Evaluating the Safety and Effectiveness of a Dengue Virus Vaccine in Healthy Adults

There are 4 types of dengue virus (DENV-1, DENV-2, DENV-3, and DENV-4); each can cause
dengue illness ranging from a mild illness to life-threatening disease. More than 2 billion
persons in tropical and subtropical regions of the world are at risk for acquiring dengue,
which is why development of a dengue vaccine is a top public health priority.

The purpose of this study is to evaluate the ability of a single dose of TetraVax-DV-TV003
(TV003) vaccine to protect against infection with rDEN2∆30, an attenuated candidate DENV-2
vaccine.

This study will enroll healthy adults with no history of previous infection with a
flavivirus (any of a group of viruses that includes the dengue virus). Participants will be
randomly assigned to receive either the TV003 vaccine or placebo vaccine on Day 0 (study
entry). At Day 180, all participants will receive an injection of the "challenge" virus,
rDEN2∆30, an attenuated (weakened) DENV-2 vaccine. For at least 30 minutes after each
vaccination, participants will remain in the study clinic to be monitored for any adverse
effects of the vaccines. Participants will record their temperature at least 3 times a day
for 16 days after the first and second vaccinations.

In addition to vaccination visits at Day 0 and Day 180, participants will attend study
visits at Day 2, 4, 6, 8, 10, 12, 14, 16, 21, 28, 56, 90, 150, 182, 184, 186, 188, 190, 192,
194, 196, 201, 208, 236, 270, and 360. At all study visits, participants will give a medical
history and undergo a blood collection; at most study visits, participants will undergo a
physical examination. Female participants will have a pregnancy test at select study visits.

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 after second
inoculation

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

- Females Only: Female participants of childbearing potential willing to use effective
contraception. Reliable methods of contraception include: hormonal birth control,
condoms with spermicide, diaphragm with spermicide, surgical sterilization,
intrauterine device, and abstinence (6 months or more since last sexual encounter).
All female participants will be considered having child-bearing potential except for
those with hysterectomy, tubal ligation, tubal coil (at least 3 months prior to
vaccination), or post-menopausal status documented as at least 1 year since last
menstrual period.

Exclusion Criteria:

- Females Only: Currently pregnant, as determined by positive beta-human
choriogonadotropin (HCG) test, breast-feeding

- 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 the study
protocol.

- Any other condition that in the opinion of the investigator would jeopardize the
safety or rights of a participant participating 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 which 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
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 14
days or longer.

- 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

- History or serologic evidence of previous dengue virus infection or other flavivirus
infection (e.g., yellow fever virus, St. Louis encephalitis virus, West Nile virus)

- Previous receipt of a flavivirus vaccine (licensed or experimental)

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

- Participant 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 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 the second dose

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

- Females Only: Female participants of childbearing potential willing to use effective
contraception for the duration of the trial. Reliable methods of contraception
include: hormonal birth control, condoms with spermicide, diaphragm with spermicide,
surgical sterilization, intrauterine device, and abstinence (6 months or more since
last sexual encounter). All female participants will be considered having
child-bearing potential except for those with hysterectomy, tubal ligation, tubal
coil (at least 3 months prior to vaccination), or post-menopausal status documented
as at least 1 year since last menstrual period.

Exclusion Criteria for Second Vaccine

- Anaphylaxis or angioedema following the first dose of vaccine

- Females Only: Currently pregnant, as determined by positive beta-HCG test,
breast-feeding

- 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

- Any other condition that in the opinion of the investigator would jeopardize the
safety or rights of a participant participating 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 which 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
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 14
days or longer.

- 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

- Participant 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 Study Days 28 and 56 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.

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

- Chronic administration (14 days or longer) 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 after vaccination (topical
and nasal steroids are allowed)

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

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

- Pregnancy