Safety and Immunogenicity Study of Influenza Vaccines in HIV-infected and HIV-uninfected Pregnant Women in Western Kenya
|First Received Date ICMJE||March 12, 2013|
|Last Updated Date||July 8, 2013|
|Start Date ICMJE||January 2014|
|Estimated Primary Completion Date||April 2015 (final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
|Original Primary Outcome Measures ICMJE
|Change History||Complete list of historical versions of study NCT01810731 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Safety and Immunogenicity Study of Influenza Vaccines in HIV-infected and HIV-uninfected Pregnant Women in Western Kenya|
|Official Title ICMJE||A Double-Blind, Randomized, Controlled Trial to Evaluate the Safety, Immunogenicity, and Efficacy of Trivalent Inactivated Influenza Vaccine, High-Dose Trivalent Inactivated Influenza Vaccine and/or Intradermal Trivalent Inactivated Influenza Vaccine in HIV-Infected and HIV-Uninfected Pregnant Women in a Malaria-Endemic Area of Rural Western Kenya|
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. High-dose influenza vaccine has been shown to induce higher antibody titers in older adults and HIV-infected adults. Intradermal TIV has also shown higher rates of seroconversion in older adults. Therefore, we propose to conduct a double-blind randomized controlled trial of influenza vaccines stratified by HIV status in up to 960 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 traditional TIV and high-dose TIV (and/or intradermal TIV) in HIV-infected and HIV-uninfected pregnant women. Findings will inform maternal influenza vaccination policies in Kenya and other African countries.
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 high-dose trivalent inactivated influenza vaccine (hdTIV) or intradermal trivalent inactivated influenza vaccine (idTIV) 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 traditional TIV (VAXIGRIP® (Sanofi Pasteur SA, Lyon, France)or FLUZONE® (Sanofi Pasteur Inc., Swiftwater, PA, USA), high-dose TIV FLUZONE® High-Dose (Sanofi Pasteur Inc., Swiftwater, PA, USA), and/or intradermal TIV (INTANZA® (Sanofi Pasteur SA, Lyon, France) or FLUZONE® Intradermal(Sanofi Pasteur Inc., Swiftwater, PA, USA) in HIV-infected and HIV-uninfected pregnant women.
This trial will be conducted as a double-blind, randomized, controlled trial stratified by HIV status in up to 960 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 TIV, hdTIV, idTIV 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 320 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 Type ICMJE||Interventional|
|Study Phase||Phase 2
|Study Design ICMJE||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
|Study Arm (s)||
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Not yet recruiting|
|Estimated Enrollment ICMJE||960|
|Estimated Completion Date||April 2016|
|Estimated Primary Completion Date||April 2015 (final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||13 Years to 49 Years|
|Accepts Healthy Volunteers||No|
|Location Countries ICMJE||Kenya|
|NCT Number ICMJE||NCT01810731|
|Other Study ID Numbers ICMJE||CDC-NCIRD-6393|
|Has Data Monitoring Committee||Yes|
|Responsible Party||Centers for Disease Control and Prevention|
|Study Sponsor ICMJE||Centers for Disease Control and Prevention|
|Collaborators ICMJE||Not Provided|
|Information Provided By||Centers for Disease Control and Prevention|
|Verification Date||March 2013|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP