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Dose, Safety, Tolerability and Immunogenicity of a Stabilized Prefusion RSV F Subunit Protein Vaccine, VRC-RSVRGP084-00-VP (DS-Cav1), Alone or With Alum Adjuvant, in Healthy Adults

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ClinicalTrials.gov Identifier: NCT03049488
Recruitment Status : Completed
First Posted : February 10, 2017
Results First Posted : October 23, 2020
Last Update Posted : October 23, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Tracking Information
First Submitted Date  ICMJE February 9, 2017
First Posted Date  ICMJE February 10, 2017
Results First Submitted Date  ICMJE September 29, 2020
Results First Posted Date  ICMJE October 23, 2020
Last Update Posted Date October 23, 2020
Actual Study Start Date  ICMJE February 22, 2017
Actual Primary Completion Date October 3, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 21, 2020)
  • Number of Subjects Reporting Local Reactogenicity Signs and Symptoms Within 7 Days of the First Product Administration of DS-Cav1 Alone or With Alum Adjuvant [ Time Frame: 7 days after the first product administration (Day 7) ]
    Subjects recorded the occurrence of solicited symptoms on a diary card for 7 days after the first study product administration and reviewed the diary card with clinic staff at a follow up visit. Subjects were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than one time at any severity during the reporting period. The number reported for "Any Local Symptom" is the number of subjects reporting any local symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (FDA Guidance - September 2007).
  • Number of Subjects Reporting Local Reactogenicity Signs and Symptoms Within 7 Days of the Second Product Administration of DS-Cav1 Alone or With Alum Adjuvant [ Time Frame: 7 days after the second product administration (Day 91) ]
    Subjects recorded the occurrence of solicited symptoms on a diary card for 7 days after the second study product administration and reviewed the diary card with clinic staff at a follow up visit. Subjects were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than one time at any severity during the reporting period. The number reported for "Any Local Symptom" is the number of subjects reporting any local symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (FDA Guidance - September 2007).
  • Number of Subjects Reporting Local Reactogenicity Signs and Symptoms Within 7 Days of Any Product Administration of DS-Cav1 Alone or With Alum Adjuvant [ Time Frame: 7 days after each product administration ]
    Subjects recorded the occurrence of solicited symptoms on a diary card for 7 days after each study product administration and reviewed the diary card with clinic staff at a follow up visit. Subjects were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than one time at any severity during the reporting period. The number reported for "Any Local Symptom" is the number of subjects reporting any local symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (FDA Guidance - September 2007).
  • Number of Subjects Reporting Systemic Reactogenicity Signs and Symptoms Within 7 Days of the First Product Administration of DS-Cav1 Alone or With Alum Adjuvant [ Time Frame: 7 days after the first product administration (Day 7) ]
    Subjects recorded the occurrence of solicited symptoms on a diary card for 7 days after the first study product administration and reviewed the diary card with clinic staff at a follow up visit. Subjects were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than one time at any severity during the reporting period. The number reported for "Any Systemic Symptom" is the number of subjects reporting any systemic symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (FDA Guidance - September 2007).
  • Number of Subjects Reporting Systemic Reactogenicity Signs and Symptoms Within 7 Days of the Second Product Administration of DS-Cav1 Alone or With Alum Adjuvant [ Time Frame: 7 days after the second product administration (Day 91) ]
    Subjects recorded the occurrence of solicited symptoms on a diary card for 7 days after the second study product administration and reviewed the diary card with clinic staff at a follow up visit. Subjects were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than one time at any severity during the reporting period. The number reported for "Any Systemic Symptom" is the number of subjects reporting any systemic symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (FDA Guidance - September 2007).
  • Number of Subjects Reporting Systemic Reactogenicity Signs and Symptoms Within 7 Days of Any Product Administration of DS-Cav1 Alone or With Alum Adjuvant [ Time Frame: 7 days after each product administration ]
    Subjects recorded the occurrence of solicited symptoms on a diary card for 7 days after each study product administration and reviewed the diary card with clinic staff at a follow up visit. Subjects were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than one time at any severity during the reporting period. The number reported for "Any Systemic Symptom" is the number of subjects reporting any systemic symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (FDA Guidance - September 2007).
  • Number of Subjects With Abnormal Laboratory Measures of Safety [ Time Frame: Day 0 through Day 308 ]
    Any abnormal laboratory results recorded as unsolicited AEs are summarized. Safety laboratory parameters included hematology (hemoglobin, hematocrit, mean corpuscular volume (MCV), platelets, white blood cell (WBC) and red blood cell (RBC) counts, and neutrophil, lymphocyte, monocyte, eosinophil and basophil percents and counts) and chemistry (alanine aminotransferase (ALT) and creatinine). Complete blood count (CBC) differential, platelet, creatinine and ALT results were collected at screening (≤ 56 days before enrollment), Day 0 prior to study product administration (baseline), and at Days 7, 28, 84, 91 and 112. 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 were used.
  • Number of Subjects With One or More Unsolicited Non-Serious Adverse Events (AEs) [ Time Frame: Day 0 through Day 28 after product administration ]
    Unsolicited AEs and attribution assessments were recorded in the study database from receipt of the first study product administration through the visit scheduled for 28 days after each study product administration. At other time periods between study product administrations and when greater than 28 days after the last study product administration, only serious AEs (SAEs reported as a separate outcome and in the AE module) and new chronic medical conditions that required ongoing medical management were recorded through the last study visit. The relationship between an AE and the study product was assessed by the investigator on the basis of his or her clinical judgment and the definitions outlined in the protocol. A subject with multiple experiences of the same event is counted once using the event of worst severity.
  • Number of Subjects With Serious Adverse Events (SAEs) [ Time Frame: Day 0 through Day 308 ]
    SAEs were reported from receipt of first study product administration through the last expected study visit at Day 308. The relationship between a SAE and the study product was assessed by the investigator on the basis of his or her clinical judgment and the definitions outlined in the protocol. A subject with multiple experiences of the same event is counted once using the event of worst severity.
  • Number of Subjects Who Had Respiratory Syncytial Virus (RSV) Infection Following Product Administration [ Time Frame: Day 0 through Day 308 ]
    Respiratory Syncytial Virus (RSV) cases were recorded in the study database from receipt of the first study product administration through the last study visit.
Original Primary Outcome Measures  ICMJE
 (submitted: February 9, 2017)
To evaluate the safety and tolerability of DS-Cav1 alone or with adjuvant when administered IM at 50 mcg, or 150 mcg, or 500 mcg to healthy adults. [ Time Frame: Through 44 weeks of study participation. ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 21, 2020)
  • Respiratory Syncytial Virus Subtype A (RSV A) Antigen-specific Neutralizing Antibody Geometric Mean Titers (GMTs) at 4 Weeks After the First Product Administration of DS-Cav1 Alone or With Alum Adjuvant [ Time Frame: 4 weeks after the first product administration (Week 4) ]
    Neutralizing antibody titers were determined against a reporter RSV A2 virus (RSV A), and were summarized using geometric mean 50% inhibitory concentration (IC50). Negative samples were reported and IC50 titers were calculated using half the limit of detection. Measurements were normalized to international units per milliliter.
  • Respiratory Syncytial Virus Subtype A (RSV A) Antigen-specific Neutralizing Antibody Geometric Mean Titers (GMTs) at 4 Weeks After the Second Product Administration of DS-Cav1 Alone or With Alum Adjuvant [ Time Frame: 4 weeks after the second product administration (Week 16) ]
    Neutralizing antibody titers were determined against a reporter RSV A2 virus (RSV A), and were summarized using geometric mean 50% inhibitory concentration (IC50). Negative samples were reported and IC50 titers were calculated using half the limit of detection. Measurements were normalized to international units per milliliter.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 9, 2017)
  • To evaluate the antibody response as measured by neutralization assay of DS-Cav1 alone or with adjuvant. [ Time Frame: 4 weeks posted first injection. ]
  • To evaluate the antibody response as measured by neutralization assay of DS-Cav 1 alone or with adjuvant. [ Time Frame: 4 weeks post second injection. ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Dose, Safety, Tolerability and Immunogenicity of a Stabilized Prefusion RSV F Subunit Protein Vaccine, VRC-RSVRGP084-00-VP (DS-Cav1), Alone or With Alum Adjuvant, in Healthy Adults
Official Title  ICMJE VRC 317: A Phase I Randomized, Open-Label Clinical Trial to Evaluate Dose, Safety, Tolerability and Immunogenicity of a Stabilized Prefusion RSV F Subunit Protein Vaccine, VRC-RSVRGP084-00-VP (DS-Cav1), Alone or With Alum Adjuvant, in Healthy Adults
Brief Summary

Background:

Respiratory Syncytial Virus (RSV) is a virus that infects the lungs and breathing passages. Healthy adults who are infected generally have mild cold symptoms for a week or two. But it can also be serious, especially for infants and older adults. It can be spread by direct or indirect contact with respiratory secretions. Researchers want to study a new vaccine to prevent RSV.

Objective:

To see if a vaccine for RSV is safe and if it causes side effects.

Eligibility:

Healthy adults 18-50 years old

Design:

Volunteers were screened in a separate screening protocol.

Subjects had 13 visits over 1 year.

Some subjects received just vaccine. Some received vaccine mixed with alum adjuvant.

All subjects received their dose by injection in the upper arm. They received up to two doses, one at the beginning of the study and another 12 weeks later.

Subjects were monitored for 1 hour after injection and called to check on their safety 1 day after.

Subjects recorded their temperature and side effects for 7 days after each vaccination.

Subjects were provided with a thermometer to measure their temperature and a ruler to measure any changes if these occurred on their skin at the injection site.

At all visits, subjects were checked for health changes or problems. They may have had blood drawn.

At some visits, subjects had samples collected from their nose and mouth.

Detailed Description

Study Design:

This is a Phase I, open-label, dose escalation study to evaluate the dose, safety, tolerability, and immunogenicity of VRC-RSVRGP084-00-VP vaccine alone or with alum adjuvant in a 2-injection regimen. The hypotheses are that the vaccine will be safe and tolerable for human administration, and will induce detectable immune response. The primary objective is to evaluate the safety and tolerability of the investigational vaccine at 3 dose levels administered alone or with alum adjuvant in healthy adults. Secondary objectives relate to humoral and cellular immunogenicity of the investigational vaccine regimen.

Product Description:

VRC-RSVRGP084-00-VP (DS-Cav1) was developed by VRC, NIAID and is composed of the respiratory syncytial virus (RSV) fusion (F) glycoprotein ectodomain assembled as a trimer stabilized in its prefusion native conformation with a foldon trimerization domain at the C-terminus and 4 internal mutations designated DS-Cav1 (4.1DHFR_RSVAF). The sequence is based on the RSV A2 strain from subtype A. The product was provided at a concentration of 0.5 mg/mL in 3 mL glass vials filled to 1.2 mL. Adjuvant was an aluminum hydroxide suspension (alum) provided in a sterile, pyrogen-free suspension at a concentration of 5 mg/mL in 3 mL glass vials filled to 0.7 mL. The alum dose was 500 mcg and was field mixed.

Subjects:

Healthy adult subjects ages 18-50 years

Study Plan:

Subjects were randomized into DS-Cav1 or DS-Cav1 plus alum in each dose during the study. Dose continuation and dose escalation evaluations occurred to ensure the safety data support proceeding to the higher doses. Subjects were evaluated for safety and immune responses through blood and mucosal sample collection at specified timepoints throughout the study.

VRC 317 Study Schema:

  • Group: 1; Subjects: 15; Dose: 50mcg; Day 0: DS-Cav1; Week 12 [1]: DS-Cav1
  • Group: 2; Subjects: 15; Dose: 50mcg; Day 0: DS-Cav1 + alum; Week 12 [1]: DS-Cav1 + alum
  • Group: 3; Subjects: 15; Dose: 150mcg; Day 0: DS-Cav1; Week 12 [1]: DS-Cav1
  • Group: 4; Subjects: 15; Dose: 150mcg; Day 0: DS-Cav1 + alum; Week 12 [1]: DS-Cav1 + alum
  • Group: 5; Subjects: 15; Dose: 500mcg; Day 0: DS-Cav;1 Week 12 [1]: DS-Cav1
  • Group: 6; Subjects: 15; Dose: 500mcg; Day 0: DS-Cav1 + alum; Week 12 [1]: DS-Cav1 + alum

All DS-Cav1 vaccinations were administered with needle and syringe into the deltoid muscle.

Total Planned Subjects: 90 (Up to 100 subjects could have been enrolled if needed to evaluate safety or immunogenicity.)

• [1] Week 12 dose: Optional for the last 5 subjects enrolled in each group who received the Day 0 injection and any additional subjects needed to evaluate safety or immunogenicity of a single injection.

Duration:

The study schedule required 13 clinic visits and a telephone contact after each injection.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE Respiratory Syncytial Virus
Intervention  ICMJE
  • Biological: VRC-RSVRGP084-00-VP
    VRC-RSVRGP084-00-VP is an investigational respiratory syncytial virus (RSV) vaccine.
    Other Name: DS-Cav1
  • Other: Aluminum Hydroxide Suspension
    Aluminum Hydroxide Suspension, alum, is an adjuvant.
    Other Name: Alum
Study Arms  ICMJE
  • Experimental: Group 1: DS-Cav1 (50 mcg)

    DS-Cav1 (50 mcg) administered intramuscularly (IM) by Needle/Syringe (Day 0 and Week 12*)

    *To evaluate the safety or immunogenicity of a single vaccine dose, the Week 12 dose was optional for the last 5 subjects who enrolled in this group and received the Day 0 injection.

    Intervention: Biological: VRC-RSVRGP084-00-VP
  • Experimental: Group 2: DS-Cav1 (50 mcg) + alum

    DS-Cav1 (50 mcg) + alum administered IM by Needle/Syringe (Day 0 and Week 12*)

    *To evaluate the safety or immunogenicity of a single vaccine dose, the Week 12 dose was optional for the last 5 subjects who enrolled in this group and received the Day 0 injection.

    Interventions:
    • Biological: VRC-RSVRGP084-00-VP
    • Other: Aluminum Hydroxide Suspension
  • Experimental: Group 3: DS-Cav1 (150 mcg)

    DS-Cav1 (150 mcg) administered IM by Needle/Syringe (Day 0 and Week 12*)

    *The Week 12 dose was optional for the last 5 subjects who enrolled in this group and received the Day 0 injection, and for 5 additional subjects who were enrolled to evaluate the safety or immunogenicity of a single vaccine dose.

    Intervention: Biological: VRC-RSVRGP084-00-VP
  • Experimental: Group 4: DS-Cav1 (150 mcg) + alum

    DS-Cav1 (150 mcg) + alum administered IM by Needle/Syringe (Day 0 and Week 12*)

    *To evaluate the safety or immunogenicity of a single vaccine dose, the Week 12 dose was optional for the last 5 subjects who enrolled in this group and received the Day 0 injection.

    Interventions:
    • Biological: VRC-RSVRGP084-00-VP
    • Other: Aluminum Hydroxide Suspension
  • Experimental: Group 5: DS-Cav1 (500 mcg)

    DS-Cav1 (500 mcg) administered IM by Needle/Syringe (Day 0 and Week 12*)

    *To evaluate the safety or immunogenicity of a single vaccine dose, the Week 12 dose was optional for the last 5 subjects who enrolled in this group and received the Day 0 injection.

    Intervention: Biological: VRC-RSVRGP084-00-VP
  • Experimental: Group 6:DS-Cav1 (500 mcg) + alum

    DS-Cav1 (500 mcg) + alum administered IM by Needle/Syringe (Day 0 and Week 12*)

    *To evaluate the safety or immunogenicity of a single vaccine dose, the Week 12 dose was optional for the last 5 subjects who enrolled in this group and received the Day 0 injection.

    Interventions:
    • Biological: VRC-RSVRGP084-00-VP
    • Other: Aluminum Hydroxide Suspension
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 5, 2019)
95
Original Estimated Enrollment  ICMJE
 (submitted: February 9, 2017)
100
Actual Study Completion Date  ICMJE October 3, 2019
Actual Primary Completion Date October 3, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA:

    1. 18 to 50 years of age.
    2. Willing and able to complete the informed consent process.
    3. Available for clinic visits through 44 weeks after enrollment.
    4. Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process.
    5. Willing to donate blood and mucosal samples to be stored and used for future research.
    6. In good general health without clinically significant medical history.
    7. Physical examination and laboratory results without clinically significant findings and a Body Mass Index (BMI) less than or equal to 40 within the 56 days prior to enrollment. Laboratory criteria within 56 days prior to enrollment:
    8. White Blood Cell (WBC) and differential either within institutional normal range or accompanied by Principal Investigator (PI) or designee approval.
    9. Platelets = 125,000-500,000/mm^3.
    10. Hemoglobin within institutional normal range.
    11. Creatinine less than or equal to 1.1 x upper limit of normal (ULN).
    12. Alanine aminotransferase (ALT) less than or equal to 1.25 x ULN.
    13. Negative for HIV infection by an FDA approved method of detection.

      Criteria applicable to women of childbearing potential:

    14. Negative result on a human chorionic gonadotropin pregnancy test on day of enrollment before receiving study product.
    15. Agree to use effective means of birth control from at least 21 days before enrollment through 4 weeks after the last injection.
  • EXCLUSION CRITERIA:

Criteria applicable to women of childbearing potential:

  1. Breast-feeding or planning to become pregnant through 4 weeks after the last injection.

    Subject has received any of the following:

  2. More than 10 days of systemic immunosuppressive medications or cytotoxic medications within the 4 weeks prior to enrollment or any within the 14 days prior to enrollment.
  3. Blood products within 16 weeks prior to enrollment.
  4. Live attenuated vaccines within 4 weeks prior to enrollment.
  5. Inactivated vaccines within 2 weeks prior to enrollment.
  6. Investigational research agents within 4 weeks prior to enrollment or planning to receive investigational products while on the study.
  7. Current allergen immunotherapy with antigen injections, unless on maintenance schedule.
  8. Current anti-tuberculosis(TB) prophylaxis or therapy.

    Subject has any of the following:

  9. Serious reactions to vaccines that preclude receipt of study injections as determined by the investigator.
  10. Hereditary angioedema, acquired angioedema, or idiopathic forms of angioedema.
  11. Asthma that is not well controlled.
  12. Diabetes mellitus (type I or II), with the exception of gestational diabetes.
  13. Thyroid disease that is not well controlled.
  14. Hypertension that is not well controlled.
  15. Evidence of autoimmune disease or immunodeficiency.
  16. Idiopathic urticaria within the past year.
  17. 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.
  18. Malignancy that is active or history of malignancy that is likely to recur during the study.
  19. Seizure disorder other than: 1) febrile seizures, 2) seizures secondary to alcohol withdrawal more than 3 years ago, or 3) seizures that have not required treatment within the last 3 years.
  20. Asplenia, functional asplenia or any condition resulting in the absence or removal of the spleen.
  21. Psychiatric condition that precludes compliance with the protocol; past or present psychoses; or within 5 years prior to enrollment, a history of suicide plan or attempt.
  22. Any medical, psychiatric, or social condition that, in the judgment of the investigator, is a contraindication to protocol participation or impairs a subject s ability to give informed consent.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 50 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03049488
Other Study ID Numbers  ICMJE 170058
17-I-0058 ( Other Identifier: NIH NIAID IRB )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
Study Sponsor  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Grace L Chen, M.D. National Institute of Allergy and Infectious Diseases (NIAID)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP