Evaluating the Safety and Immune Response to Two Admixtures of a Tetravalent Dengue Virus Vaccine

Dengue viruses cause dengue fever and the more severe condition, dengue hemorrhagic
fever/shock syndrome. Dengue viruses are common in most tropical and subtropical regions of
the world and infection with dengue viruses is the leading cause of hospitalization and
death in children in many tropical Asian countries. For these reasons, the World Health
Organization (WHO) has made the development of a dengue virus vaccine a top priority. This
study will evaluate the safety and immunogenicity of two doses of a live attenuated,
tetravalent dengue virus vaccine called TetraVax-DV in healthy adults (18-50 years old) who
have previously been infected with a dengue virus or other flavivirus or have previously
received a flavivirus vaccine. Two different formulations of the TetraVax-DV vaccine will be
evaluated.

Participants will be randomly assigned to receive one of two admixtures of the TetraVax-DV
vaccine or a placebo. At a baseline study visit (Day 0), participants will undergo a medical
history review, physical examination, blood collection, vital sign measurements, and a
pregnancy test for females. Participants will then receive one subcutaneous (SC) injection
of their assigned vaccine or placebo in the upper arm. After receiving the vaccine,
participants will remain in the clinic for 30 minutes for observation and monitoring. At
home, participants will monitor and record their temperature three times a day for 16 days
after the first vaccination (from Day 0 through Day 16) and for 16 days after the second
vaccination (from Day 180 through Day 196). Additional study visits will occur at Days 3, 8,
10, 12, 14, 16, 21, 28, 56, 90, and 150 and will include a physical examination, vital sign
measurements, and blood collection. On Day 180, participants will receive a second SC
injection of their assigned vaccine or placebo. Additional study visits will then occur at
Days 183, 188, 190, 192, 194, 196, 201, 208, 236, 270, and 360, and will include the same
study procedures and monitoring that occurred after the first vaccination.

Inclusion Criteria:

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

- Documented history or serologic evidence of previous dengue virus infection or other
flavivirus infection (e.g., yellow fever virus [YFV], St. Louis encephalitis virus
[SLE], West Nile virus [WNV], Japanese encephalitis virus [JEV], or tick-borne
encephalitis virus [TBEV]) or documented previous receipt of a flavivirus vaccine
(licensed or experimental)

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

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

- Female participants of childbearing potential must be 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 the 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 12 months prior to study entry that has
caused medical, occupational, or family problems, as indicated by a participant's
history

- History of a severe allergic reaction or anaphylaxis

- Severe asthma (emergency room visit or hospitalization within the 6 months prior to
study entry)

- 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 42 days following
vaccination

- Asplenia

- Receipt of blood products within the 6 months prior to study entry, including
transfusions or immunoglobulin or anticipated receipt of any blood products or
immunoglobulin during the 42 days following vaccination

- Anticipated receipt of any investigational agent in the 42 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

Additional Inclusion Criteria for Second Dose of Vaccine:

- In good general health, as determined by physical examination and review of medical
history

- Available for the duration of the study, approximately 6 months post-vaccination

- Female participants of childbearing potential must be 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, 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

- 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 12 months prior to study entry that has
caused medical, occupational, or family problems, as indicated by a participant's
history

- History of a severe allergic reaction or anaphylaxis

- Severe asthma (emergency room visit or hospitalization within the 6 months prior to
study entry)

- 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
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 42 days following
vaccination

- Asplenia

- Receipt of blood products within the 6 months prior to study entry, including
transfusions or immunoglobulin or anticipated receipt of any blood products or
immunoglobulin during the 42 days following vaccination

- Anticipated receipt of any other investigational agent in the 42 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 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.

Ongoing Exclusion Criteria:

- Use of any investigational drug or investigational vaccine other than the study
vaccine during the 42-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 42-day period post-vaccination
(topical and nasal steroids are allowed)

- Receipt of a licensed vaccine during the 42-day period post-vaccination

- Receipt of immunoglobulins and/or any blood products during the 42-day period
post-vaccination

- Pregnant