摘要
在北美和南美,大部分的汉坦病毒肺综合征( HPS )病例分别由辛诺柏病毒( SNV )和安第斯病毒( ANDV )导致。汉坦病毒肺综合征患者的存活率只有三分之二。先前,我们证实了 SNV 和ANDV病毒的 DNA疫苗编码的病毒包膜糖蛋白在实验动物上诱发高滴度的中和抗体,在非人类的灵长类动物((NHPs)身上(对于ANDV病毒)也有此作用。在这些研究中,疫苗通过基因枪或肌肉电穿孔投递。本文,我们测试了SNV / ANDV DNA联合疫苗( HPS DNA疫苗)是否能使用一次性注射器喷射( DSJI )系统( PharmaJet公司)有效地投递。PharmaJet公司的肌肉( IM)和皮内( ID)无针设备已获得美国FDA的510 ( k)认证,使用简单,并且不需要电或压缩气体。首先,我们在兔和非人类的灵长类身上进行测试,使用PharmaJet肌注或皮内设备注射SNV DNA疫苗,两种设备都能在兔和非人类的灵长类身上产生高滴度的抗SNV中和抗体。但是,皮内注射设备在非人类的灵长类动物身上需要至少接种两次才能在大部分动物身上检测到中和抗体,而所有的动物只需用肌肉注射设备接种一次即可产生抗体。因为肌肉接种设备对非人类的灵长类动物更为有效,所以Stratis®(PharmaJet公司)的肌肉接种设备被选择用于后续的研究。我们评估了使用Stratis® 注射的 HPS疫苗,通过经典的噬斑减少中和试验和新的假病毒中和实验评估,发现该疫苗在兔身上(n = 8 /组)产生了高滴度的抗SNV和抗ANDV中和抗体。我们对于确定DSJI投递系统(例如高速液体渗透通过组织)和其他疫苗注射方法如针头/注射器的区别很感兴趣,这可能会导致研制出更强的免疫原性DNA疫苗。为此,我们比较了在非人类的灵长类动物身上(n = 8 /组)用DSJI和与之相对的针头/注射器注射HPS DNA疫苗,我们发现运用DSJI接种组产生的抗SNV和抗ANDV中和抗体滴度比针头/注射器组有显著升高( P值为0.0115 )。例如,抗 SNV和抗ANDV PRNT50的几何平均滴度(GMT水平)在DSJI接种组中分别为 1,974和349,相对应的在针/注射器组中为87和42。这些数据第一次表明,以弹簧为动力的DSJI装置能够有效地对非人类的灵长类动物接种DNA疫苗,但由弹簧驱动的DSJI装置接种的此种 HPS DNA疫苗或任何DNA疫苗,能否在人身上引起强免疫应答,仍需要临床试验。
关键词: DNA疫苗,汉坦病毒,喷射注射
Current Gene Therapy
Title:A Hantavirus Pulmonary Syndrome (HPS) DNA Vaccine Delivered Using a Spring-powered Jet Injector Elicits a Potent Neutralizing Antibody Response in Rabbits and Nonhuman Primates
Volume: 14 Issue: 3
Author(s): Steve Kwilas, Jennifer M. Kishimori, Matthew Josleyn, Kurt Jerke, John Ballantyne, Michael Royals and Jay W. Hooper
Affiliation:
关键词: DNA疫苗,汉坦病毒,喷射注射
摘要: Sin Nombre virus (SNV) and Andes virus (ANDV) cause most of the hantavirus pulmonary syndrome (HPS) cases in North and South America, respectively. The chances of a patient surviving HPS are only two in three. Previously, we demonstrated that SNV and ANDV DNA vaccines encoding the virus envelope glycoproteins elicit high-titer neutralizing antibodies in laboratory animals, and (for ANDV) in nonhuman primates (NHPs). In those studies, the vaccines were delivered by gene gun or muscle electroporation. Here, we tested whether a combined SNV/ANDV DNA vaccine (HPS DNA vaccine) could be delivered effectively using a disposable syringe jet injection (DSJI) system (PharmaJet, Inc). PharmaJet intramuscular (IM) and intradermal (ID) needle-free devices are FDA 510(k)-cleared, simple to use, and do not require electricity or pressurized gas. First, we tested the SNV DNA vaccine delivered by PharmaJet IM or ID devices in rabbits and NHPs. Both IM and ID devices produced high-titer anti-SNV neutralizing antibody responses in rabbits and NHPs. However, the ID device required at least two vaccinations in NHP to detect neutralizing antibodies in most animals, whereas all animals vaccinated once with the IM device seroconverted. Because the IM device was more effective in NHP, the Stratis® (PharmaJet IM device) was selected for follow-up studies. We evaluated the HPS DNA vaccine delivered using Stratis® and found that it produced high-titer anti-SNV and anti-ANDV neutralizing antibodies in rabbits (n=8/group) as measured by a classic plaque reduction neutralization test and a new pseudovirion neutralization assay. We were interested in determining if the differences between DSJI delivery (e.g., high-velocity liquid penetration through tissue) and other methods of vaccine injection, such as needle/syringe, might result in a more immunogenic DNA vaccine. To accomplish this, we compared the HPS DNA vaccine delivered by DSJI versus needle/syringe in NHPs (n=8/group). We found that both the anti-SNV and anti-ANDV neutralizing antibody titers were significantly higher (p-value 0.0115) in the DSJI-vaccinated groups than the needle/syringe group. For example, the anti-SNV and anti-ANDV PRNT50 geometric mean titers (GMTs) were 1,974 and 349 in the DSJI-vaccinated group versus 87 and 42 in the needle/syringe group. These data demonstrate, for the first time, that a spring-powered DSJI device is capable of effectively delivering a DNA vaccine to NHPs. Whether this HPS DNA vaccine, or any DNA vaccine, delivered by spring-powered DSJI will elicit a strong immune response in humans, requires clinical trials.
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Kwilas Steve, Kishimori M. Jennifer, Josleyn Matthew, Jerke Kurt, Ballantyne John, Royals Michael and Hooper W. Jay, A Hantavirus Pulmonary Syndrome (HPS) DNA Vaccine Delivered Using a Spring-powered Jet Injector Elicits a Potent Neutralizing Antibody Response in Rabbits and Nonhuman Primates, Current Gene Therapy 2014; 14 (3) . https://dx.doi.org/10.2174/1566523214666140522122633
DOI https://dx.doi.org/10.2174/1566523214666140522122633 |
Print ISSN 1566-5232 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5631 |
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