Clinical trial NCT04041570: Ebola Sudan Chimpanzee Adenovirus Vector Vaccine in Healthy Adults
Official title: A Phase I Open-Label, Dose-Escalation Clinical Trial to Evaluate the Safety, Tolerability and Immunogenicity of Two Doses of an Ebola Sudan Chimpanzee Adenovirus Vector Vaccine, VRC-EBOADC086-00-VP (cAd3-EBO S), in Healthy Adults
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Ebola Virus
Keywords: Ebola virus
Ebola vaccine
cAd3-EBO S
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: US Military HIV Research Program
First posted: 2019-08-01
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Sequential Assignment Dose Escalation
Primary purpose: PREVENTION

Brief summary: RV 508 was a Phase I, open-label, dose-escalation study to examine the safety, tolerability and immunogenicity of an investigational Ebola vaccine in healthy adults. VRC-EBOADC086-00-VP, a chimpanzee adenovirus serotype 3 vector-based Ebola vaccine, encodes wild type (WT) glycoprotein (GP) from the Sudan strain of Ebolavirus and is administered intramuscularly (IM).

Detailed description: A total of 40 participants were evenly split, with 20 in each of the two dosage groups to receive the investigational cAd3-EBO S vaccine at a dose of either 1x10\^10 particle units (PU) (Group 1) or 1x10\^11 PU (Group 2). The dose escalation plan included daily review of any new safety data by a study clinician, regular review of safety data by the protocol team and a staged enrollment plan with required interim safety reviews. The study began with enrollment of 3 participants into Group 1 (1x10\^10 PU) at a rate of 1 participant per day. After at least 7 days of follow-up for the first 3 vaccinated participants, an interim safety review occurred before enrollment of additional participants into the group. No safety issues were identified; therefore, an additional 17 participants were enrolled to complete Group 1. When there was a minimum of seven days of follow-up safety data from the last enrolled participant in Group 1, an interim safety review occurred. No safety issues were identified, and enrollment of participants into the next dose level (Group 2) began with the enrollment of 3 participants at a rate of 1 participant per day. After at least 7 days of follow-up for the first 3 vaccinated participants in Group 2 (1x10\^11 PU), an interim safety review occurred before the enrollment of additional participants into Group 2. No safety issues were identified, and an additional 17 participants were enrolled to complete Group 2. Participants were followed for approximately 48 weeks.

Eligibility criteria: Inclusion Criteria:

1. 18 to 50 years old.
2. Available for clinical follow-up through Week 48 after enrollment.
3. Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process.
4. Able and willing to provide fingerprints and have their photographs taken including injection site photographs.
5. Must allow home visits
6. Must complete an Assessment of Understanding (AoU) prior to enrollment by answering 9 out of 10 questions at least once in 3 attempts.
7. Able to read (English or Luganda) and willing to complete the informed consent process.
8. In good general health without clinically significant medical history.
9. Physical examination and laboratory results without clinically significant findings and a body mass index (BMI) ≤ 40 within the 56 days prior to enrollment.
10. Laboratory Criteria within 56 days prior to enrollment:

    1. Hemoglobin ≥ 11.0 g/dL for women; ≥12.5 g/dL for men.
    2. White blood cells (WBC) = 2,500-12,000 cells/mm\^3.
    3. Total lymphocyte count ≥ 800 cells/mm\^3.
    4. Platelets = 125,000 - 400,000/mm\^3.
    5. Alanine aminotransferase (ALT) ≤ 1.25 x upper limit of normal.
    6. Serum creatinine ≤ 1 x upper limit of normal.
    7. HIV-uninfected as evidenced by a negative FDA-approved HIV diagnostic test.

    Female-Specific Criteria:
11. Negative β-HCG (human chorionic gonadotropin) pregnancy test; serum β-HCG at screening and urine β-HCG at enrollment if woman is of reproductive potential.
12. Agrees to use an effective means of birth control from at least 21 days prior to enrollment through 24 weeks after study vaccination if assessed to be of reproductive potential.

Exclusion Criteria:

Volunteer has received any of the following substances:

1. Investigational Ebola or Marburg vaccine in a prior clinical trial or prior receipt of a cAd3 adenoviral vectored investigational vaccine.
2. Chronic use of immunomodulators and systemic glucocorticoids in daily doses of glucocorticoid equivalence \> 20 mg of prednisolone, for periods exceeding 10 days. Non-steroidal anti-inflammatory drugs \[NSAIDS\] are permitted. Participants that have used less than the stated glucocorticoid dose may still be excluded at the Investigator's discretion.
3. Blood products within 112 days (16 weeks) prior to enrollment.
4. Investigational research agents within 28 days (4 weeks) prior to enrollment.
5. Live attenuated vaccines within 28 days (4 weeks) prior to enrollment.
6. Subunit or killed vaccines within 14 days (2 weeks) prior to enrollment.
7. Current anti-tuberculosis prophylaxis or therapy.

   Female-specific criteria:
8. Woman who is pregnant, breast-feeding or planning to become pregnant during the first 24 weeks after study vaccine administration.

   Volunteer has a history of any of the following clinically significant conditions:
9. Serious adverse reactions to vaccines such as anaphylaxis, urticaria (hives), respiratory difficulty, angioedema, or abdominal pain.
10. Allergic reaction to excipients in the study vaccine including gentamycin, neomycin or streptomycin.
11. Clinically significant autoimmune disease or immunodeficiency.
12. Asthma that is not well controlled.
13. Positive result on a rapid plasma reagin (RPR) test.
14. Diabetes mellitus (type I or II).
15. Thyroid disease that is not well controlled.
16. A history of hereditary angioedema (HAE), acquired angioedema (AAE), or idiopathic forms of angioedema.
17. Idiopathic urticaria within the last 1 year.
18. Hypertension that is not well controlled.
19. 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 injections or blood draws.
20. A malignancy that is active, currently being treated, or not surgically cured.
21. Seizure in the past 3 years or treatment for seizure disorder in the past 3 years.
22. Asplenia or functional asplenia.
23. Psychiatric condition that precludes compliance with the protocol; past or present psychoses; or within five years prior to enrollment, history of a suicide plan or attempt.
24. Any medical, psychiatric, social condition, occupational reason or other responsibility that, in the judgment of the investigator, is a contraindication to protocol participation or impairs a volunteer's ability to give informed consent.

Primary outcomes:
measure: Number of Participants Reporting Local Reactogenicity Signs and Symptoms for 7 Days After the cAd3-EBO S Vaccine Administration
timeFrame: 7 days after study product administration
measure: Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms for 7 Days After the cAd3-EBO S Vaccine Administration
timeFrame: 7 days after study product administration
measure: Total Number of Participants Reporting Any Reactogenicity Signs and Symptoms for 7 Days After the cAd3-EBO S Vaccine Administration
timeFrame: 7 days after study product administration
measure: Number of Participants With Abnormal Laboratory Measures of Safety
timeFrame: Through 48 weeks after study product administration
measure: Number of Participants With One or More Unsolicited Non-Serious Adverse Events (AEs)
timeFrame: Through 28 days after study product administration
measure: Number of Participants With Serious Adverse Events (SAEs)
timeFrame: Through 48 weeks after study product administration
Secondary outcomes:
measure: Geometric Mean Titers of Antibodies to the Recombinant Chimpanzee Adenovirus Serotype 3 (cAd3) Vector at 28 Days After the cAd3-EBO S Vaccine Administration
timeFrame: Through 28 days after study product administration
measure: Percentage of Participants With a Positive Ebola-Specific Antibody Response After the cAd3-EBO S Vaccine Administration
timeFrame: Through 28 days after study product administration
measure: Baseline-subtracted Geometric Mean Titers of cAd3-EBO S Antibodies After the cAd3-EBO S Vaccine Administration
timeFrame: Through 28 days after study product administration
measure: Percentage of Participants With Positive Ebola-specific T Cell Responses After the cAd3-EBO S Vaccine Administration
timeFrame: Through 28 days after study product administration
measure: Magnitude of T Cell Response as a Percentage of EBO S-specific T Cell Subset After the cAd3-EBO S Vaccine Administration
timeFrame: Through 28 days after study product administration
Other outcomes:
Locations:
city: Kampala
country: Uganda
facility: Makerere University-Walter Reed Project
Study officials:
References:
citation: Sarwar UN, Costner P, Enama ME, Berkowitz N, Hu Z, Hendel CS, Sitar S, Plummer S, Mulangu S, Bailer RT, Koup RA, Mascola JR, Nabel GJ, Sullivan NJ, Graham BS, Ledgerwood JE; VRC 206 Study Team. Safety and immunogenicity of DNA vaccines encoding Ebolavirus and Marburgvirus wild-type glycoproteins in a phase I clinical trial. J Infect Dis. 2015 Feb 15;211(4):549-57. doi: 10.1093/infdis/jiu511. Epub 2014 Sep 14.
citation: Kibuuka H, Berkowitz NM, Millard M, Enama ME, Tindikahwa A, Sekiziyivu AB, Costner P, Sitar S, Glover D, Hu Z, Joshi G, Stanley D, Kunchai M, Eller LA, Bailer RT, Koup RA, Nabel GJ, Mascola JR, Sullivan NJ, Graham BS, Roederer M, Michael NL, Robb ML, Ledgerwood JE; RV 247 Study Team. Safety and immunogenicity of Ebola virus and Marburg virus glycoprotein DNA vaccines assessed separately and concomitantly in healthy Ugandan adults: a phase 1b, randomised, double-blind, placebo-controlled clinical trial. Lancet. 2015 Apr 18;385(9977):1545-54. doi: 10.1016/S0140-6736(14)62385-0. Epub 2014 Dec 23.
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citation: Paris R, Kuschner RA, Binn L, Thomas SJ, Colloca S, Nicosia A, Cortese R, Bailer RT, Sullivan N, Koup RA. Adenovirus type 4 and 7 vaccination or adenovirus type 4 respiratory infection elicits minimal cross-reactive antibody responses to nonhuman adenovirus vaccine vectors. Clin Vaccine Immunol. 2014 May;21(5):783-6. doi: 10.1128/CVI.00011-14. Epub 2014 Mar 12.
citation: U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1. [July 2017]. Available from: https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf
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