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.
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。