BoHV-4-Based Vector Single Heterologous Antigen Delivery Protects STAT1(-/-) Mice from Monkeypoxvirus Lethal Challenge.
BoHV-4-Based Vector Single Heterologous Antigen Delivery Protects STAT1(-/-) Mice from Monkeypoxvirus Lethal Challenge.
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DOI：
10.1371/journal.pntd.0003850
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发表时间：
2015-06
影响因子：
3.8
通讯作者：
Donofrio G
中科院分区：
文献类型：
--
作者：
Franceschi V;Parker S;Jacca S;Crump RW;Doronin K;Hembrador E;Pompilio D;Tebaldi G;Estep RD;Wong SW;Buller MR;Donofrio G
猴痘病毒（Monkeypox virus，MPXV）是人痘病毒（MPX）的病原。它是非洲热带雨林中一种新出现的正痘病毒人兽共患病，在刚果盆地流行，在西非零星分布;它仍然是贫困农村地区人们的一种被忽视的热带疾病。人类与野生动物的相互作用增加了MPX病毒（MPXV）的人类感染，并且人与人之间的感染是可能的。天花疫苗接种对MPX提供了良好的交叉保护;然而，非洲的疫苗接种运动于1980年结束，这意味着大部分人口目前对MPXV感染没有保护。疾病控制的关键在于阻止人畜共患接触病毒，否则，就必须阻断人与人之间的传播。然而，没有FDA批准的针对MPX的疗法，并且由于安全性问题，目前的疫苗受到限制。因此，关于发病机制、预防和治疗的新研究仍然引起了科学界和政府的极大兴趣，因为MPXV可能被用作生物恐怖剂。在本研究中，一种新的疫苗接种策略的基础上的三个重组牛疱疹病毒4型（BoHV-4）载体，每个表达不同的MPXV糖蛋白，A29 L，M1 R和B6 R的方法进行了研究，从一个致命的MPXV攻击在STAT 1基因敲除小鼠的保护。通过重组工程技术成功构建了BoHV-4-A-CMV-A29 LgD 106 ΔTK、BoHV-4-A-EF 1 α-M1 RgD 106 ΔTK和BoHV-4-A-EF 1 α-B6 RgD 106 ΔTK，并证明了其表达转基因的能力。进行了一项小规模的攻击研究，所有三种重组BoHV-4在腹膜内给药后都是安全的（没有体重减轻或明显的不良事件）。此外，BoHV-4-A-EF 1 α-M1 RgD 106 ΔTK单独或与BoHV-4-A-CMV-A29 LgD 106 ΔTK和BoHV-4-A-EF 1 α-B6 RgD 106 ΔTK组合显示能够100%单独和80%组合保护STAT 1（-/-）小鼠免于死亡和发病。这项工作证明了基于BoHV-4的载体的功效以及BoHV-4作为疫苗载体平台的用途。人猴痘是一种被忽视的人畜共患热带疾病，大多数人感染发生在中非贫穷的农村地区。人类猴痘是在天花疫苗接种运动停止时发现的，使免疫未受保护的人群面临猴痘病毒感染的风险。目前，没有安全有效的预防猴痘的疫苗可用于流行环境，需要进一步研究以开发安全有效的疫苗。在本研究中，在合适的小鼠模型中评价了三种重组牛疱疹病毒4型载体的安全性和保护性，每种载体均递送猴痘糖蛋白。所有三种重组体似乎都是安全的，其中一种，提供单剂量的猴痘M1 R糖蛋白，保护60%的小鼠免受致死剂量的猴痘病毒的侵害;当作为初免/加强时，它提供了100%的保护。尽管需要对其他猴痘模型（包括非人灵长类动物）进行进一步研究，以评估基于牛疱疹病毒4型的载体提供M1 R的安全性和保护性，但这项工作的发现为基于牛疱疹病毒4型的载体用于其他A类药物的潜在用途铺平了道路。
Monkeypox virus (MPXV) is the etiological agent of human (MPX). It is an emerging orthopoxvirus zoonosis in the tropical rain forest of Africa and is endemic in the Congo-basin and sporadic in West Africa; it remains a tropical neglected disease of persons in impoverished rural areas. Interaction of the human population with wildlife increases human infection with MPX virus (MPXV), and infection from human to human is possible. Smallpox vaccination provides good cross-protection against MPX; however, the vaccination campaign ended in Africa in 1980, meaning that a large proportion of the population is currently unprotected against MPXV infection. Disease control hinges on deterring zoonotic exposure to the virus and, barring that, interrupting person-to-person spread. However, there are no FDA-approved therapies against MPX, and current vaccines are limited due to safety concerns. For this reason, new studies on pathogenesis, prophylaxis and therapeutics are still of great interest, not only for the scientific community but also for the governments concerned that MPXV could be used as a bioterror agent. In the present study, a new vaccination strategy approach based on three recombinant bovine herpesvirus 4 (BoHV-4) vectors, each expressing different MPXV glycoproteins, A29L, M1R and B6R were investigated in terms of protection from a lethal MPXV challenge in STAT1 knockout mice. BoHV-4-A-CMV-A29LgD106ΔTK, BoHV-4-A-EF1α-M1RgD106ΔTK and BoHV-4-A-EF1α-B6RgD106ΔTK were successfully constructed by recombineering, and their capacity to express their transgene was demonstrated. A small challenge study was performed, and all three recombinant BoHV-4 appeared safe (no weight-loss or obvious adverse events) following intraperitoneal administration. Further, BoHV-4-A-EF1α-M1RgD106ΔTK alone or in combination with BoHV-4-A-CMV-A29LgD106ΔTK and BoHV-4-A-EF1α-B6RgD106ΔTK, was shown to be able to protect, 100% alone and 80% in combination, STAT1(-/-) mice against mortality and morbidity. This work demonstrated the efficacy of BoHV-4 based vectors and the use of BoHV-4 as a vaccine-vector platform. Human Monkeypox is a zoonotic neglected tropical disease, and the majority of human infections occur in the poor rural areas of central Africa. Human Monkeypox was discovered when the Smallpox vaccination campaign stopped, exposing the immunologically unprotected population to the risk of Monkeypoxvirus infection. Currently, no safe and efficacious vaccines for prevention of Monkeypox are available for an epidemic setting, and further studies are needed for the development of a safe and efficacious vaccine. In this study, safety and protection of three recombinant Bovine Herpesvirus 4-based vectors, each delivering a Monkeypox glycoprotein, was evaluated in a suitable mouse model. All three recombinants appeared safe, and one of them, delivering a single dose of Monkeypox M1R glycoprotein, protected 60% of mice against a lethal dose of Monkeypoxvirus; when given as a prime/boost, it afforded 100% protection. Although further investigation into other Monkeypox models, including non-human primate, is needed to assess bovine herpesvirus 4-based vector delivering M1R safety and protection, the findings of this work pave the way for the potential use of Bovine Herpesvirus 4-based vectors for other category A agents.
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DOI：
10.1530/rep-08-0171
发表时间：
2008-09
期刊：
Reproduction (Cambridge, England)
影响因子：
--
作者：
Donofrio G;Ravanetti L;Cavirani S;Herath S;Capocefalo A;Sheldon IM
通讯作者：
Sheldon IM
影响因子：
3.7
作者：
Donofrio, Gaetano;Franceschi, Valentina;Tempesta, Maria
通讯作者：
Tempesta, Maria
影响因子：
5.4
作者：
Americo, Jeffrey L.;Moss, Bernard;Earl, Patricia L.
通讯作者：
Earl, Patricia L.
影响因子：
3.7
作者：
Americo, Jeffrey L.;Sood, Cindy L.;Cotter, Catherine A.;Vogel, Jodi L.;Kristie, Thomas M.;Moss, Bernard;Earl, Patricia L.
通讯作者：
Earl, Patricia L.
影响因子：
5.5
作者：
Capocefalo, Antonio;Mangia, Carlo;Donofrio, Gaetano
通讯作者：
Donofrio, Gaetano