Park Hong-Su, Matsuoka Yumiko, Santos Celia, Luongo Cindy, Liu Xueqiao, Yang Lijuan, Kaiser Jaclyn A, Duncan Eleanor F, Johnson Reed F, Teng I-Ting, Kwong Peter D, Buchholz Ursula J, Le Nouën Cyril
RNA Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
SARS-CoV-2 Virology Core, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
bioRxiv. 2024 Sep 13:2024.09.12.612598. doi: 10.1101/2024.09.12.612598.
The continuous emergence of new SARS-CoV-2 variants requires that COVID vaccines be updated to match circulating strains. We generated B/HPIV3-vectored vaccines expressing 6P-stabilized S protein of the ancestral, B.1.617.2/Delta, or B.1.1.529/Omicron variants as pediatric vaccines for intranasal immunization against HPIV3 and SARS-CoV-2 and characterized these in hamsters. Following intranasal immunization, these B/HPIV3 vectors replicated in the upper and lower respiratory tract and induced mucosal and serum anti-S IgA and IgG. B/HPIV3 expressing ancestral or B.1.617.2/Delta-derived S-6P induced serum antibodies that effectively neutralized SARS-CoV-2 of the ancestral and B.1.617.2/Delta lineages, while the cross-neutralizing potency of B.1.1.529/Omicron S-induced antibodies was lower. Despite the lower cross-neutralizing titers induced by B/HPIV3 expressing S-6P from B.1.1.529/Omicron, a single intranasal dose of all three versions of B/HPIV3 vectors was protective against matched or heterologous WA1/2020, B.1.617.2/Delta or BA.1 (B.1.1.529.1)/Omicron challenge; hamsters were protected from challenge virus replication in the lungs, while low levels of challenge virus were detectable in the upper respiratory tract of a small number of animals. Immunization also protected against lung inflammatory response after challenge, with mild inflammatory cytokine induction associated with the slightly lower level of cross-protection of WA1/2020 and B.1.617.2/Delta variants against the BA.1/Omicron variant. Serum antibodies elicited by all vaccine candidates were broadly reactive against 20 antigenic variants, but the antigenic breadth of antibodies elicited by B/HPIV3-expressed S-6P from the ancestral or B.1.617.2/Delta variant exceeded that of the S-6P B.1.1.529/Omicron expressing vector. These results will guide development of intranasal B/HPIV3 vectors with S antigens matching circulating SARS-CoV-2 variants.
新型严重急性呼吸综合征冠状病毒2（SARS-CoV-2）变体不断出现，这就要求新冠疫苗进行更新，以匹配正在传播的毒株。我们构建了表达原始毒株、B.1.617.2/德尔塔变体或B.1.1.529/奥密克戎变体的6P稳定化刺突（S）蛋白的B型副流感病毒3（B/HPIV3）载体疫苗，作为用于鼻内免疫以预防HPIV3和SARS-CoV-2的儿科疫苗，并在仓鼠中对其进行了特性分析。鼻内免疫后，这些B/HPIV3载体在上、下呼吸道中复制，并诱导产生黏膜和血清抗S IgA和IgG。表达原始毒株或B.1.617.2/德尔塔衍生的S-6P的B/HPIV3诱导产生的血清抗体可有效中和原始毒株和B.1.617.2/德尔塔谱系的SARS-CoV-2，而B.1.1.529/奥密克戎S诱导的抗体的交叉中和效力较低。尽管表达来自B.1.1.529/奥密克戎的S-6P的B/HPIV3诱导的交叉中和滴度较低，但单剂量鼻内接种的所有三种版本的B/HPIV3载体对匹配的或异源的WA1/2020、B.1.617.2/德尔塔或BA.1（B.1.1.529.1）/奥密克戎攻击均具有保护作用；仓鼠可免受攻击病毒在肺部的复制，而在少数动物的上呼吸道中可检测到低水平的攻击病毒。免疫接种还可预防攻击后的肺部炎症反应，轻度炎症细胞因子诱导与WA1/2020和B.1.617.2/德尔塔变体对BA.1/奥密克戎变体的交叉保护水平略低有关。所有候选疫苗引发的血清抗体对20种抗原变体具有广泛反应性，但由表达原始毒株或B.1.617.2/德尔塔变体的B/HPIV3的S-6P引发的抗体的抗原广度超过了表达B.1.1.529/奥密克戎的S-6P载体。这些结果将指导开发具有与正在传播的SARS-CoV-2变体相匹配的S抗原的鼻内B/HPIV3载体。
