Evaluation of Anti-Hemagglutinin (Anti-HA) Antibodies as Protection From the Flu in Healthy People

The high morbidity and mortality associated with both pandemic and seasonal influenza, and
the threat of new pandemic strains emerging, continues to keep influenza at the forefront of
infectious disease and public health research. Mean annual estimates of influenza deaths due
to seasonal influenza alone, attributes 36,000 deaths in the US and 250,000 to 500,000
deaths in industrialized countries to influenza. Pandemics can have an even more devastating
effect, and we must continue to be prepared by making attempts to reduce the public health
impact of this important virus.

Currently, influenza vaccination is the cornerstone of prophylaxis and most effective method
available to reduce the impact of influenza on the world s population each year. Data from
the 2013 influenza season suggest that current seasonal vaccines held to these standards are
greatly underperforming especially in those that really need protection such as the elderly,
young, and infirmed.

Multiple factors could play a role in defining the true correlates of protection to
influenza infection and disease and many of these factors are yet to be clearly defined. In
our own influenza challenge study, protocol 12-I-0077, we have clearly seen evidence that
not everyone with a low HAI titer is susceptible to influenza, and that there must be other
factors protecting certain individuals. There are many examples like this that demonstrate
that there may be much more to immune protection to influenza than just anti-HA antibodies.

Live virus challenge studies have played an important role in defining the correlates of
protection of influenza in the past, and we believe they can continue to do so in the
future. Since the last time a wild-type influenza challenge has been performed to
investigate correlates of protection over 20 years ago, many new scientific tools and a
significant increase in knowledge of the immune system have developed. In this study we will
enroll participants at different hemagglutinin inhibition titer levels and evaluate this as
a correlate of protection to the 2009 H1N1 while exploring the other possible correlates of
protection that may be identified. This study represents the first opportunity to examine
the correlates of protection of influenza in a fully validated and described wild-type virus
challenge model. We believe that studies like this are an ideal use of a wild-type influenza
challenge study and can lead to intelligent universal vaccine design as well as a basis to
begin evaluating novel vaccine strategies in wild-type challenge studies in the future.

-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 greater 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 (HAI) titer against the challenge
virus of greater than or equal to 1:40 or less than or equal to 1:10 during a
screening visit in protocol #11-I-0183

7. HIV uninfected.

EXCLUSION CRITEIRA:

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 greater 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 metabolic disease (e.g., diabetes mellitus,
renal dysfunction, hemoglobinopathies).

- Immunosuppression or cancer.

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

- Individuals 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. Neutropenia below 1,500 cells/mm(3) (Grade 2 or greater)

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

9. Clinically significant abnormality on electrocardiogram.

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

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

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

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

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

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

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

17. Receipt of any non-influenza related unlicensed vaccine within 6 months prior to
enrollment.

18. 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 tetrahydrocannabinol (THC) or metabolites).

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

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

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