Mucosal and Systemic Immunity After Viral Challenge of Healthy Volunteers Vaccinated With Inactivated Influenza Vaccine Via the Intranasal Versus Intramuscular Route

The high morbidity and mortality associated with both pandemic and seasonal influenza and the
threat of new potentially pandemic strains emerging makes influenza an important infectious
disease and public health problem. Public health agencies must continue attempts to reduce
the public health impact of this important virus.

Currently, influenza vaccination is the cornerstone of prophylaxis and the most effective
method available to reduce the impact of influenza on the population. Current vaccines target
the major surface protein, hemagglutinin (HA), and are standardized by stimulation of serum
anti-HA antibodies as the primary correlate of protection. Measurements of serum antibodies
to HA have become the gold standard for evaluating vaccines. The Food and Drug Administration
(FDA) and the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use
(CHMP) both define protective titers as a hemagglutination inhibition (HAI) titer of greater
than or equal to 40. Recent vaccine effectiveness has been limited and, in some populations,
estimated at as low as 10%. Improved methods of vaccination must be developed, but limited
information regarding the true correlates of protection is available. Correlates of
protection in the systemic circulation may be less informative than those located in the
nasopharyngeal mucosa, which is the site of exposure to and infection with influenza virus.

This study is designed to characterize the mucosal and systemic immunologic correlates of
protection from influenza infection in persons vaccinated and unvaccinated against influenza.
Half of participants will receive current licensed quadrivalent inactivated influenza vaccine
(IIV) administered via the intramuscular (IM) route at the standard dose, prior to challenge
with influenza virus. The other half will receive no vaccination prior to challenge.
Immunologic response and clinical outcomes in the human challenge model will be determined to
characterize the two cohorts. In the vaccinated cohort, mucosal and systemic immune responses
induced by IM administration of quadrivalent IIV will also be carefully explored. The
thoughtful study of mucosal immunity to influenza is expected to identify novel correlates of
protection. By administering quadrivalent IIV and then infecting participants with human
challenge virus, we can evaluate in detail the immunologic responses after immunization and
subsequent virus exposure. This controlled setting offers the ideal environment to query
these responses and to identify targets of mucosal stimulation for future vaccine strategies.
In addition, the detailed characterization of the mucosal and systemic immune responses after
vaccination and challenge will represent a true advancein understanding influenza immunity.

- INCLUSION CRITERIA:

1. Greater than or equal to 18 and less than or equal to 55 years of age.

2. Non-smoker.

3. Have not received influenza vaccination of any type (whether licensed or
unlicensed experimental vaccine) on or after September 1, 2018. Participants who
enroll in our study must be informed of the Centers for Disease Control and
Prevention (CDC) recommendation to receive seasonal influenza vaccination
annually. Enrollees accept that half of study participants will receive licensed
approved vaccination per the usual route, and half will receive it by an
unapproved route with unknown efficacy and side effects. Enrollees should not
plan to receive seasonal influenza vaccination from another source from
enrollment through the final study visit (Phase 2, Day 56).

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

5. A male subject is eligible for the study if he agrees to practicing abstinence or
using a condom with spermicide plus an acceptable form of contraception (see
inclusion criteria 6) being used by any female partner from the day of
vaccination until 12 weeks after administration of the human challenge virus.

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

1. 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).

2. Of childbearing potential but agrees to practice effective contraception or
abstinence from the day of vaccination until 8 weeks after administration of
the human challenge virus. Acceptable methods of contraception include a
male partner who is sterile and is the sole sexual partner of the female
participant, or a male partner who uses a condom with spermicide, plus use
of 1 or more of the following by the female participant: 1) implants of
levonorgestrel; 2) injectable progestogen; 3) an intrauterine device with a
documented failure rate of < 1%; 4) oral contraceptives; and/or 5) double
barrier method including diaphragm.

7. Willing to have samples stored for future research.

8. Willing to allow genetic testing on biological samples.

9. HIV uninfected with a negative test within 60 days of Phase 2, Day 0.

10. Does not use intranasal medications (including but not limited to nasal sprays,
sinus rinses), over-the-counter medications (including but not limited to
aspirin, decongestants, antihistamines, and other non-steroidal anti-inflammatory
drugs), and herbal medications (including but not limited to herbal tea or St.
John s Wort), and agrees not to use these medications from 14 days prior to study
enrollment through the final study visit (Phase 2, Day 56), unless approved by
the investigator.

11. Agrees not to donate blood or blood products from enrollment through the final
study visit (Phase 2, Day 56).

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, immune deficiency (such as IgA deficiency) or ongoing
malignancy.

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

6. Postinfectious or postvaccine neurological sequelae including Guillain Barre
syndrome.

7. Individual with body mass index less than or equal to 18 and greater than or
equal to 40.

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., severe asthma, chronic obstructive
pulmonary disease).

- 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., insulin-dependent 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. Acute illness within 7 days prior to quadrivalent IIV administration or inoculation
with the human challenge virus.

4. Individuals who have grade 3 or above clinically significant laboratory values outside
the limits thus specified by normal laboratory parameters.

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

6. Clinically significant abnormality as deemed by the PI on the pulmonary function test
(PFT).

7. Known allergy to influenza vaccination or excipients contained in the influenza
vaccine used.

8. Known allergy to lidocaine or phenylephrine.

9. Known allergy to treatments for influenza (including but not limited to oseltamivir or
nonsteroidal anti-inflammatory medications).

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

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

12. Donation of blood or blood products within 3 months prior to study enrollment.

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

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

15. Self-reported or known history of alcoholism or drug abuse within 6 months prior to
enrollment, or positive urine test for drugs of abuse (i.e., amphetamines, cocaine,
benzodiazepines, opiates, metabolites, or tetrahydrocannabinol) at time of admission
for viral challenge.

16. Self-reported or known history of psychiatric or psychological issues that require
treatment and are deemed by the PI to be a contraindication to protocol participation.

17. History of a previous systemic allergic reaction with generalized urticaria,
angioedema, or anaphylaxis.

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