Interaction between live-attenuated influenza vaccine, Streptococcus pneumoniae and the nasal microbiota. variant of Metagenome

Background – S. pneumoniae is the main bacterial pathogen in pneumonia. Pneumococcal acquisition and colonization is likely affected the ecological environment, including viral co-infections, the local resident microbiota composition and mucosal immunity. However, the exact interplay and relative importance of these factors is unknown. Methods – We studied the interaction between live-attenuated influenza vaccine (LAIV), successive S. pneumoniae challenge, and the nasal microbiota in healthy adults who participated in a randomized controlled trial using a human experimental challenge model. Findings – Since all participants received a pneumococcal challenge, we stratified the cohort according to pneumococcal acquisition, i.e. high-dense or low-dense colonization, and no pneumococcal acquisition following pneumococcal challenge. Nasal microbiota profiles at baseline were significantly associated with consecutive pneumococcal acquisition and density, independent of LAIV co-administration. Especially, Corynebacterium/Dolosigranulum-dominated profiles were associated with low-dense colonization, whereas a consortium of (facultative) anaerobic oral-type of bacteria, including Prevotellaceae, was related to high-dense carriage. Viral co-infection at baseline was also associated with carriage outcome, with lower baseline viral co-infections in low-dense carriers compared to the high-dense and no carriage groups. Low-dense carriers were also less likely to have (replicating) influenza virus following LAIV and showed the least ecological disruption following pneumococcal challenge compared to volunteers who became either high-dense or not colonized. We found that the baseline nasal microbiota composition was associated with mucosal cytokine responses (GM-CSF and VEGF) following LAIV. Finally, associations between mucosal cytokine levels and carriage outcome were observed with significantly lower GM-CSF, IFN-α, IL-12, IL-17, IL-1β, IL-2 and IL-4 in volunteers who became low-dense carriers compared to non-carriers. Interpretation – Our results indicate that the respiratory ecosystem as a whole affects pneumococcal acquisition and density following challenge. From ecological perspective, the most beneficial baseline and post-challenge ecological situation was observed in the group of individuals who became low-densely colonized with pneumococci following challenge.