Comparison of Three Licensed Influenza Vaccines
Comparison of Three Licensed Influenza Vaccines
This study will evaluate in detail the way that the immune system responds to three different
 kinds of flu shots that are licensed in the United States.
Previous observations to date lead to the following model: Traditional egg-derived TIV have
 contaminating internal virion proteins that preferentially elicit memory CD4 T cells specific
 for these proteins. These CD4 T cells will have limited efficacy as helpers for the
 neutralizing Ab response and will suppress the CD4 T cell response to new HA epitopes in the
 vaccine. The current study will test this hypothesis by comparing CD4 cell responses to
 specific epitopes, and the subsequent B cell and antibody response, in subjects receiving a
 vaccine containing only HA protein to vaccines with more complex antigenic characteristics.
 The CD4 T cell reactivity to pools of unique, conserved, and total pH1 HA peptides as well as
 H3, influenza B HA, NP, and M1 peptides will be quantified using cytokine Elispot assays and
 flow cytometry, and then compared to the subsequent antibody and B cell response.

 Investigators will also use this study as an opportunity to evaluate the effects of prior
 vaccination. Recent studies have emphasized the potential negative effect of vaccination in
 prior years on both the immune response as well as the protective effectiveness of current
 vaccine. In order to evaluate this phenomenon in the context of multiple vaccine
 formulations, prior vaccination history of the subjects will be reviewed and subjects
 stratify vaccination based on vaccine history.

 In addition, subjects who participated in this study in a previous year are eligible to
 re-enroll, and will receive the same vaccine that they were randomized to previously. This
 will allow an evaluation of differences between vaccine formulations in the responsiveness to
 multiple vaccinations.

 Furthermore, recent studies indicate reports that the glycosylation pattern of viral
 hemagglutinins produced in cell culture can vary depending on the host cell used, and that
 this can affect CD4 T cell immunogenicity and antibody recognition. As a cell culture-based
 influenza vaccine production platform offers many advantages and may eventually supplant the
 traditional egg-based approach, it is of great value to understand the CD4 T cell response
 induced by this vaccine and how this affects neutralizing Ab production.

 Recent data have also suggested that the failure of seasonal influenza infection to induce
 substantial levels of stalk specific antibody may be due to the relatively inaccessible
 nature of this epitope. As part of this study, investigators will also compare the
 specificity of the human antibody response between the vaccine groups, with the hypothesis
 that the rHA vaccine will more readily allow targeting of these important, broadly conserved
 epitopes. There is compelling preliminary data demonstrating that multiple antibodies that we
 have isolated have a particularly slow on rate when they bind to the HA-stalk versus the
 HA-globular head epitopes on whole virions, but not on recombinant HA trimmers expressed in
 baculovirus. The hypothesis is that a free, recombinant HA vaccine will allow more efficient
 targeting of the HA-Stalk epitopes.
Inclusion Criteria:

 1. Aged between 18 and 49 years of age (inclusive).

 2. Female subjects must fulfill one of the following: (i) not able to bear children
 because she has been surgically sterilized (tubal ligation or hysterectomy) or (ii)
 agrees to practice effective methods of contraception that may include, but are not
 limited to abstinence, barrier methods, monogamous relationship with vasectomized
 partner, birth control pills, patches, hormonal shots or hormonal implants, NuvaRing
 and IUDs (intrauterine devices), from 30 days prior to study enrollment through 30
 days following receipt of the last dose of vaccine.

 3. Female subjects of childbearing potential must have a negative pregnancy test (urine
 or serum) within 24 hours prior to vaccination.

 4. The subject must be in good health, as determined by: vital signs (heart rate >55 to
 <100 bpm; blood pressure: systolic ≥ 90 mm Hg and ≤150 mm Hg; diastolic ≤ 90 mm Hg;
 oral temperature <100.0ºF); medical history; and targeted physical examination, when
 necessary, based on medical history. Stable medical condition is defined as: no recent
 increase in prescription medication, dose, or frequency of medication in the last 3
 months and health outcomes of the specific disease are considered to be within
 acceptable limits in the last 6 months.

 5. The subject is able to understand and comply with the planned study procedures,
 including being available for all study visits.

 6. The subject has provided informed consent prior to any study procedures.

 7. Subjects who have not received seasonal flu vaccine for the current year.

 Exclusion Criteria

 1. Subject report of known hypersensitivity to allergy to components of the study vaccine
 or other components of the study vaccine.

 2. Subject report of known latex allergy

 3. Subject report of a history of severe reactions following previous immunization with
 licensed or unlicensed influenza virus vaccines.

 4. Subject report of a history of Guillain-Barre syndrome within 6 weeks of receipt of a
 previous influenza vaccine.

 5. The subject is a woman who is pregnant or breastfeeding or intends to become pregnant
 during the study period between enrollment and 30 days following receipt of vaccine.

 6. The subject is immunosuppressed as a result of an underlying illness or treatment with
 immunosuppressive or cytotoxic drugs, or use of anticancer chemotherapy or radiation
 therapy within the preceding 36 months.

 7. The subject has an active neoplastic disease (excluding non-melanoma skin cancer or
 prostate cancer that is stable in the absence of therapy) or a history of any
 hematological malignancy. For this criterion, "active" is defined as having received
 treatment within the past 5 years.

 8. The subject has long-term (greater than 2 weeks) use of oral or parenteral steroids,
 or high-dose inhaled steroids (>800 mcg/day of beclomethasone dipropionate or
 equivalent) within the preceding 6 months (nasal and topical steroids are allowed).

 9. The subject received immunoglobulin or another blood product within the 3 months prior
 to enrollment in this study.

 10. The subject has received an inactivated vaccine within the 2 weeks or a live vaccine
 within the 4 weeks prior to enrollment in this study or plans to receive another
 vaccine within the next 28 days.

 11. The subject has an acute or chronic medical condition that, in the opinion of the
 investigator or appropriate sub-investigator, would render vaccination unsafe or would
 interfere with the evaluation of responses. These conditions include any acute or
 chronic medical disease or conditions defined as persisting for 3 months (defines ad
 90 days) or longer, that would place the subject at an unacceptable risk of injury,
 render the subject unable to meet the requirements of the protocol, or may interfere
 with the evaluation of responses of the subject's successful completion of the study.

 12. Subjects with an active infection or that has an acute illness or an oral temperature
 greater than 99.9F (37.7C) within 3 days prior to enrollment or vaccination. Subjects
 who had an acute illness that was treated symptoms resolved are eligible to enroll as
 long as treatment is completed and symptoms resolved > 3 days prior to enrollment.

 13. The subject is currently participating or plans to participate in a study that
 involves an experimental agent (vaccine, drug, biologic, device, blood product, or
 medication) or has received an experimental agent within 1 month prior to enrollment
 in this study, or expects to receive another experimental agent during participation
 in this study, or intends to donate blood during the study period.

 14. The subject has any condition that would, in the opinion of the site investigator,
 place the subject at an unacceptable risk of injury or render the subject unable to
 meet the requirements of the protocol.

 15. Have been hospitalized for psychiatric illness, history of suicide attempt, or
 confinement for danger to self or others, within the past 10 years.

 16. The subject has a diagnosis of schizophrenia, bi-polar disease, or other severe
 (disabling) chronic psychiatric diagnosis, or is receiving psychiatric drugs. Subjects
 who are receiving a single antidepressant drug and are stable for at least 3 months
 prior to enrollment without decompensation are allowed enrollment into the study.

 17. The subject has a history of alcohol or drug abuse in the 5 years prior to enrollment.

 18. The subject has a known human immunodeficiency virus, hepatitis B, or hepatitis C
 infection.

 19. The subject has any condition that the principal investigator (PI) believes may
 interfere with successful completion of the study.