Kaufman David R, Goudsmit Jaap, Holterman Lennart, Ewald Bonnie A, Denholtz Matthew, Devoy Colleen, Giri Ayush, Grandpre Lauren E, Heraud Jean-Michel, Franchini Genoveffa, Seaman Michael S, Havenga Menzo J E, Barouch Dan H
Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
J Virol. 2008 Jul;82(14):6829-37. doi: 10.1128/JVI.00353-08. Epub 2008 Apr 30.
The development of a subunit vaccine for smallpox represents a potential strategy to avoid the safety concerns associated with replication-competent vaccinia virus. Preclinical studies to date with subunit smallpox vaccine candidates, however, have been limited by incomplete information regarding protective antigens and the requirement for multiple boost immunizations to afford protective immunity. Here we explore the protective efficacy of replication-incompetent, recombinant adenovirus serotype 35 (rAd35) vectors expressing the vaccinia virus intracellular mature virion (IMV) antigens A27L and L1R and extracellular enveloped virion (EEV) antigens A33R and B5R in a murine vaccinia virus challenge model. A single immunization with the rAd35-L1R vector effectively protected mice against a lethal systemic vaccinia virus challenge. The rAd35-L1R vector also proved more efficacious than the combination of four rAd35 vectors expressing A27L, L1R, A33R, and B5R. Moreover, serum containing L1R-specific neutralizing antibodies afforded postexposure prophylaxis after systemic vaccinia virus infection. In contrast, the combination of rAd35-L1R and rAd35-B5R vectors was required to protect mice against a lethal intranasal vaccinia virus challenge, suggesting that both IMV- and EEV-specific immune responses are important following intranasal infection. Taken together, these data demonstrate that different protective antigens are required based on the route of vaccinia virus challenge. These studies also suggest that rAd vectors warrant further assessment as candidate subunit smallpox vaccines.
开发天花亚单位疫苗是一种潜在策略，可避免与具有复制能力的痘苗病毒相关的安全问题。然而，迄今为止，针对亚单位天花疫苗候选物的临床前研究受到有关保护性抗原的信息不完整以及需要多次加强免疫以提供保护性免疫的限制。在此，我们在小鼠痘苗病毒攻击模型中探索了表达痘苗病毒细胞内成熟病毒粒子（IMV）抗原A27L和L1R以及细胞外包膜病毒粒子（EEV）抗原A33R和B5R的无复制能力的重组腺病毒血清型35（rAd35）载体的保护效力。用rAd35-L1R载体进行单次免疫可有效保护小鼠免受致死性全身性痘苗病毒攻击。rAd35-L1R载体也比表达A27L、L1R、A33R和B5R的四种rAd35载体的组合更有效。此外，含有L1R特异性中和抗体的血清在全身性痘苗病毒感染后提供暴露后预防。相比之下，需要rAd35-L1R和rAd35-B5R载体的组合来保护小鼠免受致死性鼻内痘苗病毒攻击，这表明鼻内感染后IMV特异性和EEV特异性免疫反应都很重要。综上所述，这些数据表明，根据痘苗病毒攻击途径需要不同的保护性抗原。这些研究还表明，rAd载体作为候选亚单位天花疫苗值得进一步评估。
