Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Vaccine Clinical Materials Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Nat Med. 2022 Feb;28(2):383-391. doi: 10.1038/s41591-021-01660-8. Epub 2022 Feb 3.
Currently, licensed seasonal influenza vaccines display variable vaccine effectiveness, and there remains a need for novel vaccine platforms capable of inducing broader responses against viral protein domains conserved among influenza subtypes. We conducted a first-in-human, randomized, open-label, phase 1 clinical trial ( NCT03186781 ) to evaluate a novel ferritin (H2HA-Ferritin) nanoparticle influenza vaccine platform. The H2 subtype has not circulated in humans since 1968. Adults born after 1968 have been exposed to only the H1 subtype of group 1 influenza viruses, which shares a conserved stem with H2. Including both H2-naive and H2-exposed adults in the trial allowed us to evaluate memory responses against the conserved stem domain in the presence or absence of pre-existing responses against the immunodominant HA head domain. Fifty healthy participants 18-70 years of age received H2HA-Ferritin intramuscularly as a single 20-μg dose (n = 5) or a 60-μg dose either twice in a homologous (n = 25) prime-boost regimen or once in a heterologous (n = 20) prime-boost regimen after a matched H2 DNA vaccine prime. The primary objective of this trial was to evaluate the safety and tolerability of H2HA-Ferritin either alone or in prime-boost regimens. The secondary objective was to evaluate antibody responses after vaccination. Both vaccines were safe and well tolerated, with the most common solicited symptom being mild headache after both H2HA-Ferritin (n = 15, 22%) and H2 DNA (n = 5, 25%). Exploratory analyses identified neutralizing antibody responses elicited by the H2HA-Ferritin vaccine in both H2-naive and H2-exposed populations. Furthermore, broadly neutralizing antibody responses against group 1 influenza viruses, including both seasonal H1 and avian H5 subtypes, were induced in the H2-naive population through targeting the HA stem. This ferritin nanoparticle vaccine technology represents a novel, safe and immunogenic platform with potential application for pandemic preparedness and universal influenza vaccine development.
目前，许可的季节性流感疫苗显示出可变的疫苗效力，因此仍然需要新型疫苗平台来诱导针对流感病毒亚型中保守的病毒蛋白域的更广泛反应。我们进行了一项首次人体、随机、开放标签、I 期临床试验（NCT03186781），以评估一种新型铁蛋白（H2HA-铁蛋白）纳米颗粒流感疫苗平台。自 1968 年以来，H2 亚型尚未在人类中传播。1968 年后出生的成年人仅接触过组 1 流感病毒的 H1 亚型，该亚型与 H2 具有保守的茎。在试验中包括 H2-幼稚和 H2-暴露的成年人，使我们能够评估针对保守茎域的记忆反应，而无论是否存在针对免疫显性 HA 头部域的预先存在的反应。50 名 18-70 岁的健康参与者接受 H2HA-铁蛋白肌肉内注射，剂量为 20μg（n=5）或 60μg，剂量为 25μg 同源（n=25）或 20μg 异源（n=20），在匹配的 H2 DNA 疫苗初免后进行。该试验的主要目的是评估 H2HA-铁蛋白单独或在初免-加强方案中的安全性和耐受性。次要目标是评估接种后的抗体反应。两种疫苗均安全且耐受性良好，最常见的自发症状是接种 H2HA-铁蛋白后（n=15，22%）和 H2 DNA 后（n=5，25%）轻度头痛。探索性分析鉴定了 H2HA-铁蛋白疫苗在 H2-幼稚和 H2-暴露人群中引发的中和抗体反应。此外，通过针对 HA 茎，在 H2-幼稚人群中诱导了针对组 1 流感病毒的广泛中和抗体反应，包括季节性 H1 和禽 H5 亚型。这种铁蛋白纳米颗粒疫苗技术代表了一种新型、安全且具有免疫原性的平台，具有用于大流行准备和通用流感疫苗开发的潜在应用。
