Abstract：
We previously demonstrated that an intranasal dose of 108 50% tissue culture infectious dose (TCID50) M2-deficient single replication (M2SR) influenza vaccine protected against highly drifted H3N2 influenza challenge in a subset of subjects who demonstrated ≥2-fold increase in microneutralization (MN) antibodies to Belgium2015 (the challenge strain) after vaccination. Here, we describe a phase 1b, observer-blinded, dose-escalation study demonstrating an increased proportion of responders with this signal of immune protection.
Serosusceptible subjects aged 18-49 years were randomized to receive 2 doses (108-109 TCID50) of M2SR or placebo administered 28 days apart. Clinical specimens were collected before and after each dose. The primary objective was to demonstrate safety of M2SR vaccines.
The vaccine was well tolerated at all dose levels. Against Belgium2015, ≥ 2-fold increases in MN antibodies were noted among 40% (95% confidence interval [CI], 24.9%-56.7%) of subjects following a single 108 TCID50 M2SR dose and among 80.6% (95% CI, 61.4%-92.3%) after 109 dose (P < .001). A single 109 TCID50 dose of M2SR generated ≥4-fold hemagglutination inhibition antibody seroconversion against the vaccine strain in 71% (95% CI, 52.0%-85.8%) of recipients. Mucosal and cellular immune responses were also induced.
These results indicate that M2SR may provide substantial protection against infection with highly drifted strains of H3N2 influenza.
NCT03999554.
In recent years, influenza A H3N2 viruses have evolved into multiple cocirculating clades, resulting in low vaccine efficacy and highlighting the need for more effective influenza vaccines. In a previous challenge study, a single intranasal dose of the investigational vaccine M2SR demonstrated protection against a highly drifted H3N2 influenza challenge virus in a subset of vaccine recipients with a signature immune response. Increasing the dose of the M2SR vaccine in this phase1b study demonstrated a statistically significant increase in the proportion of subjects with the signature immune responses seen previously. The vaccine-induced antibodies were cross-reactive with a panel of drifted H3N2 viruses from 2007 to 2019. Additionally, M2SR generated a rise in serum hemagglutination inhibition antibody titer in 71% of subjects. In contrast, the H3N2 seroresponse rate for the licensed intranasal vaccine FluMist is 10% in seronegative adults. Moreover, M2SR elicited mucosal and cell-mediated immune responses. This study demonstrates that the intranasal M2SR generates a multifaceted immune response and has the potential to provide better efficacy against vaccine-matched strains and influenza drift variants reducing the need to update the vaccine on an annual basis. This is a noteworthy step in the development of a broadly protective influenza vaccine.
Serosusceptible subjects aged 18-49 years were randomized to receive 2 doses (108-109 TCID50) of M2SR or placebo administered 28 days apart. Clinical specimens were collected before and after each dose. The primary objective was to demonstrate safety of M2SR vaccines.
The vaccine was well tolerated at all dose levels. Against Belgium2015, ≥ 2-fold increases in MN antibodies were noted among 40% (95% confidence interval [CI], 24.9%-56.7%) of subjects following a single 108 TCID50 M2SR dose and among 80.6% (95% CI, 61.4%-92.3%) after 109 dose (P < .001). A single 109 TCID50 dose of M2SR generated ≥4-fold hemagglutination inhibition antibody seroconversion against the vaccine strain in 71% (95% CI, 52.0%-85.8%) of recipients. Mucosal and cellular immune responses were also induced.
These results indicate that M2SR may provide substantial protection against infection with highly drifted strains of H3N2 influenza.
NCT03999554.
In recent years, influenza A H3N2 viruses have evolved into multiple cocirculating clades, resulting in low vaccine efficacy and highlighting the need for more effective influenza vaccines. In a previous challenge study, a single intranasal dose of the investigational vaccine M2SR demonstrated protection against a highly drifted H3N2 influenza challenge virus in a subset of vaccine recipients with a signature immune response. Increasing the dose of the M2SR vaccine in this phase1b study demonstrated a statistically significant increase in the proportion of subjects with the signature immune responses seen previously. The vaccine-induced antibodies were cross-reactive with a panel of drifted H3N2 viruses from 2007 to 2019. Additionally, M2SR generated a rise in serum hemagglutination inhibition antibody titer in 71% of subjects. In contrast, the H3N2 seroresponse rate for the licensed intranasal vaccine FluMist is 10% in seronegative adults. Moreover, M2SR elicited mucosal and cell-mediated immune responses. This study demonstrates that the intranasal M2SR generates a multifaceted immune response and has the potential to provide better efficacy against vaccine-matched strains and influenza drift variants reducing the need to update the vaccine on an annual basis. This is a noteworthy step in the development of a broadly protective influenza vaccine.
摘要：
背景：我们先前证明，鼻内剂量的10850％组织培养感染剂量（TCID50）M2缺陷型单次复制（M2SR）流感疫苗可在一组受试者中预防高度漂移的H3N2流感攻击，这些受试者在疫苗接种后证明对Belgium2015（攻击株）的微中性（MN）抗体增加≥2倍。这里,我们描述了一个阶段1b，观察者失明,剂量递增研究表明，具有这种免疫保护信号的应答者比例增加。
方法：18-49岁的血清敏感受试者随机接受2剂（108-109TCID50）M2SR或安慰剂，间隔28天。在每个剂量之前和之后收集临床标本。主要目的是证明M2SR疫苗的安全性。
结果：该疫苗在所有剂量水平下都具有良好的耐受性。与2015年比利时相比，40%的人注意到MN抗体增加≥2倍(95%置信区间[CI]，24.9%-56.7%）的受试者在单次108次TCID50M2SR剂量后，80.6%（95%CI，61.4%-92.3%）在109次剂量后（P<.001）。在71％（95％CI，52.0％-85.8％）的接受者中，单次109TCID50剂量的M2SR产生了针对疫苗株的≥4倍血凝抑制抗体血清转化。还诱导了粘膜和细胞免疫应答。
结论：这些结果表明，M2SR可能对高度漂移的H3N2流感病毒株的感染提供实质性保护。
背景：NCT03999554。
近年来,甲型流感H3N2病毒已经进化成多个共同循环的进化枝，导致疫苗效力低，并强调需要更有效的流感疫苗。在之前的挑战研究中，单次鼻内剂量的试验疫苗M2SR在具有特征性免疫应答的疫苗接受者亚组中证明了对高度漂移的H3N2流感攻击病毒的保护作用.在该阶段1b研究中增加M2SR疫苗的剂量表明具有先前所见的特征免疫应答的受试者的比例在统计学上显着增加。从2007年到2019年，疫苗诱导的抗体与一组漂移的H3N2病毒交叉反应。此外,M2SR在71％的受试者中导致血清血凝抑制抗体滴度升高。相比之下,获得许可的鼻内疫苗FluMist的H3N2血清反应率在血清阴性的成年人中为10％。此外，M2SR引发粘膜和细胞介导的免疫应答。这项研究表明，鼻内M2SR会产生多方面的免疫反应，并有可能提供更好的对抗疫苗匹配毒株和流感漂移变体的功效，从而减少每年更新疫苗的需求。这是开发广泛保护性流感疫苗的一个值得注意的步骤。
方法：18-49岁的血清敏感受试者随机接受2剂（108-109TCID50）M2SR或安慰剂，间隔28天。在每个剂量之前和之后收集临床标本。主要目的是证明M2SR疫苗的安全性。
结果：该疫苗在所有剂量水平下都具有良好的耐受性。与2015年比利时相比，40%的人注意到MN抗体增加≥2倍(95%置信区间[CI]，24.9%-56.7%）的受试者在单次108次TCID50M2SR剂量后，80.6%（95%CI，61.4%-92.3%）在109次剂量后（P<.001）。在71％（95％CI，52.0％-85.8％）的接受者中，单次109TCID50剂量的M2SR产生了针对疫苗株的≥4倍血凝抑制抗体血清转化。还诱导了粘膜和细胞免疫应答。
结论：这些结果表明，M2SR可能对高度漂移的H3N2流感病毒株的感染提供实质性保护。
背景：NCT03999554。
近年来,甲型流感H3N2病毒已经进化成多个共同循环的进化枝，导致疫苗效力低，并强调需要更有效的流感疫苗。在之前的挑战研究中，单次鼻内剂量的试验疫苗M2SR在具有特征性免疫应答的疫苗接受者亚组中证明了对高度漂移的H3N2流感攻击病毒的保护作用.在该阶段1b研究中增加M2SR疫苗的剂量表明具有先前所见的特征免疫应答的受试者的比例在统计学上显着增加。从2007年到2019年，疫苗诱导的抗体与一组漂移的H3N2病毒交叉反应。此外,M2SR在71％的受试者中导致血清血凝抑制抗体滴度升高。相比之下,获得许可的鼻内疫苗FluMist的H3N2血清反应率在血清阴性的成年人中为10％。此外，M2SR引发粘膜和细胞介导的免疫应答。这项研究表明，鼻内M2SR会产生多方面的免疫反应，并有可能提供更好的对抗疫苗匹配毒株和流感漂移变体的功效，从而减少每年更新疫苗的需求。这是开发广泛保护性流感疫苗的一个值得注意的步骤。
