BACKGROUND: Despite the importance of vaccinating children younger than 5 years, few studies evaluating vaccine prevention of influenza have been reported in this age group. We evaluated efficacy of an inactivated quadrivalent influenza vaccine (IIV4) in children aged 6-35 months. METHODS: In this phase 3, observer-blinded, multinational trial, healthy children from 13 countries in Europe, Central America, and Asia were recruited in five independent cohorts, each in a different influenza season. Participants were randomly assigned (1:1) to either IIV4 (15 μg haemagglutinin antigen per strain per 0·5 mL dose; a single dose on day 0 for vaccine-primed children, and two doses, on days 0 and 28, for vaccine-unprimed children) or to one or two doses of a non-influenza control vaccine. Primary endpoints were moderate-to-severe influenza or all influenza (irrespective of disease severity) confirmed by RT-PCR on nasal swabs. Cultured isolates were further characterised as antigenically matched or mismatched to vaccine strains. Efficacy was assessed in the per-protocol cohort and total vaccinated cohort (time-to-event analysis), and safety was assessed in the total vaccinated cohort. FINDINGS: Between Oct 1, 2011, and Dec 31, 2014, 12 018 children were recruited into the total vaccinated cohort (6006 children in the IIV4 group and 6012 children in the control group). 356 (6%) children in the IIV4 group and 693 (12%) children in the control group had at least one case of RT-PCR-confirmed influenza. Of these 1049 influenza strains, 138 (13%) were A/H1N1, 529 (50%) were A/H3N2, 69 (7%) were B/Victoria, and 316 (30%) were B/Yamagata. Overall, 539 (64%) of 848 antigenically characterised isolates were vaccine-mismatched (16 [15%] of 105 for A/H1N1; 368 [97%] of 378 for A/H3N2; 54 [86%] of 63 for B/Victoria; 101 [33%] of 302 for B/Yamagata). Vaccine efficacy was 63% (97·5% CI 52-72) against moderate-to-severe influenza and 50% (42-57) against all influenza in the per-protocol cohort, and 64% (53-73) against moderate-to-severe influenza and 50% (42-57) against all influenza in the total vaccinated cohort. There were no clinically meaningful safety differences between IIV4 and control. INTERPRETATION: IIV4 prevented influenza A and B in children aged 6-35 months despite high levels of vaccine mismatch. Vaccine efficacy was highest against moderate-to-severe disease, which is the most clinically important endpoint associated with greatest burden. FUNDING: GlaxoSmithKline Biologicals SA.

American University of Beirut Beirut Lebanon

Catholic University of Louvain Cliniques Universitaires St Luc Brussels Belgium

Center of Postgraduate Medical Education Warsaw Poland

Centre for Community Medicine All India institute of Medical Sciences New Delhi India

Chulalongkorn University Bangkok Thailand

Complutense University of Madrid Madrid Spain

Dr Castroviejo Primary Health Care Center Madrid Spain

EAP Sardenya IIB Sant Pau Barcelona Spain

EBA Centelles Barcelona Spain

Eskisehir Osmangazi University Eskisehir Turkey

FISABIO Public Health Valencia Spain

GSK Bangalore India

GSK King of Prussia PA USA

GSK Rockville MD USA

GSK Wavre Belgium

Hospital Clínico Universitario de Santiago Santiago Spain

Hospital Infantil Universitario La Paz Madrid Spain

Hospital of Antequera Malaga Spain

icddr b Dhaka Bangladesh

Instituto Hispalense de Pediatría Sevilla Spain

Jaume 1 University and Illes Columbretes Health Center of Castellón Castellón de la Plana Spain

Khon Kaen University Khon Kaen Thailand

Mary Chiles General Hospital Manila Philippines

Medicentrum 6 s r o Prague Czech Republic

National Autonomous University of Honduras Tegucigalpa Honduras

National Autonomous University of Santo Domingo Santo Domingo Dominican Republic

Nicolaus Copernicus University in Torun Collegium Medicum Bydgoszcz Poland; University Hospital No 2 Bydgoszcz Poland

Paediatric Institute Mares Riera Blanes Spain

Research Institute for Tropical Medicine Manila Philippines

Royal Manchester Children's Hospital Manchester UK

St Hedwig of Silesia Hospital Trzebnica Poland

Tecnologia en Investigacion San Pedro Sula Honduras

University of Hradec Kralove Hradec Kralove Czech Republic

University of Southampton Southampton UK; University Hospital Southampton NHS Foundation Trust Southampton UK

University of the Philippines Philippine General Hospital Manila Philippines

Lancet Child Adolesc Health. 2018 May;2(5):307-308. doi: 10.1016/S2352-4642(18)30074-9. PubMed

References provided by Crossref.org

Quadrivalent Influenza Vaccine Prevents Illness and Reduces Healthcare Utilization Across Diverse Geographic Regions During Five Influenza Seasons: A Randomized Clinical Trial

Anamnestic Immune Response and Safety of an Inactivated Quadrivalent Influenza Vaccine in Primed Versus Vaccine-Naïve Children