Ebolavirus Disease
Conditions
Keywords
Ebolavirus Vaccines
Brief summary
The hemorrhagic fever resulting from Ebola infection is frequently fatal; the current Ebola outbreak, still in its ascendant phase, has a mortality rate over 50%. There is no proven therapy or prevention available at this time. The vaccine candidate VSV-ZEBOV (BPSC1001) has shown promising safety and efficacy in preventing Ebola Zaire infections in non-human primates (NHP). Before it can be assessed in large Phase IIb/3 trials in affected areas, safety data from phase 1 first-in-human trials are needed. To accelerate this process, the World Health Organization (WHO) has constituted a consortium of Clinical Research Centers in Switzerland, Germany, and Africa that will use similar protocols to collectively include roughly 250 volunteers, the sample size required to identify a 2-fold difference in anti-ZEBOV IgG antibody titers following immunization with 2 different doses of BPSC1001. The joint primary objectives of this single-center, double-blind, randomized placebo-controlled phase 1 dose-finding study are to assess the safety and tolerability of the VSV-ZEBOV vaccine when administered to healthy volunteers at a lower or higher vaccine dose and to define whether seroresponses differ significantly following immunization with the lower or higher vaccine dose.
Detailed description
This single-center, double-blind, randomized placebo-controlled phase 1 dose-finding study will have two randomization schemes. Volunteers who could later be exposed to Ebolavirus while working in epidemic areas (deployable subjects) will be randomized to receive one of two vaccine doses. Non-deployable volunteers, with no identified risk of Ebola exposure in the near term, will be allocated to one of three groups and receive the lower or higher vaccine dose, or a placebo. A single immunization will be performed. All subjects will be observed in the clinical trials unit (CTU) for 1.5 hours after vaccine/placebo injection. Subjects will complete post-injection diaries for 7 days after injection, as well as post-injection follow-up visits (see below). On-site visits at the CTU will occur on days -90 to -1, 0, 1, 3, 7, 14, 28, 84, 168. Some subjects with a positive serologic response at 24 weeks may be requested to return for immune durability testing at 12 months. One or more interim analyses will be undertaken to guide decisions on 1) the potential use of the vaccine in Ph2/3 trials in affected countries and 2) potential modification of the trial(s) through an amendment to evaluate a higher dose, if immunogenicity is poor, or a lower dose if the dosage levels selected are not safe and reasonably well tolerated.
Interventions
BIOLOGICALVSV-ZEBOV
See arm/group descriptions.
Sponsors
World Health Organization
Wellcome Trust
Universitätsklinikum Hamburg-Eppendorf
Philipps University Marburg
Albert Schweitzer Hospital
Institute of Tropical Medicine, University of Tuebingen
KEMRI-Wellcome Trust Collaborative Research Program
University Hospital, Geneva
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Has provided written informed consent before screening * Adult male or non-pregnant, non-lactating female, ages 18 to 65 (inclusive) at the time of screening * Free of clinically significant health problems, as determined by pertinent medical history and clinical examination at study screening * Females of childbearing potential who are willing to use an effective method of contraception, from at least 7 days prior to vaccination through the end of the study period, and a double method from day 0 through day 28 * Males who are willing to use effective contraception from day 0 through day 28: * Be willing to minimize blood and body fluid exposure of others for 7 days after vaccination * Use of effective barrier prophylaxis, such as latex condoms, during penetrative sexual intercourse (avoiding the sharing of needles, razors, or toothbrushes, avoiding open-mouth kissing, be willing to refrain from blood donation during the course of the study)
Exclusion criteria
* Prior receipt of an Ebolavirus or Marburgvirus vaccine, a VSV-vectored vaccine, or any other investigational vaccine likely to impact on interpretation of the trial data * Serologic evidence of prior Ebola exposure * Has a household contact (HHC) who is immunodeficient, HIV-positive, pregnant, has an unstable medical condition in the opinion of the investigator (e.g., New York Heart Association Class ≥ II heart failure, severe debilitating asthma and/or chronic obstructive pulmonary disease) * Works with livestock * History of severe local or systemic reactions to any vaccination or a history of severe allergic reactions * Known allergy to the components of the BPSC1001 vaccine product * Receipt of investigational product up to 30 days prior to enrollment or ongoing participation in another interventional clinical trial * Receipt of licensed vaccines within 14 days of planned study immunization (30 days for live vaccines) or ongoing participation in another clinical interventional trial * Acute or chronic, clinically significant psychiatric, hematologic, pulmonary, cardiovascular, or hepatic or renal functional abnormality as determined by the Investigator based on medical history, physical exam, and/or laboratory screening test * Any baseline laboratory screening tests which is outside of acceptable range as defined in the protocol: ALT, AST, creatinine, hemoglobin, platelet count, total white blood cell count, urine protein, urine occult blood, urine glucose * Serologic evidence of hepatitis C infection, evidence of active hepatitis B infection * Any confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection, asplenia, cytotoxic therapy in the previous 5 years, and/or diabetes * Any chronic or active neurologic disorder, including seizures, and epilepsy, excluding febrile seizures as a child * Has a known history of Guillain-Barré Syndrome * Has an active malignancy or recent (\< 10 years) history of metastatic or hematologic malignancy * Suspected or known alcohol and/or illicit drug abuse within the past 5 years * Pregnant or lactating female, or female who intends to become pregnant during the study period * Administration of immunoglobulins and/or any blood products within the 120 days preceding study entry or planned administration during the study period * History of blood donation within 30 days of enrollment or plans to donate within the study period * Administration of chronic (\> 14 days) immunosuppressants or other immune-modifying drugs within 6 months of study entry * Any other significant finding that, in the opinion of the investigator, would increase the risk of the individual's having an adverse outcome by participating in this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Titers of ZEBOV-specific IgG Antibodies | Day 0 - 28 | Primary immunogenicity outcome (required for dose selection) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Unsolicited Adverse Events | Days 0 - 28 | Number of participants with unsolicited adverse events in the 28 days following injection |
| Number of Participants With a Serious Adverse Event (SAE) | Days 0 - 365 | Number of participants with a serious adverse event (SAE) in the 365 days (1 year) following injection. |
| Magnitude (Copies/ml) of VSVΔG-ZEBOV Viremia | Days 1, 3 and 7 | Magnitude (copies/ml) of VSVΔG-ZEBOV viremia as expressed by median VSV RNA concentrations after vaccination. |
| Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Days 0 - 14 | Number of participants with solicited local and systemic reactogenicity signs and symptoms. Day 0 is the day of the study intervention. |
| Titers of Neutralizing ZEBOV-specific IgG Antibodies | Days 0, 28 and 168 | Geometric mean titers of neutralizing ZEBOV-specific IgG antibodies. |
| Duration of VSVΔG-ZEBOV Viremia | Days 1, 3 and 7 | Percentage of participants with any detectable viremia on days 1, 3 and 7 |
| Number of Participants in Whom Shedding of VSVΔG-ZEBOV Was Detected in Urine and/or Saliva. | Days 1, 3 and 7 | This outcome was evaluated in a subset of vaccinees. |
| Persistence of Titers of ZEBOV-specific IgG Antibodies | Day 168 | The percentage of participants maintaining positive ZEBOV-specific IgG antibody titers at 168 days after vaccination. |
Countries
Switzerland
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| VSV-ZEBOV High Dose One intramuscular (deltoid) injection of a high dose (10\^7 plaque-forming units) of VSV-ZEBOV.
VSV-ZEBOV: See arm/group descriptions. | 35 |
| VSV-ZEBOV Highest Dose One intramuscular (deltoid) injection of a highest dose (5 x 10\^7 pfu) of VSV-ZEBOV.
VSV-ZEBOV: See arm/group descriptions. | 16 |
| Placebo One intramuscular (deltoid) injection of normal saline (0.5 ml)
VSV-ZEBOV: See arm/group descriptions. | 13 |
| VSV-ZEBOV Lowest Dose Study amendment (01.2015) : One intramuscular (deltoid) injection of a markedly lower dose (3x 10\^5 plaque-forming units) of VSV-ZEBOV | 51 |
| Total | 115 |
Baseline characteristics
| Characteristic | VSV-ZEBOV High Dose | VSV-ZEBOV Highest Dose | Placebo | VSV-ZEBOV Lowest Dose | Total |
|---|---|---|---|---|---|
| Age, Continuous | 44 years | 39 years | 39 years | 40 years | 41 years |
| Region of Enrollment Switzerland | 35 participants | 16 participants | 13 participants | 51 participants | 115 participants |
| Sex: Female, Male Female | 15 Participants | 4 Participants | 7 Participants | 27 Participants | 53 Participants |
| Sex: Female, Male Male | 20 Participants | 12 Participants | 6 Participants | 24 Participants | 62 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 35 | 3 / 16 | 0 / 13 | 13 / 51 |
| serious Total, serious adverse events | 1 / 35 | 0 / 16 | 0 / 13 | 1 / 51 |
Outcome results
Primary
Titers of ZEBOV-specific IgG Antibodies
Primary immunogenicity outcome (required for dose selection)
Time frame: Day 0 - 28
Population: Note that for many analyses, volunteers vaccinated with either 10\^7 or 5x 10\^7 pfu were grouped together, as these doses were indistinguishable in immunogenicity and safety profile; see Huttner et al. Lancet Infectious Diseases 2015, Agnandji et al., NEJM 2016.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| VSV-ZEBOV 5x 10^7 OR 10^7 Pfu/ml Dose | Titers of ZEBOV-specific IgG Antibodies | 1227 ELISA units per ml |
| Placebo | Titers of ZEBOV-specific IgG Antibodies | 25 ELISA units per ml |
| VSV-ZEBOV 3x 10^5 Pfu/ml Dose | Titers of ZEBOV-specific IgG Antibodies | 344.5 ELISA units per ml |
Secondary
Duration of VSVΔG-ZEBOV Viremia
Percentage of participants with any detectable viremia on days 1, 3 and 7
Time frame: Days 1, 3 and 7
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| VSV-ZEBOV 5x 10^7 OR 10^7 Pfu/ml Dose | Duration of VSVΔG-ZEBOV Viremia | day 1 | 42 Participants |
| VSV-ZEBOV 5x 10^7 OR 10^7 Pfu/ml Dose | Duration of VSVΔG-ZEBOV Viremia | day 3 | 39 Participants |
| VSV-ZEBOV 5x 10^7 OR 10^7 Pfu/ml Dose | Duration of VSVΔG-ZEBOV Viremia | day 7 | 1 Participants |
| Placebo | Duration of VSVΔG-ZEBOV Viremia | day 1 | 6 Participants |
| Placebo | Duration of VSVΔG-ZEBOV Viremia | day 3 | 8 Participants |
| Placebo | Duration of VSVΔG-ZEBOV Viremia | day 7 | 1 Participants |
Secondary
Magnitude (Copies/ml) of VSVΔG-ZEBOV Viremia
Magnitude (copies/ml) of VSVΔG-ZEBOV viremia as expressed by median VSV RNA concentrations after vaccination.
Time frame: Days 1, 3 and 7
Population: (Note that viremia data for placebo recipients is not reported because these recipients never received vaccine, were never viremic, and thus these data were not collected in these participants.)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| VSV-ZEBOV 5x 10^7 OR 10^7 Pfu/ml Dose | Magnitude (Copies/ml) of VSVΔG-ZEBOV Viremia | VSV viremia, day 1 | 323 VSV RNA copies/ml |
| VSV-ZEBOV 5x 10^7 OR 10^7 Pfu/ml Dose | Magnitude (Copies/ml) of VSVΔG-ZEBOV Viremia | VSV viremia, day 3 (±1) | 178 VSV RNA copies/ml |
| VSV-ZEBOV 5x 10^7 OR 10^7 Pfu/ml Dose | Magnitude (Copies/ml) of VSVΔG-ZEBOV Viremia | VSV viremia, day 7 (±1) | 15 VSV RNA copies/ml |
| Placebo | Magnitude (Copies/ml) of VSVΔG-ZEBOV Viremia | VSV viremia, day 1 | 15 VSV RNA copies/ml |
| Placebo | Magnitude (Copies/ml) of VSVΔG-ZEBOV Viremia | VSV viremia, day 3 (±1) | 15 VSV RNA copies/ml |
| Placebo | Magnitude (Copies/ml) of VSVΔG-ZEBOV Viremia | VSV viremia, day 7 (±1) | 15 VSV RNA copies/ml |
Secondary
Number of Participants in Whom Shedding of VSVΔG-ZEBOV Was Detected in Urine and/or Saliva.
This outcome was evaluated in a subset of vaccinees.
Time frame: Days 1, 3 and 7
Population: Participants in whom shedding of vaccine virus (VSV) was detected in urine or saliva.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| VSV-ZEBOV 5x 10^7 OR 10^7 Pfu/ml Dose | Number of Participants in Whom Shedding of VSVΔG-ZEBOV Was Detected in Urine and/or Saliva. | 0 Participants |
| Placebo | Number of Participants in Whom Shedding of VSVΔG-ZEBOV Was Detected in Urine and/or Saliva. | 0 Participants |
| VSV-ZEBOV 3x 10^5 Pfu/ml Dose | Number of Participants in Whom Shedding of VSVΔG-ZEBOV Was Detected in Urine and/or Saliva. | 0 Participants |
Secondary
Number of Participants With a Serious Adverse Event (SAE)
Number of participants with a serious adverse event (SAE) in the 365 days (1 year) following injection.
Time frame: Days 0 - 365
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VSV-ZEBOV 5x 10^7 OR 10^7 Pfu/ml Dose | Number of Participants With a Serious Adverse Event (SAE) | 1 number of participants |
| Placebo | Number of Participants With a Serious Adverse Event (SAE) | 0 number of participants |
| VSV-ZEBOV 3x 10^5 Pfu/ml Dose | Number of Participants With a Serious Adverse Event (SAE) | 1 number of participants |
Secondary
Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms
Number of participants with solicited local and systemic reactogenicity signs and symptoms. Day 0 is the day of the study intervention.
Time frame: Days 0 - 14
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| VSV-ZEBOV 5x 10^7 OR 10^7 Pfu/ml Dose | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Erythema | 1 participants |
| VSV-ZEBOV 5x 10^7 OR 10^7 Pfu/ml Dose | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Swelling/induration | 2 participants |
| VSV-ZEBOV 5x 10^7 OR 10^7 Pfu/ml Dose | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Pain at injection site | 23 participants |
| VSV-ZEBOV 5x 10^7 OR 10^7 Pfu/ml Dose | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Objective fever | 10 participants |
| VSV-ZEBOV 5x 10^7 OR 10^7 Pfu/ml Dose | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Subjective fever | 20 participants |
| VSV-ZEBOV 5x 10^7 OR 10^7 Pfu/ml Dose | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Chills | 19 participants |
| VSV-ZEBOV 5x 10^7 OR 10^7 Pfu/ml Dose | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Myalgia | 22 participants |
| VSV-ZEBOV 5x 10^7 OR 10^7 Pfu/ml Dose | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Headache | 19 participants |
| VSV-ZEBOV 5x 10^7 OR 10^7 Pfu/ml Dose | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Fatigue | 20 participants |
| VSV-ZEBOV 5x 10^7 OR 10^7 Pfu/ml Dose | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Arthralgia | 6 participants |
| Placebo | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Fatigue | 4 participants |
| Placebo | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Erythema | 0 participants |
| Placebo | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Chills | 2 participants |
| Placebo | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Subjective fever | 2 participants |
| Placebo | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Swelling/induration | 0 participants |
| Placebo | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Arthralgia | 1 participants |
| Placebo | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Headache | 4 participants |
| Placebo | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Pain at injection site | 3 participants |
| Placebo | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Myalgia | 3 participants |
| Placebo | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Objective fever | 0 participants |
| VSV-ZEBOV 3x 10^5 Pfu/ml Dose | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Headache | 12 participants |
| VSV-ZEBOV 3x 10^5 Pfu/ml Dose | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Objective fever | 1 participants |
| VSV-ZEBOV 3x 10^5 Pfu/ml Dose | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Subjective fever | 7 participants |
| VSV-ZEBOV 3x 10^5 Pfu/ml Dose | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Chills | 14 participants |
| VSV-ZEBOV 3x 10^5 Pfu/ml Dose | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Fatigue | 24 participants |
| VSV-ZEBOV 3x 10^5 Pfu/ml Dose | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Myalgia | 14 participants |
| VSV-ZEBOV 3x 10^5 Pfu/ml Dose | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Erythema | 0 participants |
| VSV-ZEBOV 3x 10^5 Pfu/ml Dose | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Arthralgia | 5 participants |
| VSV-ZEBOV 3x 10^5 Pfu/ml Dose | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Swelling/induration | 1 participants |
| VSV-ZEBOV 3x 10^5 Pfu/ml Dose | Number of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms | Pain at injection site | 9 participants |
Secondary
Number of Participants With Unsolicited Adverse Events
Number of participants with unsolicited adverse events in the 28 days following injection
Time frame: Days 0 - 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| VSV-ZEBOV 5x 10^7 OR 10^7 Pfu/ml Dose | Number of Participants With Unsolicited Adverse Events | 11 Participants |
| Placebo | Number of Participants With Unsolicited Adverse Events | 0 Participants |
| VSV-ZEBOV 3x 10^5 Pfu/ml Dose | Number of Participants With Unsolicited Adverse Events | 13 Participants |
Secondary
Persistence of Titers of ZEBOV-specific IgG Antibodies
The percentage of participants maintaining positive ZEBOV-specific IgG antibody titers at 168 days after vaccination.
Time frame: Day 168
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| VSV-ZEBOV 5x 10^7 OR 10^7 Pfu/ml Dose | Persistence of Titers of ZEBOV-specific IgG Antibodies | 51 Participants |
| Placebo | Persistence of Titers of ZEBOV-specific IgG Antibodies | 0 Participants |
| VSV-ZEBOV 3x 10^5 Pfu/ml Dose | Persistence of Titers of ZEBOV-specific IgG Antibodies | 49 Participants |
Secondary
Titers of Neutralizing ZEBOV-specific IgG Antibodies
Geometric mean titers of neutralizing ZEBOV-specific IgG antibodies.
Time frame: Days 0, 28 and 168
Population: Note that data were ultimately not collected for days 7 and 14.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| VSV-ZEBOV 5x 10^7 OR 10^7 Pfu/ml Dose | Titers of Neutralizing ZEBOV-specific IgG Antibodies | GMT, day 0 | 4.24 Geometric mean titer |
| VSV-ZEBOV 5x 10^7 OR 10^7 Pfu/ml Dose | Titers of Neutralizing ZEBOV-specific IgG Antibodies | GMT, day 168 | 7.23 Geometric mean titer |
| VSV-ZEBOV 5x 10^7 OR 10^7 Pfu/ml Dose | Titers of Neutralizing ZEBOV-specific IgG Antibodies | GMT, day 28 | 13.24 Geometric mean titer |
| Placebo | Titers of Neutralizing ZEBOV-specific IgG Antibodies | GMT, day 0 | 4.00 Geometric mean titer |
| Placebo | Titers of Neutralizing ZEBOV-specific IgG Antibodies | GMT, day 168 | 5.86 Geometric mean titer |
| Placebo | Titers of Neutralizing ZEBOV-specific IgG Antibodies | GMT, day 28 | 16.02 Geometric mean titer |
| VSV-ZEBOV 3x 10^5 Pfu/ml Dose | Titers of Neutralizing ZEBOV-specific IgG Antibodies | GMT, day 28 | 4.11 Geometric mean titer |
| VSV-ZEBOV 3x 10^5 Pfu/ml Dose | Titers of Neutralizing ZEBOV-specific IgG Antibodies | GMT, day 0 | 4.00 Geometric mean titer |
| VSV-ZEBOV 3x 10^5 Pfu/ml Dose | Titers of Neutralizing ZEBOV-specific IgG Antibodies | GMT, day 168 | 4.54 Geometric mean titer |
| VSV-ZEBOV 3x10^5 Pfu Dose | Titers of Neutralizing ZEBOV-specific IgG Antibodies | GMT, day 0 | 4.22 Geometric mean titer |
| VSV-ZEBOV 3x10^5 Pfu Dose | Titers of Neutralizing ZEBOV-specific IgG Antibodies | GMT, day 168 | 6.12 Geometric mean titer |
| VSV-ZEBOV 3x10^5 Pfu Dose | Titers of Neutralizing ZEBOV-specific IgG Antibodies | GMT, day 28 | 14.79 Geometric mean titer |