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 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.

• 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.