VRC 313: A Trivalent Virus-like Particle (VLP) Encephalitis Vaccine (WEVEE) in Healthy Adults

Overview

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.

Full Title of Study: “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”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Sequential Assignment
    • Primary Purpose: Prevention
    • Masking: None (Open Label)
  • Study Primary Completion Date: February 26, 2020

Detailed Description

This is a Phase 1, randomized, open-label, dose-escalation study to examine the safety, tolerability, and immune response of three doses (6 mcg, 30 mcg, and 60 mcg) of the WEVEE vaccine (VRC-WEVVLP073-00-VP) alone or with alum adjuvant (VRC-GENMIX083-AL-VP) in a 2-product administration regimen. Eligible subjects will be randomized to WEVEE alone (Groups 1, 3, and 5) or WEVEE plus alum (Groups 2, 4, and 6, respectively) in each dose group. No more than 1 subject will be randomized and vaccinated per day for the first 3 subjects at each dose. If the 6 mcg dose of WEVEE is assessed as not showing safety concerns by a Protocol Safety Review Team (PSRT), randomization will begin for Groups 3 and 4 (30 mcg WEVEE without alum and with alum, respectively). A second safety review will be conducted on the first 3 subjects to receive 30 mcg and if the 30 mcg dose of WEVEE is assessed as not showing safety concerns by the PSRT, randomization will begin for Groups 5 and 6 (60 mcg WEVEE without and with alum, respectively). The product will be administered in the upper arm muscle as an intramuscular (IM) injection via needle and syringe at Day 0 and 8 weeks later. For all Groups, solicited reactogenicity will be evaluated using a 7-day diary card. Assessment of vaccine safety will include clinical observation and monitoring of hematological and chemical parameters at clinical visits throughout the study.

Interventions

  • Biological: VRC-WEVVLP073-00-VP
    • VRC-WEVVLP073-00-VP is composed of 1:1:1 ratio of WEE, EEE, and VEE virus-like particles (VLP)
  • Other: VRC-GENMIX083-AL-VP
    • VRC-GENMIX083-AL-VP is an adjuvant

Arms, Groups and Cohorts

  • Experimental: Group 1: 6 mcg WEVEE vaccine
    • 6 mcg of WEVEE vaccine (VRC-WEVVLP073-00-VP) administered IM on Day 0 and Week 8
  • Experimental: Group 2: 6 mcg WEVEE vaccine + alum
    • 6 mcg of WEVEE vaccine (VRC-WEVVLP073-00-VP) and 500 mcg of Alum (VRC-GENMIX083-AL-VP) administered IM on Day 0 and Week 8
  • Experimental: Group 3: 30 mcg WEVEE vaccine
    • 30 mcg of WEVEE vaccine (VRC-WEVVLP073-00-VP) administered IM on Day 0 and Week 8
  • Experimental: Group 4: 30 mcg WEVEE vaccine + alum
    • 30 mcg of WEVEE vaccine (VRC-WEVVLP073-00-VP) and 500 mcg of Alum (VRC-GENMIX083-AL-VP) administered IM on Day 0 and Week 8
  • Experimental: Group 5: 60 mcg WEVEE vaccine
    • 60 mcg of WEVEE vaccine (VRC-WEVVLP073-00-VP) administered IM on Day 0 and Week 8
  • Experimental: Group 6: 60 mcg WEVEE vaccine + alum
    • 60 mcg of WEVEE vaccine (VRC-WEVVLP073-00-VP) and 500 mcg of Alum (VRC-GENMIX083-AL-VP) administered IM on Day 0 and Week 8

Clinical Trial Outcome Measures

Primary Measures

  • Number of subjects reporting local reactogenicity signs and symptoms
    • Time Frame: 7 days after each injection
    • Participant will record diameter of redness and swelling, pain/tenderness at injection site on a Diary Card. Reactogenicity will be reviewed using Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventative Vaccine Clinical Trials FDA Guidance, September 2007. The number of subjects developing each local reactogenicity symptom will be calculated for each study group.
  • Number of subjects reporting systemic reactogenicity signs and symptoms
    • Time Frame: 7 days after each injection
    • Participant will record unusual tiredness/feeling unwell, temperature, muscle aches (other than at injection site), arthralgia/joint pain, headache, chills and nausea on a paper Diary Card. Reactogenicity will be reviewed using Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventative Vaccine Clinical Trials FDA Guidance, September 2007. The number of subjects developing each systemic reactogenicity symptom will be calculated for each study group.
  • Number of subjects reporting abnormal laboratory measures of safety
    • Time Frame: Day 0 through Day 252
    • Laboratory safety measures to include CBC, differential, platelet count, ALT, creatinine at prescribed days as stated in the protocol. Institutional laboratory normals as well as the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventative Vaccine Clinical Trials FDA Guidance, September 2007 will be used. The number of subjects developing an abnormal laboratory safety measure will be calculated for each study group.
  • Number of subjects reporting 1 or more unsolicited Adverse Events (AEs)
    • Time Frame: Day 0 through 4 weeks of each study study product administration
    • Adverse events will be summarized by the study group
  • Number of subjects reporting Serious Adverse Events (SAEs)
    • Time Frame: Day 0 through Day 252
    • Serious adverse events will be summarized

Secondary Measures

  • Measure change of WEVEE-specific humoral immune response from baseline to 4 weeks after last product administration in subjects who received WEVEE without adjuvant
    • Time Frame: 4 weeks after the last product administration
    • WEVEE antigen-specific antibody responses as evaluated by virus-specific neutralization assays
  • Measure change of WEVEE-specific humoral immune response from baseline to 4 weeks after last product administration in subjects who received WEVEE with adjuvant
    • Time Frame: 4 weeks after the last product administration
    • WEVEE antigen-specific antibody responses as evaluated by virus-specific neutralization assays

Participating in This Clinical Trial

Inclusion Criteria

A subject must meet all of the following criteria:

  • Age 18 to 50 years – Available for clinical follow-up through 36 weeks after randomization – Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process – Able and willing to complete the informed consent process – Willing to donate blood for sample storage to be used for future research – In good general health, without clinically significant medical history, and has satisfactorily completed screening – Physical examination and laboratory results without clinically significant findings within the 28 days prior to randomization Laboratory Criteria within 28 days prior to randomization: – Hemoglobin within institutional normal range or accompanied by Principal Investigator (PI) or designee approval – White blood cell (WBC) and differential either within institutional normal range or accompanied by PI or designee approval – Total lymphocyte count: ≥800 cells/mm3 – Platelets: 125,000-500,000/mm3 – Alanine aminotransferase (ALT): ≤ 1.25 x upper limit of normal range – Serum creatinine: ≤1.1 x upper limit of normal – Negative for HIV infection by an FDA-approved method of detection Criteria applicable to women of childbearing potential: – Negative beta-human chorionic gonadotropin (β-HCG) pregnancy test (urine or serum) on day of randomization before receiving the study product – Agrees to use an effective method of birth control, if sexually active, from at least 21 days prior to randomization through the last study visit. Exclusion Criteria:
  • A volunteer will be excluded if one or more of the following conditions apply: Female-Specific Criteria • Breast-feeding or planning to become pregnant while participating in the study Volunteer has received any of the following:

  • More than 10 days of systemic immunosuppressive medications or cytotoxic medications within the 4 weeks prior to randomization or any within the 14 days prior to randomization – Blood products within 16 weeks prior to randomization – Immunoglobulin within 8 weeks prior to randomization – Prior vaccinations with an investigational alphavirus vaccine – Investigational research agents within 4 weeks prior to randomization or planning to receive investigational products while on study – Live attenuated vaccines within 4 weeks prior to randomization – Inactivated vaccines within 2 weeks prior initial study vaccine administration unless approved by the PI – Current anti-TB prophylaxis or therapy Subject has a history of any of the following clinically significant conditions: – A history of confirmed or suspected viral encephalitis infection – Serious reactions to vaccines that preclude receipt of study vaccinations as determined by the investigator – Hereditary angioedema, acquired angioedema, or idiopathic forms of angioedema – Asthma that is not well controlled – Diabetes mellitus (type I or type II) with the exception of gestational diabetes – Thyroid disease that is not well controlled – Hypertension that is not well controlled – Evidence of autoimmune disease or immunodeficiency – Idiopathic urticaria within the last year – Malignancy that is active or history of malignancy that is likely to recur during the study – Bleeding disorder diagnosed by a doctor (e.g., factor deficiency, coagulopathy, or platelet disorder requiring special precautions) or significant bruising or bleeding difficulties with IM product administration or blood draws – Seizure disorder other than: 1) febrile seizures, 2) seizures secondary to alcohol withdrawal more than 3 years ago, or 3) seizures or treatment for a seizure disorder within the last 3 years – Asplenia, functional asplenia or any condition resulting in absence or removal of the spleen – Psychiatric condition that precludes compliance with the protocol; past or present psychoses; or within 5 years prior to randomization, a history of suicide plan or attempt – Any other chronic or clinically significant medical, psychiatric or social condition that, in the judgement of the investigator is a contraindication to protocol participation or impairs a subject's ability to give informed consent.
  • Gender Eligibility: All

    Minimum Age: 18 Years

    Maximum Age: 50 Years

    Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

    Investigator Details

    • Lead Sponsor
      • National Institute of Allergy and Infectious Diseases (NIAID)
    • Collaborator
      • The Emmes Company, LLC
    • Provider of Information About this Clinical Study
      • Sponsor
    • Overall Official(s)
      • Julie E Ledgerwood, DO, Study Chair, VRC/NIAID/NIH
      • Grace Chen, MD, Study Chair, VRC/NIAID/NIH

    References

    Chang LJ, Dowd KA, Mendoza FH, Saunders JG, Sitar S, Plummer SH, Yamshchikov G, Sarwar UN, Hu Z, Enama ME, Bailer RT, Koup RA, Schwartz RM, Akahata W, Nabel GJ, Mascola JR, Pierson TC, Graham BS, Ledgerwood JE; VRC 311 Study Team. Safety and tolerability of chikungunya virus-like particle vaccine in healthy adults: a phase 1 dose-escalation trial. Lancet. 2014 Dec 6;384(9959):2046-52. doi: 10.1016/S0140-6736(14)61185-5. Epub 2014 Aug 14.

    Akahata W, Yang ZY, Andersen H, Sun S, Holdaway HA, Kong WP, Lewis MG, Higgs S, Rossmann MG, Rao S, Nabel GJ. A virus-like particle vaccine for epidemic Chikungunya virus protects nonhuman primates against infection. Nat Med. 2010 Mar;16(3):334-8. doi: 10.1038/nm.2105. Epub 2010 Jan 28.

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