Development of an IgG-Fc fusion COVID-19 subunit vaccine,AKS-452

AKS-452 is a biologically-engineered vaccine comprising an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain antigen (Ag) and human IgG1 Fc (SP/RBD-Fc) in clinical development for the induction and augmentation of neutralizing IgG titers against SARS-CoV-2 viral infection to address the COVID-19 pandemic. The Fc moiety is designed to enhance immunogenicity by increasing uptake via Fc-receptors (FcγR) on Ag-presenting cells (APCs) and prolonging exposure due to neonatal Fc receptor (FcRn) recycling. AKS-452 induced approximately 20-fold greater neutralizing IgG titers in mice relative to those induced by SP/RBD without the Fc moiety and induced comparable long-term neutralizing titers with a single dose vs. two doses. To further enhance immunogenicity, AKS-452 was evaluated in formulations containing a panel of adjuvants in which the water-in-oil adjuvant, Montanide™ ISA 720, enhanced neutralizing IgG titers by approximately 7-fold after one and two doses in mice, including the neutralization of live SARS-CoV-2 virus infection of VERO-E6 cells. Furthermore, ISA 720-adjuvanted AKS-452 was immunogenic in rabbits and non-human primates (NHPs) and protected from infection and clinical symptoms with live SARS-CoV-2 virus in NHPs (USA-WA1/2020 viral strain) and the K18 human ACE2-trangenic (K18-huACE2-Tg) mouse (South African B.1.351 viral variant). These preclinical studies support the initiation of Phase I clinical studies with adjuvanted AKS-452 with the expectation that this room-temperature stable, Fc-fusion subunit vaccine can be rapidly and inexpensively manufactured to provide billions of doses per year especially in regions where the cold-chain is difficult to maintain.     

Serological Responses of Raccoons and Striped Skunks to Ontario Rabies Vaccine Bait in West Virginia during 2012–2016

Since the 1990s, oral rabies vaccination (ORV) has been used successfully to halt the westward spread of the raccoon rabies virus (RV) variant from the eastern continental USA. Elimination of raccoon RV from the eastern USA has proven challenging across targeted raccoon (Procyon lotor) and striped skunk (Mephitis mephitis) populations impacted by raccoon RV. Field trial evaluations of the Ontario Rabies Vaccine Bait (ONRAB) were initiated to expand ORV products available to meet the rabies management goal of raccoon RV elimination. This study describes the continuation of a 2011 trial in West Virginia. Our objective was to evaluate raccoon and skunk response to ORV occurring in West Virginia for an additional two years (2012–2013) at 75 baits/km² followed by three years (2014–2016) of evaluation at 300 baits/km². We measured the change in rabies virus-neutralizing antibody (RVNA) seroprevalence in targeted wildlife populations by comparing levels pre- and post-ORV during each year of study. The increase in bait density from 75/km² to 300/km² corresponded to an increase in average post-ORV seroprevalence for raccoon and skunk populations. Raccoon population RVNA levels increased from 53% (300/565, 95% CI: 50–57%) to 82.0% (596/727, 95% CI: 79–85%) during this study, and skunk population RVNA levels increased from 11% (8/72, 95% CI: 6–20%) to 39% (51/130, 95% CI: 31–48%). The RVNA seroprevalence pre-ORV demonstrated an increasing trend across study years for both bait densities and species, indicating that multiple years of ORV may be necessary to achieve and maintain RVNA seroprevalence in target wildlife populations for the control and elimination of raccoon RV in the eastern USA.     

Efficacy of recombinant Marek’s disease virus vectored vaccines with computationally optimized broadly reactive antigen (COBRA) hemagglutinin insert against genetically diverse H5 high pathogenicity avian influenza viruses

The genetic and antigenic drift associated with the high pathogenicity avian influenza (HPAI) viruses of Goose/Guangdong (Gs/GD) lineage and the emergence of vaccine-resistant field viruses underscores the need for a broadly protective H5 influenza A vaccine. Here, we tested experimental vector herpesvirus of turkey (vHVT)-H5 vaccines containing either wild-type clade 2.3.4.4A-derived H5 inserts or computationally optimized broadly reactive antigen (COBRA) inserts with challenge by homologous and genetically divergent H5 HPAI Gs/GD lineage viruses in chickens. Direct assessment of protection was confirmed for all the tested constructs, which provided clinical protection against the homologous and heterologous H5 HPAI Gs/GD challenge viruses and significantly decreased oropharyngeal shedding titers compared to the sham vaccine. The cross reactivity was assessed by hemagglutinin inhibition (HI) and focus reduction assay against a panel of phylogenetically and antigenically diverse H5 strains. The COBRA-derived H5 inserts elicited antibody responses against antigenically diverse strains, while the wild-type-derived H5 vaccines elicited protection mostly against close antigenically related clades 2.3.4.4A and 2.3.4.4D viruses. In conclusion, the HVT vector, a widely used replicating vaccine platform in poultry, with H5 insert provides clinical protection and significant reduction of viral shedding against homologous and heterologous challenge. In addition, the COBRA-derived inserts have the potential to be used against antigenically distinct co-circulating viruses and future drift variants.     

Could non-HDL-cholesterol be a better marker of atherogenic dyslipidemia in obstructive sleep apnea?

Background/objectiveObstructive sleep apnea (OSA) is independently associated with dyslipidemia, a surrogate marker of atherosclerosis. Low-density lipoprotein (LDL)-cholesterol is accepted as a major independent risk factor for cardiovascular disease. However, non-high-density lipoprotein (HDL)-cholesterol is a better marker of atherogenic dyslipidemia and recommended as a target of lipid lowering therapy. We aimed to assess the prevalence of atherogenic dyslipidemia, and relationship between OSA severity and serum LDL-cholesterol and non-HDL cholesterol levels in OSA patients.MethodsWe retrospectively evaluated treatment naïve 2361 subjects admitted to the sleep laboratory of a university hospital for polysomnography. All subjects’ lipid profile including total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, and non-HDL-cholesterol were measured.ResultsOut of 2361 patients (mean age 49.6 ± 11.9 years; 68.9% male, apnea-hypopnea index 36.6 ± 28.4/h), 185 (7.8%) had no OSA and 2176 (92.2%) had OSA. Atherogenic dyslipidemia prevalence was high (57–66%) in OSA patients, and especially increased in severe OSA compared to other groups (p < 0.05). Though total and LDL-cholesterol did not differ between those with and without OSA, non-HDL-cholesterol (p = 0.020), and triglycerides (p = 0.001) were higher and HDL-cholesterol levels (p = 0.018) were lower in OSA patients than non-OSA. Non-HDL-cholesterol was significantly correlated with OSA severity (p < 0.001) and hypoxia parameters (p < 0.01), whereas LDL-cholesterol showed no correlation.ConclusionsAtherogenic dyslipidemia is highly prevalent and non-HDL-cholesterol levels are significantly increased, predominantly in severe OSA patients. Non-HDL-cholesterol but not LDL-cholesterol, is significantly correlated with OSA severity and hypoxia parameters. Therefore, it could be better to use non-HDL-cholesterol, which is a guideline recommended target of lipid therapy, as a marker of atherosclerotic cardiovascular risk in OSA patients.     

解偶联蛋白1基因多态性与2型糖尿病心脑血管并发症的相关性

目的探讨解偶联蛋白1(UCP1)基因多态性与2型糖尿病(T2DM)心脑血管并发症的相关性。方法选取2019年7月—2020年7月住院治疗的T2DM 440例,根据有无心脑血管并发症分为观察组(T2DM合并心脑血管并发症)221例和对照组(单纯T2DM)219例。比较两组一般资料,UCP1在rs45539933、rs10011540及rs1800592位点的基因型分布与等位基因频率;通过多因素Logistic回归分析评估T2DM发生心脑血管事件的危险因素。结果观察组病程长于对照组,糖化血红蛋白水平高于对照组,而血清高密度脂蛋白胆固醇水平低于对照组(P<0.01)。观察组C/C基因型分布及C碱基频率均高于对照组(P<0.05)。C/C基因型是T2DM患者发生心脑血管并发症的危险因素(P<0.05)。结论UCP1基因多态性与T2DM心脑血管并发症的发生显著相关。     

Clinical efficacy of bisphosphonates and monoclonal antibodies on bone mineral density following skeletal fractures

BackgroundBisphosphonates and monoclonal antibodies are drugs primarily developed to inhibit osteoclast-mediated bone resorption and are used to treat an array of skeletal pathologies. Their use is aimed at increasing bone health and therefore reducing fracture risks. The aim of this study was to evaluate the effectiveness of bone protection therapy on improving bone mineral density (BMD) in patients following a fracture.MethodsInclusion criteria consisted of patients who sustained a skeletal fracture and were subsequently commenced on bone protection therapy. Dual-energy X-ray Absorptiometry (DEXA) scans were performed at baseline and following a consented period of drug therapy. Bone health data included T-Scores, Z-Scores, FRAX Major, FRAX Hip and BMD. The clinical effectiveness of four bisphosphonates (alendronate, risedronate, pamidronate and zoledronate) and one monoclonal antibody (denosumab) were evaluated.ResultsA total of 100 patients were included in the study. Overall, bone protection therapy significantly improved Z-score Hip, Z-score Spine, T-score Spine and BMD Spine (p < 0.05). There was a marked difference between drug therapies. Denosumab and zoledronate were associated with the greatest treatment effect size. Alendronate only improved Z-score Spine and Z-score Hip (p < 0.05). Pamidronate and risedronate did not demonstrate any statistically significant improvement across any DEXA parameter.ConclusionOverall, bisphosphonates/monoclonal antibodies confer beneficial effects on bone health as measured by DEXA scans in patients following skeletal fractures. However, the magnitude of improvement varies among the commonly used drugs. Alendronate, zoledronate and denosumab were associated with greatest therapeutic benefit. Bone protection therapy did not improve fracture risk of patients (FRAX scores).     

应用锥形束CT对种植区牙槽骨质量分类方法的改良研究

目的    应用锥形束CT（cone beam CT，CBCT）测量种植区牙槽骨质量并结合Lekholm和Zarb分类法对骨质量分类方法进行改良，以期为提高牙槽骨质量分类的准确性提供指导。方法    选择2015年10月至2017年10月在呼和浩特市口腔医院种植科进行种植修复的196例患者术前CBCT影像资料，应用 Invivo5诊断设计软件测量306个种植位点的牙槽骨皮质骨厚度和松质骨密度（皮质骨与松质骨的CT值差值），以Lekholm和Zarb分类法为基础结合测量数据对骨质量进行改良后的量化分类。结果    牙槽骨皮质骨厚度为0.18 ~ 2.89 mm，中位数为0.92 mm。皮质骨与松质骨的CT值差值为88.5 ~ 667.8 HU，应用百分位数法找到33.3%和66.6%对应的数值分别为297.8 HU和356.1 HU。依据此数据结合Lekholm和Zarb分类法将196例患者的306个种植位点骨质量分为4类，其中Ⅰ类骨种植位点46个（占15.0%），Ⅱ类骨104个（占34.0%），Ⅲ类骨114个（占37.3%），Ⅳ类骨42个（占13.7%）。结论    结合Lekholm和Zarb分类法，应用CBCT测量种植区牙槽骨质量并进行分类方法的改良，可为临床医生术前评估牙槽骨质量提供一定参考。