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 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 as a homologous boost 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 is provided at a concentration of 0.5 mg/mL in 3 mL glass
vials filled to 1.2 mL. Adjuvant is an aluminum hydroxide suspension (alum) provided in a
sterile, pyrogenfree suspension at a concentration of 5 mg/mL in 3 mL glass vials filled to
0.7 +/- 0.10 mL. The alum dose is 500 mcg and will be field mixed.

Subjects:

Healthy adult subjects ages 18-50.

Study Plan:

Subject will be randomized into DS-Cav1 or DS-Cav1 plus alum in each dose during the study.
Dose continuation and dose escalation evaluations will occur to ensure the safety data
support proceeding to the higher doses. Subjects will be 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

- Total = Subjects: 90*

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

- *Up to 100 subjects may be enrolled if needed to evaluate safety or immunogenicity.

- [1] This dose is optional for the last 5 subjects enrolled in each group that
receive the Day 0 injection and any additional subjects needed to evaluate safety
or immunogenicity.

Duration:

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

- INCLUSION:

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. WBC and differential either within institutional normal range or accompanied by
Principal Investigator (PI) or designee approval.

9. Platelets = 125,000 500,000/mm3.

10. Hemoglobin within institutional normal range.

11. Creatinine less than or equal to 1.1 x ULN.

12. 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 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-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.