黏膜腺病毒载体疫苗加强免疫可持久预防非人灵长类动物感染XBB.1.16
Mucosal Adenoviral-vectored Vaccine Boosting Durably Prevents XBB.1.16 Infection in Nonhuman Primates.
作者信息
Gagne Matthew, Flynn Barbara J, Andrew Shayne F, Flebbe Dillon R, Mychalowych Anna, Lamb Evan, Davis-Gardner Meredith E, Burnett Matthew R, Serebryannyy Leonid A, Lin Bob C, Pessaint Laurent, Todd John-Paul M, Ziff Zohar E, Maule Erin, Carroll Robin, Naisan Mursal, Jethmalani Yogita, Case James Brett, Dmitriev Igor P, Kashentseva Elena A, Ying Baoling, Dodson Alan, Kouneski Katelyn, Doria-Rose Nicole A, O'Dell Sijy, Godbole Sucheta, Laboune Farida, Henry Amy R, Marquez Josue, Teng I-Ting, Wang Lingshu, Zhou Qiong, Wali Bushra, Ellis Madison, Zouantchangadou Serge, Ry Alex Van, Lewis Mark G, Andersen Hanne, Kwong Peter D, Curiel David T, Foulds Kathryn E, Nason Martha C, Suthar Mehul S, Roederer Mario, Diamond Michael S, Douek Daniel C, Seder Robert A
出版信息
bioRxiv. 2023 Nov 8:2023.11.06.565765. doi: 10.1101/2023.11.06.565765.
Waning immunity and continued virus evolution have limited the durability of protection from symptomatic infection mediated by intramuscularly (IM)-delivered mRNA vaccines against COVID-19 although protection from severe disease remains high. Mucosal vaccination has been proposed as a strategy to increase protection at the site of SARS-CoV-2 infection by enhancing airway immunity, potentially reducing rates of infection and transmission. Here, we compared protection against XBB.1.16 virus challenge 5 months following IM or mucosal boosting in non-human primates (NHP) that had previously received a two-dose mRNA-1273 primary vaccine regimen. The mucosal boost was composed of a bivalent chimpanzee adenoviral-vectored vaccine encoding for both SARS-CoV-2 WA1 and BA.5 spike proteins (ChAd-SARS-CoV-2-S) and delivered either by an intranasal mist or an inhaled aerosol. An additional group of animals was boosted by the IM route with bivalent WA1/BA.5 spike-matched mRNA (mRNA-1273.222) as a benchmark control. NHP were challenged in the upper and lower airways 18 weeks after boosting with XBB.1.16, a heterologous Omicron lineage strain. Cohorts boosted with ChAd-SARS-CoV-2-S by an aerosolized or intranasal route had low to undetectable virus replication as assessed by levels of subgenomic SARS-CoV-2 RNA in the lungs and nose, respectively. In contrast, animals that received the mRNA-1273.222 boost by the IM route showed minimal protection against virus replication in the upper airway but substantial reduction of virus RNA levels in the lower airway. Immune analysis showed that the mucosal vaccines elicited more durable antibody and T cell responses than the IM vaccine. Protection elicited by the aerosolized vaccine was associated with mucosal IgG and IgA responses, whereas protection elicited by intranasal delivery was mediated primarily by mucosal IgA. Thus, durable immunity and effective protection against a highly transmissible heterologous variant in both the upper and lower airways can be achieved by mucosal delivery of a virus-vectored vaccine. Our study provides a template for the development of mucosal vaccines that limit infection and transmission against respiratory pathogens.
尽管针对重症疾病的保护效果仍然很高,但免疫力下降和病毒持续进化限制了肌肉注射(IM)的mRNA新冠疫苗介导的针对有症状感染的保护持续时间。黏膜疫苗接种已被提议作为一种策略,通过增强气道免疫力来提高在严重急性呼吸综合征冠状病毒2(SARS-CoV-2)感染部位的保护作用,有可能降低感染率和传播率。在此,我们比较了在先前接受两剂mRNA-1273基础疫苗接种方案的非人灵长类动物(NHP)中,IM或黏膜加强免疫5个月后对XBB.1.16病毒攻击的保护作用。黏膜加强免疫由一种二价黑猩猩腺病毒载体疫苗组成,该疫苗编码SARS-CoV-2 WA1和BA.5刺突蛋白(ChAd-SARS-CoV-2-S),通过鼻内喷雾或吸入气雾剂给药。另一组动物通过IM途径用二价WA1/BA.5刺突匹配的mRNA(mRNA-1273.222)进行加强免疫作为基准对照。在加强免疫18周后,用XBB.1.16(一种异源奥密克戎谱系毒株)对NHP的上呼吸道和下呼吸道进行攻击。通过雾化或鼻内途径用ChAd-SARS-CoV-2-S加强免疫的队列,分别通过肺和鼻中亚基因组SARS-CoV-2 RNA水平评估,病毒复制水平低至检测不到。相比之下,通过IM途径接受mRNA-1273.222加强免疫的动物对上呼吸道病毒复制的保护作用最小,但下呼吸道病毒RNA水平大幅降低。免疫分析表明,黏膜疫苗比IM疫苗引发更持久的抗体和T细胞反应。雾化疫苗引发的保护作用与黏膜IgG和IgA反应相关,而鼻内给药引发的保护作用主要由黏膜IgA介导。因此,通过黏膜递送病毒载体疫苗可以实现对上呼吸道和下呼吸道中高传播性异源变体的持久免疫和有效保护。我们的研究为开发限制呼吸道病原体感染和传播的黏膜疫苗提供了一个模板。