Safety and Immunogenicity of Three Formulations of Takeda's Tetravalent Dengue Vaccine Candidate (TDV)

The vaccine being tested in this study is Takeda's Tetravalent Dengue Vaccine Candidate
(TDV). This study is designed to determine whether the lyophilized formulation provides
equivalent safety and immunogenicity as the original liquid formulation. An exploratory
analysis has been added for the purpose of understanding whether there is a manufacturing or
formulation effect on the vaccine.

The study will enroll approximately 1000 participants. Participants will be randomly assigned
(by chance, like flipping a coin) to one of the four study groups—which will remain
undisclosed to the participant and study doctor during the study (unless there is an urgent
medical need):

- Group A: TDV Liquid Formulation 1, subcutaneous (SC) injection on Day 1 and placebo
(dummy) SC at Month 3 - this is a liquid that looks like the study drug but has no
active ingredient

- Group B: TDV Liquid Formulation 1, SC injection Day 1 and Month 3

- Group C: TDV Liquid Formulation 2, SC injection Day 1 and Month 3

- Group D: TDV Lyophilized formulation SC injection Day 1 and Month 3

In order to keep the treatment arms undisclosed to the participant and the doctor,
participants will receive a placebo injection at any study visit where TDV is not being
administered (Month 3). Participants will be asked to record any adverse events that may be
related to the vaccine or the injection in a diary card for 28 days after each vaccination.

This multi-center trial will be conducted in the United States. The overall time to
participate in this study is up to 10 months. Participants will make 9 visits to the clinic
including a final visit 1 month after last dose of study drug for a follow-up assessment. A
follow up phone call will be done 6 months after the last dose to assess serious adverse
events.

Inclusion Criteria:

1. Is aged 18 to 49 years, at the time of enrollment inclusive.

2. Individuals who are in good health at the time of entry into the trial as determined
by medical history, physical examination (including vital signs) and clinical judgment
of the investigator.

3. Signs and dates a written, informed consent form and any required privacy
authorization prior to the initiation of any trial procedures, after the nature of the
trial has been explained according to local regulatory requirements.

4. Individuals who can comply with trial procedures and are available for the duration of
follow-up.

Exclusion Criteria:

1. Febrile illness (temperature ≥ 38°C or 100.4°F) or moderate or severe acute illness or
infection at the time of enrollment. Trial entry should be delayed until the illness
has improved.

2. History or any illness that, in the opinion of the investigator, might interfere with
the results of the trial or pose additional risk to the participants due to
participation in the trial, including but not limited to: a. Known hypersensitivity or
allergy to any of the vaccine components; b. Individuals with history of substance or
alcohol abuse within the past 6 months; c. Female participants who are pregnant or
breastfeeding; d. Individuals with any serious chronic or progressive disease
according to judgment of the investigator (e.g., neoplasm, insulin dependent diabetes,
cardiac, renal or hepatic disease, neurologic or seizure disorder or Guillain-Barré
syndrome); e. Known or suspected impairment/alteration of immune function, including:
i. Chronic use of oral steroids (equivalent to 20 mg/day prednisone ≥ 12 weeks / ≥ 2
mg/kg body weight / day prednisone ≥ 2 weeks) within 60 days prior to Day 1 (use of
inhaled, intranasal, or topical corticosteroids is allowed); Receipt of parenteral
steroids (equivalent to 20 mg/day prednisone ≥ 12 weeks / ≥ 2 mg/kg body weight / day
prednisone ≥ 2 weeks) within 60 days prior to Day 1; iii. Administration of
immunoglobulins and/or any blood products within the three months preceding the first
administration of the investigational vaccine or planned administration during the
trial; iv. Receipt of immunostimulants within 60 days prior to Day 1; v.
Immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within
6 months preceding (first) vaccination; vi. human immunodeficiency virus (HIV)
infection or HIV-related disease; vii. Genetic immunodeficiency.

3. Individuals who received any other vaccines within 14 days (for inactivated vaccines)
or 28 days (for live vaccines) prior to enrollment in this trial or who are planning
to receive any vaccine within 28 days of investigational vaccine administration.

4. Individuals participating in any clinical trial with another investigational product
30 days prior to first trial visit or intent to participate in another clinical trial
at any time during the conduct of this trial.

5. Individuals who are first degree relatives of individuals involved in trial conduct.

6. If female of childbearing potential, sexually active, and has not used any of the
acceptable contraceptive methods for at least 2 months prior to trial entry: a. Of
childbearing potential is defined as status post onset of menarche and not meeting any
of the following conditions: menopausal (for at least 2 years), bilateral tubal
ligation (at least 1 year previously), bilateral oophorectomy (at least 1 year
previously) or hysterectomy; b. Acceptable birth control methods are defined as one or
more of the following: i. Hormonal contraceptive (such as oral, injection, transdermal
patch, implant, cervical ring); ii. Barrier (condom with spermicide or diaphragm with
spermicide) each and every time during intercourse; iii. Intrauterine device (IUD);
iv. Monogamous relationship with vasectomized partner. Partner must have been
vasectomized for at least six months prior to the participants' trial entry.

7. If female of childbearing potential, sexually active and refuses to use an acceptable
contraceptive method through to 6 weeks after the last dose of investigational
vaccine.

8. Individuals with body mass index (BMI) greater than or equal to 35.

9. Participants who received previous vaccination (in a clinical trial or with an
approved product) against flaviviruses including dengue, yellow fever (YF), West Nile
(WN), Japanese Encephalitis (JE), and St. Louis encephalitis.

10. Documented or suspected disease caused by dengue, JE, WN, YF virus, and/or St. Louis
encephalitis.

11. History of travel to dengue endemic areas including the Caribbean, Mexico, Central
America, South America or Southeast Asia during the 6 months prior to screening or
planned travel to a dengue endemic area during the study period.

12. Clinically significant abnormality in the screening laboratory tests as judged by the
Investigator.

13. History of recurring headaches or migraines (more frequent than once per week) or on
prescription medication for treatment of recurring headaches or migraines.

14. Blood tests positive for antibodies to HIV-1/2, Hepatitis C and Hepatitis B surface
antigen.