The metabolic, virulence and antimicrobial resistance profiles of colonizing Streptococcus pneumoniae shift after pneumococcal vaccine introduction in urban Malawi

Abstract

Streptococcus pneumoniae accounts for at least 300,000 deaths from pneumonia, septicaemia and meningitis among children under 5-years-old worldwide. Protein-polysaccharide conjugate vaccines (PCVs) are highly effective at reducing vaccine serotype disease but emergence of non-vaccine serotypes and persistent nasopharyngeal carriage threaten to undermine this success. Here, we address the hypothesis that following vaccine introduction in high disease and carriage burden settings, adapted pneumococcal genotypes emerge with the potential to facilitate vaccine escape. We show that beyond serotype replacement, there are marked changes in S. pneumoniae carriage population genetics amongst 2804 isolates sampled 4-8 years after the 2011 introduction of PCV-13 in urban Malawi. These changes are characterised by metabolic genotypes with distinct virulence and antimicrobial resistance (AMR) profiles. This included exclusive genes responsible for metabolism and carbohydrate transport, and toxin-antitoxin systems located in an integrative-conjugative region suggestive of horizontal gene transfer. These emergent genotypes were found to have differential growth, haemolytic, or epithelial adhesion/invasion traits that may confer advantage in the nasopharyngeal niche. Together these data show that in the context of PCV13 introduction in a high burden population, there has been a shift in the pneumococcal population dynamics with the emergence of genotypes that have undergone multiple adaptations extending beyond simple serotype replacement, a process that could further undermine vaccine control and promote the spread of AMR.

Bacterial surface lipoproteins mediate epithelial microinvasion byStreptococcus pneumoniae

“…To determine if palA is predominantly present in more carriage-type serotypes, such as serotype 6B, we examined the presence of palA in a well-curated dataset of 2806 carriage isolates from Malawi (48). 567 of these carriage isolates (20.5%) carry palA in their chromosome.…”

“…Statistical significance was determined using Student's t-test assuming equal variance. iTOL(48,69). Potential gene functions were inferred through the results of BLASTP and NCBI Conserved Domain Database searches(67,68,70).…”

Cross-sectional health centre and community-based evaluation of the impact of pneumococcal and malaria vaccination on antibiotic prescription and usage, febrile illness and antimicrobial resistance in young children in Malawi: the IVAR study protocol

“…While promising, such impacts may be reduced in the longer term, particularly in high carriage prevalence settings42 or via serotype replacement 43. Indeed, following PCV13 introduction in Malawi, high residual pneumococcal carriage has been observed 8 years post-PCV13 introduction,25 along with emergence of resistant serotypes 15. Thus, there is a need to conduct a thorough evaluation in a high carriage, low-income setting.…”

“…Varying responses to vaccination have been observed between high-income (HIC) and low-income and middle-income countries (LMICs), with vaccines frequently underperforming expectations in LMICs despite high vaccine coverage rates 15. However, many LMICs also have severely limited access to diagnostics and appropriate antibiotics,16 with empirical and potentially unnecessary antibiotic prescriptions being a common reality of clinical practice 17.…”

“…Malawi introduced PCV13 in November 2011 using a 3+0 delivery schedule (1 dose at 6, 10 and 14 weeks of age), with vaccine coverage exceeding 90% 22. Though introduction was associated with significant reductions in invasive pneumococcal disease23 and all-cause mortality,24 vaccine serotype carriage has remained persistently high,25 and penicillin non-susceptibility in both carriage15 26 and disease samples27 has not decreased, particularly in non-vaccine serotypes 15. Hence, some have queried whether PCV13 delivery can be further optimised 28.…”