Evaluating the Safety and Immunogenicity of a Live Attenuated West Nile Virus Vaccine for West Nile Encephalitis in Adults 50 to 65 Years of Age

WNV is the leading vector-borne cause of viral encephalitis in the United States. Severe
illness is most common in older adults, and in this population, the virus can cause
hepatitis, meningitis, and encephalitis leading to paralysis, coma, and death. WNV illness
is a public health issue and is an emerging disease in the United States. This study will
evaluate the safety and immunogenicity of a live attenuated West Nile/dengue chimeric virus
vaccine (WN/DEN4Δ30) for the prevention of West Nile encephalitis in adults 50 to 65 years
old.

This study will enroll healthy adults, 50 to 65 years old, who have no history of previous
flavivirus infection. Participants will be randomly assigned to receive the WN/DEN4Δ30
vaccine or placebo vaccine at study entry (Day 0). At the entry visit, participants will
undergo a medical history review, physical examination, blood collection, and vital sign
measurements; female participants will also take a pregnancy test. Participants will then
receive their assigned vaccine, and they will remain in the clinic for 30 minutes after the
vaccination for monitoring. Participants will record their temperature and symptoms 3 times
a day for 16 days after each vaccination. Additional study visits will occur on Days 3, 6,
8, 10, 12, 14, 16, 21, 28, 56, 90, and 150. These visits may include the same study
procedures that occurred at the entry visit. At a study visit on Day 180, participants will
receive another dose of their assigned vaccine. Additional study visits will occur on Days
183, 186, 188, 190, 192, 194, 196, 201, 208, 236, 270, and 360. All study procedures after
the second vaccination will be the same that occurred after the first vaccination.

Inclusion Criteria:

- Adult males and non-pregnant, non-breastfeeding females between 50 and 65 years of
age, inclusive. Children will not be recruited or enrolled in this study for safety
considerations.

- Good general health, as determined by means of the screening procedures

- Available for the duration of the trial

- Willingness to participate in the study as evidenced by signing the informed consent
form (ICF)

Exclusion Criteria:

- Pregnancy, as determined by positive beta-human choriogonadotropin (HCG) test (if
female)

- Currently lactating and breastfeeding (if female)

- Participant is unwilling to use reliable contraception methods for the duration of
the trial (reliable methods of birth control include: pharmacologic contraceptives
including oral, parenteral, and transcutaneous delivery; condoms with spermicide;
diaphragm with spermicide; surgical sterilization; intrauterine device; abstinence;
and post-menopausal documented for at least 1 year). All female participants will be
considered as having childbearing potential except for those with documented
hysterectomy, tubal ligation, tubal coil (at least 3 months prior to vaccination), or
who are post-menopausal for at least 1 year since last menstrual period.

- 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 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

- 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

- Participant has had medical, occupational, or family problems as a result of alcohol
or illicit drug use during the past 12 months

- History of a severe allergic reaction or anaphylaxis

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

- Positive HIV-1 serology by screening and confirmatory assays

- Positive for hepatitis C virus (HCV) by screening and confirmatory assays

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

- Any confirmed or suspected immunosuppressive or immune modulating disorder (e.g.,
asplenia, lupus, rheumatoid arthritis, vasculitis, scleroderma, and diabetes
mellitus)

- 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 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

- History of a surgical splenectomy

- Receipt of blood products within the past 3 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 WNV infection or other flavivirus infection
(e.g., yellow fever virus, St. Louis encephalitis virus, and dengue virus)

- Previous receipt of yellow fever, WNV, or dengue vaccine (licensed or
investigational)

- Receipt of any investigational agent in the past 28 days or anticipation of receipt
of any investigational agent within 28 days following vaccination

- Refusal to allow storage of specimens for future research

Inclusion Criteria for Second Dose:

- 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

- Ongoing willingness to participate in the study

- 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 (greater than 6 months
since last sexual encounter). All female participants will be considered as having
childbearing potential except for those with documented hysterectomy, tubal ligation,
tubal coil (at least 3 months prior to vaccination), or who are post-menopausal for
least 1 year since last menstrual period.

Exclusion Criteria for Second Dose:

- Anaphylaxis or angioedema following the first dose of vaccine

- Females only: 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 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 confirmed or suspected immunosuppressive or immune modulating disorder (e.g.,
asplenia, lupus, rheumatoid arthritis, vasculitis, scleroderma, or diabetes mellitus)

- Current use of anticoagulant medications

- 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 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

- History of surgical splenectomy

- Receipt of blood products within the past 3 months, including transfusions or
immunoglobulin or anticipated receipt of any blood products or immunoglobulin during
the 28 days following vaccination

- Receipt of any other investigational agent in the 28 days before vaccination or
anticipated within 28 days following vaccination

- Refusal to allow storage of specimens for future research