18 remained high (96.7%) in the total IgG LIA, but was 64.8% in the cLIA. The current study illustrates potential important differences in serologic assays utilized in the clinical trials of the two currently available HPV VLP vaccines (quadrivalent and bivalent). Differences in seropositivity status are attributed to the measurement parameters and sensitivity of the individual immunoassays and do not indicate reduced anti-HPV18 protective antibodies.
目前已有安全有效的抗肛门生殖器人乳头瘤病毒（HPV）疫苗。这些疫苗由特定HPV类型的L1主要衣壳蛋白制成的病毒样颗粒（VLP）组成，可诱导针对VLP上显示的特定构象和线性表位的多克隆抗体反应。大量研究表明中和抗体在预防感染中的重要性。然而，我们对这些疫苗的抗体反应的理解并不完整，也没有既定的保护免疫相关指标或与预防HPV感染或疾病相关的抗体阈值。在本研究中，通过48个月（M）的总IgG和竞争性Luminex免疫测定（总IgG LIA和cLIA）评估了年轻女性对加德西（Gardasil®）（四价HPV 6、11、16和18 L1 VLP疫苗（qHPV））的抗体反应。总IgG LIA是作为一种研究测定法开发的，用于评估临床前多价HPV VLP疫苗制剂。cLIA同时评估对四价疫苗中存在的四种HPV类型（HPV 6、11、16和18）中每种独特构象的中和表位的抗体反应。用qHPV疫苗接种的女性的相同血清在总IgG LIA和cLIA测定中进行检测。根据每种免疫测定定义的血清学切点，总结了在第7个月（M7）、第24个月（M24）、第48个月（M48）时接种疫苗的女性达到血清阳性的比例以及抗HPV VLP总IgG和cLIA几何平均滴度（GMT）。总体而言，在两种测定中，超过99%的受试者对所有四种疫苗类型血清阳转；GMT在M7时达到峰值。对于所有四种HPV类型，无论使用何种免疫测定，在M7和M24之间观察到GMT最显著的下降。到M24时，抗体滴度已达到平台期，并且在两种免疫测定中，对于所有四种HPV类型，在M24和M48之间观察到抗体滴度的下降最小。检测相同血清时，在总IgG LIA中，M48时HPV18的血清阳性率仍然很高（96.7%），但在cLIA中为64.8%。本研究说明了目前两种可用的HPV VLP疫苗（四价和二价）临床试验中使用的血清学测定法可能存在的重要差异。血清阳性状态的差异归因于各个免疫测定的测量参数和灵敏度，并不表明抗HPV18保护性抗体减少。
