This study assessed the safety and immunogenicity of Takeda's Tetravalent Dengue Vaccine Candidate (TDV) previously referred to as DENVax of various dosing schedules via subcutaneous (SC) or intramuscular (IM) administration with needle/syringe or needle-free injector (PharmaJet Stratis™).

The vaccine tested in this study was TDV. TDV was tested to assess safety and immunogenicity of various dosing schedules, routes of administration, and delivery methods in healthy flavivirus-seronegative adults living in a dengue non-endemic country.

The study enrolled 80 participants. Participants were randomly assigned to one of the five treatment groups:

• Group 1: TDV SC injection on Day 0 in each arm using needle/syringe
• Group 2: TDV IM injection on Day 0 in each arm using needle/syringe
• Group3: TDV IM injection on Days 0 and 90 using needle/syringe
• Group 4: TDV SC on Day 0 in each arm using the PharmaJet Stratis™ device
• Group 5: TDV IM on Day 0 in each arm using the PharmaJet Stratis™ device

This single-center trial was conducted in the United States. The overall time to participate in this study was up to 5 months. Participants made multiple visits to the clinic including a final visit at Day 120 for a safety follow-up assessment.

This work was supported by the US Army Medical Research and Materiel Command under Contract No. W81XWH-12-C-0278.

The views, opinions and/or findings contained in this report are those of the author(s) and should not be construed as an official Department of the Army position, policy or decision unless so designated by other documentation.

Inclusion Criteria:

1. Men and women at least 18 years and ≤ 45 years of age at time of screening.
2. In good health as determined by medical history and physical examination (including blood pressure and heart rate).
3. Weight: Body Mass Index (BMI) ≤ 35.
4. Blood tests negative for antibodies to human immunodeficiency virus-1 (HIV-1), Hepatitis C, and Hepatitis B surface antigen.
5. Females who are not surgically sterile or post-menopausal must have a negative urine pregnancy test immediately prior to vaccination and be willing to use oral, implantable, transdermal or injectable contraceptives or another reliable means of contraception approved by the Investigator (intrauterine device, female condom, diaphragm with spermicidal foam, cervical cap, use of condom by the sexual partner or a sterile sexual partner, or abstinence) from screening until the blood sample on Day 120.
6. Willing and able to give written informed consent to participate.
7. Willing and able to communicate with the Investigator and understand the requirements of the study.
8. Access to a fixed or mobile telephone.

Exclusion Criteria

1. Any condition which would limit the participant's ability to complete the study in the opinion of the Investigator.
2. Any Grade 2 or above abnormality in the screening laboratory tests.
3. Febrile illness (temperature ≥ 38°C or 100.4°F) or moderate or severe acute illness or infection within three days before vaccination.
4. History of any significant dermatologic disease in the last 6 months, particularly with a maculopapular or petechial rash. However, if a participant had a self-limited Candida infection that was cured, then the participant can be enrolled if there is no evidence of an infection for at least 3 weeks prior to the date of dosing. If the participant has acne limited to the face, topical medications are allowed except for 2 weeks prior and 4 weeks after each dose. Oral medications for acne are excluded for 1 month prior to the start of dosing.
5. History of dengue fever, Japanese encephalitis, West Nile, or Yellow Fever disease.
6. Seropositivity to dengue or West Nile (WN) virus.
7. History of travel to dengue endemic areas including the Caribbean, Mexico, Central America, South America or Southeast Asia during the month prior to screening, or planned travel to a dengue endemic area during the study period.
8. Extensive scarring or tattoo (> 50%) on arms, shoulders, neck, face and head that could identify a participant in photos or hinder the evaluation of injection site reactions. In addition, no tattoo on the arms is permitted during the study and for one month after the final injection.
9. History of recurring headaches or migraines (more frequent than once per week) or on prescription medication for treatment of recurring headaches or migraines.
10. Hypersensitivity to any vaccine.
11. Receipt or planned receipt of any vaccine in the 4 weeks preceding or following the Day 0 or 90 injections.
12. Previous vaccination (in a clinical trial or with an approved product) against yellow fever (YF) or Japanese Encephalitis (JE).
13. Known or suspected congenital or acquired immunodeficiency or immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, within the preceding 6 months.
14. Use of systemic corticosteroids therapy within the previous 6 months (at a dose of at least 0.5 mg/kg/day prednisone equivalent). Topical prednisone is not permitted if currently in use or used within the last month. Inhaled prednisone is permitted.
15. Use of any non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen or antihistamines for the 3 days immediately prior to each vaccination.
16. History of diabetes mellitus.
17. History of thymic pathology, thymectomy, myasthenia or any immunodeficiency.
18. Positive urine screen for cocaine, amphetamines, opiates, or cannabinoids
19. Known history of alcohol abuse.
20. Receipt of any other investigational product or participation in any other clinical trial of a product or device within 30 days before the first vaccination (Day 0) or planned participation in any other clinical trial while enrolled in this trial (though Day 120).
21. Receipt of blood products or immunoglobulins 8 weeks before the first vaccination (Day 0) or planned use during the period of this study (through Day 120).
22. Planned donation of blood during the period of this study (through Day 120).
23. Females who are pregnant or lactating.

Safety Analysis Set included all enrolled participants who received at least 1 dose of study vaccine and for whom any post-vaccination safety data has been obtained.

Unsolicited AEs: up to 30 days after each vaccination; SAEs: throughout the study (Up to Day 120)

At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study vaccine.

Due to protocol non-compliance issues, sponsor decided to only report safety data.