Maternal immunisation with trivalent inactivated influenza vaccine for prevention of influenza in infants in Mali: a prospective, active-controlled, observer-blind, randomised phase 4 trial.
Despite 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.



We 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.



We 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.



Vaccination 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.



Bill & Melinda Gates Foundation.
Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA.
Milagritos D
MD
Tapia
Le Centre pour le Développement des Vaccins du Mali (CVD-Mali), Bamako, Mali.
Samba O
SO
Sow
Le Centre pour le Développement des Vaccins du Mali (CVD-Mali), Bamako, Mali.
Boubou
B
Tamboura
Department of Obstetrics and Gynecology, Hôpital Gabriel Touré, Bamako, Mali.
Ibrahima
I
Tégueté
Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA.
Marcela F
MF
Pasetti
Le Centre pour le Développement des Vaccins du Mali (CVD-Mali), Bamako, Mali.
Mamoudou
M
Kodio
Le Centre pour le Développement des Vaccins du Mali (CVD-Mali), Bamako, Mali.
Uma
U
Onwuchekwa
Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA.
Sharon M
SM
Tennant
Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA.
William C
WC
Blackwelder
Le Centre pour le Développement des Vaccins du Mali (CVD-Mali), Bamako, Mali.
Flanon
F
Coulibaly
Le Centre pour le Développement des Vaccins du Mali (CVD-Mali), Bamako, Mali.
Awa
A
Traoré
Le Centre pour le Développement des Vaccins du Mali (CVD-Mali), Bamako, Mali.
Adama Mamby
AM
Keita
Le Centre pour le Développement des Vaccins du Mali (CVD-Mali), Bamako, Mali.
Fadima Cheick
FC
Haidara
Le Centre pour le Développement des Vaccins du Mali (CVD-Mali), Bamako, Mali.
Fatoumata
F
Diallo
Le Centre pour le Développement des Vaccins du Mali (CVD-Mali), Bamako, Mali.
Moussa
M
Doumbia
Le Centre pour le Développement des Vaccins du Mali (CVD-Mali), Bamako, Mali.
Doh
D
Sanogo
Cooperative Studies Program Coordinating Center, Department of Veterans Affairs, Perry Point, MD, USA.
Ellen
E
DeMatt
Department of Epidemiology, University of Maryland, Baltimore, MD, USA.
Nicholas H
NH
Schluterman
Department of Epidemiology, University of Maryland, Baltimore, MD, USA.
Andrea
A
Buchwald
Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA.
Karen L
KL
Kotloff
Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA.
Wilbur H
WH
Chen
Emory University School of Medicine, Atlanta, GA, USA; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia PA, USA.
Evan W
EW
Orenstein
Emory University School of Medicine, Atlanta, GA, USA; Department of Dermatology, University of Pennsylvania Hospital, Philadelphia PA, USA.
Lauren A V
LAV
Orenstein
National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA.
Julie
J
Villanueva
National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA.
Joseph
J
Bresee
Division of Infectious Diseases, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
John
J
Treanor
Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address: mlevine@medicine.umaryland.edu.
Myron M
MM
Levine
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000328:Adult; D005260:Female; D006801:Humans; D007114:Immunization; D007115:Immunization Schedule; D007223:Infant; D007231:Infant, Newborn; D007252:Influenza Vaccines / Q000008:administration & dosage*; D007251:Influenza, Human / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control*; D008302:Mali; D022401:Meningococcal Vaccines / Q000008:administration & dosage; D011446:Prospective Studies; D014611:Vaccination / Q000379:methods
D000276:Adjuvants, Immunologic; D007252:Influenza Vaccines; D022401:Meningococcal Vaccines