Influenza A 2009 H1N1 Challenge Study in Healthy Adults

The high morbidity and mortality associated with both pandemic and seasonal influenza, and
the anticipation of future influenza pandemics, puts influenza front and center in
infectious disease research. Because the natural history and pathogenesis of human influenza
has not been well characterized and cannot be adequately studied in animal models or with
current in vitro techniques, important questions about influenza pathogenesis can only be
approached through human challenge studies.

Previous human challenge studies have addressed some aspects of the natural history of
influenza by evaluating the timing of viral replication, shedding, clinical symptoms, and
innate and adaptive immune responses. Although these studies have provided important
information, in the United States, all but 1 were performed prior to 1990. Without
exception, these studies had limitations due to the scope of the study and/or the scientific
techniques available at that time.

The primary objective of this study is to determine the dose of influenza A 2009 H1N1 human
challenge virus that will induce a mild to moderate uncomplicated influenza infection in
healthy volunteers. This protocol will examine some of the basic questions that remain
unanswered regarding the pathogenesis of influenza in humans, namely, a detailed clinical
and immunological characterization of uncomplicated influenza viral pathogenesis in healthy
adult volunteers.

Secondary objectives will evaluate clinical disease, length of viral shedding, and
pathogenesis in those with influenza infection including identification of clinical markers
of the disease. Notably, the exploratory objectives will seek to discover viral factors
necessary for human infection/adaptation and to evaluate host immune response, viral
replication, viral fitness, and the intrahost evolution.

Collaboration between NIAID investigators and outside scientists will generate opportunities
to further develop and expand areas of clinical influenza research based on the proposed
challenge model.

-INCLUSION CRITERIA:

1. Greater than or equal to 18 and less than or equal to 50 years of age.

2. Agrees to not use tobacco products during participation in this study.

3. Willingness to remain in isolation for the duration of viral shedding (at a minimum 9
days) and to comply with all study requirements.

4. A female participant is eligible for this study if she is not pregnant or breast
feeding and 1 of the following:

- Of nonchildbearing potential (i.e., women who have had a hysterectomy or tubal
ligation or are postmenopausal, as defined by no menses in lessgreater than or
equal to 1 year).

- Of childbearing potential but agrees to practice effective contraception or
abstinence for 4 weeks prior to and 8 weeks after administration of the
influenza challenge virus. Acceptable methods of contraception include 1 or more
of the following: 1) male partner who is sterile prior to the female participant
s entry into the study and is the sole sexual partner for the female
participant; 2) implants of levonorgestrel; 3) injectable progestogen; 4) an
intrauterine device with a documented failure rate of < 1%; 5) oral
contraceptives; and 6) double barrier methods including diaphragm or condom with
a spermicide.

5. Willing to have samples stored for future research.

6. Prechallenge serum hemagglutination-inhibition titer against the challenge strain of
1:16 or less.

7. HIV uninfected.

EXCLUSION CRITERIA:

1. Presence of self-reported or medically documented significant medical condition
including but not limited to:

1. Chronic pulmonary disease (e.g., asthma, emphysema).

2. Chronic cardiovascular disease (e.g., cardiomyopathy, congestive heart failure,
cardiac surgery, ischemic heart disease, known anatomic defects).

3. Chronic medical conditions requiring close medical follow-up or hospitalization
during the past 5 years (e.g., diabetes mellitus, renal dysfunction,
hemoglobinopathies).

4. Immunosuppression or ongoing malignancy.

5. Neurological and neurodevelopmental conditions (e.g., cerebral palsy, epilepsy,
stroke, seizures).

6. Postinfectious or postvaccine neurological sequelae.

2. Have close or household (i.e., share the same apartment or house) high-risk contacts
including but not limited to:

1. Persons less greater than or equal to 65 years of age.

2. Children < 5 years of age.

3. Residents of nursing homes.

4. Persons of any age with significant chronic medical conditions such as:

- Chronic pulmonary disease (e.g., asthma).

- Chronic cardiovascular disease (e.g., cardiomyopathy, congestive heart
failure, cardiac surgery, ischemic heart disease, known anatomic defects).

- Contacts who required medical follow-up or hospitalization during the past
5 years because of chronic metabolic disease (e.g., diabetes mellitus,
renal dysfunction, hemoglobinopathies).

- Immunosuppression or cancer.

- Neurological and neurodevelopmental conditions (e.g., cerebral palsy,
epilepsy, stroke, seizures).

- Children and teenagers who are receiving long-term aspirin therapy.

- Women who are pregnant or who are trying to become pregnant.

3. Individual with body mass index (BMI) less than or equal to 18.5 and greater than
or equal to 40.

4. Smokes more than 4 cigarettes or other tobacco products on weekly basis.

5. Complete blood count (CBC) with differential outside of the NIH DLM normal reference
range and deemed clinically significant by the PI.

6. Chemistries in the acute care, mineral, and/or hepatic panels, and/or any of the
following: lactate dehydrogenase, uric acid, creatine kinase, and total protein
outside of the NIH DLM normal reference range and deemed clinically significant by
the PI.

7. Urinalysis outside of the NIH DLM normal reference range and deemed clinically
significant by the PI.

8. Clinically significant abnormality on electrocardiogram .

9. Clinically significant abnormality as deemed by the PI on echocardiographic testing.

10. Recent acute illness within 1 week of admission to the isolation facility.

11. Known allergy to treatments for influenza (including but not limited to oseltamivir,
nonsteroidals).

12. Known allergy to 2 or more classes of antibiotics (e.g., penicillins, cephalosporins,
floroquinolones, or glycopeptides).

13. Receipt of blood or blood products (including immunoglobulins) within 3 months prior
to enrollment.

14. Receipt of any unlicensed drug within 3 months or 5.5 half lives (whichever is
greater) prior to enrollment.

15. Receipt of any unlicensed vaccine within 6 months prior to enrollment.

16. Self-reported or known history of current alcoholism or drug abuse, or positive
urine/serum test for drugs of abuse (i.e., amphetamines, cocaine, benzodiazepines,
opiates, or metabolites, but not THC or metabolites).

17. Self-reported or known history of psychiatric or psychological issues deemed by the
PI to be a contraindication to protocol participation

18. Known close contact with anyone known to have influenza in the past 7 days.

19. Any condition that, in the judgment of the Principal Investigator, is a
contraindication to protocol participation or impairs the volunteer s ability to
give informed consent.