A Phase 1 Open Label, Dose-Escalation Clinical Trial to Evaluate the Safety and Immunogenicity of a Trivalent Virus-Like Particle (VLP) Encephalitis Vaccine, VRC-WEVVLP073-00-VP, in Healthy Adults

Western Equine Encephalitis Virus (WEEV), Eastern Equine Encephalitis Virus (EEEV), and Venezuelan Equine Encephalitis Virus (VEEV) are transmitted to humans by infected mosquitoes and can cause encephalitis (swelling of the brain) and other neurological manifestations, including fever, chills, discomfort, feeling sick, muscle pain and then headache, vomiting, restlessness, irritability, seizures, coma, and death.
Vaccines teach the body to prevent or fight an infection. When the body learns to fight an infection, this is called an immune response. Researchers developed a vaccine against Western, Eastern and Venezuelan equine encephalitis viruses to help the body make an immune response. There are no live or killed viruses in the vaccine, so you cannot get infected with any of these 3 viruses from getting the vaccine.
The experimental trivalent encephalitis vaccine, VRC-WEVVLP073-00-VP, is composed of Western equine encephalitis (WEE), Eastern equine encephalitis (EEE), and Venezuelan equine encephalitis (VEE) virus-like particles (VLP).
The purpose of this study is to test three doses (6 mcg, 30 mcg, and 60 mcg) of this experimental vaccine against Western, Eastern and Venezuelan equine encephalitis viruses.

开始日期2019-04-02

申办/合作机构

National Institute of Allergy & Infectious Diseases

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项与 VRC-WEVVLP073-00-VP(National Institute of Allergy & Infectious Diseases) 相关的文献（医药）

2022-08-01·The Lancet Infectious Diseases1区 · 医学

Safety and immunogenicity of a trivalent virus-like particle vaccine against western, eastern, and Venezuelan equine encephalitis viruses: a phase 1, open-label, dose-escalation, randomised clinical trial

1区 · 医学

Article

作者: Strom, Larisa ; Ledgerwood, Julie E ; Lankford-Turner, Pamela ; Larkin, Brenda ; Vazquez, Sandra ; Carter, Cristina ; Lai, Lilin ; Alger, Mandy ; Mascola, John R ; Coates, Emily E ; Fernald, Alissa ; Florez, Maria Burgos ; Burch, Gena ; Phadke, Varun ; Yamshchikov, Galina ; Nguyen, Thuy ; Rosales-Zavala, Erwin ; Fredrick, Rameses ; Sherman, Amy ; Dennis, Renata ; Weng, Shaojie ; Chen, Grace L ; Rouphael, Nadine ; Butler, Ellie ; Yi, Sha ; Edupuganti, Srilatha ; Kaltovich, Florence ; Demirji, Jacob ; Bray, Amy ; Stein, Judy ; Gupta, Shanker ; Xu, Jianguo ; Ola, Abidemi ; Widge, Alicia ; Winter, Jean ; Liu, Jie ; Kueltzo, Lisa ; Holland-Linn, Janel ; Liang, C Jason ; Lynch Chamberlain, Amy ; Bahorich, Jessica ; Yang, Fan ; Carlton, Kevin ; Wang, Xin ; Curate-Ingram, Sharon ; Sands, Jason ; Kelley, Colleen ; Taylor, Stephanie ; Chaudhuri, Rajoshi ; Witter, Sara ; Lee, James ; Case, Christopher L ; O'Connell, Sarah ; Cox, Josephine H ; Plummer, Sarah ; Chang, Ya-chen ; Cooper, Jonathan ; Nagar, Shashi ; Fineman, Rebecca ; Berkowitz, Nina ; Alvarez, Alicarmen ; Happe, Myra ; Morgan, Patricia ; Gollapudi, Deepika ; Collins, Matthew H ; Liu, Xun ; Whitney, Cynthia ; Mowery, Rachel ; Wycuff, Diane ; Gordon, Ingelise ; Beck, Allison ; Andrews, Charla

BACKGROUNDWestern (WEEV), eastern (EEEV), and Venezuelan (VEEV) equine encephalitis viruses are mosquito-borne pathogens classified as potential biological warfare agents for which there are currently no approved human vaccines or therapies. We aimed to evaluate the safety, tolerability, and immunogenicity of an investigational trivalent virus-like particle (VLP) vaccine, western, eastern, and Venezuelan equine encephalitis (WEVEE) VLP, composed of WEEV, EEEV, and VEEV VLPs.METHODSThe WEVEE VLP vaccine was evaluated in a phase 1, randomised, open-label, dose-escalation trial at the Hope Clinic of the Emory Vaccine Center at Emory University, Atlanta, GA, USA. Eligible participants were healthy adults aged 18-50 years with no previous vaccination history with an investigational alphavirus vaccine. Participants were assigned to a dose group of 6 μg, 30 μg, or 60 μg vaccine product and were randomly assigned (1:1) to receive the WEVEE VLP vaccine with or without aluminium hydroxide suspension (alum) adjuvant by intramuscular injection at study day 0 and at week 8. The primary outcomes were the safety and tolerability of the vaccine (assessed in all participants who received at least one administration of study product) and the secondary outcome was immune response measured as neutralising titres by plaque reduction neutralisation test (PRNT) 4 weeks after the second vaccination. This trial is registered at ClinicalTrials.gov, NCT03879603.FINDINGSBetween April 2, 2019, and June 13, 2019, 30 trial participants were enrolled (mean age 32 years, range 21-48; 16 [53%] female participants and 14 [47%] male participants). Six groups of five participants each received 6 μg, 30 μg, or 60 μg vaccine doses with or without adjuvant, and all 30 participants completed study follow-up. Vaccinations were safe and well tolerated. The most frequently reported symptoms were mild injection-site pain and tenderness (22 [73%] of 30) and malaise (15 [50%] of 30). Dose-dependent differences in the frequency of pain and tenderness were found between the 6 μg, 30 μg, and 60 μg groups (p=0·0217). No significant differences were observed between dosing groups for any other reactogenicity symptom. Two adverse events (mild elevated blood pressure and moderate asymptomatic neutropenia) were assessed as possibly related to the study product in one trial participant (60 μg dose with alum); both resolved without clinical sequelae. 4 weeks after second vaccine administration, neutralising antibodies were induced in all study groups with the highest response seen against all three vaccine antigens in the 30 μg plus alum group (PRNT₈₀ geometric mean titre for EEEV 60·8, 95% CI 29·9-124·0; for VEEV 111·5, 49·8-249·8; and for WEEV 187·9, 90·0-392·2). Finally, 4 weeks after second vaccine administration, for all doses, the majority of trial participants developed an immune response to all three vaccine components (24 [83%] of 29 for EEEV; 26 [90%] of 29 for VEEV; 27 [93%] of 29 for WEEV; and 22 [76%] of 29 for EEEV, VEEV, and WEEV combined).INTERPRETATIONThe favourable safety profile and neutralising antibody responses, along with pressing public health need, support further evaluation of the WEVEE VLP vaccine in advanced-phase clinical trials.FUNDINGThe Vaccine Research Center of the National Institute of Allergy and Infectious Diseases, National Institutes of Health funded the clinical trial. The US Department of Defense contributed funding for manufacturing of the study product.

2022-06-01·International Journal of Pharmaceutics2区 · 医学

Dendritic cell activation by a micro particulate based system containing the influenza matrix-2 protein virus-like particle (M2e VLP)

2区 · 医学

Article

作者: Kang, Sang-Moo ; Allotey-Babington, Grace Lovia ; D'Souza, Martin J ; D'Sa, Sucheta ; Gomes, Kimberly Braz

M2e VLP was previously described as a vaccine that incorporates the extracellular region of the matrix 2 protein (M2e), which is highly conserved amongst all the strains of influenza. In this study, we analyzed activation status of dendritic cells (DCs) after exposure to M2e VLP, stimulating DCs with M2e VLP and co-culturing the stimulated DCs with T cells to observe innate and adaptive immune responses. The M2e VLP microparticle was prepared by encapsulating into a polymer matrix using the one-step spray drying method. Adjuvants Alhydrogel®, MPL-A® or Addavax^TM were used to enhance the DC stimulatory effects by the M2e VLP microparticle. The M2e VLP microparticle yield was found to be 92% and the encapsulation yield was around 84% with a size of approximately 2.78 μm. There was no short-term cytotoxicity found in DCs and macrophages with concentrations up to 1500 μg/mL of M2e VLP microparticle, however long-term exposure resulted in 25% decrease in viability of cells with concentrations more than or equal to 500 μg/mL. The M2e VLP microparticle vaccine with Alhydrogel® and MPL-A® induced high levels of TNFα in both DCs and macrophages. The high levels of MHC I, II, CD28, B7-1, ICAM-1, LFA-1 expression and IL-12 release in the M2e VLP microparticle group with Alhydrogel® suggests that the M2e VLP vaccine with this adjuvant activated T cells via the Th2 pathway. The increased expression of MHC I, II, CD40, CD154, ICAM-1 and LFA-1 on DCs and the release of IL-12 in the M2e VLP microparticle culture of DCs with MPL-A® demonstrated that the M2e VLP vaccine with this adjuvant activated T cells via the Th1 pathway. The decrease in fluorescence in the Alhydrogel® and MPL-A® group illustrates the proliferation of T cells took place following exposure of DCs to the M2e VLP microparticle with these adjuvants. The M2e VLP microparticle exhibited higher stimulatory responses of DCs than the M2e VLP in suspension. Furthermore, the presence of Alhydrogel® and MPL-A® enhanced the stimulatory effects of DCs by the M2e VLP microparticle (MP) vaccine.

Virology Journal

VLPs containing stalk domain and ectodomain of matrix protein 2 of influenza induce protection in mice

Article

作者: Feng, Hao ; Sun, Xianliang ; Shi, Lili ; Zhu, Yanyan ; Chen, Yan ; Dong, Jingjian ; Long, Ying

AbstractBackgroundAs a result of antigenic drift, current influenza vaccines provide limited protection against circulating influenza viruses, and vaccines with broad cross protection are urgently needed. Hemagglutinin stalk domain and ectodomain of matrix protein 2 are highly conserved among influenza viruses and have great potential for use as a universal vaccine.MethodsIn this study, we co-expressed the stalk domain and M2e on the surface of cell membranes and generated chimeric and standard virus-like particles of influenza to improve antigen immunogenicity. We subsequently immunized BALB/c mice through intranasal and intramuscular routes.ResultsData obtained demonstrated that vaccination with VLPs elicited high levels of serum-specific IgG (approximately 30-fold higher than that obtained with soluble protein), induced increased ADCC activity to the influenza virus, and enhanced T cell as well as mucosal immune responses. Furthermore, mice immunized by VLP had elevated level of mucosal HA and 4M2e specific IgA titers and cytokine production as compared to mice immunized with soluble protein. Additionally, the VLP-immunized group exhibited long-lasting humoral antibody responses and effectively reduced lung viral titers after the challenge. Compared to the 4M2e-VLP and mHA-VLP groups, the chimeric VLP group experienced cross-protection against the lethal challenge with homologous and heterologous viruses. The stalk domain specific antibody conferred better protection than the 4M2e specific antibody.ConclusionOur findings demonstrated that the chimeric VLPs anchored with the stalk domain and M2e showed efficacy in reducing viral loads after the influenza virus challenge in the mice model. This antibody can be used in humans to broadly protect against a variety of influenza virus subtypes. The chimeric VLPs represent a novel approach to increase antigen immunogenicity and are promising candidates for a universal influenza vaccine.

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适应症	最高研发状态	国家/地区	公司	日期
东部马脑脊髓炎	药物发现	美国	National Institute of Allergy & Infectious Diseases	2019-04-02
委内瑞拉马脑脊髓炎	药物发现	美国	National Institute of Allergy & Infectious Diseases	2019-04-02
西马脑炎病毒感染	药物发现	美国	National Institute of Allergy & Infectious Diseases	2019-04-02

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03879603 (VRC 313, CTgov)	临床1期	西马脑炎病毒感染 \| 东部马脑脊髓炎 \| 委内瑞拉马脑脊髓炎	30	VRC-WEVVLP073-00-VP (Group 1: 6 mcg WEVEE Vaccine)	鏇製鑰衊襯製顧獵簾願(夢製夢淵夢網艱鬱選壓) = 繭齋構簾構壓遞觸簾鏇糧顧鬱鏇製艱齋蓋鹹網 (膚觸鏇積憲窪網衊積鏇, 構鏇鬱鬱鑰廠糧廠夢艱 ~ 鹽憲選夢遞窪襯鹹齋網) 更多	-	2021-03-19
				VRC-GENMIX083-AL-VP+VRC-WEVVLP073-00-VP (Group 2: 6 mcg WEVEE Vaccine + Alum)	鏇製鑰衊襯製顧獵簾願(夢製夢淵夢網艱鬱選壓) = 廠顧繭壓鏇淵願積願壓糧顧鬱鏇製艱齋蓋鹹網 (膚觸鏇積憲窪網衊積鏇, 窪鏇衊鹽繭顧積糧艱獵 ~ 艱積窪壓範範遞夢蓋襯) 更多