Influenza Vaccine Trial in HIV Uninfected Pregnant Women (MatfluHIVneg)
Randomised, double blind, placebo controlled trial to assess safety, immunogenicity and efficacy of Trivalent Influenza vaccine in HIV uninfected pregnant women
Biological: Trivalent influenza vaccine
Biological: Normal saline
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
|Official Title:||Vaccination of HIV-uninfected Pregnant Women With Trivalent Influenza Vaccine in the Prevention of Influenza Illness During Early Infancy and in Mothers: Randomized Controlled Phase III Trial Evaluating Safety, Immunogenicity and Efficacy|
- The number of laboratory-confirmed influenza cases in infants born to mothers who received TIV or placebo will be used to determine efficacy of TIV vaccination of pregnant women against laboratory-confirmed influenza illness in their infants [ Time Frame: 24 weeks of age ] [ Designated as safety issue: No ]All infants (up to 24 weeks of age) born to women enrolled on trial will be assessed by study staff if they have any signs or symptoms (including fever, hospitalisation, apnea, cough, nasal catarrh/ congenstion, tachypnea) which could indicate influenza like illness. Nasopharyngeal aspirate samples collected at illness visits will be processed for viruses using real time reverse transcriptase-polymerase chain reaction (rRTPCR) assays.
- Humoral and cell-mediated immune (CMI) responses to influenza strains in the vaccine will be measured to assess the immunogenicity of TIV in pregnant women vaccinated between 20-34 weeks of gestational age [ Time Frame: one month post vaccination, delivery (+7 days), 24 weeks post natal ] [ Designated as safety issue: No ]Humoral immunity will be measured by hemagglutination inhibition (HAI) assay. Blood will be collected at enrolment (pre-vaccination), one month post vaccination, delivery (+7 days) and 24 weeks post delivery. Humoral immune response definitions: HAI titers < 1:10 = seronegative; ≥ 1:10 = seropositive; > 1:40 = protected against influenza; Response to TIV = serconversion (from <1:10 to ≥1:10) and/or 4-fold increase of HAI titers. Cell mediated immunity will be measured by ELISPOT response to TIV. Blood will be collected at enrollment (pre-vaccination) and one month post vaccination.
- Hemagglutinin (HA) antibody measurements in blood taken from mother and infants up to 24 weeks post delivery will be used to assess kinetics of transplacentally acquired antibodies [ Time Frame: Birth (+7 days), 8, 16 & 24 weeks of age ] [ Designated as safety issue: No ]Hemagglutinin (HA) antibody measurements in blood taken from mother at birth and infants at birth, 8,16 and 24 weeks post delivery will be used to assess kinetics of transplacentally acquired antibodies
- Clinical influenza like illnesses in infants born to TIV and placebo recipients will be used to assess efficacy of TIV in pregnant women against ILI in their infants [ Time Frame: 24 weeks of age ] [ Designated as safety issue: No ]All infants participants will have illness visits conducted if they have any signs or symptoms which may be suggestive of influenza-like illness (ILI). Infants with ILI, but with no Influenza virus isolated from nasopharyngeal aspirates will be classified as having clinical ILI. Clinical ILI cases in infants of TIV and placebo recipients will be compared to determine efficacy of TIV against ILI.
- The number of laboratory-confirmed influenza illnesses in maternal participants during pregnancy and for 24 weeks post-partum will be used to assess efficacy of TIV against laboratory confirmed influenza [ Time Frame: 24 weeks post delivery ] [ Designated as safety issue: No ]All maternal participants with signs and/ or symptoms of influenza like illness (ILI) will have nasopharyngeal and oropharyngeal swabs collected at illness visits and processed by rRTPCR assays. Participants from whom influenza virus is isolated at illness visits will be included in analysis to evaluate the efficacy of TIV against laboratory-confirmed influenza illness in mothers during pregnancy and until 24 weeks post-partum
- The number of maternal participants who have ILI in whom influenza is not isolated from NP or OP swabs will be used to determine efficacy of TIV against clinical ILI in mothers [ Time Frame: 24 weeks post delivery ] [ Designated as safety issue: No ]Maternal participants will be followed up from enrollment until 24 weeks post delivery for any influenza like illness. Women who have ILI episodes during which influenza is not isolated from NP/ OP swabs will be included in analysis to define the efficacy of TIV against protocol defined clinical ILI in women during pregnancy and until 24 weeks post-partum
- Infants born to TIV/ placebo recipients will have nasopharyngeal swabs collected at 8, 16 and 24 weeks of age to determine acquisition of pneumococcal carriage [ Time Frame: 24 weeks of age ] [ Designated as safety issue: No ]Infants born to women on immunogenicity cohorts will have nasopharyngeal swabs collected at 8, 16 and 24 weeks of age. The swabs will be processed for pneumococcal carriage and results will be used to define the efficacy of TIV against acquisition of pneumococcal carriage in infants up to 24 weeks of chronological age
|Study Start Date:||March 2011|
|Study Completion Date:||May 2013|
|Primary Completion Date:||May 2013 (Final data collection date for primary outcome measure)|
Active Comparator: Trivalent influenza vaccine
Single dose administration of trivalent influenza vaccine prior to onset of influenza season
Biological: Trivalent influenza vaccine
single dose of 0.5ml of Trivalent influenza vaccine for season will be administered into deltoid muscle of non-dominant arm
Other Name: Vaxigrip
|Placebo Comparator: Normal saline||
Biological: Normal saline
Single dose of 0.5ml of normal saline will be administered into deltoid muscle of non-dominant arm
Other Name: NaCl
Acute respiratory illness is a significant contributor to neonatal mortality and the leading cause of under- 5 childhood mortality particularly during infancy. Infants under 6 months of age have the highest rate of excess influenza-associated hospitalization in industrialized countries among paediatric age groups. Determining the contribution of influenza to early childhood morbidity and mortality in sub-Saharan Africa and the potential to prevent influenza disease through vaccination may contribute to reducing childhood deaths; since influenza illness is a vaccine preventable disease for which vaccines are developed, licensed and available at reasonable cost. Unfortunately, infants at highest risk for serious disease are those under 6 months of age, for whom trivalent inactivated influenza vaccine (TIV) is poorly immunogenic and not licensed. As pregnant women also have an increased risk of serious illness (3.3-5.5 fold for hospitalization for influenza-associated acute cardio-respiratory illness) from influenza infection, one strategy to prevent the complications of influenza in pregnant women and young infants is through maternal TIV immunization, which is recommended by the WHO. This could result in direct protection of the women and protection of the young infant consequent to transplacental transfer of TIV induced antibody.
Barriers to administration of vaccines during pregnancy including lack of information on effectiveness and concerns about safety probably explain the virtual non-existent use of TIV in pregnant women from low-middle income countries. Recently data have become available from Bangladesh in which the benefit of maternal TIV vaccination was demonstrated by a 63% (95%CI 5 to 85) reduction in laboratory-confirmed influenza illness in infants under 24 weeks of age in children born to mothers vaccinated with TIV and a 36% reduction in clinical illness in vaccinated mothers.
Much of the influenza virus-associated morbidity and mortality may be due to the synergistic lethality of influenza with bacterial pathogens leading to pneumonia as well as other viral co-infections. Superimposed bacterial infections, especially Streptococcus pneumoniae, contribute to a large proportion of pneumonia deaths associated with influenza illness during pandemics.
The overall aim of this project is to evaluate the safety, immunogenicity and efficacy of TIV vaccination of HIV-uninfected pregnant women in preventing influenza related illness in their young infants, as well as among the women.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01306669
|RMPRU, Chris Hani Baragwanath Hospital|
|Soweto, Johannesburg, Gauteng, South Africa, 2013|
|Study Chair:||Shabir A Madhi, MD, PhD||University of the Witwatersrand|
|Study Director:||Keith P Klugman, MD, PhD||Emory University|
|Study Director:||Adriana Weinberg||University of Denver|