Immunogenicity of chimeric haemagglutinin-based, universal influenza virus vaccine candidates: interim results of a randomised, placebo-controlled, phase 1 clinical trial.,The Lancet Infectious Diseases

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Immunogenicity of chimeric haemagglutinin-based, universal influenza virus vaccine candidates: interim results of a randomised, placebo-controlled, phase 1 clinical trial.
The Lancet Infectious Diseases ( IF 36.4 ) Pub Date : 2019-10-17 , DOI: 10.1016/s1473-3099(19)30393-7
David I Bernstein ₁ , Jeffrey Guptill ₂ , Abdollah Naficy ₃ , Raffael Nachbagauer ₄ , Francesco Berlanda-Scorza ₃ , Jodi Feser ₃ , Patrick C Wilson ₅ , Alicia Solórzano ₄ , Marie Van der Wielen ₆ , Emmanuel B Walter ₇ , Randy A Albrecht ₈ , Kristen N Buschle ₁ , Yao-Qing Chen ₉ , Carine Claeys ₆ , Michelle Dickey ₁ , Haley L Dugan ₁₀ , Megan E Ermler ₁₁ , Debra Freeman ₂ , Min Gao ₂ , Christopher Gast ₃ , Jenna J Guthmiller ₉ , Rong Hai ₁₂ , Carole Henry ₉ , Linda Yu-Ling Lan ₁₀ , Monica McNeal ₁ , Anna-Karin E Palm ₉ , Dustin G Shaw ₁₀ , Christopher T Stamper ₁₀ , Weina Sun ₄ , Victoria Sutton ₂ , Micah E Tepora ₉ , Rahnuma Wahid ₃ , Heather Wenzel ₃ , Teddy John Wohlbold ₄ , Bruce L Innis ₃ , Adolfo García-Sastre ₁₃ , Peter Palese ₁₄ , Florian Krammer ₄

Affiliation

Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Duke Early Phase Clinical Research Unit, Duke Clinical Research Institute, Durham, NC, USA.
Center for Vaccine Innovation and Access, PATH, Seattle, WA, USA.
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Section of Rheumatology, Department of Medicine, University of Chicago, Chicago, IL, USA; The Committee on Immunology, University of Chicago, Chicago, IL, USA.
GlaxoSmithKline, Wavre, Belgium.
Duke Early Phase Clinical Research Unit, Duke Clinical Research Institute, Durham, NC, USA; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA.
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Section of Rheumatology, Department of Medicine, University of Chicago, Chicago, IL, USA.
The Committee on Immunology, University of Chicago, Chicago, IL, USA.
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; GlaxoSmithKline, Collegeville, PA, USA.
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Microbiology and Plant Pathology, Institute for Integrative Genome Biology, University of California, Riverside, CA, USA.
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

BACKGROUND Influenza viruses cause substantial annual morbidity and mortality globally. Current vaccines protect against influenza only when well matched to the circulating strains. However, antigenic drift can cause considerable mismatches between vaccine and circulating strains, substantially reducing vaccine effectiveness. Moreover, current seasonal vaccines are ineffective against pandemic influenza, and production of a vaccine matched to a newly emerging virus strain takes months. Therefore, there is an unmet medical need for a broadly protective influenza virus vaccine. We aimed to test the ability of chimeric H1 haemagglutinin-based universal influenza virus vaccine candidates to induce broadly cross-reactive antibodies targeting the stalk domain of group 1 haemagglutinin-expressing influenza viruses. METHODS We did a randomised, observer-blinded, phase 1 study in healthy adults in two centres in the USA. Participants were randomly assigned to one of three prime-boost, chimeric haemagglutinin-based vaccine regimens or one of two placebo groups. The vaccine regimens included a chimeric H8/1, intranasal, live-attenuated vaccine on day 1 followed by a non-adjuvanted, chimeric H5/1, intramuscular, inactivated vaccine on day 85; the same regimen but with the inactivated vaccine being adjuvanted with AS03; and an AS03-adjuvanted, chimeric H8/1, intramuscular, inactivated vaccine followed by an AS03-adjuvanted, chimeric H5/1, intramuscular, inactivated vaccine. In this planned interim analysis, the primary endpoints of reactogenicity and safety were assessed by blinded study group. We also assessed anti-H1 haemagglutinin stalk, anti-H2, anti-H9, and anti-H18 IgG antibody titres and plasmablast and memory B-cell responses in peripheral blood. This trial is registered with ClinicalTrials.gov, number NCT03300050. FINDINGS Between Oct 10, 2017, and Nov 27, 2017, 65 participants were enrolled and randomly assigned. The adjuvanted inactivated vaccine, but not the live-attenuated vaccine, induced a substantial serum IgG antibody response after the prime immunisation, with a seven times increase in anti-H1 stalk antibody titres on day 29. After boost immunisation, all vaccine regimens induced detectable anti-H1 stalk antibody (2·2-5·6 times induction over baseline), cross-reactive serum IgG antibody, and peripheral blood plasmablast responses. An unsolicited adverse event was reported for 29 (48%) of 61 participants. Solicited local adverse events were reported in 12 (48%) of 25 participants following prime vaccination with intramuscular study product or placebo, in 12 (33%) of 36 after prime immunisation with intranasal study product or placebo, and in 18 (32%) of 56 following booster doses of study product or placebo. Solicited systemic adverse events were reported in 14 (56%) of 25 after prime immunisation with intramuscular study product or placebo, in 22 (61%) of 36 after immunisation with intranasal study product or placebo, and in 21 (38%) of 56 after booster doses of study product or placebo. Disaggregated safety data were not available at the time of this interim analysis. INTERPRETATION The tested chimeric haemagglutinin-based, universal influenza virus vaccine regimens elicited cross-reactive serum IgG antibodies that targeted the conserved haemagglutinin stalk domain. This is the first proof-of-principle study to show that high anti-stalk titres can be induced by a rationally designed vaccine in humans and opens up avenues for further development of universal influenza virus vaccines. On the basis of the blinded study group, the vaccine regimens were tolerable and no safety concerns were observed. FUNDING Bill & Melinda Gates Foundation.

中文翻译：

基于嵌合血凝素的通用流感病毒候选疫苗的免疫原性：随机、安慰剂对照、1 期临床试验的中期结果。

背景技术流感病毒在全球范围内导致每年大量的发病率和死亡率。目前的疫苗只有与流行毒株完全匹配时才能预防流感。然而，抗原漂移可能导致疫苗和流行毒株之间存在相当大的不匹配，从而大大降低疫苗的有效性。此外，目前的季节性疫苗对大流行性流感无效，并且生产与新出现的病毒株相匹配的疫苗需要数月时间。因此，对具有广泛保护性的流感病毒疫苗的医疗需求尚未得到满足。我们的目的是测试基于嵌合 H1 血凝素的通用流感病毒候选疫苗诱导针对表达 1 组血凝素的流感病毒的茎结构域的广泛交叉反应抗体的能力。方法我们在美国两个中心对健康成年人进行了一项随机、观察者盲法的第一阶段研究。参与者被随机分配到三种初免-加强、基于嵌合血凝素的疫苗方案之一或两个安慰剂组之一。疫苗方案包括在第1天注射嵌合H8/1鼻内减毒活疫苗，然后在第85天注射无佐剂嵌合H5/1肌内灭活疫苗；相同的方案，但灭活疫苗添加了 AS03 佐剂；以及AS03佐剂的嵌合H8/1肌内灭活疫苗，随后是AS03佐剂的嵌合H5/1肌内灭活疫苗。在这项计划的中期分析中，反应原性和安全性的主要终点由盲法研究组进行评估。我们还评估了外周血中的抗 H1 血凝素杆、抗 H2、抗 H9 和抗 H18 IgG 抗体滴度以及浆母细胞和记忆 B 细胞反应。该试验已在 ClinicalTrials.gov 注册，编号为 NCT03300050。结果 2017 年 10 月 10 日至 2017 年 11 月 27 日期间，共招募了 65 名参与者并随机分配。初次免疫后，含佐剂的灭活疫苗（而非减毒活疫苗）诱导了显着的血清 IgG 抗体反应，第 29 天抗 H1 茎抗体滴度增加了 7 倍。加强免疫后，所有疫苗方案均诱导可检测到的血清 IgG 抗体反应。抗 H1 茎抗体（比基线诱导 2·2-5·6 倍）、交叉反应血清 IgG 抗体和外周血浆母细胞反应。 61 名参与者中有 29 名 (48%) 报告了未经请求的不良事件。在使用肌内研究产品或安慰剂初次免疫后，25 名参与者中有 12 名 (48%) 报告了引起的局部不良事件，在鼻内研究产品或安慰剂初次免疫后，36 名参与者中有 12 名 (33%) 报告了局部不良事件，18 名 (32%) 报告了不良事件56 次加强剂量的研究产品或安慰剂。在使用肌内研究产品或安慰剂初次免疫后，25 例中有 14 例（56%）报告了引起的全身不良事件，在鼻内研究产品或安慰剂免疫后，36 例中报告了 22 例（61%），在 56 例中报告了 21 例（38%）加强剂量的研究产品或安慰剂后。在进行本中期分析时，尚无分类安全数据。解释测试的基于嵌合血凝素的通用流感病毒疫苗方案引发了针对保守血凝素茎结构域的交叉反应性血清IgG抗体。这是第一项原理验证研究，表明合理设计的疫苗可以在人体中诱导高抗茎滴度，并为进一步开发通用流感病毒疫苗开辟了途径。在盲法研究组的基础上，疫苗方案是可以耐受的，没有观察到安全问题。资助比尔及梅琳达·盖茨基金会。

更新日期：2019-12-25

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