Grosenbach Douglas W, Jordan Robert, King David S, Berhanu Aklile, Warren Travis K, Kirkwood-Watts Dana L, Tyavanagimatt Shanthakumar, Tan Ying, Wilson Rebecca L, Jones Kevin F, Hruby Dennis E
SIGA Technologies, 4575 SW Research Way, Suite 230, Corvallis, OR 97333, United States.
Vaccine. 2008 Feb 13;26(7):933-46. doi: 10.1016/j.vaccine.2007.11.095. Epub 2007 Dec 26.
The re-emerging threat of smallpox and the emerging threat of monkeypox highlight the need for effective poxvirus countermeasures. Currently approved smallpox vaccines have unacceptable safety profiles and, consequently, the general populace is no longer vaccinated, leading to an increasingly susceptible population. ST-246, a small-molecule inhibitor of poxvirus dissemination, has been demonstrated in various animal models to be safe and effective in preventing poxviral disease. This suggests that it may also be used to improve the safety of the traditional smallpox vaccine provided that it does not inhibit vaccine-induced protective immunity. In this study, we compared the immune responses elicited by the smallpox vaccine alone or in combination with ST-246 in mice. Normal lesion formation following dermal scarification with the attenuated New York City Board of Health strain (Dryvax), commonly referred to as a vaccine "take", was not inhibited although severe lesions and systemic disease due to vaccination with the virulent Western Reserve (VV-WR) strain were prevented. The vaccine given with ST-246 did not affect cellular immune responses or neutralizing antibody titers although anti-vaccinia ELISA titers were slightly reduced. Vaccination in combination with ST-246 provided equivalent short- and long-term protection against lethal intranasal challenge with VV-WR when compared to vaccine alone. These results suggest that ST-246 does not compromise protective immunity elicited by the vaccine and provide the basis for future studies examining the efficacy of ST-246 in preventing or treating adverse events due to vaccination.
天花再次出现的威胁以及猴痘新出现的威胁凸显了有效应对痘病毒措施的必要性。目前获批的天花疫苗具有不可接受的安全性，因此，普通民众不再接种疫苗，导致人群易感性日益增加。ST-246是一种痘病毒传播的小分子抑制剂，已在各种动物模型中证明其在预防痘病毒疾病方面安全有效。这表明，只要它不抑制疫苗诱导的保护性免疫，它也可用于提高传统天花疫苗的安全性。在本研究中，我们比较了单独使用天花疫苗或与ST-246联合使用在小鼠中引发的免疫反应。用减毒的纽约市卫生局毒株（Dryvax）进行皮肤划痕接种后正常的损伤形成，通常称为疫苗“接种成功”，并未受到抑制，尽管接种强毒的西储毒株（VV-WR）引起的严重损伤和全身性疾病得到了预防。与ST-246联合使用的疫苗虽然抗痘苗ELISA滴度略有降低，但并未影响细胞免疫反应或中和抗体滴度。与单独使用疫苗相比，与ST-246联合接种在短期和长期内都能提供同等的保护，抵抗VV-WR的致死性鼻内攻击。这些结果表明，ST-246不会损害疫苗引发的保护性免疫，并为未来研究ST-246在预防或治疗疫苗引起的不良事件中的疗效提供了依据。
