1048. Double-Blind, Randomized, Placebo-Controlled Phase 2b Multicenter Trial of V160, a Replication-Defective Human Cytomegalovirus (CMV) Vaccine
1048. Double-Blind, Randomized, Placebo-Controlled Phase 2b Multicenter Trial of V160, a Replication-Defective Human Cytomegalovirus (CMV) Vaccine
复制标题
DOI：
10.1093/ofid/ofab466.1242
复制
发表时间：
2021-12-04
影响因子：
4.2
通讯作者：
Russell K
中科院分区：
文献类型：
--
作者：
Das R;Blazquez-Gamero D;Bernstein DI;Gantt S;Bautista O;Beck K;Conlon A;Rosenbloom D;Wang D;Ritter M;Arnold B;Annunziato P;Russell K
预防先天性巨细胞病毒感染(CMVi)是一项尚未得到满足的重要需求。孕妇在怀孕前获得的对巨细胞病毒的自然免疫似乎可以减少胎儿的传播。在第一阶段试验中，表达五聚体复合体的复制缺陷CMV疫苗V160诱导了与自然免疫相当的体液和细胞介导免疫(CMI)反应。年龄16-35岁的健康、巨细胞病毒血清阴性的妇女被随机分为3或2剂量方案或安慰剂，接受双盲V160治疗。采用固定事件设计，V160的3剂或2剂方案与安慰剂相比，主要和次要终点分别有效地降低了CMVi的发生率。每月收集尿液和唾液样本，通过聚合酶链式反应(PCR)鉴定CMVi，其中单一阳性样本被认为是感染的证据。检测所有受试者的免疫球蛋白G(Ig G)与糖蛋白B(GB)的结合和CMV特异性中和抗体(NAB)，并在一个亚组中测定CMI反应。分别于每次接种后5天和14天收集注射部位不良反应和全身不良反应，并在试验期内收集严重不良反应。来自7个国家的2200名妇女参加了调查(筛查了7458人)。超过80%的参与者接受了所有剂量的治疗，唾液和尿液样本的依从性为95%。与安慰剂相比，三剂疫苗组的疫苗效力(VE)为42.4%(95%CI-13.5，71.1%)。2剂组VE为-32.0%(95%CI-135.0，25.0%)。与安慰剂相比，CMVi患者的尿液和唾液中CMV的排泄量和持续时间均在3剂中减少，但2剂组与安慰剂相比并不减少。两种V160方案均可通过CMV特异性NAB、GB IgG和ELISpot检测到体液和CMI反应，这些反应在7个月时达到峰值，并在24个月时继续检测到。V160与安慰剂组相比，轻度到中度的不良反应发生率更高，但没有疫苗相关的严重不良反应或死亡的报告。V160具有良好的耐受性和免疫原性，但3剂和2剂方案均未显示出本试验所定义的对CMVi的显著疗效。3剂组CMV脱落量减少，持续时间减少，提示V160可改善CMVi后病毒复制的免疫控制。Rituparna Das，MD，Merck&Co，Inc.(员工)Daniel Blazquez-Gamero，MD，MSD(其他财务或物质支持，教育活动讲座费用)Soren Gantt，MD，Altona Diagnostics(研究资助或支持)Merck(顾问，资助/研究支持)子午线生物科学(研究资助或支持)Modna(顾问，研究资助或支持)VBI疫苗公司(研究资助或支持)Oliver Bautista，PhD，Merck&Co，Inc.(员工)Karen Beck，RN，BSN，Merck&Co，Inc.(员工)Anthony Conlon，PhD，Merck&Co，Inc.(员工)戴旺，博士，默克公司(员工)迈克尔·里特，BA，BA，默克公司(员工)Beth Arnold，MS，Merck&Co，Inc.(员工，股东)Paula Annunziato，MD，Merck&Co，Inc.(员工，股东)
Preventing congenital cytomegalovirus infection (CMVi) is an important unmet need. Natural maternal immunity to CMV acquired prior to pregnancy appears to reduce fetal transmission. In a Phase 1 trial, V160, a replication-defective CMV vaccine expressing the pentameric complex, induced humoral and cell-mediated immune (CMI) responses comparable to natural immunity. Healthy, CMV-seronegative women aged 16–35 years were randomized 1:1:1 to receive double-blind V160 in a 3- or 2-dose regimen or placebo. Primary and secondary endpoints were efficacy in reducing the incidence of CMVi with 3-dose or 2-dose regimens of V160 vs placebo, respectively, using a fixed-event design. Monthly urine and saliva samples were collected to identify CMVi by polymerase chain reaction (PCR) with a single positive sample considered evidence of infection. Immunoglobulin G (IgG) binding to glycoprotein B (gB) and CMV-specific neutralizing antibody (NAb) were measured in all participants, and CMI responses were measured in a subset. Injection-site and systemic adverse events (AEs) were collected for 5 days and 14 days, respectively, after each vaccination and serious AEs were collected for the trial duration. 2200 women from 7 countries were enrolled (of 7458 screened). Over 80% of participants received all doses, and compliance with saliva and urine samples was > 95%. Vaccine efficacy (VE) of 42.4% (95% CI -13.5, 71.1%) was demonstrated in the 3-dose group vs placebo. In the 2-dose group, VE was -32.0% (95% CI -135.0, 25.0%). Both the quantity and duration of CMV shedding in urine and saliva among cases of CMVi decreased in the 3-dose, but not the 2-dose group vs placebo. Both V160 regimens elicited humoral and CMI responses detected by CMV-specific NAb, gB IgG, and ELISpot, which peaked at Month 7 and continued to be detectable at Month 24. Mild to moderate AEs were more frequently reported in V160 vs placebo recipients, but no vaccine-related serious AEs or deaths were reported. V160 was well tolerated and immunogenic, but neither the 3-dose nor 2-dose regimen demonstrated significant efficacy against CMVi as defined in this trial. The quantity and duration of CMV shedding was reduced in the 3-dose group, suggesting V160 may improve immune control of viral replication after CMVi. Rituparna Das, MD, Merck & Co, Inc. (Employee) Daniel Blazquez-Gamero, MD, MSD (Other Financial or Material Support, Fees for lectures in educational activities) Soren Gantt, MD, Altona Diagnostics (Research Grant or Support)Merck (Consultant, Grant/Research Support)Meridian Biosciences (Research Grant or Support)Moderna (Consultant, Research Grant or Support)VBI Vaccines Inc (Research Grant or Support) Oliver Bautista, PhD, Merck & Co, Inc. (Employee) Karen Beck, RN, BSN, Merck & Co, Inc. (Employee) Anthony Conlon, PhD, Merck & Co, Inc. (Employee) Daniel Rosenbloom, PhD, Merck & Co, Inc. (Employee) Dai Wang, PhD, Merck & Co, Inc. (Employee) Michael Ritter, BA, Merck & Co, Inc. (Employee) Beth Arnold, MS, Merck & Co, Inc. (Employee, Shareholder) Paula Annunziato, MD, Merck & Co, Inc. (Employee) Kevin Russell, MD, MTM&H, Merck & Co., Inc. (Employee, Shareholder)