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 Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Respiratory Syncytial Virus

Intervention / Treatment
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* Biological: VRC-RSVRGP084-00-VP
* Other: Aluminum Hydroxide Suspension


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: 18 to 50 years of age. Willing and able to complete the informed consent process. Available for clinic visits through 44 weeks after enrollment. Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process. Willing to donate blood and mucosal samples to be stored and used for future research. In good general health without clinically significant medical history. 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: White Blood Cell (WBC) and differential either within institutional normal range or accompanied by Principal Investigator (PI) or designee approval. Platelets = 125,000-500,000/mm^3. Hemoglobin within institutional normal range. Creatinine less than or equal to 1.1 x upper limit of normal (ULN). Alanine aminotransferase (ALT) less than or equal to 1.25 x ULN. Negative for HIV infection by an FDA approved method of detection. Criteria applicable to women of childbearing potential: Negative result on a human chorionic gonadotropin pregnancy test on day of enrollment before receiving study product. 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: Breast-feeding or planning to become pregnant through 4 weeks after the last injection. Subject has received any of the following: 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. Blood products within 16 weeks prior to enrollment. Live attenuated vaccines within 4 weeks prior to enrollment. Inactivated vaccines within 2 weeks prior to enrollment. Investigational research agents within 4 weeks prior to enrollment or planning to receive investigational products while on the study. Current allergen immunotherapy with antigen injections, unless on maintenance schedule. Current anti-tuberculosis(TB) prophylaxis or therapy. Subject has any of the following: Serious reactions to vaccines that preclude receipt of study injections as determined by the investigator. Hereditary angioedema, acquired angioedema, or idiopathic forms of angioedema. Asthma that is not well controlled. Diabetes mellitus (type I or II), with the exception of gestational diabetes. Thyroid disease that is not well controlled. Hypertension that is not well controlled. Evidence of autoimmune disease or immunodeficiency. Idiopathic urticaria within the past year. 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. Malignancy that is active or history of malignancy that is likely to recur during the study. 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. Asplenia, functional asplenia or any condition resulting in the absence or removal of the spleen. 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: DS-Cav1 (50 mcg)<br>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. | Biological: VRC-RSVRGP084-00-VP<br>* VRC-RSVRGP084-00-VP is an investigational respiratory syncytial virus (RSV) vaccine.<br>* Other names: DS-Cav1;|
| Experimental: Group 2: DS-Cav1 (50 mcg) + alum<br>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. | Biological: VRC-RSVRGP084-00-VP<br>* VRC-RSVRGP084-00-VP is an investigational respiratory syncytial virus (RSV) vaccine.<br>* Other names: DS-Cav1;Other: Aluminum Hydroxide Suspension<br>* Aluminum Hydroxide Suspension, alum, is an adjuvant.<br>* Other names: Alum;|
| Experimental: Group 3: DS-Cav1 (150 mcg)<br>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. | Biological: VRC-RSVRGP084-00-VP<br>* VRC-RSVRGP084-00-VP is an investigational respiratory syncytial virus (RSV) vaccine.<br>* Other names: DS-Cav1;|
| Experimental: Group 4: DS-Cav1 (150 mcg) + alum<br>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. | Biological: VRC-RSVRGP084-00-VP<br>* VRC-RSVRGP084-00-VP is an investigational respiratory syncytial virus (RSV) vaccine.<br>* Other names: DS-Cav1;Other: Aluminum Hydroxide Suspension<br>* Aluminum Hydroxide Suspension, alum, is an adjuvant.<br>* Other names: Alum;|
| Experimental: Group 5: DS-Cav1 (500 mcg)<br>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. | Biological: VRC-RSVRGP084-00-VP<br>* VRC-RSVRGP084-00-VP is an investigational respiratory syncytial virus (RSV) vaccine.<br>* Other names: DS-Cav1;|
| Experimental: Group 6:DS-Cav1 (500 mcg) + alum<br>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. | Biological: VRC-RSVRGP084-00-VP<br>* VRC-RSVRGP084-00-VP is an investigational respiratory syncytial virus (RSV) vaccine.<br>* Other names: DS-Cav1;Other: Aluminum Hydroxide Suspension<br>* Aluminum Hydroxide Suspension, alum, is an adjuvant.<br>* Other names: Alum;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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). | 7 days after the first product administration (Day 7) | 
| 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 | 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). | 7 days after the second product administration (Day 91) | 
| Number of Subjects Reporting Local Reactogenicity Signs and Symptoms Within 7 Days of Any Product Administration of DS-Cav1 Alone or With Alum Adjuvant | 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). | 7 days after each product administration | 
| 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 | 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). | 7 days after the first product administration (Day 7) | 
| 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 | 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). | 7 days after the second product administration (Day 91) | 
| Number of Subjects Reporting Systemic Reactogenicity Signs and Symptoms Within 7 Days of Any Product Administration of DS-Cav1 Alone or With Alum Adjuvant | 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). | 7 days after each product administration | 
| Number of Subjects With Abnormal Laboratory Measures of Safety | 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. | Day 0 through Day 308 | 
| Number of Subjects With One or More Unsolicited Non-Serious Adverse Events (AEs) | 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. | Day 0 through Day 28 after product administration | 
| Number of Subjects With Serious Adverse Events (SAEs) | 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. | Day 0 through Day 308 | 
| Number of Subjects Who Had Respiratory Syncytial Virus (RSV) Infection Following Product Administration | Respiratory Syncytial Virus (RSV) cases were recorded in the study database from receipt of the first study product administration through the last study visit. | Day 0 through Day 308 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | 4 weeks after the first product administration (Week 4) | 
| 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 | 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. | 4 weeks after the second product administration (Week 16) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immune Response, Respiratory Syncytial Virus, Vaccine-Mediated Protection, Neutralizing Antibody, Antibody Response