Influenza HA Ferritin Vaccine, Alone or in Prime-Boost Regimens With an Influenza DNA Vaccine 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-FLUNPF081-00-VP (HA-F A/Sing) vaccine alone
or in prime-boost regimens with VRC-FLUDNA082-00-VP (DNA A/Sing) vaccine. The ypotheses are
that VRC-FLUNPF081-00-VP and VRC-FLUDNA082-00-VP vaccines are safe, well-tolerated, and
induce an immune response to the H2 antigen. The primary objectives are to evaluate the
safety and olerability of two different doses of the HA-F A/Sing vaccine alone and in
prime-boost regimens in healthy adults. Secondary objectives are related to the evaluation of
the immunogenicity of the HA-F A/Sing and DNA A/Sing vaccines in prime-boost regimens.

Study Products: The investigational HA-F A/Sing vaccine, developed by the Vaccine Research
Center (VRC), National Institute of Allergy and Infectious Diseases (NIAID), is composed of
Helicobacter pylori non-haem ferritin with an influenza virus H2 hemagglutinin (HA) insert to
form a nanoparticle displaying eight HA trimers from A/Singapore/1/57 (H2N2) influenza.

The investigational DNA A/Sing vaccine, developed by the VRC, NIAID, is composed of a single
closed-circular DNA plasmid that encodes the H2 protein of A/Singapore/1/57 influenza.

Subjects: Up to 80 healthy adults ages 18-70 will be enrolled; adults born between 1966 and
1969 will be excluded from the trial.

Study Plan: Vaccines will be administered intramuscularly (IM) in the deltoid muscle. This
study has two parts:

Part I will evaluate the safety, tolerability, and immunogenicity of 1 or 2 doses of the HA-F
A/Sing vaccine in a dose-escalation design. In Group 1, five subjects will receive a low dose
of the HA-F A/Sing vaccine via needle and syringe on Day 0. If this low dose is assessed as
safe and well tolerated, enrollment will begin for Group 2. In Group 2, five subjects will
receive the

higher dose of the HA-F A/Sing vaccine via needle and syringe on Day 0 and Week 16. If this
higher dose is assessed as safe, enrollment will begin for Part II.

Part II will evaluate the safety, tolerability, and immunogenicity of HA-F A/Sing vaccine in
prime-boost regimens. Subjects will be stratified by age and randomized equally into Groups 3
and Group 4 as shown in the vaccination schema. In Group 3, subjects will receive DNA A/Sing
vaccine via PharmaJet Needle-Free Injector on Day 0 and HA-F A/Sing vaccine via needle and
syringe on Week 16. In Group 4, subjects will receive HA-F A/Sing vaccine via needle and
syringe on Day 0 and Week 16.

For Group 1, the protocol requires about 8 clinic visits and 1 telephone follow up contact
after the injection.

For Group 2, Group 3 and Group 4, the protocol requires about 10 clinic visits and 2
telephone follow-up contacts after each injection.

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.

Study

Duration: Subjects will be evaluated for 40 weeks following the first vaccine administration.

- INCLUSION CRITERIA:

A subject must meet all of the following criteria:

- Healthy subjects aged 18-70 (excluding subjects born between 1966-1969)

- Based on history and examination, must be in good general health and without history
of any of the conditions listed in the exclusion criteria

- Received at least one licensed current seasonal influenza vaccine from 2014 to the
present

- Able and willing to complete the informed consent process

- Available for clinic visits for 40 weeks after enrollment

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

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

- Physical examination and laboratory results without clinically significant findings
and a

Body Mass Index (BMI) less than or equal to 40 within the 84 days before enrollment

Laboratory Criteria within 84 days before enrollment:

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

- Total lymphocyte count greater than or equal to 800 cells/mm (3)

- Platelets = 125,000 500,000/mm(3)

- Hemoglobin within institutional normal range

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

- Alanine aminotransferase (ALT) less than or equal to 1.25 times institutional upper
limit of normal (ULN)

- Aspartate aminotransferase (AST) less than or equal to 1.25 times institutional ULN

- Alkaline phosphatase (ALP) less than or equal to 1.1 times institutional ULN

- Total bilirubin within institutional upper limit of normal (ULN)

- Serum creatinine less than or equal to 1.1 times institutional ULN

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

Criteria applicable to women of childbearing potential:

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

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

EXCLUSION CRITERIA:

A subject will be excluded if one or more of the following conditions apply:

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

Subject has received any of the following substances:

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

- Current anti-TB prophylaxis or therapy

- Previous H2 influenza investigational vaccine

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

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

- Serious reactions to vaccines that preclude receipt of study vaccinations 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

- Idiopathic urticaria within the past year

- Evidence of autoimmune disease or immunodeficiency

- Hypertension that is not well controlled

- 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
period of 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

- Guillain-Barr(SqrRoot)(Copyright) Syndrome

- 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, 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.