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

Summary 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 log 10 copies per μL, SE 0·105, p=0·050) and day 21 (+0·280 log 10 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 log 10 copies per μL, SE 0·005, p=0·0030), with the presence of asymptomatic respiratory viruses at baseline (+0·259 log 10 copies per μL, SE 0·097, p=0·017), and greater LAIV shedding at day 7 (+0·380 log 10 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). ...

Impact of respiratory viral infections on nasopharyngeal pneumococcal colonization dynamics in children

“…While no differences in colonization prevalence were observed between the vaccine and control groups, LAIV recipients had significantly higher pneumococcal colonization densities 28 days after the first dose compared with controls [28]. Similarly, recent study from the Gambia found that the prevalence and densities of pneumococcal colonization increased by day 21 following an LAIV dose among vaccine recipients but not in the control group [29]. Neither study revealed evidence of increased risk of pneumococcal disease associated with LAIV receipt in their respective follow-up periods.…”

Associated virus-bacterial vaccine based on seasonal LAIV and S. pneumoniae chimeric peptide provide protection against post-influenza pneumococcal infection in mouse model

“…The data obtained in the present study that the seasonal LAIV facilitated the course of post-influenza pneumococcal infections protecting 50% of immunized animals is important taking into account that live influenza vaccines in many countries are used for the general population, including preschool and school age children [ 21 ]. Administration of LAIV may be the key to reducing the burden of bacteria in the upper respiratory tract [ 22 ].…”

Streptococcus pyogenescolonization in children aged 24-59 months in The Gambia: Impact of Live Attenuated Influenza Vaccine and associated serological responses

“…Children were randomized 2:1 to receive LAIV at study entry (day 0, D0, LAIV group) or on day 21 (D21, control group), which was the end of active follow up. The study (NCT02972957) was conducted across two years in Sukuta, an urban region in The Gambia, Africa during February to April 2017, and January to March 2018 [10, 11]. Children were recruited to the parent study following community sensitization.…”

“…Comparison of S. pyogenes colonization status and incident acquisition between children who received LAIV and those who did not was performed using chi-squared test. In addition, logistic and generalized mixed effects logistic regression models, accounting for multiple timepoint sampling from individuals, were used to explore the change in colonization status over time within the vaccinated and unvaccinated groups, as previously described [10]. Co-variates included were age in months, sex, the presence of asymptomatic respiratory viruses at baseline, timepoint (D0 vs D7, D0 vs D21) and receipt of LAIV [10, 11].…”

“…It is important to understand whether respiratory viruses increase colonization with pathogenic bacteria such as S. pyogenes in the nasopharynx, as colonization may be a necessary preceding event to pharyngitis and invasive disease. We have recently demonstrated that intranasal live attenuated influenza vaccine (LAIV), used as a surrogate viral challenge agent, induces modest increases in nasopharyngeal Streptococcus pneumoniae colonization and density in the 21 days following vaccination in Gambian children [10]. In the current study, we conducted a post-hoc analysis of this randomized controlled trial of LAIV in children aged 24-59 months to explore whether LAIV also induced an increase in nasopharyngeal S. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint…”