TY - JOUR T1 - Use of a pandemic H1N1 strain with updated haemagglutinin and neuraminidase results in increased nasopharyngeal shedding and improved immunogenicity to Russian-backbone live attenuated influenza vaccine among children aged 2 – 4 years old: an open-label, prospective, observational, phase 4 study in The Gambia JF - bioRxiv DO - 10.1101/519256 SP - 519256 AU - Benjamin B. Lindsey AU - Ya Jankey Jagne AU - Edwin P. Armitage AU - Anika Singanayagam AU - Hadijatou J. Sallah AU - Sainabou Drammeh AU - Elina Senghore AU - Nuredin I. Mohammed AU - David Jeffries AU - Katja Höschler AU - John S. Tregoning AU - Adam Meijer AU - Ed Clarke AU - Tao Dong AU - Wendy Barclay AU - Beate Kampmann AU - Thushan I. de Silva Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/01/18/519256.abstract N2 - Background Poor efficacy and effectiveness of the pandemic H1N1 (pH1N1) component in intranasal live attenuated influenza vaccine (LAIV) has been demonstrated in several studies. The reasons for this are unclear, but may be due to impaired replicative fitness of pH1N1 A/California/07/2009-like (Cal09) LAIV strains.Methods In an open-label, prospective, observational, phase 4 study, we evaluated the impact of updating the pH1N1 component in the Russian-backbone trivalent LAIV from Cal09 in 2016-17 (n=118) to an A/Michigan/45/2015-like strain (A/17/New York/15/5364, NY15) in 2017-18 (n=126), on shedding and immunogenicity in Gambian children aged 2-4 years old. The study was nested within a larger randomised controlled trial investigating LAIV-microbiome interactions (ClinicalTrials.gov NCT02972957).Findings Cal09 showed impaired nasopharyngeal shedding compared to H3N2 and influenza B, along with sub-optimal serum antibody and T-cell responses. Following the switch to NY15, a significant increase in pH1N1 shedding was seen, along with improvements in seroconversion and influenza-specific CD4+ T-cell responses. Viral kinetics in vitro mirrored these findings, with NY15 showing greater replicative ability than Cal09 in human nasal epithelial cells. Persistent shedding to day 7 was independently associated with both seroconversion and CD4+ T cell response in multivariable logistic regression.Interpretation Our results suggest that the pH1N1 component switch in LAIV may have overcome problems in prior formulations. LAIV effectiveness against pH1N1 should therefore improve in upcoming influenza seasons. Our data also highlight the importance of evaluating replicative fitness, in addition to antigenicity, when selecting annual LAIV components and design of potentially more effective vaccines.Funding The Wellcome Trust. ER -