A simian-adenovirus-vectored rabies vaccine suitable for thermostabilisation and clinical development for low-cost single-dose pre-exposure prophylaxis
A simian-adenovirus-vectored rabies vaccine suitable for thermostabilisation and clinical development for low-cost single-dose pre-exposure prophylaxis
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一种猿猴腺病毒载体狂犬病疫苗，适用于低成本单剂量暴露前预防的热稳定和临床开发
DOI：
10.1101/408013
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Wang C
中科院分区：
文献类型：
--
作者：
Wang C
背景目前全球狂犬病死亡率估计为每年2.6万至5.9万例。虽然使用灭活狂犬病毒疫苗（IRVs）进行暴露前预防是有效的，但它需要两到三剂，而且被认为过于昂贵，不适合纳入常规儿童免疫规划。方法/主要发现在此，我们报告了一种猿猴腺病毒载体狂犬病疫苗的开发，旨在实现具有成本效益的人群暴露前狂犬病预防。ChAdOx2 RabG利用黑猩猩腺病毒血清型68 （AdC68）主干，在非人类灵长类动物中实现了狂犬病暴露前保护。ChAdOx2与AdC68的不同之处在于，它含有人腺病毒血清型5 (AdHu5) E4或f6/7区域，以取代AdC68的等量物，从而提高了在提供AdHu5 E1反式蛋白的细胞系中制造的便利性。我们发现ChAdOx2 RabG在小鼠中的免疫原性与AdC68 RabG和其他表达狂犬病毒糖蛋白的腺病毒血清型相当。单次注射可产生高滴度的狂犬病毒中和抗体（VNA）。接种腺病毒载体疫苗和IRV疫苗后，VNA活性水平与狂犬病毒糖蛋白单体结合抗体的关系不同，这为进一步增强腺病毒载体候选疫苗的效力提供了途径。我们还证明，ChAdOx2 RabG可以使用一种适合临床生物制造和热带气候环境温度分布的低成本方法进行热稳定。最后，我们证明了用一种简单的化学佐剂配制ChAdOx2 RabG可以实现剂量节约效应。这种方法可以降低ChAdOx2 RabG和其他腺病毒载体疫苗的成本。结论/意义echadox2 RabG可能被证明是降低人类狂犬病死亡人数的有用工具。我们已经为该候选药物的符合gmp的生物制造和I期临床试验获得了资金。
BackgroundEstimates of current global rabies mortality range from 26,000 to 59,000 deaths per annum. Although pre-exposure prophylaxis using inactivated rabies virus vaccines (IRVs) is effective, it requires two to three doses and is regarded as being too expensive and impractical for inclusion in routine childhood immunization programmes.Methodology/ Principal findingsHere we report the development of a simian-adenovirus-vectored rabies vaccine intended to enable cost-effective population-wide pre-exposure prophylaxis against rabies. ChAdOx2 RabG uses the chimpanzee adenovirus serotype 68 (AdC68) backbone previously shown to achieve pre-exposure protection against rabies in non-human primates. ChAdOx2 differs from AdC68 in that it contains the human adenovirus serotype 5 (AdHu5) E4 orf6/7 region in place of the AdC68 equivalents, enhancing ease of manufacturing in cell lines which provide AdHu5 E1 proteinsin trans.We show that immunogenicity of ChAdOx2 RabG in mice is comparable to that of AdC68 RabG and other adenovirus serotypes expressing rabies virus glycoprotein. High titers of rabies virus neutralizing antibody (VNA) are elicited after a single dose. The relationship between levels of VNA activity and rabies virus glycoprotein monomer-binding antibody differs after immunization with adenovirus-vectored vaccines and IRV vaccines, suggesting routes to further enhancement of the efficacy of the adenovirus-vectored candidates. We also demonstrate that ChAdOx2 RabG can be thermostabilised using a low-cost method suitable for clinical bio-manufacture and ambient-temperature distribution in tropical climates. Finally, we show that a dose-sparing effect can be achieved by formulating ChAdOx2 RabG with a simple chemical adjuvant. This approach could lower the cost of ChAdOx2 RabG and other adenovirus-vectored vaccines.Conclusions/ SignificanceChAdOx2 RabG may prove to be a useful tool to reduce the human rabies death toll. We have secured funding for Good Manufacturing Practice- compliant bio-manufacture and Phase I clinical trial of this candidate.
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影响因子：
5.5
作者：
Geue, Lutz;Schares, Susann;Mueller, Thomas
通讯作者：
Mueller, Thomas
狂犬病实验室技术：NIH 效力测试。
DOI：
--
发表时间：
1973
期刊：
Monograph series. World Health Organization
影响因子：
--
作者：
Seligmann Eb
通讯作者：
Seligmann Eb
影响因子：
11.1
作者：
Kessels JA;Recuenco S;Navarro-Vela AM;Deray R;Vigilato M;Ertl H;Durrheim D;Rees H;Nel LH;Abela-Ridder B;Briggs D
通讯作者：
Briggs D
长期腹膜透析治疗慢性肾功能衰竭。
影响因子：
168.9
作者：
R. A. Palmer;W. Quinton;J. Gray
通讯作者：
J. Gray
一次就诊进行暴露前狂犬病疫苗接种（一项为期一年的初步研究）。
影响因子：
5.5
作者：
P. Khawplod;W. Jaijaroensup;Artikaya Sawangvaree;S. Prakongsri;H. Wilde
通讯作者：
H. Wilde