Boigard Hélène, Alimova Alexandra, Martin George R, Katz Al, Gottlieb Paul, Galarza Jose M
TechnoVax, Inc., Tarrytown, NY, United States of America.
Department of Molecular, Cellular and Biomedical Sciences, City University of New York, School of Medicine, New York City, NY, United States of America.
PLoS Negl Trop Dis. 2017 May 8;11(5):e0005608. doi: 10.1371/journal.pntd.0005608. eCollection 2017 May.
The newly emerged mosquito-borne Zika virus poses a major public challenge due to its ability to cause significant birth defects and neurological disorders. The impact of sexual transmission is unclear but raises further concerns about virus dissemination. No specific treatment or vaccine is currently available, thus the development of a safe and effective vaccine is paramount. Here we describe a novel strategy to assemble Zika virus-like particles (VLPs) by co-expressing the structural (CprME) and non-structural (NS2B/NS3) proteins, and demonstrate their effectiveness as vaccines. VLPs are produced in a suspension culture of mammalian cells and self-assembled into particles closely resembling Zika viruses as shown by electron microscopy studies. We tested various VLP vaccines and compared them to analogous compositions of an inactivated Zika virus (In-ZIKV) used as a reference. VLP immunizations elicited high titers of antibodies, as did the In-ZIKV controls. However, in mice the VLP vaccine stimulated significantly higher virus neutralizing antibody titers than comparable formulations of the In-ZIKV vaccine. The serum neutralizing activity elicited by the VLP vaccine was enhanced using a higher VLP dose and with the addition of an adjuvant, reaching neutralizing titers greater than those detected in the serum of a patient who recovered from a Zika infection in Brazil in 2015. Discrepancies in neutralization levels between the VLP vaccine and the In-ZIKV suggest that chemical inactivation has deleterious effects on neutralizing epitopes within the E protein. This along with the inability of a VLP vaccine to cause infection makes it a preferable candidate for vaccine development.
新出现的蚊媒寨卡病毒对公众构成了重大挑战，因为它能够导致严重的出生缺陷和神经紊乱。性传播的影响尚不清楚，但引发了对病毒传播的进一步担忧。目前尚无特效治疗方法或疫苗，因此开发安全有效的疫苗至关重要。在此，我们描述了一种通过共表达结构蛋白（CprME）和非结构蛋白（NS2B/NS3）来组装寨卡病毒样颗粒（VLP）的新策略，并证明了它们作为疫苗的有效性。VLP在哺乳动物细胞的悬浮培养物中产生，并通过电子显微镜研究显示自组装成与寨卡病毒非常相似的颗粒。我们测试了各种VLP疫苗，并将它们与用作参考的灭活寨卡病毒（In-ZIKV）的类似组合物进行比较。VLP免疫引发了高滴度的抗体，In-ZIKV对照也是如此。然而，在小鼠中，VLP疫苗刺激产生的病毒中和抗体滴度明显高于In-ZIKV疫苗的类似制剂。使用更高的VLP剂量并添加佐剂可增强VLP疫苗引发的血清中和活性，中和滴度高于2015年在巴西从寨卡感染中康复的患者血清中检测到的滴度。VLP疫苗和In-ZIKV之间中和水平的差异表明化学灭活对E蛋白内的中和表位有有害影响。这与VLP疫苗无法引起感染一起使其成为疫苗开发的优选候选物。
