Post-Partum Immunization With Live Attenuated Influenza Vaccine (LAIV) or Trivalent Influenza Vaccine (TIV) in Post-Partum Breast Feeding Women

Official Title: “A Randomized, Double-Blind Trial, Comparing the Safety in Mothers and Their Infants and Immunogenicity in Mothers of Live Attenuated Influenza Vaccine (LAIV) to Inactivated Trivalent Influenza Vaccine (TIV) When Administered to Breast Feeding Women”

The purpose of this research study is to learn more about the safety of 2 licensed flu vaccines, nasal spray and flu vaccine shot, in mothers and their infants, when given to women who are breastfeeding and to compare the immune response (body's defense against foreign substances) of breastfeeding mothers, who receive intranasal flu vaccine, with breastfeeding mothers receiving the flu vaccine shot. Healthy post-partum women (240 volunteers, 28-120 days post delivery) who plan to breastfeed through 28 days post vaccination and who have not received 2010-2011 influenza vaccine will be assigned by chance to 1 of the 2 vaccines in the following manner: flu vaccine nasal spray and a placebo (inactive substance) shot or a flu vaccine shot and a placebo nasal spray. Study procedures include: nasal swabs, blood samples, and completion of memory aids. Participants will be involved in this United States based study for about 6 months.

Due to limited data available on the safety and immune response to live attenuated influenza vaccine (LAIV) in breast-feeding post-partum women and the lack of information on the induction of immunoglobulin (Ig) A and IgG against influenza virus in breast milk, this study compares the safety in mothers and their infants and immunogenicity in mothers of standard dose inactivated trivalent influenza vaccine (TIV) and LAIV when administered between 28-120 days of delivery in breastfeeding post partum women. This is a randomized, placebo-controlled, double-blinded trial in 240 post-partum breastfeeding women, 18-49 years of age. Study subjects will receive 1 dose of TIV or LAIV and the relevant placebo given by nasal or intramuscular (IM) route. Once enrolled, a blood sample and a breast milk sample will be collected. Nasal swabs will be obtained and targeted physical examinations (TPE) will be conducted from mother and infant, if indicated. Each subject will receive either a single intramuscular (IM) 0.5 milliliter (mL) dose of TIV and 0.2 mL of placebo administered intranasally, or, 0.2 mL intranasal dose of LAIV and 0.5 mL of placebo administered IM.

Vaccination will occur on Day 0. Study products should be administered one after the other and subjects will be observed for 30 minutes following administration of the second study product. All subjects will maintain a memory aid recording oral temperature, and systemic and local adverse events (AEs) for 7 days after study products have been administered.

Approximately day 2 and 7 all subjects will return to the clinic for collection of a breast milk sample and nasal swabs (mother and infant) and the memory aid will be reviewed.

Approximately Day 28 after vaccination, all subjects will return to the clinic for breast milk and a blood sampling. At these clinic visits, concomitant medications will be collected as well as any AEs. A TPE will be conducted, if indicated. During the time between vaccination and the day 28 visit, if mother or infant has an influenza-like illness (ILI), a clinic visit may be required within 48 hr of illness onset. The clinic visit will be required for any illness that meets the Centers for Disease Control and Prevention's definition of an ILI for the mother. Investigator discretion will be used to discern if an illness in the infant requires an ILI visit. Any respiratory or gastrointestinal (GI) serious adverse event (SAE) in the infant will also require a visit to the clinic. At these visits, nasal swabs will be collected to document whether influenza (vaccine or wild type) virus is present. If the mother has an ILI, nasal swabs will be collected on her and an attempt will be made to collect samples from the infant. If the infant has an ILI, nasal swabs will be collected on both the mother and infant. At approximately Day 42 after vaccination, all subjects will have a phone call for assessment of any medically attended GI or respiratory illness in the infant from Day 28-42. Approximately 6 months after vaccination all subjects will have a phone call for assessment of any serious adverse events (SAEs) in the subject or the infant since Day 28. Any new onset chronic medical conditions in the mother will be collected since Day 28. At all study visits, subjects will be asked about acute, temporary breast diseases (mastitis, abscesses) and any changes in breastfeeding, i.e., interruption and if so, how long (in weeks). Subjects will report information on current breast milk consumption by infant. Unsolicited non-serious AE data will be captured Day 0-28. Respiratory and GI AEs will be captured for the infant from Day 28-42. SAE data will be captured from Day 0-180 for both mother and infant. Blood samples will be tested for hemagglutination inhibition (HAI), IgG, and IgA as measured by enzyme linked-immunosorbent assay (ELISA). Breast milk samples will be assayed for IgA and IgG antibodies by ELISA. Breast milk and nasal swabs will also be tested for LAIV.

Intervention(s) in this Clinical Trial

• Biological: Inactivated Trivalent Influenza Vaccine
  • Preservative free, licensed product formulated for the 2011-2012 influenza season. Standard dose of TIV (Fluzone®) 0.5 ml administered to maternal subjects, IM in the deltoid.
• Biological: Live Attenuated Influenza Vaccine
  • Licensed product formulated for the 2011-2012 influenza season. Standard dose LAIV (Flumist®) 0.1 ml administered to maternal subjects intranasally in each nostril for a total of 0.2 mL.
• Drug: Placebo (IN)
  • Intranasal placebo study product will be sucrose phosphate placebo filled sprayers, administered to maternal subjects
• Drug: Placebo (IM)
  • Sterile saline containing 10 mL of 0.9 percent Sodium Chloride for injection, administered to maternal subjects

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Group 1: LAIV
  • Live attenuated influenza vaccine (LAIV) intranasally (IN) and placebo intramuscular (IM) injection administered to maternal subjects.
• Experimental: Group 2: TIV
  • Inactivated Trivalent Influenza Vaccine (TIV) intramuscularly (IM) and placebo intranasally (IN) administered to maternal subjects.

Primary Measures

• Occurrence of solicited systemic and local adverse events (AEs) within 8 days after vaccination (Day 0-7) in the maternal subject.
  • Time Frame: Day 0-7 in the maternal subject
    Safety Issue?: Yes
• Occurrence of medically attended respiratory or gastrointestinal AEs in the infant subject within 28-42 days of vaccination.
  • Time Frame: Within 28-42 days after vaccination in the infant subject
    Safety Issue?: Yes
• Comparison of breast milk ELISA IgA and IgG GMT to each of the vaccine components in Trivalent Influenza Vaccine (TIV) versus Live Attenuated Influenza Vaccine (LAIV) vaccine recipients 28 days after receipt of vaccine.
  • Time Frame: 28 days after maternal receipt of vaccine.
    Safety Issue?: No
• Occurrence of serious adverse events (SAEs) or new onset chronic medical conditions in maternal and infant subjects through 180 days after vaccination.
  • Time Frame: Day 0 through Day 180 for maternal and infant subjects
    Safety Issue?: Yes
• Occurrence of solicited systemic AEs within 11 days (Day 0-10) in the infant subject
  • Time Frame: Day 0-10 in the infant subject
    Safety Issue?: Yes
• Occurrence of non-serious AEs related to vaccination within 28 days of vaccination for both maternal and infant subject.
  • Time Frame: Day 0 to day 28 in both infant and maternal subjects
    Safety Issue?: Yes

Secondary Measures

• Detection of LAIV virus in breast milk.
  • Time Frame: 2 and 8 days after maternal receipt of LAIV.
    Safety Issue?: No
• Detection of LAIV in maternal and infant respiratory secretions.
  • Time Frame: 2 and 8 days after maternal receipt of LAIV, in both maternal and infant subjects
    Safety Issue?: No
• Comparison of hemagglutination inhibition antibodies and ELISA IgA and IgG GMT to each of the vaccine components in sera of maternal subjects.
  • Time Frame: 28 days post-vaccination of maternal subjects.
    Safety Issue?: No

Inclusion Criteria:

• Maternal Subject
• Post partum women age 18-49 years of age (inclusive) within 28-120 days of delivery.
• Is in good health, as determined by vital signs (heart rate <100 beats per minute (bpm); blood pressure: systolic less than or equal to 150 mm Hg; diastolic <90 mm Hg;
• oral temperature <100.0 degrees Fahrenheit), medical history and a targeted physical examination if indicated based on medical history.
• Willing and capable of providing written informed consent for herself and infant.
• Available for entire study duration, clinic visits and phone calls.
• Planning on breast feeding from time of vaccination through 28 days post-vaccination.
• Breast milk must be at least one half of the source of the infant's feeding.
• Willing to practice adequate contraception for at least 28 days after receipt of study vaccine if not surgically sterile via post-partum tubal ligation, bilateral oophorectomy or hysterectomy. Adequate contraception may include, but is not limited to, abstinence, monogamous relationship with a vasectomized partner, barrier methods such as condoms or diaphragms with spermicides, or licensed hormonal methods that are compatible with breastfeeding an infant.
• May be reached by any IRB-approved form of communication during study period. May include telephone, email, web based, social media, and/or text messaging, based on specific local IRB recommendations.
• Agree to sign a medical release for herself and her infant (if needed) so that study personnel may obtain medical information about her or her infant's health.
• Infant The infant(s) should be in good health as assessed by medical history, interview, and a targeted physical examination based on medical history.
• Infant born greater than or equal to 36 weeks gestation.
• Successful receipt of breast milk for at least two days prior to enrollment.
• Breastfeeding must be at least one half of the source of feeding, i.e., some supplementation is acceptable.

Exclusion Criteria:

• Maternal Subject
• History of receipt of 2011-2012 licensed influenza vaccine.
• Known allergy to eggs, egg proteins or other components in the vaccines (i.e.
• formaldehyde, polyethylene glycol, p-isooctylphenyl ether, sucrose, gelatin, polysorbate 80, gentamicin, arginine, sodium phosphate, sodium chloride, octylphenol ethoxylate).
• History of severe reactions following immunization with contemporary influenza virus vaccines.
• Received any other licensed vaccines within 14 days (for inactivated vaccines) or 28 days (for live vaccines) prior to vaccination in this study, or expects to receive a licensed vaccine during the 28 days after vaccination in this study.
• Received an experimental/investigational agent (vaccine, drug, biologic, device, blood product, or medication) within 28 days prior to vaccination in this study, or expects to receive an experimental/investigational agent within the study time period (180 days after vaccination in this study).
• Received antiviral agent against influenza A and/or B within 48 hours prior to vaccination in this study. Antiviral agents should not be administered until 2 weeks after vaccination in this study unless medically necessary.
• A moderate to severe acute illness and/or an oral temperature greater than or equal to 100.0 F, within 72 hr prior to vaccination. (This may result in a temporary delay of vaccination).
• Immunosuppression as a result of an underlying illness or treatment, or use of anti-cancer chemotherapy or radiation therapy within the preceding 36 months.
• Active neoplastic disease or a history of any hematologic malignancy (cancers of blood or bone marrow) or current bleeding or blood clotting disorder.
• Current diagnosis of asthma or a history of asthma, wheezing, or bronchospasm in the last 5 years.
• Long term (at least 14 days of prednisone 2 mg/kg or equivalent other glucocorticoid) use of oral or parenteral steroids, high-dose inhaled steroids (>800 g/day of beclomethasone dipropionate or equivalent) within the preceding 6 months (topical steroids are allowed).
• Use of intranasal steroids within 14 days prior to vaccination in this study or within 14 days after receipt of study vaccine.
• Use of intranasal products within 6 hours prior to vaccination in this study or expects to use intranasal products within 6 hours post study vaccination.
• History of receiving immunoglobulin or other blood product (with exception of RhoGAM) within the 3 months prior to vaccination in this study.
• Diagnosis of a current and uncontrolled major psychiatric disorder.
• Has been hospitalized within the past 10 years for psychiatric illness, suicide attempt, or confinement for danger to self or others.
• The subject is receiving listed 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 a single antidepressant drug and are stable for at least 3 months prior to enrollment without decompensating are allowed enrollment into the study.
• The subject is receiving medications contraindicated with breast feeding.
• Known active human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection.
• An active neurological (such as, but not limited to seizure disorder), auto-immune or vascular disease.
• Active breast infection or breast abscess. (Study vaccination will be delayed until this breast infection or breast abscess has been treated and is resolved.)
• History of frequent epistaxis (nose bleeds).
• History of alcohol or drug abuse in the 1 year prior to enrollment.
• History of Guillain-Barré syndrome.
• Any known immunocompromised family member/household contact (such as active cancer, lupus, inflammatory bowel disease, HIV infection, or receipt of an organ or bone marrow transplant).
• Has an acute or chronic medical condition that, in the opinion of the investigator would interfere with the evaluation of responses (this includes, but is not limited to: known chronic liver, lung or heart disease, chronic anemia, metabolic disorders such as diabetes (resolved gestational diabetes is acceptable), significant renal disease, transplant recipients).
• Pregnant or planning to become pregnant during the 28 days after receipt of study vaccine.
• 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.
• Infant
• Major congenital malformations.
• Syndromes that affect breastfeeding or immune response.
• Progressive neurological disease or a history of any seizure.
• Chronic lung disease or oxygen requirement for heart disease.
• History of bronchopulmonary dysplasia, wheezing, reactive airway disease, hospitalization for respiratory illness, or use of bronchodilators.
• Any receipt of glucocorticoids.
• Immunodeficiency disease or use of immunosuppressive therapy including perinatal exposure to or infection with HIV, or known infection with hepatitis B or hepatitis
• C.
• Received an experimental/investigational agent (vaccine, drug, biologic, device, blood product, or medication) within 28 days prior to this study, or expects to receive an experimental/investigational agent within the study time period (180 days after mother's vaccination in this study).
• A moderate to severe acute illness and/or a rectal temperature greater than or equal to 100.0 F (37.8 C), within 72 hours prior to mother's vaccination (This may result in a temporary delay of vaccination in mother).
• Received any licensed vaccines within 7 days prior to mother's vaccination in this study, or expects to receive a licensed vaccine during the 10 days after mother's vaccination in this study (This may result in a temporary delay of vaccination in mother).
• History of documented laboratory-confirmed influenza infection.
• Receipt of blood or blood products.
• Have a condition that may place the infant at an unacceptable risk of injury or would make it difficult for the infant to meet the requirements of the study.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 49 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Investigator: National Institute of Allergy and Infectious Diseases (NIAID) NIH

Overall Clinical Trial Officials and Contacts

Overall Contact: Mark Steinhoff (513) 636-1376 mark.steinhoff@cchmc.org

Information obtained from ClinicalTrials.gov on February 02, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT01181323

Study ID Number: 09-0007

ClinicalTrials.gov Identifier: NCT01181323

Health Authority: United States: Federal Government