Clinical trial NCT03049488: 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: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Respiratory Syncytial Virus
Keywords: Immune Response
Respiratory Syncytial Virus
Vaccine-Mediated Protection
Neutralizing Antibody
Antibody Response
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2017-02-10
Enrollment: 95
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: PREVENTION

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.

Eligibility criteria: * 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.

Primary outcomes:
measure: 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
timeFrame: 7 days after the first product administration (Day 7)
measure: 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
timeFrame: 7 days after the second product administration (Day 91)
measure: Number of Subjects Reporting Local Reactogenicity Signs and Symptoms Within 7 Days of Any Product Administration of DS-Cav1 Alone or With Alum Adjuvant
timeFrame: 7 days after each product administration
measure: 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
timeFrame: 7 days after the first product administration (Day 7)
measure: 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
timeFrame: 7 days after the second product administration (Day 91)
measure: Number of Subjects Reporting Systemic Reactogenicity Signs and Symptoms Within 7 Days of Any Product Administration of DS-Cav1 Alone or With Alum Adjuvant
timeFrame: 7 days after each product administration
measure: Number of Subjects With Abnormal Laboratory Measures of Safety
timeFrame: Day 0 through Day 308
measure: Number of Subjects With One or More Unsolicited Non-Serious Adverse Events (AEs)
timeFrame: Day 0 through Day 28 after product administration
measure: Number of Subjects With Serious Adverse Events (SAEs)
timeFrame: Day 0 through Day 308
measure: Number of Subjects Who Had Respiratory Syncytial Virus (RSV) Infection Following Product Administration
timeFrame: Day 0 through Day 308
Secondary outcomes:
measure: 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
timeFrame: 4 weeks after the first product administration (Week 4)
measure: 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
timeFrame: 4 weeks after the second product administration (Week 16)
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Institute of Allergy and Infectious Diseases (NIAID)
name: Grace L Chen, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ruckwardt TJ, Morabito KM, Graham BS. Determinants of early life immune responses to RSV infection. Curr Opin Virol. 2016 Feb;16:151-157. doi: 10.1016/j.coviro.2016.01.003. Epub 2016 Mar 15.
citation: Ngwuta JO, Chen M, Modjarrad K, Joyce MG, Kanekiyo M, Kumar A, Yassine HM, Moin SM, Killikelly AM, Chuang GY, Druz A, Georgiev IS, Rundlet EJ, Sastry M, Stewart-Jones GB, Yang Y, Zhang B, Nason MC, Capella C, Peeples ME, Ledgerwood JE, McLellan JS, Kwong PD, Graham BS. Prefusion F-specific antibodies determine the magnitude of RSV neutralizing activity in human sera. Sci Transl Med. 2015 Oct 14;7(309):309ra162. doi: 10.1126/scitranslmed.aac4241.
citation: Graham BS, Modjarrad K, McLellan JS. Novel antigens for RSV vaccines. Curr Opin Immunol. 2015 Aug;35:30-8. doi: 10.1016/j.coi.2015.04.005. Epub 2015 Jun 10.
citation: Crank MC, Ruckwardt TJ, Chen M, Morabito KM, Phung E, Costner PJ, Holman LA, Hickman SP, Berkowitz NM, Gordon IJ, Yamshchikov GV, Gaudinski MR, Kumar A, Chang LA, Moin SM, Hill JP, DiPiazza AT, Schwartz RM, Kueltzo L, Cooper JW, Chen P, Stein JA, Carlton K, Gall JG, Nason MC, Kwong PD, Chen GL, Mascola JR, McLellan JS, Ledgerwood JE, Graham BS; VRC 317 Study Team. A proof of concept for structure-based vaccine design targeting RSV in humans. Science. 2019 Aug 2;365(6452):505-509. doi: 10.1126/science.aav9033.
citation: Ruckwardt TJ, Morabito KM, Phung E, Crank MC, Costner PJ, Holman LA, Chang LA, Hickman SP, Berkowitz NM, Gordon IJ, Yamshchikov GV, Gaudinski MR, Lin B, Bailer R, Chen M, Ortega-Villa AM, Nguyen T, Kumar A, Schwartz RM, Kueltzo LA, Stein JA, Carlton K, Gall JG, Nason MC, Mascola JR, Chen G, Graham BS; VRC 317 study team. Safety, tolerability, and immunogenicity of the respiratory syncytial virus prefusion F subunit vaccine DS-Cav1: a phase 1, randomised, open-label, dose-escalation clinical trial. Lancet Respir Med. 2021 Oct;9(10):1111-1120. doi: 10.1016/S2213-2600(21)00098-9. Epub 2021 Apr 14.