2010-2011 Trivalent Influenza Vaccine (TIV) in Pregnant Women

Influenza is a significant cause of morbidity and mortality in the United States. Pregnant women and infants are at an increased risk for the complications of influenza. Pregnant women are considered a high risk population. In the United States, routine vaccination with inactivated trivalent influenza vaccine (TIV) for women who are pregnant or deliver during the influenza season is recommended. However, few studies exist on the safety and immunogenicity of administration of seasonal inactivated TIV. Although influenza vaccination has been recommended during pregnancy, the rates of immunization remain low, at about 13 percent, which partly reflects concern of safety among pregnant women and providers. It is important to gather prospective data on the safety and immunogenicity of inactivated TIV vaccine in pregnant women. This is a multi-site randomized, double-blinded clinical trial in 180 healthy 18-39 year old, pregnant women in their second or third trimester of pregnancy (from 14 weeks of gestation to 33 weeks/6 days gestation, inclusive) and 60 healthy 18-39 year old non-pregnant controls. Study subjects will be randomized 1:1:1 to receive one of the following three 2010-2011 seasonal inactivated trivalent influenza vaccines: Fluarix®, Agriflu®, or Fluzone® (60 pregnant women and 20 non-pregnant women per group). The study will begin enrollment when at least 2 of the 4 study products are available. Once enrolled, a blood sample will be collected and each subject will receive a single 0.5 mL dose of the assigned vaccine. Subjects will be observed for at least 15 minutes after immunization, and the subjects will maintain a memory aid to record oral temperature and systemic and local adverse events (AEs) for 8 days after immunization. Subjects will have a phone call on Day 2 and 8 for review of memory aid, concomitant medication assessment, and assessment of AEs. At approximately Day 28 post-vaccination, subjects will return to the clinic for blood sample collection, AE and concomitant medication assessment, and a targeted physical examination (if indicated). Pregnant subjects will also have scheduled phone calls from Day 28 until the time of delivery or Day 180, whichever is later, to assess for any new-onset chronic medical conditions, and pregnancy-related problems such as miscarriage or serious adverse events (SAEs) since the last visit. At approximately Day 180 post-vaccination, subjects will return to the clinic for blood sample collection and assessment of the receipt of any vaccines since the last visit. Subjects will be asked about any new-onset chronic medical conditions, SAEs since the last visit and pregnancy-related problems such as miscarriage (for the pregnant women cohort). The duration of the study will be approximately 6 months for the non-pregnant subjects and about 6-8 months for the pregnant subjects, depending on delivery date for the pregnant women. Pregnant subjects will have collection of maternal and cord blood at the time of delivery. Pregnant subjects will also have a phone call 1 month after delivery to assess for any new-onset chronic medical conditions or SAEs since the last visit. The primary objectives are to evaluate the safety of a single 0.5 mL intramuscular injection of the 2010-2011 inactivated TIV in pregnant women and to evaluate the immunogenicity of the 2010-2011 inactivated TIV in pregnant women by hemagglutination inhibition assay (HAI). The secondary objectives are to evaluate the persistence of antibodies to the 2010-2011 inactivated TIV in pregnant women at Day 180 and to assess the transfer of maternally derived antibody against viruses in the 2010-2011 inactivated TIV to infants bor

Inclusion criteria

Pregnant women:

• Pregnant female between the ages of 18 and 39 years, inclusive.
• Is a singleton pregnancy and is from 14 weeks/0 days through 33 weeks/6 days of gestation.
• Had at least one prenatal visit during which pregnancy was confirmed.
• Is in good health, as determined by vital signs [heart rate <100 beats per minute (bpm); blood pressure: systolic <140 mm Hg; diastolic less than or equal to 90 mm Hg; oral temperature <100 degrees Fahrenheit], medical history to ensure any existing medical diagnoses or conditions are stable and not considered clinically significant, and targeted physical examination based on medical history. A stable medical condition is defined as health outcomes of a specific disease are considered to be within acceptable limits in the last 3 months.
• Intends to be available through 6 months following receipt of 2010-2011 seasonal influenza vaccine or until all delivery record information has been obtained, whichever is longer.
• Able to understand and comply with planned study procedures.
• Provides written informed consent prior to initiation of any study procedures.
• Agrees to sign medical release for herself and her infant to allow study staff to gather pertinent medical information and pregnancy outcome data, if needed per clinical site policy.

Non-pregnant women:

• Female between the ages of 18-39 years, inclusive.
• For the 30 days prior to enrollment through 30 days following receipt of 2010-2011 inactivated trivalent influenza vaccine (TIV) in the study must fulfill one of the following: (i) she is not able to bear children because she has been surgically sterilized (hysterectomy) or is at least 1 year status post tubal ligation or 1 year post-menopausal or (ii) she agrees to practice effective methods of contraception including, but not limited to, abstinence, barrier methods (such as a condom or diaphragm) used with a spermicide, birth control pills, patches or hormonal shots or hormonal implants, NuvaRing and IUDs (intrauterine devices), or monogamy with vasectomized partner.
• For a female subject of childbearing potential, must have a negative pregnancy test (urine or serum) within 24 hours prior to vaccination.
• Is in good health, as determined by vital signs, medical history to ensure any existing medical diagnoses or conditions are stable and not considered clinically significant, and targeted physical examination based on medical history (if indicated). A stable chronic medical condition is defined as no change 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. Any change that is due to change of health care provider, insurance company etc, or that is done for financial reasons, as long as in the same class of medication will not be considered a violation of this inclusion criterion. Any change in prescription medication due to improvement of a disease outcome will not be considered a violation of this inclusion criterion.
• Intends to be available through 6 months following receipt of 2010-2011 inactivated TIV.
• Able to understand and comply with planned study procedures.
• Provides written informed consent prior to initiation of any study procedures.

Infants born to pregnant women:

• Infant aged 6 weeks (plus/minus 14 days), born to mothers enrolled in this study.
• Had a cord blood sample collected at time of labor and delivery.
• Parent(s)/legal guardian(s) must be willing and able to comply with planned study procedures and be available for study visit.
• Subject and/or parent(s)/legal guardian(s) must provide written informed consent prior to initiation of any study procedures.

Exclusion criteria

Pregnant women:

• Has received the 2010-2011 trivalent influenza vaccine (inactivated or live).
• Has a known allergy or hypersensitivity to eggs, egg proteins, latex or other components in the vaccines (including, but not limited to: formaldehyde, polyethylene glycol p-isooctylphenyl ether, sucrose, gelatin, polysorbate 80, kanamycin, polymyxin and neomycin).
• Has a history of severe reactions following previous immunization with influenza virus vaccines.
• Has received any other live licensed vaccines within 4 weeks or inactivated licensed vaccines within 2 weeks prior to vaccination in this study or plan receipt of such vaccines within 28 days following vaccination. Measles, mumps, and rubella vaccine and tetanus, diphtheria, and acellular pertussis vaccine and human papillomavirus vaccine are permitted post-partum.
• Is enrolled or plans to enroll in another interventional clinical trial with an investigational product during the current pregnancy and while participating in this study (observational studies are allowed).
• Has an acute illness and/or an oral temperature >/= 100.0 degrees F, within 72 hours of vaccination (This may result in a temporary delay of vaccination).
• Has immunosuppression as a result of an underlying illness or treatment, or use of anti-cancer chemotherapy or radiation therapy within the preceding 36 months.
• Has an active neoplastic disease (excluding non-melanoma skin cancer), a history of any hematologic malignancy, current bleeding disorder, or taking anticoagulants (a daily aspirin may be acceptable).
• Long term use of glucocorticoids, including oral or parenteral, or high-dose inhaled steroids (>800 mcg/day of beclomethasone dipropionate or equivalent) within the preceding 6 months (nasal and topical steroids are allowed) or has received betamethasone or dexamethasone to accelerate fetal lung maturity.
• Has a history of receiving immunoglobulin or other blood product (with exception of Rhogam) within the 3 months prior to enrollment in this study.
• Has a diagnosis of a current and uncontrolled major psychiatric disorder.
• Has been hospitalized for psychiatric illness, history of suicide attempt, or confinement for danger to self or others, within the past 10 years.
• The subject is receiving any of the following psychiatric drugs: aripiprazole, clozapine, ziprasidone, haloperidol, molindone, loxapine, thioridazine, thiothixene, pimozide, fluphenazine, risperidone, mesoridazine, quetiapine, trifluoperazine, trifluopromazine, chlorprothixene, chlorpromazine, perphenazine, olanzapine, carbamazepine, divalproex sodium, lithium carbonate or lithium citrate. Subjects who are receiving an antidepressant drug (not listed above) and are stable for at least 3 months prior to enrollment without decompensating are allowed enrollment into the study.
• Known active infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C.
• History of alcohol or drug abuse in the last 5 years.
• Has a seizure disorder or is on an anti-seizure medication.
• Has a history of Guillain-Barré Syndrome.
• Has an acute or chronic medical condition that, in the opinion of the investigator would render vaccination unsafe, or would interfere with the evaluation of responses (this includes, but is not limited to, known cardiac disease, chronic hypertension, chronic liver disease, significant renal disease, unstable or progressive neurological disorder, transplant recipients or diabetes, juvenile diabetes [Type I] or advanced diabetes with renal disease or eye disease. Gestational diabetes controlled by diet or insulin is acceptable).
• Has any of the following active medical conditions at the time of enrollment:

Hyperemesis gravidarium, premature labor (regular uterine contractions with cervical change), fetus with known major congenital anomaly or genetic abnormality, fetal growth restriction, preeclampsia, or known uterine anomaly (e.g. bicornuate uterus, submucosal fibroids > 5cm).

• Has a history of preeclampsia or preterm birth <35 weeks gestation during a previous pregnancy
• 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.

Non-pregnant women:

• Has received the 2010-2011 trivalent influenza vaccine (inactivated or live).
• Has a known allergy or hypersensitivity to eggs, egg proteins, latex or other components in the vaccines (these may include, but not limited to: formaldehyde, polyethylene glycol p-isooctylphenyl ether, sucrose, gelatin, polysorbate 80, kanamycin, polymyxin and neomycin).
• Has a history of severe reactions following previous immunization with influenza virus vaccines.
• Has received any other live licensed vaccines within 4 weeks or inactivated licensed vaccines within 2 weeks prior to vaccination in this study or plan receipt of such vaccines within 28 days following vaccination.
• Is enrolled or plans to enroll in another interventional clinical trial with an investigational product at the time of enrollment or during participation in this trial (observational studies are allowed).
• Has an acute illness and/or an oral temperature greater than or equal to 100.0 degrees F, within 72 hours of vaccination (This may result in a temporary delay of vaccination).
• Has immunosuppression as a result of an underlying illness or treatment, or use of anti-cancer chemotherapy or radiation therapy within the preceding 36 months.
• Has an active neoplastic disease (excluding non-melanoma skin cancer), a history of any hematologic malignancy, current bleeding disorder, or taking anticoagulants (daily aspirin may be acceptable.
• Long term use of glucocorticoids, including oral or parenteral, or high-dose inhaled steroids (>800 mcg/day of beclomethasone dipropionate or equivalent) within the preceding 6 months (nasal and topical steroids are allowed).
• Has a history of receiving immunoglobulin or other blood product within the 3 months prior to enrollment in this study.
• Has a diagnosis of a current and uncontrolled major psychiatric disorder.
• Has been hospitalized for psychiatric illness, history of suicide attempt, or confinement for danger to self or others, within the past 10 years.
• The subject is receiving any of the following psychiatric drugs: aripiprazole, clozapine, ziprasidone, haloperidol, molindone, loxapine, thioridazine, thiothixene, pimozide, fluphenazine, risperidone, mesoridazine, quetiapine, trifluoperazine, trifluopromazine, chlorprothixene, chlorpromazine, perphenazine, olanzapine, carbamazepine, divalproex sodium, lithium carbonate or lithium citrate. Subjects who are receiving an antidepressant drug (not listed below) and are stable for at least 3 months prior to enrollment without decompensating are allowed enrollment into the study.
• Known active infection with HIV, hepatitis B, or hepatitis C.
• History of alcohol or drug abuse in the last 5 years.
• Has a seizure disorder or is on an anti-seizure medication.
• Has a history of Guillain-Barré Syndrome.
• Has an acute or chronic medical condition that, in the opinion of the investigator would render vaccination unsafe, or would interfere with the evaluation of responses (this includes, but is not limited to, known cardiac disease, chronic liver disease, significant renal disease, unstable or progressive neurological disorder, transplant recipients or uncontrolled diabetes, juvenile diabetes [Type I] or advanced diabetes with renal disease or eye disease. Diabetes controlled by diet or oral agents is acceptable).
• 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.

Infants born to pregnant women:

• Have any condition that would, in the opinion of the site investigator, place them at an unacceptable risk of injury or render them unable to meet the requirements of the protocol.