Evaluating the Safety and Immune Response to Two Doses of a Dengue Virus Vaccine Administered 12 Months Apart

Dengue viruses are a major health concern, particularly in the tropical and subtropical
regions of the world. The World Health Organization (WHO) has made the development of a
dengue vaccine a top priority. There are four types of dengue viruses (DEN1, DEN2, DEN3, and
DEN4), each of which can cause various illnesses, including dengue fever, or the more severe
disease, dengue hemorrhagic fever/shock syndrome (DHF/DSS). This study will evaluate the
safety and immune response to two doses of a dengue virus vaccine (TV003) when administered
12 months apart in healthy adults. The study will also evaluate whether the candidate
vaccine may protect against all four types of dengue viruses.

Participants will be randomly assigned to receive the TV003 study vaccine or placebo
vaccine. At study entry, participants will undergo a blood collection and physical
examination, and female participants will take a pregnancy test. Participants will then
receive an injection of their assigned vaccine. They will take their temperature three times
a day for 16 days after each vaccination and record the results on a diary card, which
research staff will review during participants' study visits. Additional study visits will
occur on Days 3, 10, 14, 21, 28, 56, 90, 180, 270, and 330. All study visits will include
blood collection and a physical examination; select visits will include a pregnancy test for
female participants. At a study visit on Day 360, all participants will receive an injection
of the same vaccine they received at study entry. Additional study visits will occur on Days
363, 370, 374, 381, 388, 416, 450, and 540, and will include the same study procedures as
previously performed.

Inclusion Criteria:

- Good general health as determined by physical examination, laboratory screening, and
review of medical history

- Available for the duration of the study, approximately 26 weeks post-second
vaccination

- Willingness to participate in the study as evidenced by signing the informed consent
document

- Female participants of childbearing potential willing to use effective contraception
for the duration of the trial. More information on this criterion can be found in the
protocol.

Exclusion Criteria:

- Currently pregnant, as determined by positive beta-human choriogonadotropin (HCG)
test, or breastfeeding

- Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic,
rheumatologic, autoimmune, or renal disease by history, physical examination, and/or
laboratory studies

- Behavioral, cognitive, or psychiatric disease that in the opinion of the investigator
affects the ability of the participant to understand and cooperate with the
requirements of the study protocol

- Screening laboratory values of Grade 1 or above for absolute neutrophil count (ANC),
alanine aminotransferase (ALT), and serum creatinine, as defined in this protocol

- Any other condition that in the opinion of the investigator would jeopardize the
safety or rights of a participant in the trial or would render the participant unable
to comply with the protocol

- Any significant alcohol or drug abuse in the past 12 months that has caused medical,
occupational, or family problems, as indicated by participant history

- History of a severe allergic reaction or anaphylaxis

- Severe asthma (emergency room visit or hospitalization within the last 6 months)

- HIV infection, by screening and confirmatory assays

- Hepatitis C virus (HCV) infection, by screening and confirmatory assays

- Hepatitis B virus (HBV) infection, by hepatitis B surface antigen (HBsAg) screening

- Any known immunodeficiency syndrome

- Use of anticoagulant medications

- Use of corticosteroids (excluding topical or nasal) or immunosuppressive drugs within
42 days prior to or following vaccination. Immunosuppressive dose of corticosteroids
is defined as greater than or equal to 10 mg prednisone equivalent per day for
greater than or equal to 14 days.

- Receipt of a live vaccine within 28 days or a killed vaccine within the 14 days prior
to vaccination or anticipated receipt of any vaccine during the 28 days following
vaccination

- Asplenia

- Receipt of blood products within the past 6 months, including transfusions or
immunoglobulin or anticipated receipt of any blood products or immunoglobulin during
the 28 days following vaccination

- Anticipated receipt of any investigational agent in the 28 days before or after
vaccination

- Has definite plans to travel to a dengue endemic area during the study

- Refusal to allow storage of specimens for future research

Inclusion Criteria for Second Dose of Vaccine:

- Good general health as determined by physical examination and review of medical
history

- Available for the duration of the study, approximately 26 weeks after second dose

- Ongoing willingness to continue to participate in the study

- Female participants of childbearing potential willing to use effective contraception
for the duration of the trial. More information on this criterion can be found in the
protocol.

Exclusion Criteria for Second Dose of Vaccine:

- Anaphylaxis or angioedema following the first dose of vaccine

- Currently pregnant (as determined by positive beta-HCG test), breastfeeding, or, for
those of childbearing potential, no longer using a reliable method of contraception

- Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic,
rheumatologic, autoimmune, or renal disease by history, physical examination, and/or
laboratory studies

- Behavioral, cognitive, or psychiatric disease that in the opinion of the investigator
affects the ability of the participant to understand and cooperate with the
requirements of the study protocol

- Day 330 laboratory values of Grade 1 or above for serum ALT and creatinine, as
defined in this protocol

- Any other condition that in the opinion of the investigator would jeopardize the
safety or rights of a participant in the trial or would render the participant unable
to comply with the protocol

- Any significant alcohol or drug abuse in the past 12 months that has caused medical,
occupational, or family problems, as indicated by participant history

- History of a severe allergic reaction or anaphylaxis

- Severe asthma (emergency room visit or hospitalization within the last 6 months)

- HIV infection, by screening and confirmatory assays

- HCV infection, by screening and confirmatory assays

- HBV infection, by HBsAg screening

- Any known immunodeficiency syndrome

- Use of anticoagulant medications

- Use of corticosteroids (excluding topical or nasal) or immunosuppressive drugs within
28 days prior to or following vaccination. Immunosuppressive dose of corticosteroids
is defined as greater than or equal to 10 mg prednisone equivalent per day for
greater than or equal to 14 days.

- Receipt of a live vaccine within 28 days or a killed vaccine within the 14 days prior
to vaccination or anticipated receipt of any vaccine during the 28 days following
vaccination

- Asplenia

- Receipt of blood products within the past 6 months, including transfusions or
immunoglobulin or anticipated receipt of any blood products or immunoglobulin during
the 28 days following vaccination

- Anticipated receipt of any other investigational agent in the 28 days before or after
vaccination

- Has definite plans to travel to a dengue endemic area during the study

- Refusal to allow storage of specimens for future research

Other Treatments and Ongoing Exclusion Criteria:

The following criteria will be reviewed on Days 28, 56, and 90 following each vaccination.
If any become applicable during the study, the participant will not be included in further
immunogenicity evaluations, as of the exclusionary visit. The participant will, however,
be encouraged to remain in the study for safety evaluations for the duration of the study.

Ongoing Exclusion Criteria:

- Use of any investigational drug or investigational vaccine other than the study
vaccine during the 28-day period post-vaccination

- Chronic administration (greater than or equal to 14 days) of steroids (defined as
prednisone equivalent of greater than or equal to 10 mg per day), immunosuppressants,
or other immune-modifying drugs initiated during the 28-day period post-vaccination
(topical and nasal steroids are allowed)

- Receipt of a licensed vaccine during the 28-day period post-vaccination

- Receipt of immunoglobulins and/or any blood products during the 28-day period
post-vaccination

- Pregnancy