Development of vaccination strategies to elicit broadly protective immunity against influenza

制定疫苗接种策略以引发针对流感的广泛保护性免疫力

• 批准号: 10620353
• 负责人: Peter Palese
• 金额: $ 84.75万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-18 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10620353
• 关键词: Affinity; Antibodies; Antibody Response; Antigen-Antibody Complex; Antigenic Variation; Antigens; Avian Influenza A Virus; B-Lymphocytes; Cell Maturation; Cell physiology; Cellular Immunity; Containment; Dendritic Cells; Development; Disease Outbreaks; Domestic Fowls; Engineering; Epitopes; Exposure to; Fc domain; Formulation; Glycoproteins; Head; Hemagglutinin; Human; Humoral Immunities; IgG(T); Immune response; Immunity; Immunization; Immunodominant Epitopes; Immunoglobulin G; Immunologics; In Vitro; Infection; Influenza; Influenza A Virus, H5N1 Subtype; Influenza A virus; Influenza Hemagglutinin; Influenza vaccination; Knowledge; Leukocytes; Licensing; Mediating; Modification; Mutation; Pathway interactions; Phylogenetic Analysis; Prevention Measures; Process; Production; Proteins; Regimen; Regulatory Pathway; Research; Seasons; Series; Signal Transduction; Site; Specificity; Surface; T cell response; T-Lymphocyte; Vaccination; Vaccine Production; Vaccines; Viral; Virus; adaptive immune response; adaptive immunity; anti-influenza; antiviral immunity; cost; cost effective; design; egg; epidemic virus; immunoengineering; immunogenic; immunogenicity; immunoregulation; improved; in vivo; influenza infection; influenza virus strain; influenza virus vaccine; innovation; manufacture; mosaic; mouse model; new pandemic; next generation; novel; pandemic disease; pandemic virus; preclinical evaluation; receptor; response; seasonal influenza; universal influenza vaccine; universal vaccine; vaccination strategy; vaccine immunogenicity; vaccine platform

ABSTRACT The most effective measure for the prevention of influenza virus infection is vaccination. However, due to ongoing antigenic drift, current influenza vaccines need annual reformulation to provide sufficient protection. Furthermore, immune responses elicited upon influenza vaccination are strain-specific and fail to provide protection against novel seasonal and pandemic viruses, necessitating the development of a universal influenza vaccine with the capacity to elicit lifelong protection against diverse influenza virus strains. A major target for the development of protective immunity against influenza is the hemagglutinin glycoprotein (HA), which comprises two distinct functional domains: the globular head, which participates in viral entry and is subject to antigenic drift, and the stalk domain, which is highly conserved and mediates viral fusion. Immunodominant antigenic sites on the HA head elicit high-affinity, strain-specific anti-HA Ab responses, whereas in contrast, Abs against conserved epitopes can mediate broadly protective activity, but are immunosubdominant. To overcome the inherent immunodominance of the HA head and refocus immunity towards conserved, cross-protective epitopes, we will engineer innovative mosaic HA protein immunogens in which HA head antigenic sites will be silenced. Our prior research demonstrated that vaccination with HA:anti-HA IgG immune complexes (ICs) can modulate adaptive immunity through specific interactions of the Fc domain of the IgG with Fcγ receptors (FcγR) on the surface of effector leukocytes. Our in-depth studies revealed that engagement of specific FcγRs: CD23 on B-cells and FcγRIIa on dendritic cells (DCs), is critical for the induction of high-affinity IgG responses and T-cell immunity, respectively. Based on this knowledge, we will exploit these pathways to broaden specificity, increase affinity and select for long-lived humoral and cellular immunity to conserved influenza epitopes. We will design and evaluate the immunogenicity of IC-based immunogens comprising mosaic HAs and Fc-engineered anti-HA IgGs with selective affinity for specific human FcγR types. These studies will lead to the development and pre-clinical evaluation of vaccination strategies to elicit robust and long-lasting antiviral immunity, which could improve the breadth of current seasonal vaccines, but could also be employed in the development of novel, next-generation universal influenza virus vaccines.

抽象的 预防流感病毒感染的最有效度量是疫苗接种。但是，由于持续 抗原漂移，目前的影响疫苗需要年度重新启动以提供足够的保护。此外， 影响疫苗接种后引起的免疫反应是特定于应变的，无法提供防止 新颖的季节性和大流行病毒，对于发展具有普遍影响者的发展所必需 引起对潜水员终身保护的能力影响病毒菌株。开发的主要目标 对影响力的保护性免疫是血凝素糖蛋白（HA），它包括两个不同的 功能领域：参与病毒入口并受抗原漂移的全球头部 茎结构域，高度保守和介导的病毒融合。 HA上的免疫主导抗原部位 头部引起高亲和力，特异性抗HA AB反应，而相反，ABS与保守 表位可以介导广泛保护的活性，但是免疫抑制剂。克服继承 HA头和重新聚焦免疫组织派保守的交叉保护表位的免疫降级，我们将 工程师创新的马赛克HA蛋白免疫原，其中HA头抗原部位将被沉默。我们的先验 研究表明，HA：抗HA IgG免疫复合物（IC）的疫苗接种可以调节适应性 通过IgG的FC结构域与Fcγ受体（FcγR）在表面上的特异性相互作用的免疫力 效应子白细胞。我们深入的研究表明，特定FcγR的参与：B细胞和B细胞的CD23 树突状细胞（DC）上的FcγRIIA对于诱导高亲和力IgG反应和T细胞免疫力至关重要， 分别。基于这些知识，我们将利用这些途径来扩大特异性，增加亲和力 并选择长寿命的体液和细胞免疫以构成影响力表位。我们将设计和 评估包括Mosaic具有和FC设计的抗HA IgGs的IC的免疫原性 具有对特定人类FcγR类型的选择性亲和力。这些研究将导致发展和临床前的发展 评估疫苗接种策略以引发强大而持久的抗病毒免疫，这可以改善 当前季节性疫苗的广度，但也可以在小说的下一代发展中进行 通用流感病毒疫苗。

项目成果

Mosaic Hemagglutinin-Based Whole Inactivated Virus Vaccines Induce Broad Protection Against Influenza B Virus Challenge in Mice.

• DOI: 10.3389/fimmu.2021.746447
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Liu Y;Strohmeier S;González-Domínguez I;Tan J;Simon V;Krammer F;García-Sastre A;Palese P;Sun W
• 通讯作者: Sun W

Safety and immunogenicity of an egg-based inactivated Newcastle disease virus vaccine expressing SARS-CoV-2 spike: Interim results of a randomized, placebo-controlled, phase 1/2 trial in Vietnam.

• DOI: 10.1016/j.vaccine.2022.04.078
• 发表时间: 2022-06-09
• 期刊: VACCINE
• 影响因子: 5.5
• 作者: Anh Duc Dang;Thiem Dinh Vu;Ha Hai Vu;Van Thanh Ta;Anh Thi Van Pham;Mai Thi Ngoc Dang;Be Van Le;Thai Huu Duong;Duoc Van Nguyen;Lawpoolsri, Saranath;Chinwangso, Pailinrut;McLellan, Jason S.;Hsieh, Ching-Lin;Garcia-Sastre, Adolfo;Palese, Peter;Sun, Weina;Martinez, Jose L.;Gonzalez-Dominguez, Irene;Slamanig, Stefan;Carreno, Juan Manuel;Tcheou, Johnstone;Krammer, Florian;Raskin, Ariel;Huong Minh Vu;Thang Cong Tran;Huong Mai Nguyen;Mercer, Laina D.;Raghunandan, Rama;Lal, Manjari;White, Jessica A.;Hjorth, Richard;Innis, Bruce L.;Scharf, Rami
• 通讯作者: Scharf, Rami

Safety and immunogenicity of a live recombinant Newcastle disease virus-based COVID-19 vaccine (Patria) administered via the intramuscular or intranasal route: Interim results of a non-randomized open label phase I trial in Mexico.

• DOI: 10.1101/2022.02.08.22270676
• 发表时间: 2022-02-09
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Ponce-de-Leon, Samuel;Torres, Martha;Lozano-Dubernard, Bernardo
• 通讯作者: Lozano-Dubernard, Bernardo

Influenza chimeric hemagglutinin structures in complex with broadly protective antibodies to the stem and trimer interface.

• DOI: 10.1073/pnas.2200821119
• 发表时间: 2022-05-24
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1

An influenza hemagglutinin stem nanoparticle vaccine induces cross-group 1 neutralizing antibodies in healthy adults.

• DOI: 10.1126/scitranslmed.ade4790
• 发表时间: 2023-04-19
• 期刊: SCIENCE TRANSLATIONAL MEDICINE
• 影响因子: 17.1
• 作者: Widge, Alicia T.;Hofstetter, Amelia R.;V. Houser, Katherine;Awan, Seemal F.;Chen, Grace L.;Florez, Maria C. Burgos;Berkowitz, Nina M.;Mendoza, Floreliz;Hendel, Cynthia S.;Holman, LaSonji A.;Gordon, Ingelise J.;Apte, Preeti;Liang, C. Jason;Gaudinski, Martin R.;Coates, Emily E.;Strom, Larisa;Wycuff, Diane;Vazquez, Sandra;Stein, Judy A.;Gall, Jason G.;Adams, William C.;Carlton, Kevin;Gillespie, Rebecca A.;Creanga, Adrian;Crank, Michelle C.;Andrews, Sarah F.;Castro, Mike;Serebryannyy, Leonid A.;Narpala, Sandeep R.;Hatcher, Christian;Lin, Bob C.;O'Connell, Sarah;Freyn, Alec W.;Rosado, Victoria C.;Nachbagauer, Raffael;Palese, Peter;Kanekiyo, Masaru;McDermott, Adrian B.;Koup, Richard A.;Dropulic, Lesia K.;Graham, Barney S.;Mascola, John R.;Ledgerwood, Julie E.
• 通讯作者: Ledgerwood, Julie E.