Paramyxoviruses as Vaccine Vectors Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

副粘病毒作为针对严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 的疫苗载体

• 批准号: 10692252
• 负责人: Ursula Buchholz
• 金额: $ 32.13万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10692252
• 关键词: 2019-nCoV; 5 year old; Adult; Americas; Animals; Antibodies; Antibody Response; Attenuated; Avulavirus; Body Weight decreased; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; COVID-19; COVID-19 vaccine; Cattle; Child; Childhood; Clinical Research; Clinical Trials; Complementary DNA; Cyclic GMP; Dose; Engineering; Evaluation; Exhibits; Hamsters; Holly; Human; Immune response; Immunity; Immunization; Immunize; Immunoglobulin A; Immunoglobulin G; In Vitro; Infant; Infection; Lead; Lower respiratory tract structure; Lung; Martens; Modeling; Molecular Conformation; Morbidity - disease rate; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Nose; Para-Influenza Virus Type 3; Paramyxovirus; Phase; Pneumovirus; Protein Engineering; Proteins; Pulmonary Inflammation; Recovery; Respiratory System; SARS-CoV-2 B.1.1.7; SARS-CoV-2 B.1.351; SARS-CoV-2 antibody; SARS-CoV-2 antigen; SARS-CoV-2 infection; SARS-CoV-2 spike protein; Safety; Serum; Site; System; T cell response; Tissues; United States National Academy of Sciences; Vaccines; Viral Vector; Virus; Yang; age group; airway epithelium; base; chicken egg; clinical development; immunogenic; immunogenicity; improved; insight; interest; lead candidate; mucosal vaccine; neutralizing antibody; nonhuman primate; parainfluenza virus; pathogen; phase 1 study; preclinical study; protective efficacy; receptor binding; response; reverse genetics; tissue culture; translational goal; transmission process; vaccine candidate; vaccine development; variants of concern; vector; vector vaccine; vector-based vaccine

We are developing paramyxovirus vectored vaccines for intranasal immunization against SARS-CoV-2. The vaccine vectors express prefusion-stabilized versions of the SARS-CoV-2 S protein and are designed to be highly attenuated in humans while maintaining a high level of immunogenicity at the primary sites of infection of SARS-CoV-2. The viral vectors replicate in the superficial layers of the respiratory epithelium, inducing strong local mucosal and systemic immune responses to the SARS-CoV-2 S protein, including virus-neutralizing serum antibodies, and a systemic and mucosal response of multifunctional SARS-CoV-2 S-specific CD8+ and CD4+ T cells. Pediatric SARS-CoV-2 infections, though generally mild, are associated with substantial morbidity and contribute to transmission dynamics. We developed live intranasal vector vaccine candidates for infants and children against coronavirus disease-2019 (COVID-19) based on replication-competent chimeric bovine/human parainfluenza virus type 3 (B/HPIV3) expressing the prefusion-stabilized (S-2P) SARS-CoV-2 S spike protein, the major protective and neutralization antigen of SARS-CoV-2. Prefusion stabilization increased S expression by B/HPIV3 in vitro. In hamsters, a single intranasal dose of B/HPIV3/S-2P induced high levels of serum SARS-CoV-2-neutralizing antibodies, and serum IgA and IgG to SARS-CoV-2 S protein. Serum antibodies exhibited broad neutralizing activity against SARS-CoV-2 of lineages A, B.1.1.7, and B.1.351. Four weeks after immunization, hamsters were challenged intranasally with 4.5 log10 50% tissue-culture infectious-dose (TCID50) of SARS-CoV-2. In B/HPIV3 empty vector-immunized hamsters, SARS-CoV-2 replicated to mean titers of 6.6 log10 TCID50/g in lungs and 7 log10 TCID50/g in nasal tissues and induced moderate weight loss. In B/HPIV3/S-2P-immunized hamsters, infectious SARS-CoV-2 challenge virus was undetectable in nasal tissues and lungs; immunization with B/HPIV3/S-2P protected against weight loss after SARS-CoV-2 challenge. Based on these results, B/HPIV3 expressing a prefusion-stabilized version of the S protein is a promising vaccine candidate to protect infants and young children against HPIV3 and SARS-CoV-2 (Liu X, Luongo C, Matsuoka Y, Park HS, Santos C, Yang L, Moore IN, Afroz S, Johnson RF, Lafont BAP, Martens C, Best SM, Munster VJ, Holly J, Yewdell JW, Le Nouen C, Munir S, Buchholz UJ. A single intranasal dose of a live-attenuated parainfluenza virus-vectored SARS-CoV-2 vaccine is protective in hamsters. Proceedings of the National Academy of Sciences of the United States of America. 2021;118(50)). Clinical trial material of the lead B/HPIV3-based vaccine candidate was manufactured under cGMP for evaluation of safety and immunogenicity in a Phase 1 study. Single-dose vaccines with the ability to restrict SARS-CoV-2 replication in the respiratory tract are needed for all age groups, aiding efforts towards control of COVID-19. In addition to the B/HPIV3/S-2P candidate described above, we are developing vector vaccine candidates based on vector platforms without pre-existing anti-vector immunity in humans, including avian paramyxovirus type 3 (APMV3). In a preclinical study, we found that APMV3 expressing the prefusion-stabilized S-6P version of the S protein (APMV3/S-6P) replicated to high titers in embryonated chicken eggs and was genetically stable. In hamsters, a single intranasal dose of APMV3/S-6P induced strong serum IgG and IgA responses to the S protein and its receptor-binding domain, and strong serum neutralizing antibody responses to the vaccine-matched SARS-CoV-2 isolate WA1/2020 (lineage A). Sera from APMV3/S-6P-immunized hamsters also efficiently neutralized Alpha and Beta variants of concern. Immunized hamsters challenged with WA1/2020 did not exhibit the weight loss and lung inflammation observed in empty vector-immunized controls; SARS-CoV-2 replication in the upper and lower respiratory tract of immunized animals was low or undetectable compared to the substantial replication in controls. Thus, a single intranasal dose of APMV3/S-6P was highly immunogenic and protective against SARS-CoV-2 challenge, suggesting that APMV3/S-6P is suitable for clinical development (Park HS, Matsuoka Y, Luongo C, Yang L, Santos C, Liu X, Ahlers LRH, Moore IN, Afroz S, Johnson RF, Lafont BAP, Dorward DW, Fischer ER, Martens C, Samal SK, Munir S, Buchholz UJ, Le Nouen C. Intranasal immunization with avian paramyxovirus type 3 expressing SARS-CoV-2 spike protein protects hamsters against SARS-CoV-2. NPJ Vaccines. 2022;7(1):72).

我们正在开发副粘病毒载体疫苗，用于SARS-CoV-2的鼻内免疫。疫苗载体表达预灌注稳定版本的SARS-CoV-2 S蛋白，设计用于在人体内高度减毒，同时在SARS-CoV-2的主要感染部位保持高水平的免疫原性。病毒载体在呼吸道上皮浅层复制，诱导对sars - cov - 2s蛋白的强烈局部粘膜和全身免疫反应，包括病毒中和血清抗体，以及多功能sars - cov - 2s特异性CD8+和CD4+ T细胞的全身和粘膜反应。