Abstract
SummaryBackgroundDespite the heightened risk of serious influenza during infancy, vaccination is not recommended in infants younger than 6 months. We aimed to assess the safety, immunogenicity, and efficacy of maternal immunisation with trivalent inactivated influenza vaccine for protection of infants against a first episode of laboratory-confirmed influenza.MethodsWe did this prospective, active-controlled, observer-blind, randomised phase 4 trial at six referral centres and community health centres in Bamako, Mali. Third-trimester pregnant women (≥28 weeks' gestation) were randomly assigned (1:1), via a computer-generated, centre-specific list with alternate block sizes of six or 12, to receive either trivalent inactivated influenza vaccine or quadrivalent meningococcal vaccine. Study personnel administering vaccines were not masked to treatment allocation, but allocation was concealed from clinicians, laboratory personnel, and participants. Infants were visited weekly until age 6 months to detect influenza-like illness; laboratory-confirmed influenza diagnosed with RT-PCR. We assessed two coprimary objectives: vaccine efficacy against laboratory-confirmed influenza in infants born to women immunised any time prepartum (intention-to-treat population), and vaccine efficacy in infants born to women immunised at least 14 days prepartum (per-protocol population). The primary outcome was the occurrence of a first case of laboratory-confirmed influenza by age 6 months. This trial is registered with ClinicalTrials.gov, number NCT01430689.FindingsWe did this trial from Sept 12, 2011, to Jan 28, 2014. Between Sept 12, 2011, and April 18, 2013, we randomly assigned 4193 women to receive trivalent inactivated influenza vaccine (n=2108) or quadrivalent meningococcal vaccine (n=2085). There were 4105 livebirths; 1797 (87%) of 2064 infants in the trivalent inactivated influenza vaccine group and 1793 (88%) of 2041 infants in the quadrivalent meningococcal vaccine group were followed up until age 6 months. We recorded 5279 influenza-like illness episodes in 2789 (68%) infants, of which 131 (2%) episodes were laboratory-confirmed influenza. 129 (98%) cases of laboratory-confirmed influenza were first episodes (n=77 in the quadrivalent meningococcal vaccine group vs n=52 in the trivalent inactivated influenza vaccine group). In the intention-to-treat population, overall infant vaccine efficacy was 33·1% (95% CI 3·7–53·9); in the per-protocol population, vaccine efficacy was 37·3% (7·6–57·8). Vaccine efficacy remained robust during the first 4 months of follow-up (67·9% [95% CI 35·1–85·3] by intention to treat and 70·2% [35·7–87·6] by per protocol), before diminishing during the fifth month (57·3% [30·6–74·4] and 60·7 [33·8–77·5], respectively). Adverse event rates in women and infants were similar among groups. Pain at the injection site was more common in women given quadrivalent meningococcal vaccine than in those given trivalent inactivated influenza vaccine (n=253 vs n=132; p<0·0001), although 354 [92%] reactions were mild. Obstetrical and non-obstetrical serious adverse events were reported in 60 (3%) women in the quadrivalent meningococcal vaccine group and 61 (3%) women in the trivalent inactivated influenza vaccine group. Presumed neonatal infection was more common in infants in the trivalent inactivated influenza vaccine group than in those in the quadrivalent meningococcal vaccine group (n=60 vs n=37; p=0·02). No serious adverse events were related to vaccination.InterpretationVaccination of pregnant women with trivalent inactivated influenza vaccine in Mali—a poorly resourced country with high infant mortality—was technically and logistically feasible and protected infants from laboratory-confirmed influenza for 4 months. With adequate financing to procure the vaccine, implementation will parallel the access to antenatal care and immunisation coverage of pregnant women with tetanus toxoid.FundingBill & Melinda Gates Foundation.
Highlights
Correspondence to: Prof Myron M Levine, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD 21201, USA mlevine@medicine.umaryland. edu Pregnant women and young infants are at increased risk of developing severe, complicated, and sometimes fatal influenza infection;[1,2,3,4] no influenza vaccines are approved for infants younger than 6 months.[5,6,7]
Remaining questions include more precise determination of the duration of protection for infants that can accrue from maternal immunisation,[8] and the technical and logistical feasibility and effectiveness of implementation of programmes in resource-limited settings with high to moderate infant mortality rates.[13]
We aimed to address these questions in the course of a post-licensure clinical trial of the safety, immunogenicity, and efficacy of maternal influenza immunisation for prevention of influenza in infants younger than 6 months in Mali, west Africa—one of the world’s least developed countries, with the world’s seventh highest infant mortality rate.[14,15]
Summary
Pregnant women and young infants are at increased risk of developing severe, complicated, and sometimes fatal influenza infection;[1,2,3,4] no influenza vaccines are approved for infants younger than 6 months.[5,6,7] Maternal immunisation against influenza is a promising strategy to reduce disease in pregnant women and young infants.[8,9] Trials in Bangladesh[10] and South Africa[11] showed protection against laboratory-confirmed influenza in infants born to mothers who received trivalent inactivated influenza vaccine, but additional health benefits in those infants (eg, higher birthweight and reduced likelihood of being small for gestational age) have been inconsistent.[11,12] Remaining questions include more precise determination of the duration of protection for infants that can accrue from maternal immunisation,[8] and the technical and logistical feasibility and effectiveness of implementation of programmes in resource-limited settings with high to moderate infant mortality rates.[13]
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