Safety and Immunogenicity Study of Influenza Vaccines in HIV-infected and HIV-uninfected Pregnant Women in Western Kenya

Brief Title

Safety and Immunogenicity Study of Influenza Vaccines in HIV-infected and HIV-uninfected Pregnant Women in Western Kenya

Official Title

A Double-Blind, Randomized, Controlled Trial to Evaluate the Safety, Immunogenicity, and Efficacy of Standard Dose Quadrivalent Inactivated Influenza Vaccine, and Double Dose Quadrivalent Inactivated Influenza Vaccine in HIV-Infected and HIV-Uninfected Pregnant Women in a Malaria-Endemic Area of Rural Western Kenya

Brief Summary

      In 2012, the WHO Strategic Advisory Group of Experts (SAGE) concluded that pregnant women are
      the most important risk group for season influenza vaccination based upon "compelling
      evidence of substantial risk of severe disease in this group and evidence that seasonal
      influenza vaccine is safe and effective in preventing disease in pregnant women as well as
      their young infants, in whom disease burden is also high". Recent data from Kenya, similarly
      suggest rates of influenza-associated hospitalizations in children under age 1 to be as high,
      or higher, than those observed in the United States. However, TIV may have reduced
      immunogenicity in HIV-infected adults, and HIV infection has been shown to reduce placental
      transfer of both tetanus and measles antibodies. Therefore, we propose to conduct a
      double-blind randomized controlled trial of influenza vaccines stratified by HIV status in up
      to 720 pregnant women in their second and third trimesters and their infants residing in
      health and demographic surveillance sites (HDSS) in Nyanza Province, Western Kenya. We
      propose to assess the safety, immunogenicity, and efficacy of standard dose QIV and double
      dose QIV in HIV-infected and HIV-uninfected pregnant women. Findings will inform maternal
      influenza vaccination policies in Kenya and other African countries.
    

Detailed Description

      Recent investments in influenza surveillance in many African countries confirm results from
      other countries that young children, pregnant women, and those with chronic medical
      conditions are at increased risk of hospitalization and death from influenza infection.
      Annual influenza vaccination is the most effective method for preventing influenza virus
      infection and its complications. Vaccination is currently recommended in high risk groups in
      many developed countries and the WHO Strategic Advisory Group of Experts (SAGE) on
      Immunization made a recommendation for vaccination of pregnant women in their 2005 position
      paper on influenza vaccine. In 2012, the SAGE further concluded that pregnant women are the
      most important risk group for inactivated seasonal influenza vaccination based upon
      "compelling evidence of substantial risk of severe disease in this group and evidence that
      seasonal influenza vaccine is safe and effective in preventing disease in pregnant women as
      well as their young infants, in whom disease burden is also high".

      Maternal influenza immunization is viewed as the most effective way to protect infants less
      than 6 months of age who are not yet eligible for immunization. In the United States,
      children under 6 months experience very high rates of influenza-associated hospitalization
      and are among those most at risk of severe outcomes. Recent data from Kenya, similarly
      suggest rates of influenza-associated hospitalizations in children under age 1 to be as high,
      or higher, than those observed in the United States. Vaccination of pregnant women provides
      protection to their infants against laboratory-confirmed influenza illness in the first
      months of life. Furthermore, vaccination of pregnant women has been associated with a
      decreased risk of pre-term birth and small for gestational age in Canada and the state of
      Georgia in the US, and increased birth weight in infants during periods of high transmission
      in Bangladesh. However, traditional TIV may have reduced immunogenicity in HIV-infected
      adults, and HIV infection has been shown to reduce placental transfer of both tetanus and
      measles antibodies. The high prevalence of other diseases, including malaria and
      malnutrition, may also impact the effectiveness of influenza vaccination for pregnant women
      and their infants in sub-Saharan Africa.

      Use of double dose QIV may produce a greater immune response in pregnant women and increased
      antibody production may improve transplacental transfer of influenza antibodies to the
      developing fetus, conferring a better or possibly longer duration of protection from
      influenza infection. Therefore, we propose to conduct a randomized controlled trial of
      influenza vaccines in a high HIV-prevalence, malaria-endemic setting in Kenya, using
      inactivated polio vaccine (IPV) as a comparator/control. We propose to assess the safety,
      immunogenicity, and efficacy of standard dose (15 µg) QIV (FLUARIX® (GlaxoSmithKline
      Biologicals, Dresden, Germany) and double dose (30 µg) QIV in HIV-infected and HIV-uninfected
      pregnant women.

      OBJECTIVES:

        1. To evaluate the immunogenicity of standard dose (15 µg) QIV and double dose (30 µg) QIV
           in HIV-infected and uninfected pregnant women

        2. To evaluate the level of vaccine-induced influenza antibody transfer to infants of
           HIV-infected and uninfected pregnant women who receive standard dose (15 µg) QIV or
           double dose (30 µg) QIV

        3. To evaluate the safety of standard dose (15 µg) QIV and double dose (30 µg) QIV in
           HIV-infected and HIV-uninfected pregnant women and fetus

      DESIGN:

      This trial will be conducted as a double-blind, randomized, controlled trial stratified by
      HIV status in up to 720 pregnant women in their second and third trimesters and their infants
      residing in health and demographic surveillance sites (HDSS) around Siaya District Hospital
      and Lwak Mission Hospital in Nyanza Province, Western Kenya. The study will be conducted in
      accordance with International Conference on Harmonization Good Clinical Practice (GCP)
      standards. Mothers must agree to be counseled and tested for HIV at the time of screening and
      enrollment unless there is written documentation of HIV infection or a negative HIV test in
      the last 3 months. After initial screening for eligibility and informed consent, enrolled
      women will be stratified by HIV status (infected, uninfected) and block randomized in a
      1:1:1:1 ratio to receive standard dose (15 µg) QIV, double dose (30 µg) QIV or IPV. The day
      of vaccination will be considered study Day 0 for each subject. Each subject will receive a
      single vaccination. For the first 240 enrolled women, study personnel will visit their homes
      on Days 1, 2, and 3 to do active surveillance for adverse events following vaccination.
      Pregnancy outcomes will be recorded for all subjects (live birth, still birth, or spontaneous
      abortion). HIV testing will be repeated at birth for all women with negative results at
      screening. Live and still born infants will be examined by trained study personnel in the
      first 24 hours after delivery to determine birth weight, length, assess gestational age, and
      identify possible congenital anomalies associated with vaccination.

      All enrolled subjects will be asked to return to the antenatal study clinic on Study Day 7,
      Day 28, Day 56 (if not delivered), for delivery, and for any febrile or respiratory illness
      or other concern. During the enrollment process, their mobile telephone number will be
      recorded (or a number will be recorded for someone they identify in the village with a mobile
      telephone who will be willing to transmit information to them). Participants will be
      contacted by phone or in person every 2 weeks to determine if they have had fever and/or
      cough during the prior 2 weeks. Subjects with fever only will receive a malaria smear and
      other treatment as appropriate per Kenya Ministry of Health (MOH) guidelines. Subjects with
      fever or cough will have respiratory specimens collected via placement of NP/OP swabs by
      trained clinical personnel for influenza testing. After delivery, subjects will be asked to
      bring infants to the study clinic for evaluation on Days 7, 42, and 70 of life and when the
      child is approximately 6 months of age. Infants will also be under surveillance for fever,
      history of fever, hypothermia and/or cough for the first 6 months of life. All febrile,
      hypothermic, and/or coughing infants will receive testing for malaria and nasopharyngeal
      (NP)and oropharyngeal (OP) swabs for influenza. Febrile infants under 2 months of age will
      receive additional testing and treatment per national guidelines. Any infant admitted to the
      hospital with any respiratory symptom, hypothermia, apnea or fever will receive testing for
      influenza by real-time reverse transcriptase-polymerase chain reaction (rRT-PCR) of NP/OP
      specimens.

      Vaccine immunogenicity will be evaluated by comparing hemagglutination inhibition (HI) titers
      on Day 0 and Day 28 and at delivery in the mother, in cord blood, in the mother and infant at
      infant Day 70 of life, and in the infant at approximately 6 months of age. We will determine
      the proportion of vaccinated women who achieve a fourfold rise in HI titers post-vaccination
      compared to pre-vaccination or an HI titer ≥40 for subjects with baseline HI titer <10,
      compared to the same outcome in controls. The proportion of HI titers ≥40 in cord blood and
      in infants will also be measured and compared among vaccine recipients and controls.
      Geometric means of HI titers will also be compared.
    

Study Phase

Phase 2/Phase 3

Study Type

Interventional


Primary Outcome

Proportion of women with an appropriate rise in Hemagglutination Inhibition (HI) titers

Secondary Outcome

 Vaccine efficacy of standard dose (15 µg) QIV and double dose (30 µg) QIV in mothers and infants compared to control mothers and infants.

Condition

Influenza, Human

Intervention

Quadrivalent Inactivated Influenza Vaccine (QIV)

Study Arms / Comparison Groups

 Quadrivalent Influenza Vaccine (QIV)
Description:  15µg of each of 2 influenza A strains (H1N1 and H3N2) and 2 influenza B strains in a buffer solution totaling 0.5mL which is administered intramuscularly.
Administered as a single dose on the day of enrollment.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

0

Start Date

April 2014

Completion Date

April 2014

Primary Completion Date

April 2014

Eligibility Criteria

        Inclusion Criteria:

          1. Resident of HDSS village

          2. Singleton pregnancy

          3. Second or third trimester (after quickening) but before 33 weeks of gestation by
             fundal height

          4. Does not plan to relocate out of the HDSS area or population-based surveillance site
             in the next 12 months and agrees to all follow-up visits/contact by phone

          5. Is not currently enrolled in another intervention study

          6. Provides informed consent by signature or thumb print

          7. Consents to HIV testing and counseling as required

          8. Willing to deliver in the labor ward of the study hospital

          9. No history of chronic illness requiring multiple hospitalizations or prolonged medical
             therapy (except HIV on ART)

        Exclusion Criteria:

          1. History of allergic reaction to any component of the study vaccines

          2. Residence outside the study area or planning to relocate out in the 9 months following
             enrollment

          3. Received immunoglobulin or blood products within 45 days of study entry

          4. Used immunosuppressive medication within 45 days of study entry (inhaled and topical
             corticosteroids permitted)

          5. High risk pregnancy including any pre-existing condition likely to cause complications
             of pregnancy (hypertension, diabetes, current asthma, eclampsia or pre-eclampsia,
             epilepsy, heart disease, renal disease, liver disease, fistula repair, leg or spine
             deformity)

          6. Unable to give informed consent (for example due to mental disability)

          7. Previous enrollment in a study with similar interventions

          8. Gestational age >32 weeks by last menstrual period or fundal height

          9. Acutely ill with temperature ≥37.5°C on the day of randomization/vaccination

         10. Hemoglobin <7.0 g/dL

         11. Influenza vaccination in previous 12 months
      

Gender

Female

Ages

13 Years - 49 Years

Accepts Healthy Volunteers

No

Contacts

Meredith L McMorrow, MD, MPH, , 

Location Countries

Kenya

Location Countries

Kenya

Administrative Informations


NCT ID

NCT01810731

Organization ID

CDC-NCIRD-6393


Responsible Party

Sponsor

Study Sponsor

Centers for Disease Control and Prevention


Study Sponsor

Meredith L McMorrow, MD, MPH, Study Director, Centers for Disease Control and Prevention


Verification Date

April 2014