Clinical Trials of Biodefense Vaccines (Dengue)

生物防御疫苗（登革热）的临床试验

• 批准号: 10927804
• 负责人: Stephen Whitehead
• 金额: $ 50.09万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10927804
• 关键词: Admixture; Age; Antiviral Agents; Area; Attenuated; Attenuated Vaccines; Brazil; CD8-Positive T-Lymphocytes; Cells; Child; Clinical; Clinical Research; Clinical Trials; Contracts; Cooperative Research and Development Agreement; Cyclic GMP; Dengue; Dengue Vaccine; Dengue Virus; Development; Dose; Elderly; Ensure; Evaluation; Exposure to; Flavivirus; Formulation; Goals; Human; Immune response; Immunization; India; Infant; Infection; Innate Immune Response; Intention; Intervention; Manufacturer; Medical; MicroRNAs; Modeling; Mus; National Institute of Allergy and Infectious Disease; Neurologic; Nicaragua; Phase; Phenotype; Preparation; Publications; Research; Safety; Sampling; Serotyping; Serum; T cell response; Taiwan; Technology; Testing; Tissues; Tropism; United States; Vaccination; Vaccines; Vietnam; Virus; Virus Replication; Zika Virus; Zika virus vaccine; age group; biodefense; clinical development; clinical research site; cross immunity; cross reactivity; effectiveness evaluation; immunogenic; immunogenicity; improved; neutralizing antibody; novel; panacea; pathogen; phase 3 testing; reproductive; research clinical testing; response; seropositive; vaccine candidate; vaccine development; vaccine evaluation; vaccine response

The development strategy for an effective tetravalent dengue vaccine has consisted of the clinical evaluation of monovalent vaccine candidates for each of the four serotypes with the goal of selecting suitable candidates for inclusion in a tetravalent formulation. Optimal admixtures (TV003 and TV005: DEN1del30, DEN2/4del30, DEN3del30/31, DEN4del30) have been selected and induce an unprecedented level of infectivity and neutralizing antibody in sero-naive subjects after a single dose. This vaccine response is well balanced among the serotypes and sufficient to provide protection against safety-tested challenge strains of DENV-2 and DENV-3. This indicates a significant advantage of the NIAID vaccine compared to other live attenuated DENV vaccines which require two or three doses to achieve a similar result and which require the prior exposure to DENV to ensure safety and full efficacy. The selection of an optimal tetravalent admixture has enabled the further development of the vaccine by several manufacturers located in Brazil, India, Vietnam, Taiwan and the United States. Through ongoing technological and scientific support, these licensees are making significant progress in the development of the vaccine and a Phase III has been completed in Brazil. Phase I/II studies have been completed in India and are separately sponsored by Panacea Biotec and Serum Institute of India and plans are under development for Phase III evaluations by both companies. Through our intramural clinical contract with the JHU Center for Immunization Research, numerous clinical evaluations have been successfully completed and have demonstrated that the NIAID vaccine is fully immunogenic after a single dose, elicits a well-balanced immune response across all four serotypes in DENV-nave recipients, is capable of eliciting catch-up responses for missing serotypes in DENV sero-positive recipients, is safe and immunogenic in infants and children, and elicits a strong cross-reactive CD8+ T-cell response. We have recently completed several studies and they are undergoing final analysis and preparation for publication: Safety and immunogenicity of TV005 in older adults (age 50 70 years); TV005 vaccination followed by challenge with DENV-3; TV005 vaccination followed by DENV-2 challenge after one month to investigate the use of the vaccine in travelers to DENV endemic areas; and a study in which subjects received a trivalent preparation of vaccine viruses (lacking DENV-2) and were then challenged with DENV-2 to evaluate cross-protection from DENV-1, -3, and -4. Through a CRADA with Janssen Pharmaceutica, we are using our DENV-3 controlled human infection model to evaluate the effectiveness of a novel antiviral drug at our clinical site at JHU. The development strategy for an effective live attenuated Zika virus vaccine consists of the clinical evaluation of attenuated vaccine candidates as monovalent presentations prior to their eventual combination with TV003 or TV005 tetravalent DENV vaccines to generate a pentavalent vaccine for both DENV and ZIKV. We completed our first clinical study to evaluate the safety and immunogenicity of a live-attenuated chimeric vaccine candidate rZIKV/D4del30. Although this candidate appears to be safe for use in humans, low infectivity was observed with limited immunogenicity. We have repeated the clinical trial using a higher dose inoculum, but we were unable to improve the overall infectivity and resulting immunogenicity. Additional ZIKV vaccine candidates containing microRNA targets to restrict virus replication in placental, reproductive, and neurological tissues have been produced under cGMP conditions and IND applications for their clinical evaluation are pending confirmation of cell tropism phenotypes in mice. After a protracted review period and clinical holds imposed by the FDA, the controlled human infection model for ZIKV has finally progressed to clinical safety evaluation at JHU. To date the safety profile is acceptable and the clinical endpoints have been achieved for both SJRP/2015 and Nicaragua/2015 strain without the need for additional escalation of the dose. This model will allow us to evaluate the protective capacity of a variety of ZIKV vaccines and interventions.

有效的四卫登革热疫苗的开发策略包括对四种血清型中每种候选疫苗的临床评估，目的是选择合适的候选物，以纳入四含量的配方。已经选择了最佳混合物（TV003和TV005：DEN1DEL30，DEN2/4DEL30，DEN3DEL30/31，DEN4DEL30），并在单剂剂量后引起空前的感染性和中和抗体的水平。这种疫苗反应在血清型中平衡，足以防止DENV-2和DENV-3的安全测试挑战株进行保护。这表明与其他活衰减的DENV疫苗相比，NIAID疫苗具有显着优势，这些疫苗需要两到三剂才能获得相似的结果，并且需要事先接触DENV才能确保安全性和充分效率。选择最佳的四位化混合物已使位于巴西，印度，越南，台湾和美国的几家制造商对疫苗的进一步开发。通过持续的技术和科学支持，这些被许可人在疫苗的开发中取得了重大进展，在巴西已经完成了III期。 I/II期研究已经在印度完成，并由印度Panacea Biotec和Serum Institute分别赞助，并且正在制定计划对两家公司进行III期评估。 Through our intramural clinical contract with the JHU Center for Immunization Research, numerous clinical evaluations have been successfully completed and have demonstrated that the NIAID vaccine is fully immunogenic after a single dose, elicits a well-balanced immune response across all four serotypes in DENV-nave recipients, is capable of eliciting catch-up responses for missing serotypes in DENV sero-positive recipients, is safe and immunogenic in婴儿和儿童，并引起强烈反应的CD8+ T细胞反应。 我们最近完成了几项研究，他们正在进行最终分析和出版准备：老年人TV005的安全性和免疫原性（50岁70岁）； TV005疫苗接种，然后是DENV-3的挑战； TV005疫苗接种，然后在一个月后进行DENV-2挑战，以调查在旅行者中使用疫苗到DENV流行地区的使用；以及一项研究，受试者接受了疫苗病毒（缺乏DENV-2）的三价制备，然后对DENV-2挑战以评估DENV-1，-3和-4的交叉保护。通过与Janssen Pharmaceutica的Crada，我们正在使用DENV-3受控的人类感染模型来评估我们在JHU的临床部位新型抗病毒药的有效性。 有效的活死寨卡病毒疫苗的开发策略包括临床评估衰减的疫苗候选物作为单价演示，然后在其最终与TV003或TV005 TETRAVALENT DENV疫苗结合使用之前，为DENV和ZIKV提供了Pentavalent疫苗。 我们完成了第一项临床研究，以评估活体添加的嵌合疫苗RZIKV/D4DEL30的安全性和免疫原性。 尽管该候选人似乎可以安全地用于人类，但免疫原性有限观察到低感染力。 我们已经使用较高剂量接种物重复了临床试验，但是我们无法改善总体感染力和产生的免疫原性。 在CGMP条件下，已经产生了含有microRNA靶标的含有microRNA靶标的ZIKV疫苗候选物，以限制胎盘，生殖和神经组织中的病毒复制。 经过旷日持久的审查期和FDA施加的临床持有，ZIKV的受控人类感染模型最终在JHU上发展为临床安全评估。 迄今为止，SJRP/2015和Nicaragua/2015菌株都可以接受安全性，并且已经实现了临床终点，而无需额外升级剂量。 该模型将使我们能够评估各种ZIKV疫苗和干预措施的保护能力。

项目成果

Effects of dengue immunity on Zika virus infection.

登革热免疫对寨卡病毒感染的影响。

• DOI: 10.1038/d41586-019-00868-6
• 发表时间: 2019
• 期刊: Nature
• 影响因子: 64.8
• 作者: Whitehead,StephenS;Pierson,TheodoreC
• 通讯作者: Pierson,TheodoreC

Phase 1 trial of the dengue virus type 4 vaccine candidate rDEN4{Delta}30-4995 in healthy adult volunteers.

• DOI: 10.4269/ajtmh.2009.09-0131
• 发表时间: 2009-11
• 期刊: The American journal of tropical medicine and hygiene
• 作者: Wright PF;Durbin AP;Whitehead SS;Ikizler MR;Henderson S;Blaney JE;Thumar B;Ankrah S;Rock MT;McKinney BA;Murphy BR;Schmidt AC
• 通讯作者: Schmidt AC

In a randomized trial, the live attenuated tetravalent dengue vaccine TV003 is well-tolerated and highly immunogenic in subjects with flavivirus exposure prior to vaccination.

• DOI: 10.1371/journal.pntd.0005584
• 发表时间: 2017-05
• 期刊: PLoS neglected tropical diseases
• 影响因子: 3.8
• 作者: Whitehead SS;Durbin AP;Pierce KK;Elwood D;McElvany BD;Fraser EA;Carmolli MP;Tibery CM;Hynes NA;Jo M;Lovchik JM;Larsson CJ;Doty EA;Dickson DM;Luke CJ;Subbarao K;Diehl SA;Kirkpatrick BD
• 通讯作者: Kirkpatrick BD

Using NS1 Flavivirus Protein Microarray to Infer Past Infecting Dengue Virus Serotype and Number of Past Dengue Virus Infections in Vietnamese Individuals.

• DOI: 10.1093/infdis/jiaa018
• 发表时间: 2021-06-15
• 期刊: The Journal of infectious diseases
• 作者: Thao TTN;de Bruin E;Phuong HT;Thao Vy NH;van den Ham HJ;Wills BA;Tien NTH;Le Duyen HT;Trung DT;Whitehead SS;Boni MF;Koopmans M;Clapham HE
• 通讯作者: Clapham HE

The Dengue Human Challenge Model: Has the Time Come to Accept This Challenge?

• DOI: 10.1093/infdis/jis749
• 发表时间: 2013-03-01
• 期刊: JOURNAL OF INFECTIOUS DISEASES
• 影响因子: 6.4
• 作者: Durbin, Anna P.;Whitehead, Stephen S.
• 通讯作者: Whitehead, Stephen S.