Abstract
The pneumococcal conjugate vaccine (PCV) primarily reduces disease burden in adults through a reduction in carriage prevalence of invasive serotypes in children. Current vaccine formulations are the same for both adults and children, but tailoring these formulations to age category could optimize vaccine efficacy. Identification of specific pneumococcal genetic factors associated with carriage in younger or older age groups may suggest alternative formulations and contribute to a better mechanistic understanding of immunity. Here, we used whole genome sequencing to dissect pneumococcal variation associated with age. We performed genome sequencing in a large carriage cohort, and conducted a meta-analysis with an existing carriage study. We compiled a dictionary of pathogen genetic variation including serotype, sequence cluster, sequence elements, SNPs, burden combined rare variants, and clusters of orthologous genes (COGs) for each cohort – all of which used in a genome-wide association with host age. Age-dependent colonization had some heritability, though this varied between cohorts (h2 = 0.10, 0.00 – 0.69 95% CI in the first; h2 = 0.46, 0.33 – 0.60 95% CI in the second cohort). We found that serotypes and genetic background (strain) explained most of the heritability in each cohort (h2serotype = 0.06 and h2GPSC = 0.04 in the first; h2 serotype= 0.20 and h2 GPSC = 0.23 in the second cohort). When looking for genetic effects independent of genetic background and serotype, no individual genetic variants were robustly associated with carriage age. Overall, association with age was highly cohort and strain dependent, supporting proposals for a future vaccination strategy which is primarily targeted using serotypes rather than proteins, and is tailored towards specific pathogen populations.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Funding statement This work was supported by grants from the European Research Council (ERC Starting Grant, proposal/contract 281156; https://erc.europa.eu) and the Netherlands Organization for Health Research and Development (ZonMw; NWO-Vici grant, proposal/contract 91819627; www.zonmw.nl), both to DvdB. Work at the Wellcome Trust Sanger Institute was supported by Wellcome Trust core funding (098051; https://wellcome.ac.uk). JAL was funded by Wellcome [219699], and received support from the Medical Research Council (grant number MR/R015600/1). This award is jointly funded by the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement and is also part of the EDCTP2 program supported by the European Union. PT was funded in part by the Wellcome Trust [Grant number 083735/Z/07/Z]. The Netherlands Reference Laboratory for Bacterial Meningitis was supported by the National Institute for Health and Environmental Protection, Bilthoven (www.rivm.nl). For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.