Influenza A H3N2 Human Challenge Study in Healthy Adult Volunteers

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.

Although studies of influenza in healthy volunteers have played an important role in
addressing aspects of the natural history of influenza disease and developing novel
antivirals, prior to recently these important studies had not been performed in the US in
over a decade. The H1N1 challenge studies we have performed since 2012 have sought to improve
upon the studies done in the past and address many of the limitations due to the scope of the
studies and/or the scientific techniques available at that time. We have successfully
developed an H1N1 model that had been used to address important questions regarding
correlates of protection and is now being implemented to develop new drugs and vaccines. We
hope to develop H3N2 models that can be just as useful.

The primary objective of this study is to determine the dose of influenza A H3N2 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 H3N2 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 H3N2
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
breastfeeding and meets 1 of the following criteria:

- Of nonchildbearing potential (i.e., women who have had a hysterectomy or tubal
ligation or are postmenopausal, as defined by no menses in more 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. Pre-challenge serum hemaglutination-inhibition titer against the challenge strain of
less than 1:40.

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., insulin-dependent diabetes mellitus, renal
dysfunction, hemoglobinopathies).

4. Immunosuppression or ongoing malignancy.

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

6. Post infectious or post vaccine 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 more than or equal to 65 years of age.

2. Children less than or equal to 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 medical conditions (e.g., insulindependent diabetes
mellitus, renal dysfunction, hemoglobinopathies).

- Immunosuppression or cancer.

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

- Persons who are receiving long-term aspirin therapy.

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

3. Individual with body mass index (BMI) less than or equal to 18.5 and more than 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 as deemed by the PI on electrocardiogram (EKG)

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

10. Clinically significant abnormality as deemed by the PI on the Pulmonary Function Test
(PFT).

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

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

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

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

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

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

17. 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).

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

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

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