The effect of live attenuated influenza vaccine on pneumococcal colonisation densities among children aged 24-59 months in The Gambia: a phase 4, open label, randomised, controlled trial

Abstract

Background: Influenza and other respiratory viruses promote Streptococcus pneumoniae proliferation in the upper respiratory tract. We sought to investigate for what we believe is the first time, the effect of intranasal live attenuated influenza vaccine (LAIV) on nasopharyngeal S pneumoniae density in a low-income to middle-income country population with high pneumococcal carriage rates.

Methods: In an open-label, randomised, controlled trial in The Gambia, 330 healthy children aged 24-59 months were randomly assigned 2:1 to receive one trivalent LAIV dose at enrolment (day 0, intervention) or at the end of active follow-up (day 21, control). The investigator team were initially masked to block size and randomisation sequence to avoid allocation bias. Group allocation was later revealed to the investigator team. The primary outcome was PCR-quantified day 7 and 21 pneumococcal density. Asymptomatic respiratory viral infection at baseline and LAIV strain shedding were included as covariates in generalised mixed-effects models, to assess the effect of LAIV and other variables on pneumococcal densities. The study is registered at ClinicalTrials.gov, NCT02972957, and is closed to recruitment.

Findings: Between Feb 8 and April 12, 2017, and Jan 15 and March 28, 2018, of 343 children assessed for eligibility, 213 in the intervention group and 108 in the control group completed the study and were included in the final analysis. Although no significant differences were seen in pneumococcal carriage or density at each timepoint when comparing groups, changes from baseline were observed in the LAIV group. The baseline S pneumoniae carriage prevalence was high in both LAIV and control groups (75%) and increased by day 21 in the LAIV group (85%, p=0·0037), but not in the control group (79%, p=0·44). An increase in pneumococcal density from day 0 amounts was seen in the LAIV group at day 7 (+0·207 log10 copies per μL, SE 0·105, p=0·050) and day 21 (+0·280 log10 copies per μL, SE 0·105, p=0·0082), but not in the control group. Older age was associated with lower pneumococcal density (-0·015 log10 copies per μL, SE 0·005, p=0·0030), with the presence of asymptomatic respiratory viruses at baseline (+0·259 log10 copies per μL, SE 0·097, p=0·017), and greater LAIV shedding at day 7 (+0·380 log10 copies per μL, SE 0·167, p=0·024) associated with higher pneumococcal density. A significant increase in rhinorrhoea was reported in the LAIV group compared with the control group children during the first 7 days of the study (103 [48%] of 213, compared with 25 [23%] of 108, p<0·0001), and between day 7 and 21 (108 [51%] of 213, compared with 28 [26%] of 108, p<0·0001).

Interpretation: LAIV was associated with a modest increase in nasopharyngeal pneumococcal carriage and density in the 21 days following vaccination, with the increase in density lower in magnitude than previously described in the UK. This increase was accelerated when LAIV was administered in the presence of pre-existing asymptomatic respiratory viruses, suggesting that nasopharyngeal S pneumoniae proliferation is driven by cumulative mixed-viral co-infections. The effect of LAIV on pneumococcal density is probably similar to other respiratory viral infections in children. Our findings provide reassurance for the use of LAIV to expand influenza vaccine programmes in low-income to middle-income country populations with high pneumococcal carriage.

Funding: Wellcome Trust.

Conflict of interest statement

We declare no competing interests.

© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

Figures

Figure 1

Trial profile Overview of participants recruited and retained in the study. Recruitment in 2017 (A). Recruitment in 2018 (B). Children randomly assigned to the LAIV group received one dose of Russian-backbone trivalent LAIV containing either A/17/California/2009/38 in 2017 or A/17/New York/15/5364 in 2018 at day 0. H3N2 strain and influenza B lineages included in the vaccine remained consistent across the 2 years. LAIV=live attenuated influenza vaccine.

Figure 2

Effect of the presence of asymptomatic respiratory viral infection at baseline on Streptococcus pneumoniae densities during the study period in the LAIV group (A) and the control group (B) LAIV=live attenuated influenza vaccine.

Figure 3

Effect of LAIV viral shedding on Streptococcus pneumoniae densities Mean densities of S pneumoniae in LAIV recipients stratified by LAIV shedding at (A) day 2 or (B) day 7. High LAIV shedding was defined as a Ct value equal to or lower than the median Ct-value in any of the three LAIV strains at each timepoint. Values above the median Ct value were classified as low LAIV shedding. All individuals with no shedding detected at each timepoint were included in the low shedding group. Note, lower Ct values denote higher amounts of virus. LAIV=live attenuated influenza vaccine. Ct=cycle threshold. *A significant association between high day 7 LAIV shedding and day 7 pneumococcal density seen in generalised linear models (+0·380 log10 copies per μL compared with low LAIV shedding at day 7, p=0·024, appendix p 7), but not between day 2 LAIV shedding and day 7 pneumococcal density (+0·036, p=0·83, appendix p 8).