Department of Preventive Medicine and Biometrics, Uniformed University of the Health Sciences, Bethesda, MD, USA.
Vaccine. 2013 Sep 23;31(41):4501-7. doi: 10.1016/j.vaccine.2013.06.079. Epub 2013 Jul 26.
A recent clinical trial of a live-attenuated tetravalent chimeric yellow fever-dengue vaccine afforded no protection against disease caused by dengue 2 (DENV-2). This outcome was unexpected as two or more doses of this vaccine had raised broad neutralizing antibody responses. Data from pre-clinical subhuman primate studies revealed that vaccination with the monotypic DENV-2 component failed to meet established criteria for solid protection to homotypic live virus challenge. Accordingly, it is suggested that preclinical testing adopt more rigorous criteria for protection and that Phase I testing be extended to require evidence of solid monotypic protective immunity for each component of a dengue vaccine by direct challenge with live-attenuated DENV. Because live-attenuated tetravalent DENV vaccines exhibit evidence of immunological interference phenomena, during Phase II, volunteers given mixtures of DENV 1-4 vaccines should be separately challenged with monotypic live-attenuated DENV. Immune responses to live-attenuated challenge viruses and vaccine strains should be studied in an attempt to develop useful in vitro correlates of in vivo protection. Finally, it will be important to learn if DENV non-structural protein 1 (NS1) contributes to pathogenesis of the vascular permeability syndrome in humans. If so, immunity to dengue 1-4 NS1 may be crucial to prevent severe disease.
最近一项针对减毒活四价嵌合黄热病-登革热疫苗的临床试验未能提供针对登革热 2 型（DENV-2）疾病的保护。这一结果出人意料，因为两剂或更多剂量的这种疫苗引发了广泛的中和抗体反应。来自非人类灵长类动物临床前研究的数据表明，接种单型 DENV-2 成分未能达到针对同源活病毒挑战的可靠保护的既定标准。因此，建议临床前测试采用更严格的保护标准，并且 I 期测试延长到要求每个登革热疫苗成分具有可靠的单型保护免疫的证据，通过直接用减毒活 DENV 进行挑战。由于减毒活四价 DENV 疫苗表现出免疫干扰现象的证据，在 II 期，给予 DENV 1-4 疫苗混合物的志愿者应分别用单型减毒活 DENV 进行单独挑战。应研究对减毒活挑战病毒和疫苗株的免疫反应，以试图开发有用的体外相关性，以预测体内保护。最后，了解 DENV 非结构蛋白 1（NS1）是否有助于人类血管通透性综合征的发病机制非常重要。如果是这样，对登革热 1-4 NS1 的免疫可能对预防严重疾病至关重要。
