Impact of Human STING Variants on Pneumococcal Vaccine Effectiveness

人类 STING 变体对肺炎球菌疫苗有效性的影响

• 批准号: 9165880
• 负责人: LEI JIN
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-10 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9165880
• 关键词: Adjuvant; Asians; B-Lymphocytes; Caucasians; Cells; Cyclic GMP; Data; Development; Dinucleoside Phosphates; Disease; Effectiveness; Equilibrium; Exhibits; FDA approved; Figs - dietary; Gene Expression; Gene Targeting; Genes; Genotype; Goals; Heterogeneity; Human; Immune response; Immunity; Individual; Infection; Interferons; Knock-in Mouse; Knowledge; Mediating; Mucosal Immunity; Mus; Pathway interactions; Pneumococcal Infections; Pneumococcal vaccine; Polysaccharides; Polyvalent pneumococcal vaccine; Prevnar; Production; Proteins; Reporting; Serotyping; Streptococcus pneumoniae; T-Lymphocyte; Testing; Vaccine Adjuvant; Vaccines; abstracting; aluminum sulfate; genetic variant; in vivo; interest; killings; mucosal vaccine; novel vaccines; pneumococcal surface protein A; pre-clinical; precision medicine; receptor; response; vaccination strategy; vaccine effectiveness

Abstract The goal of this proposal is to determine the effectiveness of pneumococcal vaccines influenced by the common human STING (stimulator of interferon genes) variant R71H-G230A-R293Q (HAQ). Pneumococcal diseases kill more people than all other vaccine-preventable diseases combined. Pneumovax® 23 and Prevnar 13® are polysaccharide vaccines providing serotype-specific protection. Since its approval in 1983, Pneumovax 23® results in only ~57% of overall disease reduction. Recently, Dr. Bruce Beutler’s group showed that polysaccharide Ag generates a cyclic dinucleotide (CDN) called 2’5’-3’5’-cyclic GMP-AMP (2’3’-cGAMP) in B cells leading to the activation of STING-Type I IFN pathway. STING is a receptor for CDN. STING-/- mice have decreased Ab production to Pneumovax® 23. Our own data showed that STING-/- mice also have decreased Ab production to Prevnar® 13. We previously identified a human STING variant HAQ that is common in non-Africans. ~3% of Caucasians and ~16% of East Asians are HAQ/HAQ. In fact, R232(wt)/HAQ, not the R232(wt)/R232(wt), is the most common STING genotype in East Asians. Examining B cells derived from human HAQ/HAQ individuals, we found that HAQ B cells have dramatically decreased STING expression. We hypothesize that Pneumovax ® 23 and Prevnar 13® vaccine effectiveness is influenced by HAQ STING variant. To test this hypothesis and uncover the in vivo mechanism, we generated the HAQ, AQ and Q293 STING knock-in mice. In Aim 1, we will determine (a) the impact of HAQ STING on the effectiveness of Pneumovax® 23 and Prevnar13® vaccines in vivo (Aim 1.1); (b) the in vivo mechanism by which HAQ STING influences Pneumovax® 23 and Prevnar13® effectiveness (Aim 1.2). Pneumovax® 23 and Prevnar 13® do not elicit strong mucosal immunity. A mucosal pneumococcal vaccine consists of a common protein Ag and a potent mucosal adjuvant can provide serotype-independent mucosal protection. Recently, a synthetic CDN, RpRp-c-di-AMPss, was reported to activate all human STING variants in HEK293T cells. Our preliminary data demonstrated that RpRp-c-di-AMPss has mucosal vaccine adjuvant activity eliciting strong Ab production and balanced Th1/Th2/Th17 response that depends on STING. In Aim 2, we will determine (a) the impact of HAQ STING on the mucosal adjuvant activity of RpRp-c-di-AMPss in vivo (Aim 2.1); (b) the in vivo mechanism by which HAQ STING influences RpRp-c-di-AMPss mucosal adjuvant activity (Aim 2.2). We will evaluate RpRp-c-di-AMPss adjuvanted pneumococcal surface protein A (PspA) vaccine induced humoral, cellular immune responses, and the protective immunity against S. pneumoniae infection in our knock-in mice. Achieving these Aims will pave the way for the development of STING-targeting precision medicine in humans.

摘要