VRC 309: A Multi-Center, Open-Label, Randomized Phase I Study of an Investigational Influenza DNA Vaccine Followed by 2009/2010 Seasonal Influenza Trivalent Inactivated Vaccine (TIV) Compared to Two Injections of TIV in Adults 45-70 Years

* INCLUSION CRITERIA: A SUBJECT MUST MEET ALL OF THE FOLLOWING CRITERIA: 1. 45 to 70 years old. 2. Available for clinical follow-up through Week 27. 3. Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process. 4. Complete an AoU prior to enrollment and verbalize understanding of all questions answered incorrectly. 5. Able and willing to complete the informed consent process. 6. Willing to donate blood for sample storage to be used for future research. 7. No evidence of previously undiagnosed clinically significant chronic diseases. 8. Physical examination and laboratory results without clinically significant findings and a Body Mass Index (BMI) \< 42 within the 56 days prior to enrollment. LABORATORY CRITERIA WITHIN 56 DAYS PRIOR TO ENROLLMENT: 9. Hemoglobin greater than or equal to 11.5 g/dL for women; greater than or equal to 13.5 g/dL for men 10. White blood cells (WBC) equal to 3,300-12,000 cells/mm(3) 11. Differential either within institutional normal range or accompanied by site physician approval as a differential that is consistent with healthy volunteer status 12. Total lymphocyte count greater than or equal to 800 cells/mm(3) 13. Platelets equal to 125,000 - 500,000/mm(3) 14. Alanine aminotransferase (ALT) less than or equal to 2.5 times upper limit of normal (ULN) 15. Serum creatinine less than or equal to 1 times ULN (less than or equal to 1.3 mg/dL for females; less than or equal to 1.4 mg/dL for males). 16. Negative FDA-approved HIV blood test. \[Note: Results of HIV enzyme-linked immunosorbent assay (ELISA) will be documented, but a negative HIV polymerase chain reaction (PCR) test result will be sufficient for eligibility screening of subjects with positive HIV ELISA that is due to prior participation in an HIV vaccine study\]. FEMALE-SPECIFIC CRITERIA: 17. Negative human chorionic gonadotropin (Beta-HCG) pregnancy test (urine or serum) for women presumed to be of reproductive potential on the day of enrollment. 18. A female subject must meet one of the following criteria: * No reproductive potential because of menopause \[one year without menses\] or because of a hysterectomy, bilateral oophorectomy, or tubal ligation, OR -Agrees to be heterosexually inactive at least 21 days prior to enrollment and through the last study visit, OR * Agrees to consistently practice contraception at least 21 days prior to enrollment and through the last study visit by one of the following methods: * condoms, male or female, with or without a spermicide; * diaphragm or cervical cap with spermicide; * intrauterine device; * contraceptive pills, patch, implant or any other FDA-approved contraceptive method; * male partner has previously undergone a vasectomy. EXCLUSION CRITERIA: A subject will be excluded if one or more of the following conditions apply: Women Specific: 1. Breast-feeding or planning to become pregnant during the 27 weeks after enrollment in the study. Subject has received any of the following substances: 2. Seasonal influenza TIV within the 12 weeks prior to enrollment. 3. Systemic immunosuppressive medications or cytotoxic medications within the 12 weeks prior to enrollment. \[With the exceptions that a short course (duration of 10 days or less or a single injection) of corticosteroids for a self-limited condition at least 2 weeks prior to enrollment in this study will not exclude study participation.\] 4. Blood products within 112 days (16 weeks) prior to HIV screening 5. Immunoglobulin within 56 days (8 weeks) prior to HIV screening 6. Live attenuated vaccines within 28 days (4 weeks) prior to initial study vaccine administration 7. Investigational research agents within 28 days (4 weeks) prior to initial study vaccine administration 8. Medically indicated subunit or killed vaccines (e.g., pneumococcal, or allergy treatment with antigen injections) within 14 days (2 weeks) of initial study vaccine administration 9. Current anti-TB prophylaxis or therapy Subject has a history of any of the following clinically significant conditions: 10. Contraindication to receiving an FDA approved current seasonal influenza vaccination (e.g., egg allergy). 11. Serious reactions to vaccines that preclude receipt of study vaccinations as determined by investigator. 12. Hereditary angioedema (HAE), acquired angioedema (AAE), or idiopathic forms of angioedema. 13. Asthma that is severe, unstable or required emergent care, urgent care, hospitalization or intubation during the past two years or that requires the use of oral, intravenous or high dose inhaled corticosteroids. 14. Diabetes mellitus type I. 15. Thyroid disease that is not well-controlled. 16. Generalized idiopathic urticaria within the last 1 year. 17. Hypertension that is not well controlled by medication or is more than 145/95 at enrollment. 18. 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. 19. 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. 20. 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. 21. Asplenia, functional asplenia or any condition resulting in the absence or removal of the spleen. 22. Guillain-Barre Syndrome. 23. Psychiatric condition that precludes compliance with the protocol; past or present psychoses; past or present bipolar disorder; disorder requiring lithium; or within 5 years prior to enrollment, a history of suicide plan or attempt. 24. 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 volunteer's ability to give informed consent.