背景:与含有单磷酰脂质A和QS-21(SpFN/ALFQ)的军用脂质体制剂(ALFQ)佐剂共同配制的自组装SARS-CoV-2WA-1重组刺突铁蛋白纳米颗粒(SpFN)疫苗在动物攻击模型中显示出保护功效。该试验旨在评估SpFN/ALFQ在首次人体临床试验中的安全性和免疫原性。
方法:在第一阶段,随机,双盲,安慰剂对照,首次人体临床试验,成年人被随机分配(5:5:2),分别在第1天和第29天接受25μg或50μgSpFN/ALFQ或生理盐水安慰剂,并在第181天接受任选的开放标签第三次疫苗接种.按组顺序进行登记和随机化;随机化是通过基于网络的交互式随机化系统完成的,只有指定的未掩盖研究人员才能访问随机化代码。成人必须是血清阴性和未接种疫苗才能纳入。局部和全身反应原性,不良事件,结合和中和抗体,和抗原特异性T细胞应答定量。对于安全分析,计算每组发生任何非自愿不良事件概率的95%Clopper-PearsonCI.对于免疫原性结果,二元变量的CIs是使用精确的Clopper-Pearson方法计算的,而几何平均滴度的CI基于10,000个经验自举样本。事后,我们采用配对单样本t检验,评估主要SARS-CoV-2目标靶点在第29天至第43天(第二次疫苗接种后)平均log-10中和抗体滴度的增加.该试验在ClinicalTrials.gov注册,NCT04784767,并对新参与者关闭。
结果:在2021年4月7日至6月29日之间,29名参与者被纳入研究。20个人被分配接受25μgSpFN/ALFQ,4至50μgSpFN/ALFQ,和五个安慰剂。中和抗体应答在第43天,即第二剂量后2周达到峰值。对于两个剂量组,在第二次接种后5个月,针对多种omicron亚变体的中和活性比针对D614G或β变体的中和活性衰减更慢。对于两个剂量组,CD4+T细胞应答在第一剂量后4周引起,并且在SpFN/ALFQ的第二剂量后增强。在两次免疫后可检测到针对早期omicron亚变体和进化枝1肉瘤病毒的中和抗体滴度,并且在第三次免疫后两个剂量组均达到峰值。在三次接种后检测到针对XBB.1.5的中和抗体滴度。攻击后,从接种疫苗的志愿者被动将IgG转移到叙利亚金仓鼠中,控制了SARS-CoV-1的复制。
结论:SpFN/ALFQ具有良好的耐受性,并针对多种SARS-CoV-2变体和其他sarbecovirus产生了强大而持久的结合抗体和中和抗体滴度。
背景:美国国防部,国防卫生局。
BACKGROUND: A self-assembling SARS-CoV-2 WA-1 recombinant spike ferritin nanoparticle (SpFN) vaccine co-formulated with Army Liposomal Formulation (ALFQ) adjuvant containing monophosphoryl lipid A and QS-21 (SpFN/ALFQ) has shown protective efficacy in animal challenge models. This
trial aims to assess the safety and immunogenicity of SpFN/ALFQ in a first-in-human clinical
trial.
METHODS: In this phase 1, randomised, double-blind, placebo-controlled, first-in-human clinical
trial, adults were randomly assigned (5:5:2) to receive 25 μg or 50 μg of SpFN/ALFQ or saline placebo intramuscularly at day 1 and day 29, with an optional open-label third vaccination at day 181. Enrolment and randomisation occurred sequentially by group; randomisation was done by an interactive web-based randomisation system and only designated unmasked
study personnel had access to the randomisation code. Adults were required to be seronegative and unvaccinated for inclusion. Local and systemic reactogenicity, adverse events, binding and neutralising antibodies, and antigen-specific T-cell responses were quantified. For safety analyses, exact 95% Clopper-Pearson CIs for the probability of any incidence of an unsolicited adverse event was computed for each group. For immunogenicity results, CIs for binary variables were computed using the exact Clopper-Pearson methodology, while CIs for geometric mean titres were based on 10 000 empirical bootstrap samples. Post-hoc, paired one-sample t tests were used to assess the increase in mean log-10 neutralising antibody titres between day 29 and day 43 (after the second vaccination) for the primary SARS-CoV-2 targets of interest. This
trial is registered at ClinicalTrials.gov, NCT04784767, and is closed to new participants.
RESULTS: Between April 7, and June 29, 2021, 29 participants were enrolled in the
study. 20 individuals were assigned to receive 25 μg SpFN/ALFQ, four to 50 μg SpFN/ALFQ, and five to placebo. Neutralising antibody responses peaked at day 43, 2 weeks after the second dose. Neutralisation activity against multiple omicron subvariants decayed more slowly than against the D614G or beta variants until 5 months after second vaccination for both dose groups. CD4+ T-cell responses were elicited 4 weeks after the first dose and were boosted after a second dose of SpFN/ALFQ for both dose groups. Neutralising antibody titres against early omicron subvariants and clade 1 sarbecoviruses were detectable after two immunisations and peaked after the third immunisation for both dose groups. Neutralising antibody titres against XBB.1.5 were detected after three vaccinations. Passive IgG transfer from vaccinated volunteers into Syrian golden hamsters controlled replication of SARS-CoV-1 after challenge.
CONCLUSIONS: SpFN/ALFQ was well tolerated and elicited robust and durable binding antibody and neutralising antibody titres against a broad panel of SARS-CoV-2 variants and other sarbecoviruses.
BACKGROUND: US Department of Defense, Defense Health Agency.