Side-by-Side Comparison of Gene-Based Smallpox Vaccine with MVA in Nonhuman Primates
Side-by-Side Comparison of Gene-Based Smallpox Vaccine with MVA in Nonhuman Primates
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DOI：
10.1371/journal.pone.0042353
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发表时间：
2012-07-31
期刊：
影响因子：
3.7
通讯作者：
Hooper, Jay W.
中科院分区：
文献类型：
--
作者：
Golden, Joseph W.;Josleyn, Matthew;Hooper, Jay W.
正痘病毒仍然是生物武器和人畜共患病的威胁。许可的活病毒疫苗与严重的健康风险有关，使其普遍使用不可接受。正在开发减毒疫苗作为替代品，其中最先进的是改良安卡拉牛痘病毒（MVA）。我们以前开发了一种基于基因的疫苗，称为4pox，它针对四种正痘病毒抗原，A33，B5，A27和L1。这种疫苗保护小鼠和非人灵长类动物免受致命的正痘病毒病。在这里，我们研究了分子佐剂GM-CSF和大肠杆菌不耐热肠毒素（LT）的能力，以提高4pox基因为基础的疫苗的效力。两种佐剂均显著增加小鼠的保护性抗体应答。我们在猴痘病毒（MPXV）非人灵长类动物（NHP）攻毒模型中直接比较了4痘加LT疫苗对MVA的影响。NHP通过肌肉注射接种MVA两次或使用一次性基因枪装置递送4pox/LT疫苗。作为阳性对照，用ACAM 2000接种一个NHP。接种每种疫苗的NHP产生了抗正痘病毒抗体应答，包括针对4痘抗原的抗体应答。在MPXV静脉内攻击后，所有对照NHP都发生了严重疾病，而ACAM 2000疫苗接种的动物得到了良好的保护。所有接种MVA疫苗的NHP都不会致死，但五分之三的动物发生了严重的疾病，所有动物都脱落了病毒。所有5名接种4pox/LT的NHP均存活，只有1名发生严重疾病。4pox/LT接种动物均未散毒。我们的研究结果首次表明，通过相同的时间表提供的亚单位正痘病毒疫苗可以提供至少与MVA一样高的保护程度。
Orthopoxviruses remain a threat as biological weapons and zoonoses. The licensed live-virus vaccine is associated with serious health risks, making its general usage unacceptable. Attenuated vaccines are being developed as alternatives, the most advanced of which is modified-vaccinia virus Ankara (MVA). We previously developed a gene-based vaccine, termed 4pox, which targets four orthopoxvirus antigens, A33, B5, A27 and L1. This vaccine protects mice and non-human primates from lethal orthopoxvirus disease. Here, we investigated the capacity of the molecular adjuvants GM-CSF and Escherichia coli heat-labile enterotoxin (LT) to enhance the efficacy of the 4pox gene-based vaccine. Both adjuvants significantly increased protective antibody responses in mice. We directly compared the 4pox plus LT vaccine against MVA in a monkeypox virus (MPXV) nonhuman primate (NHP) challenge model. NHPs were vaccinated twice with MVA by intramuscular injection or the 4pox/LT vaccine delivered using a disposable gene gun device. As a positive control, one NHP was vaccinated with ACAM2000. NHPs vaccinated with each vaccine developed anti-orthopoxvirus antibody responses, including those against the 4pox antigens. After MPXV intravenous challenge, all control NHPs developed severe disease, while the ACAM2000 vaccinated animal was well protected. All NHPs vaccinated with MVA were protected from lethality, but three of five developed severe disease and all animals shed virus. All five NHPs vaccinated with 4pox/LT survived and only one developed severe disease. None of the 4pox/LT-vaccinated animals shed virus. Our findings show, for the first time, that a subunit orthopoxvirus vaccine delivered by the same schedule can provide a degree of protection at least as high as that of MVA.