DISCUSSION
VIRUS, INFLUENZA B, INFLUENZA, VIRUS SHEDDING, INFLUENZA A, INFLUENZA A(H3N2), VIRAL SHEDDING, INFLUENZA
This study evaluated post‐vaccination nasal shedding of LAIV viruses among children aged 2–10 years during the 2‐year, phase IV, community‐based, triple‐blinded, randomized, placebo‐controlled trial primarily designed to assess vaccine efficacy, which was conducted in rural north India. Our key findings were high post‐vaccine nasal shedding in year 1, and reduced shedding in year 2, lower shedding for A(H1N1)pdm09 compared to the other viruses in both years, and higher shedding of influenza B virus.We observed that in year 1, on day 2 post‐vaccination, about 70% of included LAIV recipients shed at least one vaccine virus strain. Since mucociliary clearance usually occurs within minutes, shedding at day 2 is likely due to viral replication in the nasopharynx, indicating vaccine virus viability.The reduction of nasal shedding from 68.3% on day 2 of the first year to 29.6% in year 2 might be attributed to suppressed replication of LAIV viruses due to previous receipt of LAIV in year 1. Pre‐existing immunity is thought to influence LAIV viral recovery, and studies support the idea that viral shedding declines with repeated use of LAIV.Low shedding of the A/California/7/2009 (H1N1)pdm09‐like virus seems to be a common observation among various studies. We observed that during year 1, 2 days post‐immunization, there was evidence of LAIV‐A(H1N1)pdm09 in nasal swabs of about 12% LAIV recipients. This was consistent with what was observed in the Senegal trial, where LAIV‐A(H1N1)pdm09 was detected in 19% of LAIV recipients.In our study, shedding varied among strains; during year 1, 2 days post‐vaccination, the proportion of children with LAIV‐B virus shedding was highest, followed by LAIV‐A(H3N2) and LAIV‐A(H1N1)pdm09. This was also observed in the Senegal trial (LAIV‐B [52%] > LAIV‐A(H3N2) [48%] > LAIV‐A(H1N1)pdm09 [19%]) and the phase II Bangladesh trial (LAIV‐B [59.3%] > LAIV‐A(H3N2) [40.0%] > LAIV‐A(H1N1)pdm09 [0.0%]).While examining individual level data of 15 individuals who were sampled for shedding in both years (Table Viral shedding findings reported in this study were part of a randomized controlled trial evaluating the efficacy of a Russian‐backbone trivalent LAIV among children in rural North India. Influenza vaccine administered in year 2 had different strains of influenza A (H3N2) and influenza B viruses as compared to year 1. As per WHO southern hemisphere vaccine recommendation in Year 1, vaccines included influenza A/Switzerland/9715293/2013 (A(H3N2)‐like) and influenza B/Phuket/3073/2013 (Yamagata‐like) viruses. In year 2, LAIV included influenza A/Hong Kong/4801/2014 (A(H3N2)‐like) and influenza B/Brisbane/60/2008 (Victoria‐like) viruses. In both years, LAIV demonstrated significant vaccine efficacy against influenza A(H3N2) virus and matched influenza B viruses. However, LAIV had no statistically significant efficacy against influenza A(H1N1)pdm09 virus in either year.Several hypotheses have been proposed as potential reasons underlying reduced LAIV effectiveness against A(H1N1)pdm09‐like viruses. Importantly, reduced replicative fitness of the A/California/7/2009 (H1N1)pdm09‐like strains was suggested as the most likely reason underlying decreased vaccine effectiveness in the United States during the 2013–2014 and 2015–2016 influenza seasons. Reduced replicative fitness of the A(H1N1)pdm09 component may have led to low efficacy of LAIV observed in Senegal.Since efficacy of LAIV has varied considerably across different settings, there exists a need for testing in different populations. To our knowledge, our study is the first comprehensive analysis of nasal shedding of vaccine viruses post‐immunization with a Russian‐backbone trivalent LAIV among children in India. Although information about nasal shedding of vaccine viruses is predictive of replicative fitness, it would be valuable to support the clinical results with in vitro findings. Specifically, replication of vaccine strains could be analyzed in primary human nasal epithelium air‐liquid cultures, a physiologically relevant model for respiratory research.Although this is a post hoc analysis and not powered for this outcome, our analyses have attempted to further the understanding of mechanisms underlying varied efficacy of LAIV in developing countries and underscore the importance of assessing replicative fitness while selecting candidate vaccine viruses for inclusion in LAIV. More research is required to further determine the possible reasons that could explain lower virus shedding and vaccine efficacy for LAIV‐A(H1N1)pdm09 across different settings.