Seasonal Influenza HA DNA (VRC) With Trivalent Inactivated Vaccine (TIV) Administered ID or IM in Healthy Adults Ages 18-70 Years

Vaccines are an effective way to prevent influenza infection. Each year the World Health
Organization (WHO) and the U.S FDA recommend the influenza strains to include in the
seasonal influenza vaccines. The licensed seasonal influenza vaccines are directed against 3
influenza virus strains: an influenza A H1N1, an influenza A H3N2, and an influenza B. The
currently approved vaccines depend upon labor-intensive methods that limit manufacturing
speed and capacity. Influenza vaccines that can be more rapidly produced and that induce
stronger, broader and more persistent immune responses are a recognized public health need.

In this protocol we propose to use DNA vaccine antigen delivery to induce immune responses
against native hemagglutinin (HA) structures prior to boosting with licensed TIV ID or with
TIV IM.

The study will allow evaluation of the safety and immunogenicity of same season and
sequential season vaccination schedules. The same season regimens (2012/13 prime and boost
with a 14 week interval) consist of HA DNA prime with TIV ID boost -- or -- HA DNA prime
with TIV IM boost. The active comparator for these schedules are TIV ID or TIV IM alone
because a single dose of TIV is the standard for adult influenza vaccination within a single
season. The sequential season regimens (2012/13 prime and 2013/14 boost with a 44 week
interval) consist of concurrent administration (in different arms) of HA DNA and TIV ID
prime with TIV ID boost -- or -- HA DNA and TIV IM prime with TIV IM boost; the active
comparator for these regimens will be TIV ID followed by TIV ID boost or TIV IM followed by
TIV IM boost, also at a 44 week interval, because this is a vaccination pattern consistent
with sequential season vaccinations. Evaluation of the investigational schedules and active
comparator schedules will inform development of novel influenza vaccine strategies that may
offer improved and cross-protective immunity against diverse influenza strains.

Inclusion Criteria:

A subject must meet all of the following criteria:

- Healthy adults, 18 to 70 years old; volunteers who will be older than 64 during the
2013/2014 influenza season will not be enrolled after 11/16/2012.

- Available for clinical follow-up

- Able and willing to complete the informed consent process

- Willing to donate blood for sample storage to be used for future research

- Physical examination and laboratory results without clinically significant findings
and a Body Mass Index (BMI) ≤40 within the 70 days prior to enrollment

- Has not yet received the current year (2012/13) influenza vaccine prior to enrollment
and agrees to receive seasonal influenza vaccines during study participation only
from the study site

Laboratory Criteria within 70 days prior to enrollment:

- Hemoglobin within institutional normal limits

- White blood cells either within institutional normal range or accompanied by site
physician approval as consistent with healthy adult status

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

- Alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN)

- Serum creatinine ≤ 1 x ULN based on site institutional normal range

Criteria applicable to women of childbearing potential:

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

- Agree to use an effective means of birth control from 21 days prior to enrollment
through 3 weeks after the second study vaccination

Exclusion Criteria:

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

Women Specific:

- Breast-feeding or planning to become pregnant while participating in the study

Subject has received any of the following substances:

- More than 10 days of systemic immunosuppressive medications or cytotoxic medications
within the 12 weeks prior to enrollment or any within the 14 days prior to enrollment

- Blood products within 16 weeks prior to enrollment

- Immunoglobulin within 8 weeks prior to enrollment

- Investigational research agents within 28 days (4 weeks) prior to enrollment or
planning to receive investigational products while on the study.

- Allergy treatment with antigen injections, unless on maintenance schedule and allergy
shots could be staggered with the study vaccinations, within 14 days (2 weeks) prior
to enrollment

- Current anti-TB prophylaxis or therapy

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

- Contraindication to receiving an FDA-approved seasonal influenza vaccination

- Serious reactions to vaccines that preclude receipt of study vaccinations, as
determined by the site investigator

- Hereditary angioedema (HAE), acquired angioedema (AAE), or idiopathic forms of
angioedema

- Asthma that is severe, unstable or required emergent care, urgent care,
hospitalization or intubation during the previous two years or that is expected to
require the use of oral, intravenous or high dose inhaled corticosteroids

- Diabetes mellitus type I

- Thyroid disease that is not well-controlled

- Generalized idiopathic urticaria within the 1 year prior to enrollment

- 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, or use of blood thinners such as
Coumadin or Plavix®

- Malignancy that is active or treated malignancy for which there is not reasonable
assurance of sustained cure or 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 for which no treatment has been
required within the 3 years prior to enrollment

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

- Guillain-Barré Syndrome

- Psychiatric condition that precludes compliance with the protocol; past or present
psychoses; disorder requiring lithium; or within 5 years prior to enrollment, a
history of suicide plan or attempt

- Any medical, psychiatric, or other condition that, in the judgment of the
investigator, is a contraindication to protocol participation or impairs ability to
give informed consent