Effects of attenuated influenza virus administration to young children on pneumococcal density and acquisition in UK families: a randomised controlled trial.

backgroundThe live attenuated influenza vaccine (LAIV) is offered in the UK to young children, protecting against influenza for those vaccinated, and as an indirect protection for the wider community. LAIV has also been shown to increase carriage density of Streptococcus pneumoniae, to an extent, in children. This study sought to confirm whether the vaccine, as a viral proxy, leads to an increase in carriage density in children and, if so, whether this increase augments S pneumoniae acquisition in household contacts.

methodsWe conducted a randomised control study (ISRCTN10720581, now complete) across ten UK sites. We included families having a child aged 2 years (index child) and due to receive their first LAIV dose under National Health Service criteria, and at least two other household contacts. Participants were excluded when the index child was ineligible for LAIV, had primary or secondary immunodeficiency, or was currently enrolled in other trials or circumstances that could jeopardise participation or data integrity during the study. Families were randomly assigned (1:1) to either the early LAIV group or late LAIV group using a single central allocation service with computerised randomisation for all sites. After randomisation, families and clinical research staff were unmasked; however, laboratory and analytical research staff remained masked. Nasopharyngeal swabs were collected from all participants over five visits, each 2 weeks apart, and tested for pneumococcal carriage by quantitative PCR for lytA, with a cycle threshold (Ct) cutoff of 35, and Ct values converted to gene copies per mL. LAIV was given to index children at visit 1 in the early LAIV group and at visit 3 in the late LAIV group. The coprimary outcomes of this study were S pneumoniae density in index children at 14 and 28 days after LAIV as compared with that on day 0, and the prevalence, at days 14 and 28, of S pneumoniae colonisation in the household contacts of index children who were S pneumoniae-positive at baseline. We developed regression models to analyse the association between vaccination and whether an increase in pneumococcal density was observed 14 and 28 days later, in addition to an increase in the odds of S pneumoniae acquisition in household members after administering LAIV. Serious adverse events were recorded if reported to the study team and were assessed by the Chief Investigator for seriousness, expectedness, and relatedness to LAIV or study procedures.

findings405 families were enrolled between Oct 3, and Oct 30, 2017, and between Sept 27, and Nov 2, 2018. 205 families (703 participants) were allocated to the early LAIV group and 200 (676 participants) to the late LAIV group. Data on sex were available for 402 of 405 index participants. In the early LAIV group, 116 (58%) of 202 index children were female and 86 (42%) were male, and the median age was 2·47 years (IQR 0·331); in the late LAIV group, 91 (46%) of 200 index children were female and 108 (54%) were male, and the median age was 2·47 years (0·333). In the early LAIV group, 276 (59%) of 470 household contacts were female and 194 (41%) were male, and the median age of contacts was 33·8 (IQR 31·7); in the late LAIV group 272 (60%) of 453 household contacts were female and 181 (40%) were male, and the median age of contacts was 33·1 (IQR 31·4). 388 (96%) of 405 households, including 1309 (95%) of the 1379 participants, completed the study. Regression analyses showed that there was a 2·5-times (95% CI 1·5-4·3, p=0·0008) increase in the odds of vaccinated children having increased pneumococcal density 14 days later, compared with that in unvaccinated children, and a 2·0-times (95% CI 1·2-3·5, p=0·015) increase in the odds of household contacts S pneumoniae acquisition. These effects appear to have attenuated by day 28, on which there was a 1·5 times (95% CI 0·88-2·5, p=0·14) increase in odds of vaccinated children having increased pneumococcal density compared with that in unvaccinated children and a 0·89 times (95% CI 0·53-1·5, p=0·67) the odds of household contacts S pneumoniae acquisition. Three serious adverse events related to pregnancy and breastfeeding were reported, which were deemed to be unrelated to the study.

interpretationOur results show that in young children colonised with S pneumoniae, infection with an attenuated influenza virus in the 2 weeks after vaccination increases the risk of pneumococcal acquisition among their close contacts. This effect appears to be driven by a vaccine-induced rise in bacterial density. On the basis of our results, density of bacterial nasal colonisation in young children could be used to model transmission dynamics, both at the individual and population levels.

fundingUniversity of Bristol, Gates Foundation, Pfizer, European Society of Paediatric Infectious Diseases.