Safety of a Live Attenuated Human Parainfluenza Virus Type 2 (HPIV2) Vaccine for Adults, Children, and Infants

HPIV2 is a virus that can cause severe respiratory illnesses, such as pneumonia and
bronchiolitis, in infants and young children. Approximately 3% of all hospitalizations for
respiratory tract diseases among infants and children are the result of HPIV2. Efforts to
develop a vaccine for HPIV2 have focused on a live attenuated intranasally administered
vaccine, a type of vaccine that uses a live virus that has been modified to make it weaker
and easier for the immune system to get rid of. This approach is useful for several reasons:
it activates two of the body's natural defenses, the antibody-mediated and the cell-mediated
responses; it is immunogenic in infants who still have maternal antibodies; and it induces a
mucosal immune response. This study will test the safety and immunogenicity of an HPIV2
vaccine in adults, children, and then infants.

This study will have four groups and will proceed in a step-wise fashion. The first group
will consist only of adults receiving the HPIV2 vaccine. If it is deemed safe after that,
children from ages 15 to 59 months who already have HPIV2 antibodies will be randomly
assigned to receive either the vaccine or a placebo. The third group includes infants and
children from 6 to 59 months old who do not have HPIV2 antibodies and will be randomly
assigned either a lower dose of the vaccine or a placebo. The fourth group also includes
infants and children from 6 to 59 months old who do not have HPIV2 antibodies and will be
randomly assigned a standard dose vaccine or placebo. The vaccine will be administered as a
nose drop in a single dose for all groups.

Assessments for the first two groups will take place over the 11 days following
administration of the vaccine and at a 28-day follow-up. The third and fourth groups will
include 22 days of assessments after vaccination, one assessment between Days 23 and 26, and
assessments on Days 27, 28, 29, and 56. Measures will include a clinical assessment, a nasal
wash, a phone report, and taking a temperature. Measurement of serum HPIV2 antibodies will
take place at baseline and after 28 (for groups one and two) or 56 (for groups three and
four) days.

Inclusion Criteria for Adults:

- 18 to 49 years old

- In good health, measured by lack of significant medical illness, physical examination
findings, or significant laboratory abnormalities of urinalysis, complete blood count
(CBC), ALT, or creatinine, as determined by the investigator

Exclusion Criteria for Adults:

- Pregnancy

- Breastfeeding

- Females of childbearing potential who are unwilling to practice effective birth
control

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

- 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

- Other condition that, in the opinion of the investigator, would jeopardize the safety
or rights of a participant participating in the study or would render the participant
unable to comply with the protocol

- 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

- History of splenectomy

- Diagnosis of asthma within the past 2 years

- Positive enzyme-linked immunoassay (ELISA) and confirmatory Western blot tests for
HIV-1

- Positive ELISA and confirmatory immunoblot tests for hepatitis C virus (HCV)

- Positive ELISA hepatitis B surface antigen (HBsAg) test

- Abnormal urinalysis or urine dip

- Known immunodeficiency syndrome

- Current use of nasal or systemic steroid medications

- Receipt of blood products (including immunoglobulin) within the past 3 months

- Current smoker unwilling to stop smoking for the duration of the study

- Participation in another investigational vaccine or drug study within 30 days of
receiving the investigational vaccine

- Receipt of a live vaccine within the past 4 weeks or a killed vaccine within the past
2 weeks or immune globulin within the last 3 months prior to receiving the
investigational vaccine

- Previous immunization with an HPIV2 vaccine

- Known hypersensitivity to any vaccine component

- Professional or personal responsibilities involve caring for children less than 59
months of age or for immunosuppressed individuals

- Systolic blood pressure greater than 140 mm Hg or diastolic blood pressure greater
than 90 mm Hg

- Body mass Index (BMI) greater than 35

Inclusion Criteria for Seropositive Children:

- Children 15 to 59 months of age

- Parent or guardian understands and signs the informed consent

- Seropositive for HPIV2, as defined by serum hemagglutinin inhibition (HAI) antibody
titer in ratio greater than 1:8

- History has been reviewed and participant has undergone a physical examination
indicating good health

- Participant is expected to be available for the duration of the study

Exclusion Criteria for Seropositive Children:

- Known or suspected impairment of immunological functions, including maternal history
of positive HIV test, receiving immunosuppressive therapy, including systemic
corticosteroids or bone marrow/solid organ transplant recipients (topical steroids,
topical antibiotics, and topical antifungal medications are acceptable)

- Major congenital malformations, including congenital cleft palate, cytogenetic
abnormalities, or serious chronic disorders

- Previous immunization with an HPIV2 vaccine

- Current use of nasal or systemic steroid medications

- Previous serious vaccine-associated adverse event or anaphylactic reaction

- Known hypersensitivity to any vaccine component

- Lung or heart disease, including reactive airway disease. Participants with
clinically insignificant cardiac abnormalities requiring no treatment may be
enrolled. Participants who wheezed once or received bronchodilator therapy once in
the first year of life but who have not had any additional wheezing episodes or
bronchodilator therapy for at least 12 months may also be enrolled.

- Member of a household that includes an immunocompromised individual or infants less
than 6 months of age

- Attends day care with infants less than 6 months of age or immunosuppressed
individuals, and parent or guardian is unable or unwilling to suspend daycare for 14
days following immunization. Children who attend facilities that separate children by
age and minimize opportunities for transmission of virus through direct physical or
aerosol contact are acceptable

- Participation in another investigational vaccine or drug trial within 30 days of
receiving the investigational vaccine, or while this study is ongoing

Inclusion Criteria for Seronegative Infants and Children:

- Children and infants 6 to 59 months of age

- Parents or guardians can understand and sign the informed consent

- Seronegative for HPIV2 antibody, as defined by serum antibody titer HAI ratio less
than or equal to 1:8, as determined within 28 days prior to inoculation

- History has been reviewed and subject has undergone a physical examination indicating
good health

- Participant is expected to be available for the duration of the study

Exclusion Criteria for Seronegative Infants and Children:

- Known or suspected impairment of immunological functions, including maternal history
of positive HIV test, receiving immunosuppressive therapy, including systemic
corticosteroids or bone marrow/solid organ transplant recipients (topical steroids,
topical antibiotics, and topical antifungal medications are acceptable)

- Major congenital malformations, including congenital cleft palate, cytogenetic
abnormalities, or serious chronic disorders

- Previous immunization with an HPIV2 vaccine

- Current use of nasal or systemic steroid medications

- Previous serious vaccine-associated adverse event or anaphylactic reaction

- Known hypersensitivity to any vaccine component

- Lung or heart disease, including reactive airway disease. Participants with
clinically insignificant cardiac abnormalities requiring no treatment and those who
wheezed once or received bronchodilator therapy once in the first year of life but
who have not had any additional wheezing episodes or bronchodilator therapy for at
least 12 months may be enrolled.

- Member of a household that includes an immunocompromised individual or infant less
than 6 months of age

- Attends day care with infants less than 6 months of age or immunosuppressed
individuals, and parent or guardian is unable or unwilling to suspend daycare for 14
days following immunization. Children who attend facilities that separate children by
age and minimize opportunities for transmission of virus through direct physical or
aerosol contact are acceptable.

- Participation in another investigational vaccine or drug trial within 28 days of
receiving the investigational vaccine, or while this study is ongoing