背景:脂质纳米颗粒(LNP)封装的自扩增RNA(saRNA)是一种新型技术,可作为抗COVID-19的低剂量疫苗。
方法:saRNACOVID-19候选疫苗LNP-nCoVsaRNA的I期首次人体剂量范围试验,是在帝国临床研究机构进行的,和伦敦的参与中心,英国,2020年6月19日至10月28日。参与者接受了两种不同剂量水平的LNP-nCoVsaRNA的肌内(IM)注射,0.1-10.0μg,相隔四周。开放标签剂量递增后进行剂量评估。收集来自招募的一周的不良事件(AE),定期随访(1-8周)。通过抗Spike(S)IgGELISA测量参与者血清中产生的抗SARS-CoV-2抗体的结合和中和能力,免疫印迹,SARS-CoV-2假中和和野生型中和测定。(试验注册:ISRCTN17072692,EudraCT2020-001646-20)。
结果:192名没有COVID-19病史或血清学证据的健康个体,年龄18-45岁。疫苗耐受性良好,没有与疫苗接种相关的严重不良事件。无论通过ELISA还是免疫印迹测量,第六周的血清转换都与剂量有关(均p<0.001),在ELISA中从8%(3/39;0.1μg)到61%(14/23;10.0μg)和46%(18/39;0.3μg)到87%(20/23;5.0μg和10.0μg)。几何平均(GM)抗SIgG浓度范围为0.1μg时的74(95%CI,45-119)至5.0μg时的1023(468-2236)ng/mL(p<0.001),而在10.0μg时则不高。根据接受的剂量水平,参与者血清对SARS-CoV-2的中和可测量为15%(6/39;0.1μg)至48%(11/23;5.0μg)。
结论:封装的saRNA对于临床开发是安全的,在低剂量水平下具有免疫原性,但不能诱导100%血清转化。为了实现其作为抗SARS-CoV-2的有效疫苗的潜力,需要进行修饰以优化体液应答。
背景:这项研究由医学研究委员会UKRI(MC_PC_19076)的赠款和礼物共同资助,和国家健康研究所/疫苗工作组,城堡和城堡证券的合伙人,约瑟夫·霍东爵士慈善定居点,乔恩·莫尔顿慈善信托基金,PierreAndurand,恢复地球
BACKGROUND: Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is a novel technology formulated as a low dose vaccine against COVID-19.
METHODS: A phase I first-in-human dose-ranging trial of a saRNA COVID-19 vaccine candidate LNP-nCoVsaRNA, was conducted at Imperial Clinical Research Facility, and participating centres in London, UK, between 19th June to 28th October 2020. Participants received two intramuscular (IM) injections of LNP-nCoVsaRNA at six different dose levels, 0.1-10.0μg, given four weeks apart. An open-label dose escalation was followed by a dose evaluation. Solicited adverse events (AEs) were collected for one week from enrolment, with follow-up at regular intervals (1-8 weeks). The binding and neutralisation capacity of anti-SARS-CoV-2 antibody raised in participant sera was measured by means of an anti-Spike (S) IgG ELISA, immunoblot, SARS-CoV-2 pseudoneutralisation and wild type neutralisation assays. (The trial is registered: ISRCTN17072692, EudraCT 2020-001646-20).
RESULTS: 192 healthy individuals with no history or serological evidence of COVID-19, aged 18-45 years were enrolled. The vaccine was well tolerated with no serious adverse events related to vaccination. Seroconversion at week six whether measured by ELISA or immunoblot was related to dose (both p<0.001), ranging from 8% (3/39; 0.1μg) to 61% (14/23; 10.0μg) in ELISA and 46% (18/39; 0.3μg) to 87% (20/23; 5.0μg and 10.0μg) in a post-hoc immunoblot assay. Geometric mean (GM) anti-S IgG concentrations ranged from 74 (95% CI, 45-119) at 0.1μg to 1023 (468-2236) ng/mL at 5.0μg (p<0.001) and was not higher at 10.0μg. Neutralisation of SARS-CoV-2 by participant sera was measurable in 15% (6/39; 0.1μg) to 48% (11/23; 5.0μg) depending on dose level received.
CONCLUSIONS: Encapsulated saRNA is safe for clinical development, is immunogenic at low dose levels but failed to induce 100% seroconversion. Modifications to optimise humoral responses are required to realise its potential as an effective vaccine against SARS-CoV-2.
BACKGROUND: This study was co-funded by grants and gifts from the Medical Research Council UKRI (MC_PC_19076), and the National Institute Health Research/Vaccine Task Force, Partners of Citadel and Citadel Securities, Sir Joseph Hotung Charitable Settlement, Jon Moulton Charity Trust, Pierre Andurand, Restore the Earth.