Hemorrhagic Fever, Ebola
Conditions
Keywords
Ebola, Sierra Leone, vaccine, rVSVΔG-ZEBOV
Brief summary
The 2014 outbreak of Ebola in West Africa is the largest in recorded history with widespread and intense transmission in Guinea, Liberia, and Sierra Leone. The high infectivity of blood and secretions, lack of appropriate personal protective equipment (PPE) and challenges in following infection control and prevention protocols put healthcare workers at high risk during outbreaks, and direct contact with the bodies of deceased Ebola victims can also sustain community transmission. This study will accelerate introduction and use of monovalent recombinant vesicular stomatitis virus Ebola vaccine (rVSVΔG-ZEBOV) among healthcare workers and frontline personnel involved in the Ebola outbreak response in Sierra Leone, while concurrently evaluating the safety and efficacy of the vaccine. This is an unblinded, randomized trial with phased vaccine introduction in the target population. Participation in the study will be voluntary and open to adults 18 years of age and older who are at high risk of exposure to Ebola infection through their daily work and who work in a selected study area.
Detailed description
The Ebola outbreak was confirmed in March 2014 with widespread and intense transmission in Guinea, Liberia, and Sierra Leone. While there are no U.S. Food and Drug Administration (FDA)-approved pharmaceuticals to prevent or treat Ebola, two candidate vaccines are being tested in humans for dosing, tolerability, and safety. This study will evaluate monovalent recombinant vesicular stomatitis virus Ebola vaccine that remains replication competent (rVSVΔG-ZEBOV) in Sierra Leone. The high infectivity of blood and secretions, lack of appropriate personal protective equipment (PPE) and challenges in following infection control and prevention protocols put healthcare workers at high risk during outbreaks, and direct contact with the bodies of deceased Ebola victims can also sustain community transmission. This unblinded, randomized trial will evaluate vaccine efficacy (VE) and safety with phased vaccine introduction in the target population. Participation in the study will be voluntary and open to adults 18 years of age and older who are at high risk of exposure to Ebola infection through their daily work and who work in a selected study area. This includes: 1) personnel working in healthcare facilities where care is provided for Ebola patients; 2) personnel working in non-Ebola healthcare facilities who may have exposure to undiagnosed Ebola-infected individuals; and 3) personnel working in one of the following job categories: surveillance team, ambulance team, or laboratory worker responsible for swabbing deceased persons. Staff members involved in this study are also eligible to receive the vaccine under this protocol; study staff will be followed for 6 months post-vaccination to monitor for safety of rVSVΔG-ZEBOV. Eligible participants within a healthcare facility or frontline team will be enrolled and individually randomized to either immediate or deferred vaccination. A single dose of rVSVΔG-ZEBOV will be administered intramuscularly. Immediate vaccination is defined as vaccination within 7 days of enrollment and deferred vaccination is defined as vaccination at the end of an 18-24 week follow-up period. Participants will not be blinded to the randomized assignment of immediate or deferred vaccination. All enrolled participants will have the opportunity to receive rVSVΔG-ZEBOV by the end of the study. Enrollment and vaccination will be phased over time. Ebola events that occur during the 18-24 week post-enrollment will be included in the VE analysis, with the immediate vaccination arm contributing vaccinated follow-up time and the deferred vaccination arm contributing unvaccinated follow-up time. All participants, regardless of randomized assignment, will be followed for 6 months after vaccination to monitor for safety of rVSVΔG-ZEBOV.
Interventions
BIOLOGICALrVSVΔG-ZEBOV
The rVSVΔG-ZEBOV vaccine is comprised of a single recombinant VSV isolate (11481 nontypeable) modified to replace the gene encoding the G envelope GP with the gene encoding the envelope GP from ZEBOV (Kikwit, 1995 strain).
Sponsors
University of Sierra Leone
Ministry of Health and Sanitation, Sierra Leone
Department of Health and Human Services
eHealth Africa
Centers for Disease Control and Prevention
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Age 18 years or older. 2. Member of target population at the time of enrollment: * active worker in an Ebola care, holding, or treatment center (may include physicians, nurses, nurse aides, lab technicians, pharmacists, pharmacy technicians, cleaners, and security and administrative staff); * active worker in a facility providing non-Ebola-related healthcare (may include physicians, nurses, nurse aides, lab technicians, pharmacists, pharmacy technicians, cleaners, and security and administrative staff); * active frontline worker in one of the following job categories: surveillance team, ambulance team, burial worker, or worker responsible for swabbing deceased persons. 3. Reasonably anticipates living in Sierra Leone for the 18-24 weeks following enrollment. 4. Reachable by phone throughout the 6 month post-vaccination safety follow-up period. 5. Willing to adhere to personal protective equipment (PPE) and infection control recommendations. 6. Able and willing to complete the informed consent process and study procedures. 7. Willing to receive vaccine in either the immediate or the deferred trial arms, according to random assignment.
Exclusion criteria
1. History of Ebola (self-report). 2. Prior receipt of experimental Ebola or Marburg vaccine. 3. History of human immunodeficiency virus (HIV) or clinically important immunodeficiency (self-report). 4. Any history of allergy or anaphylaxis to prior vaccines 5. Breast-feeding an infant or child. 6. Any reason the investigator suspects that data collected from this person would be incomplete or of poor quality. 7. Current pregnancy (a negative urine pregnancy test is required for women participants \<50 years of age who self-report as not pregnant). 8. Currently being followed for known exposure to Ebola. 9. Known experimental research agents or other vaccine within 28 days (4 weeks) before vaccination. 10. Fever ≥ 38.0°C (100.4°F) at time of vaccination.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Laboratory-confirmed Ebola (Study Diagnostics) | > 21 days following vaccination | Incidence of Ebola confirmed by the STRIVE study laboratory in each treatment group during the Randomized Portion of the trial. For the vaccine efficacy endpoint, all enrolled participants in both arms were followed for 18-24 weeks after enrollment (after which point participants in the deferred cohort received crossover vaccination). Statistical analysis was to proceed as survival analysis (time-to-event/time-to-infection) of cohort follow-up data during this period. There were no laboratory-confirmed cases of Ebola among study participants, so therefore no efficacy analyses were performed. |
| Number of Participants With Occurrence of Serious Adverse Events During the 6 Months Following the Vaccination | 6 months following vaccination | Number of Participants with Occurrence of SAEs within the 6-month follow-up period following a single dose of rVSVΔG-ZEBOV. Vaccination in the immediate group occurred within 7 days of enrollment if possible, and vaccination in the deferred-vaccination group occurred 18-24 weeks after enrollment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Suspected, Probable or Laboratory-confirmed Ebola | 6 months following vaccination | Incidence of suspected, probable, or laboratory-confirmed Ebola, where suspected and probable cases are defined by the August 9, 2014 World Health Organization case definition recommendations for use during an Ebola outbreak, and laboratory-confirmed Ebola includes both study laboratory and non-study laboratory diagnostics. An Ebola Screening Form was required to be completed for all participants referred for evaluation of suspected Ebola; the Outcome Measure (Count of Participants) reflects the number of participants in each group for whom an Ebola Screening Form was completed. |
| Death Due to Laboratory-confirmed Ebola | 6 months following vaccination | Deaths due to Ebola confirmed by the STRIVE study laboratory in each treatment group during the Randomized Portion of the trial. There were no laboratory-confirmed cases of Ebola among study participants, so therefore no efficacy analyses were performed. |
| Number of Participants With Occurrence of Solicited and Unsolicited AEs During the 28 Days Following the Vaccination or Enrollment | During 28 days following vaccination | Solicited local and systemic reactogenicity symptoms and unsolicited adverse events were assessed in safety sub-study participants (the first 449 participants enrolled at the COMAHS Library site), during the 28 days after vaccination (immediate group) or after enrollment without vaccination (deferred group). |
| Number of Participants With Occurrence of Solicited Injection-site and Systemic Reactogenicity Signs and Symptoms, Including Fever, on Vaccination Day and During the 7 Days Following the Vaccination or Enrollment. | Vaccination day and for 7 days following vaccination | Solicited symptoms were assessed only in safety sub-study participants (the first 449 participants enrolled at the COMAHS Library site), during the 7 days after vaccination (immediate group) or after enrollment without vaccination (deferred group). Participants were actively solicited for the occurrence of local (injection-site) pain, redness, and swelling and the following systemic reactogenicity symptoms: fever, joint pain, joint swelling, muscle pain, fatigue, feeling unwell, chills, headache, vomiting, nausea, diarrhea, abdominal pain, rash, oral ulcers, and skin vesicles (blisters). |
| Ebola Confirmed by Non-study or Study Diagnostics | 6 months following vaccination | Incidence of Ebola confirmed by the STRIVE study laboratory or by a non-study laboratory in each treatment group during the Randomized Portion of the trial. For the vaccine efficacy endpoint, all enrolled participants in both arms were followed for 18-24 weeks after enrollment (after which point participants in the deferred cohort received crossover vaccination). Statistical analysis was to proceed as survival analysis (time-to-event/time-to-infection) of cohort follow-up data during this period. There were no laboratory-confirmed cases of Ebola among study participants, so therefore no efficacy analyses were performed. |
Countries
Sierra Leone
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| rVSVΔG-ZEBOV (Immediate Vaccination) One intramuscular (deltoid) injection of rVSVΔG-ZEBOV (2 x 10\^7 plaque forming units)
rVSVΔG-ZEBOV: The rVSVΔG-ZEBOV vaccine is comprised of a single recombinant VSV isolate (11481 nontypeable) modified to replace the gene encoding the G envelope GP with the gene encoding the envelope GP from ZEBOV (Kikwit, 1995 strain). | 4,319 |
| rVSVΔG-ZEBOV (Deferred Vaccination) One intramuscular (deltoid) injection of rVSVΔG-ZEBOV (2 x 10\^7 plaque forming units) in participants randomized to receive deferred vaccination (18-24 weeks after enrollment).
rVSVΔG-ZEBOV: The rVSVΔG-ZEBOV vaccine is comprised of a single recombinant VSV isolate (11481 nontypeable) modified to replace the gene encoding the G envelope GP with the gene encoding the envelope GP from ZEBOV (Kikwit, 1995 strain). | 4,332 |
| Total | 8,651 |
Baseline characteristics
| Characteristic | rVSVΔG-ZEBOV (Immediate Vaccination) | rVSVΔG-ZEBOV (Deferred Vaccination) | Total |
|---|---|---|---|
| Age, Continuous | 30.5 years | 31.0 years | 30.7 years |
| Region of Enrollment Sierra Leone | 4183 Participants | 3821 Participants | 8004 Participants |
| Sex: Female, Male Female | 1703 Participants | 1704 Participants | 3407 Participants |
| Sex: Female, Male Male | 2616 Participants | 2628 Participants | 5244 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 8 / 4,261 | 11 / 3,788 |
| other Total, other adverse events | 2,537 / 4,261 | 1,512 / 3,788 |
| serious Total, serious adverse events | 54 / 4,261 | 47 / 3,788 |
Outcome results
Primary
Laboratory-confirmed Ebola (Study Diagnostics)
Incidence of Ebola confirmed by the STRIVE study laboratory in each treatment group during the Randomized Portion of the trial. For the vaccine efficacy endpoint, all enrolled participants in both arms were followed for 18-24 weeks after enrollment (after which point participants in the deferred cohort received crossover vaccination). Statistical analysis was to proceed as survival analysis (time-to-event/time-to-infection) of cohort follow-up data during this period. There were no laboratory-confirmed cases of Ebola among study participants, so therefore no efficacy analyses were performed.
Time frame: > 21 days following vaccination
Population: The Overall Number of Participants Analyzed for this endpoint is the number of participants with suspected Ebola in each group who provided biological samples to the study laboratory for testing.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| rVSVΔG-ZEBOV (Immediate Vaccination) | Laboratory-confirmed Ebola (Study Diagnostics) | 0 Participants |
| rVSVΔG-ZEBOV (Deferred Vaccination) | Laboratory-confirmed Ebola (Study Diagnostics) | 0 Participants |
Primary
Number of Participants With Occurrence of Serious Adverse Events During the 6 Months Following the Vaccination
Number of Participants with Occurrence of SAEs within the 6-month follow-up period following a single dose of rVSVΔG-ZEBOV. Vaccination in the immediate group occurred within 7 days of enrollment if possible, and vaccination in the deferred-vaccination group occurred 18-24 weeks after enrollment.
Time frame: 6 months following vaccination
Population: The Overall Number of Participants Analyzed for this endpoint is the number of participants in each group who provided any safety/AE data during 6-month (18- to 24-week) follow-up.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| rVSVΔG-ZEBOV (Immediate Vaccination) | Number of Participants With Occurrence of Serious Adverse Events During the 6 Months Following the Vaccination | 54 Participants |
| rVSVΔG-ZEBOV (Deferred Vaccination) | Number of Participants With Occurrence of Serious Adverse Events During the 6 Months Following the Vaccination | 47 Participants |
Secondary
Death Due to Laboratory-confirmed Ebola
Deaths due to Ebola confirmed by the STRIVE study laboratory in each treatment group during the Randomized Portion of the trial. There were no laboratory-confirmed cases of Ebola among study participants, so therefore no efficacy analyses were performed.
Time frame: 6 months following vaccination
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| rVSVΔG-ZEBOV (Immediate Vaccination) | Death Due to Laboratory-confirmed Ebola | 0 Participants |
| rVSVΔG-ZEBOV (Deferred Vaccination) | Death Due to Laboratory-confirmed Ebola | 0 Participants |
Secondary
Ebola Confirmed by Non-study or Study Diagnostics
Incidence of Ebola confirmed by the STRIVE study laboratory or by a non-study laboratory in each treatment group during the Randomized Portion of the trial. For the vaccine efficacy endpoint, all enrolled participants in both arms were followed for 18-24 weeks after enrollment (after which point participants in the deferred cohort received crossover vaccination). Statistical analysis was to proceed as survival analysis (time-to-event/time-to-infection) of cohort follow-up data during this period. There were no laboratory-confirmed cases of Ebola among study participants, so therefore no efficacy analyses were performed.
Time frame: 6 months following vaccination
Population: The Overall Number of Participants Analyzed for this endpoint is the number of participants with suspected Ebola in each group who provided biological samples for testing, whether to the study laboratory or to a non-study laboratory.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| rVSVΔG-ZEBOV (Immediate Vaccination) | Ebola Confirmed by Non-study or Study Diagnostics | 0 Participants |
| rVSVΔG-ZEBOV (Deferred Vaccination) | Ebola Confirmed by Non-study or Study Diagnostics | 0 Participants |
Secondary
Number of Participants With Occurrence of Solicited and Unsolicited AEs During the 28 Days Following the Vaccination or Enrollment
Solicited local and systemic reactogenicity symptoms and unsolicited adverse events were assessed in safety sub-study participants (the first 449 participants enrolled at the COMAHS Library site), during the 28 days after vaccination (immediate group) or after enrollment without vaccination (deferred group).
Time frame: During 28 days following vaccination
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| rVSVΔG-ZEBOV (Immediate Vaccination) | Number of Participants With Occurrence of Solicited and Unsolicited AEs During the 28 Days Following the Vaccination or Enrollment | Solicited AEs | 203 Participants |
| rVSVΔG-ZEBOV (Immediate Vaccination) | Number of Participants With Occurrence of Solicited and Unsolicited AEs During the 28 Days Following the Vaccination or Enrollment | Unsolicited AEs | 101 Participants |
| rVSVΔG-ZEBOV (Deferred Vaccination) | Number of Participants With Occurrence of Solicited and Unsolicited AEs During the 28 Days Following the Vaccination or Enrollment | Solicited AEs | 117 Participants |
| rVSVΔG-ZEBOV (Deferred Vaccination) | Number of Participants With Occurrence of Solicited and Unsolicited AEs During the 28 Days Following the Vaccination or Enrollment | Unsolicited AEs | 27 Participants |
Secondary
Number of Participants With Occurrence of Solicited Injection-site and Systemic Reactogenicity Signs and Symptoms, Including Fever, on Vaccination Day and During the 7 Days Following the Vaccination or Enrollment.
Solicited symptoms were assessed only in safety sub-study participants (the first 449 participants enrolled at the COMAHS Library site), during the 7 days after vaccination (immediate group) or after enrollment without vaccination (deferred group). Participants were actively solicited for the occurrence of local (injection-site) pain, redness, and swelling and the following systemic reactogenicity symptoms: fever, joint pain, joint swelling, muscle pain, fatigue, feeling unwell, chills, headache, vomiting, nausea, diarrhea, abdominal pain, rash, oral ulcers, and skin vesicles (blisters).
Time frame: Vaccination day and for 7 days following vaccination
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| rVSVΔG-ZEBOV (Immediate Vaccination) | Number of Participants With Occurrence of Solicited Injection-site and Systemic Reactogenicity Signs and Symptoms, Including Fever, on Vaccination Day and During the 7 Days Following the Vaccination or Enrollment. | 202 Participants |
| rVSVΔG-ZEBOV (Deferred Vaccination) | Number of Participants With Occurrence of Solicited Injection-site and Systemic Reactogenicity Signs and Symptoms, Including Fever, on Vaccination Day and During the 7 Days Following the Vaccination or Enrollment. | 76 Participants |
Secondary
Suspected, Probable or Laboratory-confirmed Ebola
Incidence of suspected, probable, or laboratory-confirmed Ebola, where suspected and probable cases are defined by the August 9, 2014 World Health Organization case definition recommendations for use during an Ebola outbreak, and laboratory-confirmed Ebola includes both study laboratory and non-study laboratory diagnostics. An Ebola Screening Form was required to be completed for all participants referred for evaluation of suspected Ebola; the Outcome Measure (Count of Participants) reflects the number of participants in each group for whom an Ebola Screening Form was completed.
Time frame: 6 months following vaccination
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| rVSVΔG-ZEBOV (Immediate Vaccination) | Suspected, Probable or Laboratory-confirmed Ebola | 27 Participants |
| rVSVΔG-ZEBOV (Deferred Vaccination) | Suspected, Probable or Laboratory-confirmed Ebola | 17 Participants |