Harro C D, Pang Y Y, Roden R B, Hildesheim A, Wang Z, Reynolds M J, Mast T C, Robinson R, Murphy B R, Karron R A, Dillner J, Schiller J T, Lowy D R
Center for Immunization Research, Department of International Medicine, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, MD, USA.
J Natl Cancer Inst. 2001 Feb 21;93(4):284-92. doi: 10.1093/jnci/93.4.284.
Studies in animal models have shown that systemic immunization with a papillomavirus virus-like particle (VLP) vaccine composed of L1, a major structural viral protein, can confer protection against subsequent experimental challenge with the homologous virus. Here we report results of a double-blind, placebo-controlled, dose-escalation trial to evaluate the safety and immunogenicity of a human papillomavirus (HPV) type 16 (HPV16) L1 VLP vaccine in healthy adults.
Volunteers were given intramuscular injections with placebo or with 10- or 50-microg doses of HPV16 L1 VLP vaccine given without adjuvant or with alum or MF59 as adjuvants at 0, 1, and 4 months. All vaccine recipients were monitored for clinical signs and symptoms for 7 days after each inoculation. Immune responses were measured by an HPV16 L1 VLP-based enzyme-linked immunosorbent assay (ELISA) and by an HPV16 pseudovirion neutralization assay. The antibody titers were given as the reciprocals of the highest dilution showing positive reactivity in each assay. All statistical tests were two-sided.
The prevaccination geometric mean ELISA titer for six seropositive individuals was 202 (range, 40--640). All vaccine formulations were well tolerated, and all subjects receiving vaccine seroconverted. Serum antibody responses at 1 month after the third injection were dose dependent in recipients of vaccine without adjuvant or with MF59 but were similar at both doses when alum was the adjuvant. With the higher dose, the geometric means of serum ELISA antibody titers (95% confidence intervals) to purified VLP 1 month after the third injection were as follows: 10,240 (1499 to 69 938) without adjuvant, 10,240 (1114 to 94 145) with MF59, and 2190 (838 to 5723) with alum. Responses of subjects within each group were similar. Neutralizing and ELISA antibody titers were highly correlated (Spearman correlation =.85), confirming that ELISA titers are valid proxies for neutralizing antibodies.
The HPV16 L1 VLP vaccine is well tolerated and is highly immunogenic even without adjuvant, with the majority of the recipients achieving serum antibody titers that were approximately 40-fold higher than what is observed in natural infection.
动物模型研究表明，用由主要结构病毒蛋白L1组成的乳头瘤病毒病毒样颗粒（VLP）疫苗进行全身免疫，可使动物对随后同源病毒的实验性攻击产生保护作用。在此，我们报告一项双盲、安慰剂对照、剂量递增试验的结果，以评估人乳头瘤病毒16型（HPV16）L1 VLP疫苗在健康成年人中的安全性和免疫原性。
志愿者在0、1和4个月时接受肌肉注射，分别注射安慰剂、不含佐剂或含明矾或MF59佐剂的10微克或50微克剂量的HPV16 L1 VLP疫苗。每次接种后对所有疫苗接种者进行7天的临床症状和体征监测。通过基于HPV16 L1 VLP的酶联免疫吸附测定（ELISA）和HPV16假病毒中和测定来测量免疫反应。抗体滴度以每次测定中显示阳性反应的最高稀释倍数的倒数表示。所有统计检验均为双侧检验。
6名血清阳性个体接种疫苗前的ELISA几何平均滴度为202（范围为40 - 640）。所有疫苗制剂耐受性良好，所有接受疫苗接种的受试者均发生血清学转换。在第三次注射后1个月，无佐剂或含MF59佐剂的疫苗接种者的血清抗体反应呈剂量依赖性，但当明矾作为佐剂时，两种剂量的反应相似。使用较高剂量时，第三次注射后1个月针对纯化VLP的血清ELISA抗体滴度的几何平均值（95%置信区间）如下：无佐剂时为10240（1499至69938），含MF59时为10240（1114至94145），含明矾时为2190（838至5723）。每组受试者的反应相似。中和抗体滴度与ELISA抗体滴度高度相关（Spearman相关系数 = 0.85），证实ELISA滴度是中和抗体的有效替代指标。
HPV16 L1 VLP疫苗耐受性良好，即使无佐剂也具有高度免疫原性，大多数接种者的血清抗体滴度比自然感染时观察到的滴度高约40倍。
