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A Phase I Trial to Evaluate the Safety, Reactogenicity, and Immunogenicity of MVA-BN Yellow Fever Vaccine With and Without Montanide ISA-720 Adjuvant in 18-45 Year Old Healthy Volunteers

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 12, 2016 by National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT02743455
First received: April 14, 2016
Last updated: January 26, 2017
Last verified: July 12, 2016
  Purpose
This study is a multi-center, double-blind, placebo-controlled, Phase I study to evaluate the safety, reactogenicity, tolerability, and immunogenicity of MVA-BN-YF in Flavivirus-naïve healthy male and non-pregnant female adult subjects. There are six dose groups in this study. Subjects who have never received a licensed or investigational smallpox vaccine will be randomized to Groups 1-5 and vaccine administration and follow-up will be conducted in a double-blinded fashion. Subjects who have previously received two, 1 x 108 TCID50 doses of MVA-BN between 19 and 45 days apart by SC or IM routes will be enrolled in Group 6 and will be dosed open-label. Since this is a first in human, phase I study, a sentinel cohort will be utilized. The first two subjects (1st sentinel group) one at each clinical site will be randomized to Group 2 or 3 and vaccinated with MVA-BN-YF with or without ISA 720. Subjects and study personnel will be blinded as to whether ISA 720 was administered.

Condition Intervention Phase
Yellow Fever
Drug: ISA-720
Biological: MVA Smallpox Vaccine
Biological: MVA-BN Yellow Fever Vaccine
Other: Placebo
Biological: YF Vax 17D Strain
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Investigator
Primary Purpose: Prevention
Official Title: A Phase I, Double-Blind, Placebo-Controlled Trial to Evaluate the Safety, Reactogenicity, and Immunogenicity of MVA-BN Yellow Fever Vaccine With and Without Montanide ISA 720 Adjuvant in 18-45 Year Old Healthy Adults

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Comparison of grade 3 local, systemic or laboratory toxicities through Day 8 after any vaccination [ Time Frame: Days 1-8 and 29-36 ]
  • Continuous Grade 2 or greater local reactogenicity through Day 8 after any vaccination. [ Time Frame: Days 1-8 and 29-36 ]
  • Number of related AESIs [ Time Frame: Days 1-394 ]
  • Number of related SAEs [ Time Frame: Days 1-394 ]
  • Number of serious adverse events and adverse events of special interest considered related to study vaccination reported at any time after the first vaccination through the end of the study overall and in each dose group. [ Time Frame: Days 1-394 ]
  • Number of withdrawals due to any reason between dose groups [ Time Frame: Days 1-394 ]
  • Occurrence of solicited injection site and systemic reactogenicity events from the time of each study vaccination through Day 8 after each study vaccination overall and in each dose group. [ Time Frame: Days 1-8 and 29-36 ]
  • The number of subjects overall and in each dose group with new onset of a chronic medical condition at any time after the first vaccination. [ Time Frame: Days 1-394 ]
  • The number of subjects overall and in each dose group with unsolicited vaccine-related AEs from time of first vaccination through 28 days after the last vaccination. [ Time Frame: Days 1-57 ]
  • The number of vaccine-related laboratory AEs in each dose group from the time of first vaccination through 28 days after the last vaccination [ Time Frame: Days 1-57 ]

Secondary Outcome Measures:
  • Comparison of GMT (as measured by PRNT or ELISA) to MVA-BN at study D211 between subjects who received MVA-BN and one and two doses of MVA-BN-YF with or without ISA 720 (dose groups 1-4). [ Time Frame: Day 211 ]
  • Comparison of GMT (as measured by PRNT) to YF at study D211 between subjects who received YF-VAX and one and two doses of MVA-BN-YF with or without ISA 720 (dose groups 2-6). [ Time Frame: Day 211 ]
  • Comparison of GMT (as measured by PRNT) to YF at study D211 in subjects who received MVA-BN-YF between subjects previously vaccinated with MVA-BN (dose group 6) compared to subjects with no previous MVA-BN vaccination (dose groups 2-4). [ Time Frame: Day 211 ]
  • Comparison of peak GMT (as measured by PRNT or ELISA) to MVA-BN between dose groups who received MVA-BN (after two doses) and MVA-BN-YF with or without ISA 720 (dose groups 1-4). [ Time Frame: Days 1, 15, 22, 29, 36, 43, 50, 57, 211, 301 ]
  • Comparison of peak GMT (as measured by PRNT) to YF after each vaccination between dose groups who received YF-VAX or MVA-BN-YF with or without ISA-720 (dose groups 2-6). [ Time Frame: Days 1, 15, 22, 29, 36, 43, 50, 57, 211, 301 ]
  • Comparison of peak GMT (as measured by PRNT) to YF after first vaccination with MVA-BN-YF in subjects previously vaccinated with MVA-BN (dose group 6) compared to subjects with no previous MVA-BN vaccination (dose groups 2-4). [ Time Frame: Days 29, 36, 43, 50, 57, 211, 301 ]
  • Comparison of peak GMT (as measured by PRNT) to YF at any time point between dose groups who received YF-VAX or MVA-BN-YF with or without ISA-720 (dose groups 2-6). [ Time Frame: Days 1, 15, 22, 29, 36, 43, 50, 57, 211, 301 ]
  • Peak GMT (as measured by PRNT or ELISA) to MVA in dose groups 1-4 and 6. [ Time Frame: Days 1, 15, 22, 29, 36, 43, 50, 57, 211, 301 ]
  • Peak GMT (as measured by PRNT) to YF in dose groups 2-6 [ Time Frame: Days 1, 15, 22, 29, 36, 43, 50, 57, 211, 301 ]
  • Per visit GMT (as measured by PRNT) to YF in dose groups 2-6 for each post-vaccination visit [ Time Frame: Days 1, 15, 22, 29, 36, 43, 50, 57, 211, 301 ]
  • Per-visit GMT (as measured by PRNT or ELISA) to MVA in dose groups 1-4 and 6 for each post-vaccination visit. [ Time Frame: Days 1, 15, 22, 29, 36, 43, 50, 57, 211, 301 ]
  • The proportion of subjects in dose groups 1-4 seroconverting to MVA-BN for each post-vaccination visit (where seroconversion is defined as PRNT50 =/ >2 or ELISA titer =/ >50 or at least a 2-fold rise in ELISA antibody responses compared with baseline [ Time Frame: Days 1, 15, 22, 29, 36, 43, 50, 57, 211, 301 ]
  • The proportion of subjects in dose groups 2-6 seroconverting to YF for each post-vaccination visit (where seroconversion is defined as PRNT50 titer =/ >20 or at least a 4-fold increase in neutralizing antibody responses to YF compared with baseline [ Time Frame: Days 1, 15, 22, 29, 36, 43, 50, 57, 211, 301 ]

Estimated Enrollment: 90
Actual Study Start Date: July 5, 2016
Estimated Study Completion Date: December 29, 2017
Estimated Primary Completion Date: March 31, 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: (Vaccine+Placebo)MVA-BN-YF + ISA 720
MVA-BN-YF + ISA 720 1.0x10^8 TCI50 intramuscularly on day 1(Vaccine)+ day 29(Placebo), 15 subjects
Drug: ISA-720 Biological: MVA-BN Yellow Fever Vaccine Other: Placebo
Placebo
Experimental: MVA-BN
MVA-BN 1.0x10^8 TCID50 subcutaneously on days 1 and 29, 15 subjects
Biological: MVA Smallpox Vaccine
MVA (Modified Vaccinia Ankara) Smallpox Vaccine is a highly attenuated live vaccinia virus.
Experimental: MVA-BN-YF
MVA-BN-YF 1.0x10^8 TCI50 intramuscularly on days 1 and 29, 15 subjects
Biological: MVA-BN Yellow Fever Vaccine
Experimental: MVA-BN-YF + ISA 720
MVA-BN-YF + ISA 720 1.0x10^8 TCI50 intramuscularly on days 1 and 29, 15 subjects
Drug: ISA-720 Biological: MVA-BN Yellow Fever Vaccine
Experimental: MVA-BN-YF*
MVA-BN-YF 1.0x10^8 TCI50 intramuscularly on days 1 and 29, 15 subjects* *- Prior receipt of MVA-BN
Biological: MVA-BN Yellow Fever Vaccine
Experimental: YF-Vax
YF-Vax =/ > 4.74 log10 PFU subcutaneously on day 1(Vaccine)+ day 29 (Placebo), 15 subjects
Biological: YF Vax 17D Strain

Detailed Description:
This study is a multi-center, double-blind, placebo-controlled, Phase I study to evaluate the safety, reactogenicity, tolerability, and immunogenicity of MVA-BN-YF in Flavivirus-naïve healthy male and non-pregnant female adult subjects. There are six dose groups in this study. Subjects who have never received a licensed or investigational smallpox vaccine will be randomized to Groups 1-5 and vaccine administration and follow-up will be conducted in a double-blinded fashion. Subjects who have previously received two, 1 x 108 TCID50 doses of MVA-BN between 19 and 45 days apart by SC or IM routes will be enrolled in Group 6 and will be dosed open-label. Since this is a first in human, phase I study, a sentinel cohort will be utilized. The first two subjects (1st sentinel group) one at each clinical site will be randomized to Group 2 or 3 and vaccinated with MVA-BN-YF with or without ISA 720. Subjects and study personnel will be blinded as to whether ISA 720 was administered. Subjects will be monitored for safety for one day, and if no pre-defined halting rule is met (Section 9.5.1) then two additional subjects (2nd sentinel group) one at each clinical site will be assigned to the group the previous subject was not assigned to. These subjects will be vaccinated and monitored as above. A total of 4 sentinel subjects will be vaccinated. Primary objectives are assessment of the safety, tolerability, and reactogenicity of MVA-BN-YF vaccine administered with or without ISA 720; comparison of the safety, tolerability, and reactogenicity of MVA-BN-YF vaccine administered with or without ISA 720 with YF-VAX and MVA-BN. Secondary objectives are: assessment of the immunogenicity against the MVA-BN backbone and Yellow Fever virus (YF) antigen insert of MVA-BN-YF with and without ISA 720 as assessed by kinetics of the immune responses, seroconversion rates, and peak Geometric Mean Titer (GMT); assessment of the impact of previous MVA-BN vaccination on peak immune responses to YF antigen in MVA-BN-YF; comparison of the peak immunogenicity against YF antigen of 1 or 2 doses of MVA-BN-YF with or without ISA 720 with YF-VAX; comparison of the peak immunogenicity against the MVA-BN backbone of 1 or 2 doses of MVA-BN-YF with or without ISA 720 with MVA-BN; assessment of durability of immune response to YF antigen and MVA-BN at 6 months after 2nd vaccination or placebo administration.
  Eligibility

Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

1. Must be a male or female at least 18 to </=45 years old at the time of screening. 2. Must be able to read and provide written consent and complete the Informed Consent. 3. Must have a body mass index (BMI) >/=18.5 and <35.0 kg/m2. 4. Must be in good health on the basis of physical examination, vital signs, medical history, safety laboratories, and the investigator's clinical judgment. Safety laboratory normal ranges will be those used by the reference clinical lab. Protocol-specific criteria for individual subjects are listed in criteria #6 -The clinical laboratory evaluations that will be graded as laboratory AEs and be considered for the Study or Individual Halting Rules are those which are included in the laboratory toxicity grading scales (Section 9.2.3). -Vital signs must be in normal ranges as per Sections 9.2.2 and 9.2.3. If a subject has elevated systolic or diastolic blood pressure, subject may rest for 10 minutes in a quiet room and then the blood pressure may be retaken once. 5. For Group 6: subjects must have documented previous vaccination with MVA-BN. In order to be enrolled, a subject has to have received two 1 x 10^8 TCID50 doses of MVA-BN 19-45 days apart SC or IM as part of participation in DMID vaccine trials 11-0021 or 09-0002. First dose must have been administered no earlier than 2010. 6.Must have acceptable laboratory criteria within 28 days before enrollment. Acceptable lab parameters include: -Hemoglobin: women: >11.0 g/dL; men >12.5 g/dL -White blood cell count: >3,700 cells/mm3but <11,000 cells/mm3 -Platelets: >125,000 but <375,000 per mm3 -Urine dipstick (clean urine sample): protein <1+, glucose negative -Alanine aminotransferase and aspartate aminotransferase (ALT, AST) <1.25 x institutional upper limit of normal -Blood urea nitrogen (BUN) </=1 x institutional upper limit of normal -Total bilirubin <1.25x institutional upper limit of normal. Serum creatinine </=1 x institutional upper limit of normal -If laboratory screening tests are out of range, repeat of screening tests is permitted once, provided there is an alternative explanation for the out of range value. 7. Women of childbearing potential must have a negative serum pregnancy test at screening and negative urine pregnancy tests prior to each vaccination. 8. Women of childbearing potential must have an acceptable method of contraception from 28 days prior to the 1st vaccination until at least 60 days after the 2nd vaccination. Acceptable methods of contraception include the following: -Prescription oral contraceptives, contraceptive injections, intrauterine device (IUD), implants, vaginal ring, double-barrier method, contraceptive patch, male partner sterilization, abstinence ((defined as refraining from heterosexual intercourse during participation in the study [from 28 days before the first vaccination until at least 60 days after the last vaccination]). Women of non-childbearing potential, defined as postmenopausal (any age with amenorrhea for = / >12 months without other known or suspected cause for amenorrhea, or surgically sterile (hysterectomy, bilateral tubal ligation, obilateral oophorectomy, or successful Essure® placement (permanent, non-surgical, non-hormonal sterilization) with documented confirmation test at least 3 months after the procedure), are not required to use the birth control methods. 9. Female subjects must agree to not donate eggs (ova, oocytes) from the start of screening onwards until at least 60 days after the last vaccination. 10. Male subjects who have not had a vasectomy and is sexually active with a woman of childbearing potential must agree to use an acceptable measure of birth control from 28 days prior to 1st vaccination until at least 60 days after the last vaccination. Acceptable methods of birth control include the following: - Abstinence (defined as refraining from heterosexual intercourse with a female partner of childbearing potential during participation in the study [from 28 days before the first vaccination until at least 60 days after the last vaccination]. -A double-barrier method of birth control, such as condom with spermicidal foam/gel/film/cream/suppository and partner with occlusive cap (diaphragm, cervical/vault caps). -In case the female partner is using an acceptable method of birth control (see Inclusion Criterion #8), a single-barrier method of birth control for the male subject is acceptable. 11. Male subjects must agree to not donate sperm from the start of screening onwards until at least 60 days after the last vaccination. 12. Must be available and willing to participate for the duration of the study visits and follow-up. 13. Must have a means to be contacted by telephone.

Exclusion Criteria:

1. Was ever vaccinated with a licensed or investigational YF vaccine or was diagnosed with YF infection or disease. Includes YF-VAX, Stamaril, or Bio-Manguinhos yellow fever vaccine. Subject's verbal history will suffice. 2. Was ever vaccinated with a licensed or investigational Flavivirus vaccine. Including Japanese encephalitis virus (JEV) vaccine or an investigational Flavivirus vaccine including dengue virus (DENV) or West Nile virus vaccine, or has been diagnosed with an illness caused by a Flavivirus including DENV, West Nile virus (WNV), JEV, St. Louis encephalitis, or tick-borne encephalitis virus (TBEV). Subject's verbal history will suffice. 3. Positive serology for HIV, Hepatitis C virus, or Hepatitis B surface antigen. 4. Positive serology to Dengue, Yellow Fever, or West Nile virus. 5. Plans to travel to a Yellow-Fever endemic area during the course of the study or travel to a Yellow-Fever endemic area within 30 days of screening. Subjects who have a recent travel to a Yellow Fever endemic area may screen if they have returned to the U.S. 30 or more days prior to the screening visit. Refer to the CDC Yellow Fever map for countries/regions at risk for Yellow Fever virus infection. http://www.cdc.gov/yellowfever/maps/ 6. Was ever vaccinated with a licensed or investigational smallpox vaccine with the exception of subjects in Group 6. Includes Dryvax, Acam2000, LC 16 m8, MVA - based vaccine candidate or licensed vaccines, and Imvamune or Imvanex. EXCEPTION: Group 6 should have had two 1 x 10e 8 TCID 50 doses of MVA - BN 19 - 45 days apart SC or IM as part of participation in DMID vaccine trials 11-0021 or 09-0002. First dose must have been administered no earlier than 2010. 7. Has known allergy or history of anaphylaxis or other serious adverse reaction to a vaccine or vaccine products. Including egg products, aminoglycosides, gelatin, sorbitol, tris (hydroxymethyl)-amino methane (THAM), or any of the constituents of the study vaccines. 8. Has severe allergy or anaphylaxis to latex.Participants in Group 6 will not be exposed to latex and so may have history of severe allergy or anaphylaxis to latex. 9. Has an acute illness or temperature > / =38.0ºC on Day 1 or Day 29. Subjects with fever or acute illness on the Day of vaccination may be re-assessed and enrolled if healthy or only minor residual symptoms remain within 3 days. 10. Female subjects who are pregnant or breast-feeding, or planning to become pregnant while enrolled in the study. 11. Has history of chronic or acute severe neurologic condition. Including history of seizure disorder or epilepsy, history of Guillain-Barre syndrome, Bell's palsy, meningitis, or disease with any focal neurologic deficits. 12. Has history of thymus disorder including myasthenia gravis, thymoma or prior thymectomy. 13. Has history of autoimmune disease or or clinically significant cardiac, pulmonary, hepatic, rheumatologic, or renal disease by history, physical examination, and/or laboratory studies*. *Includes the conditions and diagnoses defined as AESI in Section 9.3.4 14. Has history of malignancy other than squamous cell or basal cell skin cancer, unless there has been surgical excision that is considered to have achieved cure. Subjects with a history of skin cancer must not be vaccinated at the previous tumor site. 15. Has known or suspected congenital or acquired immunodeficiency, or recent history or current use of immunosuppressive therapy. Anti-cancer chemotherapy or radiation therapy within the preceding 6 months, or long-term (at least 2 weeks within the previous 3 months) systemic corticosteroids therapy (at a dose of at least 0.5 mg/kg/d ay). Intranasal or topical prednisone (or equivalent) are allowed. 16. Is post-organ and/or stem cell transplant whether or not on chronic immunosuppressive therapy. 17.Had major surgery (per the investigator's judgment) within the 4 weeks prior to study entry or planned major surgery during the course of the study. 18.Has personal history of recurring migraines (every 6 months or more often) or on prescription medication for treatment of recurring headaches or migraines. 19.Has history of cardiac disease. Myocarditis, pericarditis, cardiomyopathy, transient ischemic attack or stroke, myocardial infarction, angina, coronary artery disease, congestive heart failure, clinically significant arrhythmia. Includes any arrhythmia requiring medication, treatment, or clinical follow-up. 20. Has electrocardiogram (ECG) with clinically significant findings, or features that would interfere with the assessment of myocarditis/pericarditis. Including any of the following: -Conduction disturbance (complete left or complete right bundle branch block or nonspecific intraventricular conduction disturbance with QRS = / >120 ms, PR interval >219 ms, any second-or third-degree atrioventricular block, or prolongation of the QT interval corrected according to Bazett's formula [QTcB] [>450 ms]) -Significant repolarization (ST-segment or T-wave) abnormality. -Significant atrial or ventricular arrhythmia; frequent atrial or ventricular ectopy (e.g., frequent premature atrial contractions, 2 premature ventricular contractions in a row). -ST-elevation consistent with ischemia or evidence of past or evolving myocardial infarction. 21. Has history of diabetes mellitus type 1 or type 2, including cases controlled with diet alone. Note: history of isolated gestational diabetes is not an exclusion criterion. 22. Has history of thyroidectomy, or thyroid disease requiring medication during the last 12 months. 23.Has history of hypertension even if medically controlled. -Note: Vital signs must be normal by protocol toxicity grading scale or determined to be normal-variant by investigator. In the event of an abnormal heart rate or blood pressure due to physiological variation or activity, the subject may rest for 10 minutes in a quiet room, and then blood pressure and/or heart rate may be re-measured. Repeated vital signs may be used to determine eligibility. 24. Received live attenuated vaccines from 30 days before Day 1 until 30 days after the 2nd vaccination. 25. Received killed or inactivated vaccines from 14 days before Day 1 until 14 days after the 2nd vaccination. 26. Received experimental therapeutic agents within 3 months prior to the first study vaccination or plans to receive any experimental therapeutic agents during the course of the study. 27. Is currently participating or plans to participate in another clinical study which would involve receipt of the following: An investigational product, blood drawing, or an invasive medical procedure that would require administration

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02743455

Contacts
Contact: Sarah L George 13149779035 georgesl@slu.edu

Locations
United States, Iowa
University of Iowa - Vaccine Research and Education Unit Recruiting
Iowa City, Iowa, United States, 52242-2600
United States, Missouri
Saint Louis University - Center for Vaccine Development Recruiting
Saint Louis, Missouri, United States, 63104-1015
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
  More Information

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT02743455     History of Changes
Other Study ID Numbers: 14-0107
HHSN272200800003C
Study First Received: April 14, 2016
Last Updated: January 26, 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Fever
Immunogenicity
MVA-BN
Reactogenicity
Vaccine
Yellow

Additional relevant MeSH terms:
Fever
Yellow Fever
Body Temperature Changes
Signs and Symptoms
Arbovirus Infections
Virus Diseases
Flavivirus Infections
Flaviviridae Infections
RNA Virus Infections
Hemorrhagic Fevers, Viral
Vaccines
Mannitol
Immunologic Factors
Physiological Effects of Drugs
Diuretics, Osmotic
Diuretics
Natriuretic Agents

ClinicalTrials.gov processed this record on May 23, 2017