Abstract：
BACKGROUND: Protection afforded by inactivated influenza vaccines can theoretically be improved by inducing T-cell responses to conserved internal influenza A antigens. We assessed whether, in an influenza controlled human infection challenge, susceptible individuals receiving a vaccine boosting T-cell responses would exhibit lower viral load and decreased symptoms compared with placebo recipients.
METHODS: In this single centre, randomised, double-blind phase 2 study, healthy adult (aged 18-55 years) volunteers with microneutralisation titres of less than 20 to the influenza A(H3N2) challenge strain were enrolled at an SGS quarantine facility in Antwerp, Belgium. Participants were randomly assigned double-blind using a permuted-block list with a 3:2 allocation ratio to receive 0·5 mL intramuscular injections of modified vaccinia Ankara (MVA) expressing H3N2 nucleoprotein (NP) and matrix protein 1 (M1) at 1·5 × 108 plaque forming units (4·3 × 108 50% tissue culture infectious dose [TCID50]; MVA-NP+M1 group) or saline placebo (placebo group). At least 6 weeks later, participants were challenged intranasally with 0·5 mL of a 1 × 106 TCID50/mL dose of influenza A/Belgium/4217/2015 (H3N2). Nasal swabs were collected twice daily from day 2 until day 11 for viral PCR, and symptoms of influenza were recorded from day 2 until day 11. The primary outcome was to determine the efficacy of MVA-NP+M1 vaccine to reduce the degree of nasopharyngeal viral shedding as measured by the cumulative viral area under the curve using a log-transformed quantitative PCR. This study is registered with ClinicalTrials.gov, NCT03883113.
RESULTS: Between May 2 and Oct 24, 2019, 145 volunteers were enrolled and randomly assigned to the MVA-NP+M1 group (n=87) or the placebo group (n=58). Of these, 118 volunteers entered the challenge period (71 in the MVA-NP+M1 group and 47 in the placebo group) and 117 participants completed the study (71 in the MVA-NP+M1 group and 46 in the placebo group). 78 (54%) of the 145 volunteers were female and 67 (46%) were male. The primary outcome, overall viral load as determined by quantitative PCR, did not show a statistically significant difference between the MVA-NP+M1 (mean 649·7 [95% CI 552·7-746·7) and placebo groups (mean 726·1 [604·0-848·2]; p=0·17). All reported treatment emergent adverse events (TEAEs; 11 in the vaccination phase and 51 in the challenge phase) were grade 1 and 2, except for two grade 3 TEAEs in the placebo group in the challenge phase. A grade 4 second trimester fetal death, considered possibly related to the MVA-NP+M1 vaccination, and an acute psychosis reported in a placebo participant during the challenge phase were reported.
CONCLUSIONS: The use of an MVA vaccine to expand CD4+ or CD8+ T cells to conserved influenza A antigens in peripheral blood did not affect nasopharyngeal viral load in an influenza H3N2 challenge model in seronegative, healthy adults.
BACKGROUND: Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority; and Barinthus Biotherapeutics.
METHODS: In this single centre, randomised, double-blind phase 2 study, healthy adult (aged 18-55 years) volunteers with microneutralisation titres of less than 20 to the influenza A(H3N2) challenge strain were enrolled at an SGS quarantine facility in Antwerp, Belgium. Participants were randomly assigned double-blind using a permuted-block list with a 3:2 allocation ratio to receive 0·5 mL intramuscular injections of modified vaccinia Ankara (MVA) expressing H3N2 nucleoprotein (NP) and matrix protein 1 (M1) at 1·5 × 108 plaque forming units (4·3 × 108 50% tissue culture infectious dose [TCID50]; MVA-NP+M1 group) or saline placebo (placebo group). At least 6 weeks later, participants were challenged intranasally with 0·5 mL of a 1 × 106 TCID50/mL dose of influenza A/Belgium/4217/2015 (H3N2). Nasal swabs were collected twice daily from day 2 until day 11 for viral PCR, and symptoms of influenza were recorded from day 2 until day 11. The primary outcome was to determine the efficacy of MVA-NP+M1 vaccine to reduce the degree of nasopharyngeal viral shedding as measured by the cumulative viral area under the curve using a log-transformed quantitative PCR. This study is registered with ClinicalTrials.gov, NCT03883113.
RESULTS: Between May 2 and Oct 24, 2019, 145 volunteers were enrolled and randomly assigned to the MVA-NP+M1 group (n=87) or the placebo group (n=58). Of these, 118 volunteers entered the challenge period (71 in the MVA-NP+M1 group and 47 in the placebo group) and 117 participants completed the study (71 in the MVA-NP+M1 group and 46 in the placebo group). 78 (54%) of the 145 volunteers were female and 67 (46%) were male. The primary outcome, overall viral load as determined by quantitative PCR, did not show a statistically significant difference between the MVA-NP+M1 (mean 649·7 [95% CI 552·7-746·7) and placebo groups (mean 726·1 [604·0-848·2]; p=0·17). All reported treatment emergent adverse events (TEAEs; 11 in the vaccination phase and 51 in the challenge phase) were grade 1 and 2, except for two grade 3 TEAEs in the placebo group in the challenge phase. A grade 4 second trimester fetal death, considered possibly related to the MVA-NP+M1 vaccination, and an acute psychosis reported in a placebo participant during the challenge phase were reported.
CONCLUSIONS: The use of an MVA vaccine to expand CD4+ or CD8+ T cells to conserved influenza A antigens in peripheral blood did not affect nasopharyngeal viral load in an influenza H3N2 challenge model in seronegative, healthy adults.
BACKGROUND: Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority; and Barinthus Biotherapeutics.
摘要：
背景：灭活流感疫苗提供的保护在理论上可以通过诱导对保守的内部甲型流感抗原的T细胞应答来改善。我们评估了是否，在流感控制的人类感染挑战中，与安慰剂接受者相比,接受疫苗增强T细胞应答的易感个体将表现出更低的病毒载量和减轻的症状.
方法：在这个单一中心，随机化，双盲第二阶段研究，在安特卫普的SGS检疫设施中招募了对甲型流感（H3N2）攻击株的微中性化滴度低于20的健康成人（18-55岁）志愿者，比利时。参与者使用3：2分配比例的排列组随机双盲分配，以1·5×108个斑块形成单位（4·3×10850％组织培养感染剂量[IDTC50]；MVA-NPM1组）或生理盐水（安慰剂组）接受0·5mL肌内注射表达H3N2核蛋白（NP）和基质蛋白1（M1）的改良牛痘安卡拉（MVA）。至少6周后,参与者鼻内接受0·5mL1×106TCID50/mL剂量的甲型流感/比利时/4217/2015(H3N2)攻击.从第2天到第11天，每天两次收集鼻拭子用于病毒PCR，从第2天到第11天记录流感症状。主要结果是确定MVA-NP+M1疫苗降低鼻咽病毒脱落程度的功效,如通过使用对数转化定量PCR的曲线下累积病毒面积所测量的。这项研究在ClinicalTrials.gov注册，NCT03883113。
结果：在2019年5月2日至10月24日之间，招募了145名志愿者，并随机分配到MVA-NPM1组（n=87）或安慰剂组（n=58）。其中,118名志愿者进入挑战期（MVA-NPM1组71名，安慰剂组47名），117名参与者完成了研究（MVA-NPM1组71名，安慰剂组46名）。145名志愿者中有78名（54％）为女性，67名（46％）为男性。主要结果，通过定量PCR确定的总病毒载量，MVA-NP+M1组(平均649·7[95%CI552·7-746·7])和安慰剂组(平均726·1[604·0-848·2];p=0·17)之间无统计学差异.所有报告的治疗紧急不良事件(TEAE;在疫苗接种阶段11和在攻击阶段51)是1级和2级,除了在攻击阶段安慰剂组中的两个3级TEAE。4年级孕中期胎儿死亡，认为可能与MVA-NP+M1疫苗接种有关，并报告了安慰剂参与者在攻击阶段的急性精神病。
结论：在血清阴性的H3N2流感攻击模型中，使用MVA疫苗扩增外周血中CD4+或CD8+T细胞以保守的甲型流感抗原并不影响鼻咽病毒载量，健康的成年人。
背景：卫生与人类服务部；战略准备和响应管理；生物医学高级研究与发展管理局；和Barinthus生物治疗。
方法：在这个单一中心，随机化，双盲第二阶段研究，在安特卫普的SGS检疫设施中招募了对甲型流感（H3N2）攻击株的微中性化滴度低于20的健康成人（18-55岁）志愿者，比利时。参与者使用3：2分配比例的排列组随机双盲分配，以1·5×108个斑块形成单位（4·3×10850％组织培养感染剂量[IDTC50]；MVA-NPM1组）或生理盐水（安慰剂组）接受0·5mL肌内注射表达H3N2核蛋白（NP）和基质蛋白1（M1）的改良牛痘安卡拉（MVA）。至少6周后,参与者鼻内接受0·5mL1×106TCID50/mL剂量的甲型流感/比利时/4217/2015(H3N2)攻击.从第2天到第11天，每天两次收集鼻拭子用于病毒PCR，从第2天到第11天记录流感症状。主要结果是确定MVA-NP+M1疫苗降低鼻咽病毒脱落程度的功效,如通过使用对数转化定量PCR的曲线下累积病毒面积所测量的。这项研究在ClinicalTrials.gov注册，NCT03883113。
结果：在2019年5月2日至10月24日之间，招募了145名志愿者，并随机分配到MVA-NPM1组（n=87）或安慰剂组（n=58）。其中,118名志愿者进入挑战期（MVA-NPM1组71名，安慰剂组47名），117名参与者完成了研究（MVA-NPM1组71名，安慰剂组46名）。145名志愿者中有78名（54％）为女性，67名（46％）为男性。主要结果，通过定量PCR确定的总病毒载量，MVA-NP+M1组(平均649·7[95%CI552·7-746·7])和安慰剂组(平均726·1[604·0-848·2];p=0·17)之间无统计学差异.所有报告的治疗紧急不良事件(TEAE;在疫苗接种阶段11和在攻击阶段51)是1级和2级,除了在攻击阶段安慰剂组中的两个3级TEAE。4年级孕中期胎儿死亡，认为可能与MVA-NP+M1疫苗接种有关，并报告了安慰剂参与者在攻击阶段的急性精神病。
结论：在血清阴性的H3N2流感攻击模型中，使用MVA疫苗扩增外周血中CD4+或CD8+T细胞以保守的甲型流感抗原并不影响鼻咽病毒载量，健康的成年人。
背景：卫生与人类服务部；战略准备和响应管理；生物医学高级研究与发展管理局；和Barinthus生物治疗。
