Development of Childhood Anti-influenza Immunity

Current guidelines recommend yearly influenza vaccination for all children ≥6 months of age;
however the effect this has on the evolution of the anti-influenza immune response through
childhood and into adulthood is poorly understood. Though far from idea, yearly vaccination
is necessary at present due to the ongoing antigenic drift that occurs as viruses continually
evolve to evade neutralizing antibody. There is currently much interest in the development of
a universal influenza vaccination that would be able to provide protection against both
seasonal and potentially pandemic strains of influenza. However, a growing body of evidence
suggests that early childhood influenza exposures result in imprinting that profoundly shapes
lifelong CD4 T cell and B cell mediated immunity to this virus. An improved understanding of
immunity to influenza virus in early childhood is thus needed if a more broadly protective
approach to influenza vaccination is to be successful.

There are profound antigenic differences between natural influenza infection, which
stimulates vigorous inflammation with abundant intracellular antigen, and inactivated
influenza vaccination, which contains predominately the surface glycoproteins (HA and NA) and
promotes weak inflammatory signalling. This study will investigate how the context of these
different routes of early childhood influenza exposure affect the functional potential of the
anti-influenza immune response and determine the consequences this has on subsequent
influenza vaccination. This improved knowledge of how early childhood influenza vaccination
shapes the establishment of anti-influenza immunologic memory will enable both optimization
of current influenza vaccination strategies and development of novel vaccines able to provide
highly efficacious universal protection against both seasonal and potentially pandemic
influenza strains.

Inclusion Criteria:

- Age

- Between 6 and 12 months at the time of enrollment to participate in the
vaccination arm of age cohort 1A

- Between 3 and 12 months at the time of enrollment to participate in the natural
infection arm of age cohort 1B

- > 12 months, birth date after 2009 for either the vaccination (A) or natural
infection (B) arm of age cohort 2

- Birth date between 2006 and 2009 for either the vaccination (A) or natural
infection (B) arm of age cohort 3

- Birth date between 2003 and 2006 for the vaccination (A) or natural infection (B)
arm of age cohort 4

- Gestational age of ≥37 weeks at birth

- Parent/LAR can provide informed consent, with children ≥8 years of age providing
informed assent

- Available for the duration of the study

- History of previous primary IIV vaccination (at least 2 previous doses for age <9 yrs,
at least 1 previous dose for age 9 and older) ONLY for participation in the
vaccination (A) arm of age cohorts 2, 3, or 4

- Acute illness documented by rapid influenza test, PCR testing, or testing done by
either URMC Labs or RGH Clinical Microbiology Labs to be due to influenza virus ONLY
for participation in the natural infection arms (B) of age cohorts 1-4

- Subjects must demonstrate age-appropriate weight and vital sign

Exclusion Criteria:

- Immunosuppression as a result of an underlying illness or condition (including HIV or
a primary immunodeficiency syndrome)

- Active neoplastic disease

- Use of potentially immunosuppressive medications currently or within the past year
(including chemotherapeutic agents) or chronic (>2 weeks) use of oral or inhaled
steroid therapy

- A diagnosis of asthma requiring chronic controller medication

- Participation in any clinical research study evaluating an investigational drug or
therapy that is inconsistent with current standard of care within two (2) months of
enrollment in this study.

- Previous administration of influenza vaccine in the current influenza season ONLY for
subjects in the vaccination arm (A) of the study (subjects presenting with acute
influenza infection with vaccine failure will be eligible to enroll in the B cohorts).

- Receipt of immunoglobulin or another blood product within the year prior to study
enrollment

- An acute illness within the previous 3 days or temperature >38oC on screening EXCEPT
for participation in the natural infection (B) cohorts

- A contraindication to influenza vaccination EXCEPT infants between 3 and 5 months
presenting with natural influenza infection whose only contraindication is their
current age

- History of anemia and/or recent (within 120) hospitalization, excluding delivery and
subjects who have been hospitalized for influenza-related reasons.