Dose, Safety, Tolerability and Immunogenicity of an Influenza H1 Stabilized Stem Ferritin Vaccine, VRCFLUNPF099-00-VP, 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-FLUNPF099-00-VP in two regimens. The
hypotheses are that the vaccine is safe and tolerable and will elicit an immune response. The
primary objective is to evaluate the safety and tolerability of the investigational vaccine
in healthy adults. Secondary objectives are related to immunogenicity of the investigational
vaccine and dosing regimen.

Study Products: The investigational vaccine, VRC-FLUNPF099-00-VP (H1ssF_3928), was developed
by the Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases
(NIAID) and is composed of Helicobacter pylori non-heme ferritin assembled with influenza
virus H1 haemagglutinin (HA) insert to form a nanoparticle displaying eight HA stabilized
stem trimers from A/New Caledonia/20/1999 (H1N1) influenza. The vaccine is supplied in
single-use vials at a concentration of 180 mcg/mL. H1ssF_3928 will be administered
intramuscularly (IM) in the deltoid muscle via needle and syringe.

Subjects: Healthy adults between the ages of 18-70 years, inclusive.

Study Plan: The study will evaluate the safety, tolerability and immunogenicity of 1 or 2
doses of the H1ssF_3928 vaccine in a dose-escalation design. In Group 1, five subjects will
receive a single low dose (20 mcg) of H1ssF_3928 on Day 0. For Group 1, the protocol requires
1 vaccination visit, about 9 follow-up visits, and a telephone contact after vaccination.

If the low dose is assessed as safe and well tolerated, enrollment will begin for Group 2A.
Groups 2A, 2B, 2C, and 2D are stratified by age as shown in the vaccination schema. In Group
2A, subjects will receive a higher dose (60 mcg) of H1ssF_3928 on Day 0. If this higher dose
is assessed as safe and well tolerated, subjects in Group 2A may receive a second vaccination
at week 16 and enrollment can begin for Groups 2B, 2C, and 2D. For Groups 2A, 2B, 2C, and 2D,
the protocol requires 2 vaccination visits, about 11 followup visits, and a telephone contact
after each vaccination.

For all groups, solicited reactogenicity will be evaluated using a 7-day diary card.
Assessment of vaccine safety will include clinical observation and monitoring of
hematological and chemical parameters at clinical visits throughout the study.

VRC 321 Vaccination Schema

Group: 1; Age Cohort: 18-40; Subjects: 5; Day 0: 20 mcg; Week 16

Group: 2A; Age Cohort: 18-40; Subjects: 12; Day 0: 60 mcg; Week 16: 60 mcg

Group: 2B; Age Cohort: 41-49; Subjects: 12; Day 0: 60 mcg; Week 16: 60 mcg

Group: 2C; Age Cohort: 50-59; Subjects: 12; Day 0: 60 mcg; Week 16: 60 mcg

Group: 2D; Age Cohort: 60-70; Subjects: 12; Day 0: 60 mcg; Week 16: 60 mcg

Total: 53*

*Enrollment up to 70 is permitted if additional subjects are needed for safety or
immunogenicity evaluations.

Study Duration: Group 1: Subjects will be evaluated for 52 weeks following the vaccine
administration and through an influenza season.

Groups 2A, 2B, 2C, 2D: Subjects will be evaluated for 52 weeks following the last vaccine
administration and through an influenza season.

- INCLUSION CRITERIA:

1. Healthy adults between the ages of 18-70 years inclusive

2. Based on history and examination, in good general health and without history of
any of the conditions listed in the exclusion criteria

3. Received at least one licensed influenza vaccine from 2014 to the present

4. Able and willing to complete the informed consent process

5. If enrolled in Group 1: Available for clinic visits for 52 weeks after enrollment
and through an influenza season

6. If enrolled in Group 2A, 2B, 2C, or 2D: Available for clinic visits for 68 weeks
after enrollment and through an influenza season

7. Willing to have blood samples collected, stored indefinitely, and used for
research purposes

8. Able to provide proof of identity to the satisfaction of the study clinician
completing the enrollment process

9. Physical examination and laboratory results without clinically significant
findings and a Body Mass Index (BMI) less than or equal to 40 within the 28 days
before enrollment

Laboratory Criteria within 28 days before enrollment

10. White blood cells (WBC) and differential either within institutional normal range
or accompanied by the site Principal Investigator (PI) or designee approval

11. Total lymphocyte count greater than or equal to 800 cells/mm^3

12. Platelets = 125,000 - 500,000/mm3

13. Hemoglobin within institutional normal range

14. Serum iron either within institutional normal range or accompanied by the site PI
or designee approval

15. Serum ferritin within institutional normal range or accompanied by the site PI or
designee approval

16. Alanine aminotransferase (ALT) less than or equal to 1.25 x institutional upper
limit of normal (ULN)

17. Aspartate aminotransferase (AST) less than or equal to 1.25 x institutional ULN

18. Alkaline phosphatase (ALP) <1.1 x institutional ULN

19. Total bilirubin within institutional normal range

20. Serum creatinine less than or equal to 1.1 x institutional ULN

21. Negative for HIV infection by an FDA-approved method of detection

Criteria applicable to women of childbearing potential:

22. Negative beta-human chorionic gonadotropin (beta-HCG) pregnancy test (urine or
serum) on the day of enrollment

23. Agrees to use an effective means of birth control from at least 21 days prior to
enrollment through the end of the study

EXCLUSION CRITIERIA:

1. Breast-feeding or planning to become pregnant during the study.

Subject has received any of the following substances:

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 allergy treatment with allergen immunotherapy with antigen injections, unless
on maintenance schedule

8. Current anti-TB prophylaxis or therapy

9. Previous investigational H1 influenza vaccine

10. Previous investigational ferritin-based vaccine

11. Receipt of a licensed influenza vaccine within 6 weeks before trial enrollment

Subject has a history of any of the following clinically significant conditions:

12. Serious reactions to vaccines that preclude receipt of study vaccinations as
determined by the investigator

13. Hereditary angioedema, acquired angioedema, or idiopathic forms of angioedema

14. Asthma that is not well controlled

15. Diabetes mellitus (type I or II), with the exception of gestational diabetes

16. Thyroid disease that is not well controlled

17. Idiopathic urticaria within the past year

18. Autoimmune disease or immunodeficiency

19. Hypertension that is not well controlled (baseline systolic > 140 mmHg or diastolic >
90 mmHg)

20. 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

21. Malignancy that is active or history of malignancy that is likely to recur during the
period of the study.

22. 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

23. Asplenia, functional asplenia or any condition resulting in the absence or removal of
the spleen

24. Guillain-Barr(SqrRoot)(Copyright) Syndrome

25. Any medical, psychiatric, social condition, occupational reason or other
responsibility that, in the judgment of the investigator, is a contraindication to
protocol participation or impairs a subject s ability to give informed consent.