PDF(Pubmed)
Abstract：
Zika virus infection is a threat to at-risk populations, causing major birth defects and serious neurological complications. Development of a safe and efficacious Zika virus vaccine is, therefore, a global health priority. Assessment of heterologous flavivirus vaccination is important given co-circulation of Japanese encephalitis virus and yellow fever virus with Zika virus. We investigated the effect of priming flavivirus naive participants with a licensed flavivirus vaccine on the safety and immunogenicity of a purified inactivated Zika vaccine (ZPIV).
This phase 1, placebo-controlled, double-blind trial was done at the Walter Reed Army Institute of Research Clinical Trials Center in Silver Spring, MD, USA. Eligible participants were healthy adults aged 18-49 years, with no detectable evidence of previous flavivirus exposure (by infection or vaccination), as measured by a microneutralisation assay. Individuals with serological evidence of HIV, hepatitis B, or hepatitis C infection were excluded, as were pregnant or breastfeeding women. Participants were recruited sequentially into one of three groups (1:1:1) to receive no primer, two doses of intramuscular Japanese encephalitis virus vaccine (IXIARO), or a single dose of subcutaneous yellow fever virus vaccine (YF-VAX). Within each group, participants were randomly assigned (4:1) to receive intramuscular ZPIV or placebo. Priming vaccinations were given 72-96 days before ZPIV. ZPIV was administered either two or three times, at days 0, 28, and 196-234. The primary outcome was occurrence of solicited systemic and local adverse events along with serious adverse events and adverse events of special interest. These data were analysed in all participants receiving at least one dose of ZPIV or placebo. Secondary outcomes included measurement of neutralizing antibody responses following ZPIV vaccination in all volunteers with available post-vaccination data. This trial is registered at ClinicalTrials.gov, NCT02963909.
Between Nov 7, 2016, and Oct 30, 2018, 134 participants were assessed for eligibility. 21 did not meet inclusion criteria, 29 met exclusion criteria, and ten declined to participate. 75 participants were recruited and randomly assigned. 35 (47%) of 75 participants were male and 40 (53%) were female. 25 (33%) of 75 participants identified as Black or African American and 42 (56%) identified as White. These proportions and other baseline characteristics were similar between groups. There were no statistically significant differences in age, gender, race, or BMI between those who did and did not opt into the third dose. All participants received the planned priming IXIARO and YF-VAX vaccinations, but one participant who received YF-VAX dropped out before receipt of the first dose of ZPIV. 50 participants received a third dose of ZPIV or placebo, including 14 flavivirus-naive people, 17 people primed with Japanese encephalitis virus vaccine, and 19 participants primed with yellow fever vaccine. Vaccinations were well tolerated across groups. Pain at the injection site was the only adverse event reported more frequently in participants who received ZPIV than in those who received placebo (39 [65%] of 60 participants, 95% CI 51·6-76·9 who received ZPIV vs three [21·4%] of 14 who received placebo; 4·7-50·8; p=0·006). No patients had an adverse event of special interest or serious adverse event related to study treatment. At day 57, the flavivirus-naive volunteers had an 88% (63·6-98·5, 15 of 17) seroconversion rate (neutralising antibody titre ≥1:10) and geometric mean neutralising antibody titre (GMT) against Zika virus of 100·8 (39·7-255·7). In the Japanese encephalitis vaccine-primed group, the day 57 seroconversion rate was 31·6% (95% CI 12·6-56·6, six of 19) and GMT was 11·8 (6·1-22·8). Participants primed with YF-VAX had a seroconversion rate of 25% (95% CI 8·7-49·1, five of 20) and GMT of 6·6 (5·2-8·4). Humoral immune responses rose substantially following a third dose of ZPIV, with seroconversion rates of 100% (69·2-100; ten of ten), 92·9% (66·1-99·8; 13 of 14), and 60% (32·2-83·7, nine of 15) and GMTs of 511·5 (177·6-1473·6), 174·2 (51·6-587·6), and 79 (19·0-326·8) in the flavivirus naive, Japanese encephalitis vaccine-primed, and yellow fever vaccine-primed groups, respectively.
We found ZPIV to be well tolerated in flavivirus naive and primed adults but that immunogenicity varied significantly according to antecedent flavivirus vaccination status. Immune bias towards the flavivirus antigen of initial exposure and the timing of vaccination may have impacted responses. A third ZPIV dose overcame much, but not all, of the discrepancy in immunogenicity. The results of this phase 1 clinical trial have implications for further evaluation of ZPIV\'s immunisation schedule and use of concomitant vaccinations.
Department of Defense, Defense Health Agency; National Institute of Allergy and Infectious Diseases; and Division of Microbiology and Infectious Disease.
This phase 1, placebo-controlled, double-blind trial was done at the Walter Reed Army Institute of Research Clinical Trials Center in Silver Spring, MD, USA. Eligible participants were healthy adults aged 18-49 years, with no detectable evidence of previous flavivirus exposure (by infection or vaccination), as measured by a microneutralisation assay. Individuals with serological evidence of HIV, hepatitis B, or hepatitis C infection were excluded, as were pregnant or breastfeeding women. Participants were recruited sequentially into one of three groups (1:1:1) to receive no primer, two doses of intramuscular Japanese encephalitis virus vaccine (IXIARO), or a single dose of subcutaneous yellow fever virus vaccine (YF-VAX). Within each group, participants were randomly assigned (4:1) to receive intramuscular ZPIV or placebo. Priming vaccinations were given 72-96 days before ZPIV. ZPIV was administered either two or three times, at days 0, 28, and 196-234. The primary outcome was occurrence of solicited systemic and local adverse events along with serious adverse events and adverse events of special interest. These data were analysed in all participants receiving at least one dose of ZPIV or placebo. Secondary outcomes included measurement of neutralizing antibody responses following ZPIV vaccination in all volunteers with available post-vaccination data. This trial is registered at ClinicalTrials.gov, NCT02963909.
Between Nov 7, 2016, and Oct 30, 2018, 134 participants were assessed for eligibility. 21 did not meet inclusion criteria, 29 met exclusion criteria, and ten declined to participate. 75 participants were recruited and randomly assigned. 35 (47%) of 75 participants were male and 40 (53%) were female. 25 (33%) of 75 participants identified as Black or African American and 42 (56%) identified as White. These proportions and other baseline characteristics were similar between groups. There were no statistically significant differences in age, gender, race, or BMI between those who did and did not opt into the third dose. All participants received the planned priming IXIARO and YF-VAX vaccinations, but one participant who received YF-VAX dropped out before receipt of the first dose of ZPIV. 50 participants received a third dose of ZPIV or placebo, including 14 flavivirus-naive people, 17 people primed with Japanese encephalitis virus vaccine, and 19 participants primed with yellow fever vaccine. Vaccinations were well tolerated across groups. Pain at the injection site was the only adverse event reported more frequently in participants who received ZPIV than in those who received placebo (39 [65%] of 60 participants, 95% CI 51·6-76·9 who received ZPIV vs three [21·4%] of 14 who received placebo; 4·7-50·8; p=0·006). No patients had an adverse event of special interest or serious adverse event related to study treatment. At day 57, the flavivirus-naive volunteers had an 88% (63·6-98·5, 15 of 17) seroconversion rate (neutralising antibody titre ≥1:10) and geometric mean neutralising antibody titre (GMT) against Zika virus of 100·8 (39·7-255·7). In the Japanese encephalitis vaccine-primed group, the day 57 seroconversion rate was 31·6% (95% CI 12·6-56·6, six of 19) and GMT was 11·8 (6·1-22·8). Participants primed with YF-VAX had a seroconversion rate of 25% (95% CI 8·7-49·1, five of 20) and GMT of 6·6 (5·2-8·4). Humoral immune responses rose substantially following a third dose of ZPIV, with seroconversion rates of 100% (69·2-100; ten of ten), 92·9% (66·1-99·8; 13 of 14), and 60% (32·2-83·7, nine of 15) and GMTs of 511·5 (177·6-1473·6), 174·2 (51·6-587·6), and 79 (19·0-326·8) in the flavivirus naive, Japanese encephalitis vaccine-primed, and yellow fever vaccine-primed groups, respectively.
We found ZPIV to be well tolerated in flavivirus naive and primed adults but that immunogenicity varied significantly according to antecedent flavivirus vaccination status. Immune bias towards the flavivirus antigen of initial exposure and the timing of vaccination may have impacted responses. A third ZPIV dose overcame much, but not all, of the discrepancy in immunogenicity. The results of this phase 1 clinical trial have implications for further evaluation of ZPIV\'s immunisation schedule and use of concomitant vaccinations.
Department of Defense, Defense Health Agency; National Institute of Allergy and Infectious Diseases; and Division of Microbiology and Infectious Disease.
摘要：
背景：寨卡病毒感染对高危人群构成威胁，导致严重的出生缺陷和严重的神经系统并发症。开发一种安全有效的寨卡病毒疫苗，因此,全球卫生优先事项。考虑到日本脑炎病毒和黄热病病毒与寨卡病毒的共同循环，评估异源黄病毒疫苗接种是重要的。我们研究了使用许可的黄病毒疫苗引发未感染黄病毒的参与者对纯化的灭活寨卡疫苗（ZPIV）的安全性和免疫原性的影响。
方法：本阶段1，安慰剂对照，在银泉的沃尔特·里德陆军研究所临床试验中心进行了双盲试验，MD,美国。符合条件的参与者是18-49岁的健康成年人，没有检测到以前的黄病毒暴露（通过感染或疫苗接种）的证据，通过微中性化测定法测量。有艾滋病毒血清学证据的人，乙型肝炎，或丙型肝炎感染被排除，孕妇或哺乳期妇女也是如此。参与者被顺序招募到三组（1：1：1）中的一组，不接受引物，两剂肌内注射日本脑炎病毒疫苗（IXIARO），或单剂量皮下黄热病病毒疫苗（YF-VAX）。在每一组中,参与者被随机分配(4:1)接受肌内注射ZPIV或安慰剂.在ZPIV之前72-96天给予启动疫苗接种。ZPIV给药两次或三次，在第0、28和196-234天。主要结果是引起的全身和局部不良事件以及严重不良事件和特别关注的不良事件的发生。在所有接受至少一剂ZPIV或安慰剂的参与者中分析这些数据。次要结果包括在具有可用的接种后数据的所有志愿者中在ZPIV接种后中和抗体应答的测量。该试验在ClinicalTrials.gov注册，NCT02963909。
结果：在2016年11月7日至2018年10月30日之间，对134名参与者进行了资格评估。21人不符合纳入标准，29符合排除标准，十个人拒绝参加。招募并随机分配75名参与者。75名参与者中有35名（47％）是男性，40名（53％）是女性。75名参与者中有25名（33％）被确定为黑人或非裔美国人，42名（56％）被确定为白人。这些比例和其他基线特征在组间相似。年龄差异无统计学意义,性别,种族,或BMI在那些选择和没有选择第三剂量的人之间。所有参与者都接受了计划的IXIARO和YF-VAX疫苗接种，但一名接受YF-VAX的参与者在接受第一剂ZPIV之前退出.50名参与者接受了第三剂ZPIV或安慰剂，包括14个感染黄病毒的人,17人接种了日本脑炎病毒疫苗，19名参与者接种了黄热病疫苗。各组的疫苗接种耐受性良好。注射部位疼痛是接受ZPIV的参与者比接受安慰剂的参与者更频繁报告的唯一不良事件（60名参与者中有39[65％]，95%CI51·6-76·9接受ZPIV，14例接受安慰剂的3例[21·4%]；4·7-50·8；p=0·006）。没有患者发生与研究治疗相关的特殊不良事件或严重不良事件。在第57天，未接受黄病毒治疗的志愿者的血清转化率为88％（63·6-98·5，17个中的15个）（中和抗体滴度≥1：10）和几何平均中和抗体滴度（GMT）针对Zika病毒的100·8（39·7-255·7）。在日本脑炎疫苗引发组，第57天血清转换率为31·6％（95％CI12·6-56·6，19中的6），GMT为11·8（6·1-22·8）。接受YF-VAX治疗的参与者血清转化率为25％（95％CI8·7-49·1，20个中的5个），GMT为6·6（5·2-8·4）。第三剂ZPIV后，体液免疫反应大幅上升，血清转化率为100%(69·2-100；十个中的十个)，92·9%（66·1-99·8；14人中的13人），和60％（32·2-83·7，15个中的9个）和GMT为511·5（177·6-1473·6），174·2（51·6-587·6），和79（19·0-326·8）的黄病毒，日本脑炎疫苗引发，和黄热病疫苗组，分别。
结论：我们发现ZPIV在未感染黄病毒和已感染黄病毒的成虫中具有良好的耐受性，但其免疫原性根据之前的黄病毒疫苗接种状态而显著变化。对初始暴露的黄病毒抗原的免疫偏见和疫苗接种的时机可能会影响应答。第三个ZPIV剂量克服了很多，但不是全部,免疫原性的差异。该1期临床试验的结果对进一步评估ZPIV的免疫接种计划和同时接种疫苗的使用具有重要意义。
背景：国防部，国防卫生局；国家过敏和传染病研究所；以及微生物学和传染病司。
方法：本阶段1，安慰剂对照，在银泉的沃尔特·里德陆军研究所临床试验中心进行了双盲试验，MD,美国。符合条件的参与者是18-49岁的健康成年人，没有检测到以前的黄病毒暴露（通过感染或疫苗接种）的证据，通过微中性化测定法测量。有艾滋病毒血清学证据的人，乙型肝炎，或丙型肝炎感染被排除，孕妇或哺乳期妇女也是如此。参与者被顺序招募到三组（1：1：1）中的一组，不接受引物，两剂肌内注射日本脑炎病毒疫苗（IXIARO），或单剂量皮下黄热病病毒疫苗（YF-VAX）。在每一组中,参与者被随机分配(4:1)接受肌内注射ZPIV或安慰剂.在ZPIV之前72-96天给予启动疫苗接种。ZPIV给药两次或三次，在第0、28和196-234天。主要结果是引起的全身和局部不良事件以及严重不良事件和特别关注的不良事件的发生。在所有接受至少一剂ZPIV或安慰剂的参与者中分析这些数据。次要结果包括在具有可用的接种后数据的所有志愿者中在ZPIV接种后中和抗体应答的测量。该试验在ClinicalTrials.gov注册，NCT02963909。
结果：在2016年11月7日至2018年10月30日之间，对134名参与者进行了资格评估。21人不符合纳入标准，29符合排除标准，十个人拒绝参加。招募并随机分配75名参与者。75名参与者中有35名（47％）是男性，40名（53％）是女性。75名参与者中有25名（33％）被确定为黑人或非裔美国人，42名（56％）被确定为白人。这些比例和其他基线特征在组间相似。年龄差异无统计学意义,性别,种族,或BMI在那些选择和没有选择第三剂量的人之间。所有参与者都接受了计划的IXIARO和YF-VAX疫苗接种，但一名接受YF-VAX的参与者在接受第一剂ZPIV之前退出.50名参与者接受了第三剂ZPIV或安慰剂，包括14个感染黄病毒的人,17人接种了日本脑炎病毒疫苗，19名参与者接种了黄热病疫苗。各组的疫苗接种耐受性良好。注射部位疼痛是接受ZPIV的参与者比接受安慰剂的参与者更频繁报告的唯一不良事件（60名参与者中有39[65％]，95%CI51·6-76·9接受ZPIV，14例接受安慰剂的3例[21·4%]；4·7-50·8；p=0·006）。没有患者发生与研究治疗相关的特殊不良事件或严重不良事件。在第57天，未接受黄病毒治疗的志愿者的血清转化率为88％（63·6-98·5，17个中的15个）（中和抗体滴度≥1：10）和几何平均中和抗体滴度（GMT）针对Zika病毒的100·8（39·7-255·7）。在日本脑炎疫苗引发组，第57天血清转换率为31·6％（95％CI12·6-56·6，19中的6），GMT为11·8（6·1-22·8）。接受YF-VAX治疗的参与者血清转化率为25％（95％CI8·7-49·1，20个中的5个），GMT为6·6（5·2-8·4）。第三剂ZPIV后，体液免疫反应大幅上升，血清转化率为100%(69·2-100；十个中的十个)，92·9%（66·1-99·8；14人中的13人），和60％（32·2-83·7，15个中的9个）和GMT为511·5（177·6-1473·6），174·2（51·6-587·6），和79（19·0-326·8）的黄病毒，日本脑炎疫苗引发，和黄热病疫苗组，分别。
结论：我们发现ZPIV在未感染黄病毒和已感染黄病毒的成虫中具有良好的耐受性，但其免疫原性根据之前的黄病毒疫苗接种状态而显著变化。对初始暴露的黄病毒抗原的免疫偏见和疫苗接种的时机可能会影响应答。第三个ZPIV剂量克服了很多，但不是全部,免疫原性的差异。该1期临床试验的结果对进一步评估ZPIV的免疫接种计划和同时接种疫苗的使用具有重要意义。
背景：国防部，国防卫生局；国家过敏和传染病研究所；以及微生物学和传染病司。
