Fuchs Jeremy, Chu Haiyan, O'Day Peter, Pyles Richard, Bourne Nigel, Das Subash C, Milligan Gregg N, Barrett Alan D T, Partidos Charalambos D, Osorio Jorge E
Takeda Vaccines, Inc., Madison, WI, USA.
Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX 77555-0436, USA.
Vaccine. 2014 Nov 12;32(48):6537-43. doi: 10.1016/j.vaccine.2014.08.087. Epub 2014 Sep 17.
Dengue (DEN) is the most important mosquito-borne viral disease, with a major impact on global health and economics, caused by four serologically and distinct viruses termed DENV-1 to DENV-4. Currently, there is no licensed vaccine to prevent DEN. We have developed a live attenuated tetravalent DENV vaccine candidate (TDV) (formally known as DENVax) that has shown promise in preclinical and clinical studies and elicits neutralizing antibody responses to all four DENVs. As these responses are lowest to DENV-4 we have used the AG129 mouse model to investigate the immunogenicity of monovalent TDV-4 or tetravalent TDV vaccines, and their efficacy against lethal DENV-4 challenge. Since the common backbone of TDV is based on an attenuated DENV-2 strain (TDV-2) we also tested the efficacy of TDV-2 against DENV-4 challenge. Single doses of the tetravalent or monovalent vaccines elicited neutralizing antibodies, anti-NS1 antibodies, and cellular responses to both envelope and nonstructural proteins. All vaccinated animals were protected against challenge at 60 days post-immunization, whereas all control animals died. Investigation of DENV-4 viremias post-challenge showed that only the control animals had high viremias on day 3 post-challenge, whereas vaccinated mice had no detectable viremia. Overall, these data highlight the excellent immunogenicity and efficacy profile of our candidate dengue vaccine in AG129 mice.
登革热（DEN）是最重要的蚊媒病毒性疾病，对全球健康和经济有重大影响，由四种血清学上不同的病毒即登革病毒1型至登革病毒4型（DENV-1至DENV-4）引起。目前，尚无预防登革热的许可疫苗。我们研发了一种减毒活四价登革病毒候选疫苗（TDV）（曾用名DENVax），该疫苗在临床前和临床研究中已显示出前景，并能引发针对所有四种登革病毒的中和抗体反应。由于针对DENV-4的这些反应最低，我们使用AG129小鼠模型来研究单价TDV-4或四价TDV疫苗的免疫原性，以及它们对致死性DENV-4攻击的效力。由于TDV的共同主干基于一种减毒的DENV-2毒株（TDV-2），我们还测试了TDV-2对DENV-4攻击的效力。单剂量的四价或单价疫苗引发了中和抗体、抗NS1抗体以及针对包膜蛋白和非结构蛋白的细胞反应。所有接种疫苗的动物在免疫后60天均受到保护，免受攻击，而所有对照动物均死亡。对攻击后DENV-4病毒血症的调查显示，仅对照动物在攻击后第3天有高病毒血症，而接种疫苗的小鼠未检测到病毒血症。总体而言，这些数据突出了我们的候选登革热疫苗在AG129小鼠中具有出色的免疫原性和效力特征。
