Challenge Infection of Healthy Adult Volunteers With RSV A2

Respiratory syncytial virus (RSV) is the leading cause of pediatric lower respiratory tract
infection. RSV also causes lower respiratory tract disease in the elderly and
life-threatening disease in immunocompromised hosts. An RSV monoclonal antibody (palivizumab)
is currently available for passive immunoprophylaxis in high-risk infants. Vaccines and
antiviral agents are under development for the treatment and prevention of RSV, but none are
licensed. The ability to challenge healthy volunteers with RSV could rapidly facilitate
efficacy studies of future antivirals and vaccines. In addition, challenge studies would
provide critical information on viral pathogenesis, including types of cells infected,
mucosal and systemic immune response, and alterations in respiratory microbiota. Clinical
trial material for human challenge studies has been prepared from live recombinant
(complementary DNA-derived) RSV of subgroup A (RSV A2).

This study will be a phase 1 study in healthy adult male and non-pregnant female subjects 18
years to 50 years of age. The main purpose of the trial is to define the safety profile,
determine the frequency of RSV shedding in nasal wash, estimate RSV illness rates, and study
immune responses in subjects given 1 dose of 10^7 PFU of RSV A2 challenge virus using a nasal
atomizer. If RSV A2 is found to be sufficiently infectious in adults, then it may be used as
a challenge virus in future studies evaluating antivirals or the protective efficacy of RSV
vaccines, or in studies of the immunopathogenesis of RSV infection.

Subjects will be admitted to the NIH Clinical Center and receive a single intranasal dose of
10^6.3 PFU or 107 PFU of RSV A2. Subjects will remain at the Clinical Center for
approximately 9-14 days after challenge infection undergoing sequential clinical evaluations.
Research specimens, nasal washes and blood, will be collected for various research assays.
Subjects will be discharged when their daily nasal wash RSV result is negative for two days
in a row, and they do not have any signs or symptoms suggestive of possible RSV-associated
lower respiratory tract disease. Subjects will return for follow-up evaluation 28 and 56 days
after viral challenge.

- INCLUSION CRITERIA:

1. Age 18-50 years inclusive.

2. General good health, without significant medical illness, physical exam findings,
or significant laboratory abnormalities as determined by the investigator.

3. Willingness to stay confined to the inpatient unit for required study duration.

4. Willingness to have samples stored for future research.

5. Subjects must be of non-childbearing potential (e.g., surgically sterilized
(bilateral oophorectomy, bilateral tubal ligation, hysterectomy)) or, if of
child-bearing potential and sexually active with a partner who can get them
pregnant, must have in place an effective method of contraception for at least 30
days prior to administration of the challenge virus and until 30 days after
challenge virus

administration:

- intrauterine device (IUD) or equivalent

- hormonal contraceptives (e.g., consistent, continuous use of contraceptive
pill, patch, ring, implant, or injection)

---if participant uses contraceptive pill, patch, or ring, they must also
use a barrier method at the time of potentially reproductive sexual activity
(e.g., (male/female condom, cap, or diaphragm) plus spermicide)

- be in a monogamous relationship with a partner who has undergone a vasectomy
at least 180 days prior to first dose of study agent

6. A plaque reduction RSV neutralization titer < 8.0 log(2).

EXCLUSION CRITERIA:

1. Subject who was previously challenged with RSV A2.

2. Female subject who is pregnant or lactating OR planning to become pregnant from 30
days prior to inoculation through 30 days after inoculation.

3. Presence of self-reported or medically documented significant medical condition(s)
including but not limited to:

-Respiratory disease (e.g., chronic obstructive pulmonary disease, emphysema,
rhinitis, sinusitis) in adulthood, and additionally:

--A history of asthma within the past 5 years, or a current diagnosis of asthma or
reactive airway disease associated with

exercise, seasonal hay fever or allergic rhinitis

--Presence of any febrile illness or symptoms suggestive of a respiratory infection
within 2 weeks prior to inoculation.

- Any significant abnormality of the nose or nasopharynx, including recurrent
epistaxis within 90 days prior to viral inoculation or nasal or sinus surgery
within 180 days prior to viral inoculation.

- Chronic cardiovascular disease (e.g., congenstive heart failure, cardiomyopathy,
ischemic heart disease).

- Chronic neurological or neurodevelopmental conditions (e.g., cerebral palsy,
epilepsty, stroke, seizures).

- Ongoing malignancy.

- Chronic medical condition requiring close medical follow-up or hospitalization
during the past 5 years (e.g., diabetes mellitus, renal dysfunction,
hemoglobinopathy, autoimmune disease).

- An immunodeficiency.

4. Use of systemic corticosteroids exceeding 10 mg/day of prednisone equivalent and nasal
steroid preparations or immunosuppressive drugs within 30 days before inoculation and
within 60 days after. Low dose topical steroid preparations used for a discrete period
of time are permitted.

5. Inhaled bronchodilator or inhaled steroid use within the last 360 days or use after
upper respiratory tract infections.

6. Behavioral or cognitive impairment or psychiatric disease that in the opinion of the
investigator affects the ability of the subject to understand and cooperate with the
study protocol.

7. Complete blood count (CBC), AST, ALT, creatinine values or other screening labs or
tests (e.g. electrocardiogram (EKG), chest x-ray (CXR)) are outside of the NIH
Department of Laboratory Medicine normal reference range and deemed clinically
significant by the PI.

8. Positive FDA-approved HIV test obtained during screening procedures.

9. Positive serology for hepatitis C virus obtained during screening period.

10. Presence of hepatitis B surface antigen obtained during screening period.

11. A smoker of tobacco products or a routine marijuana smoker currently or in the past
year.

12. Current alcohol abuse or addiction.

13. Current illicit drug abuse or addiction.

14. Receipt of a licensed vaccine within 30 days prior to RSV A2 inoculation and planned
vaccination within 60 days after inoculation..

15. Receipt of blood or blood-derived products (including immunoglobulin) within 180 days
prior to viral inoculation. Receipt of packed red blood cells given for an emergent
indication in an otherwise healthy person, and not required as ongoing treatment, is
not exclusionary.

16. Receipt of an investigational agent or vaccine within 90 days prior to scheduled RSV
A2 inoculation and planned receipt within 60 days after inoculation.

17. A body mass index (BMI) less than or equal to 18.5 or greater than or equal to 37.0.

18. A medical, occupational, or family problem that would preclude the participant from
complying with all study requirements.

19. Shares household, works closely with, or has routine contact with a child (children) <
5 years of age or with immunocompromised individual(s), adult(s) with significant
cardiopulmonary disease or asthma, institutionalized persons or persons with
functional disability, or any other individual that, in the judgment of the PI, might
be at increased risk for complications if exposed to RSV.

20. Deprived of freedom by an administrative or court order or in an emergency setting.

21. Any condition that in the opinion of the PI would jeopardize the safety or rights of a
person participating in the trial or would render the person unable to comply with the
protocol.