Robert S. Heyderman, United Kingdom

University College London NIHR Global Health Research Unit on Mucosal Pathogens, Division of Infection & Immunity

Poster Author Of 1 e-Poster

 ePoster
Online Abstracts Vaccines - Impact of Vaccine programs and Serotype Replacement C2 Impact of Vaccine programs and Serotype Replacement

PNEUMOCOCCAL SEROTYPES IN INFANTS LESS THAN 90 DAYS OLD BEFORE AND AFTER INTRODUCTION OF PNEUMOCOCCAL CONJUGATE VACCINE (PCV) IN BLANTYRE, MALAWI

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Authors
Presentation Type
Abstract_Submission
Presentation Topic
C2 Impact of Vaccine programs and Serotype Replacement

Author Of 13 Presentations

 Conference Calendar

USE OF PNEUMOCOCCAL TRANSCRIPTOMICS FROM MURINE AND HUMAN SAMPLES TO IDENTIFY NEW PROTEIN ANTIGEN VACCINE CANDIDATES (ID 1026)

Session Name
Basic Sciences - Immunology, Pathogenesis, and Host-pathogen Interactions
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Abstract

Background

Conjugate vaccines successfully target specific serotypes but also lead to serotype replacement. Alternative strategies include bacterial proteins. Selection of protein antigens would benefit from knowledge of those most abundantly expressed during stages of human pneumococcal pathogenesis. Furthermore, vaccine protein candidates must also be expressed in mice for testing of candidates.

Methods

We designed a Nanostring codeset and analyzed 200 genes encoding for bacterial surface-exposed proteins. We evaluated transcriptomic expression in mouse colonization, pneumonia and sepsis models, as well as clinical CSF samples and human controlled infection.

Results

The 30 genes most highly expressed in each system (mouse model, human samples) were identified. There was excellent correlation between mouse colonization, pneumonia and blood specimens (R>0.85). Correlations between human colonization and meningitis were moderate (R=0.56), as were those between mouse and human transcriptomic profiles. We identified several genes highly expressed in all mouse and human conditions. Two in particular encoded for proteins that we show conferred protection against colonization and induced opsonic antibodies.

Conclusions

We present a novel approach to identify putative protective pneumococcal antigens, based on transcriptomic analyses of pneumococcal RNA harvested in different conditions. We identified two novel potential candidates, which also highlights the utility of studying pneumococcal gene expression from human samples.

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STREPTOCOCCUS PNEUMONIAE VACCINE SEROTYPES ACQUIRE PENICILLIN BINDING PROTEIN GENE MOSAICS FROM STREPTOCOCCUS MITIS (ID 428)

Session Name
Basic Sciences - Genomics and Transmission
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MUTATIONS OF STREPTOCOCCUS PNEUMONIAE BIOSYNTHESIS GENES INFLUENCE EPITHELIAL MICRO-INVASION AND THE INNATE-EPITHELIAL CELL RESPONSE IN VITRO AND IN AN EXPERIMENTAL HUMAN PNEUMOCOCCAL CHALLENGE MODEL (ID 872)

Session Name
Basic Sciences - Immunology, Pathogenesis, and Host-pathogen Interactions
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Authors

PNEUMOCOCCAL SEROTYPES IN INFANTS LESS THAN 90 DAYS OLD BEFORE AND AFTER INTRODUCTION OF PNEUMOCOCCAL CONJUGATE VACCINE (PCV) IN BLANTYRE, MALAWI (ID 1071)

Session Name
Vaccines - Impact of Vaccine programs and Serotype Replacement
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Authors

Abstract

Background

Malawi introduced PCV13 into its Expanded Program on Immunization in November 2011. Our aim was to describe the change in serotype distribution causing invasive pneumococcal disease (IPD) in neonates and young infants in Blantyre, Malawi.

Methods

We conducted a retrospective study of IPD in infants aged <90 days admitted to Queen Elizabeth Central Hospital (QECH) in Blantyre, Malawi between 2005 and 2018. IPD was defined as culture-confirmed Streptococcus pneumoniae from blood or cerebrospinal fluid, collected when clinically indicated. Serotype was determined by Latex agglutination.

Results

We identified and serotyped samples of 130 cases of IPD. Results show that overall, serotypes 5 (19%), 1 (11%), 7F (5%), 6A/B (3%), and 23F (3%) were most common in this population over the time period studied. Non-vaccine serotype (NVT) accounted for 19% of cases and 40 samples were not typeable. Serotypes 5 and 1 were the predominant cause of IPD before as well as after PCV13 introduction.

Conclusions

Overall IPD cases have been on the decline in this population. Vaccine-type serotypes were the main cause of IPD in neonates and young infants, both before and after PCV13 introduction. Vaccine strategies should be considered to optimise the potential for reducing VT-IPD in this setting among this vulnerable population.

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ASSOCIATION BETWEEN PNEUMOCOCCAL CARRIAGE AND ANTIMICROBIAL ACTIVITY IN URINE OF MALAWIAN CHILDREN HOSPITALIZED WITH ACUTE RESPIRATORY INFECTION (ID 445)

Session Name
Clinical Sciences - Treatment of Pneumococcal Disease in Infants, Children/Youth, and Adults
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Abstract

Background

Following the 2011 introduction of PCV13 in Malawi, 77% of healthy children carry pneumococci in the nasopharynx, while 41% of children hospitalized for acute respiratory infection (ARI) are colonized. We assessed if there is an association between pneumococcal carriage and pre-hospital antibiotic exposure.

Methods

Participants included 69 children aged 1-4 years admitted to Queen Elizabeth Central Hospital, Blantyre, Malawi 2016-2019 due to ARI. Information on pre-hospital antibiotics was collected from parents and/or the child´s health passport. Antimicrobial activity was detected by a urine bioassay. Pneumococci were isolated from a nasopharyngeal sample and tested for antibiotic susceptibility.

Results

Among the 40/69 (58%) samples showing antibiotic activity, 6 (8.7%) were from children with no report of pre-hospital antibiotics. Pneumococci was isolated from 55% of children with urine antimicrobial activity, while carriage was 74% in children with no activity. No difference in pneumococcal penicillin susceptibility was found between children with or without urine antimicrobial activity.

Conclusions

The urine bioassay is a useful tool for assessment of antibiotic exposure in resource limited settings, since patient´s reported history may not be reliable. Pre-hospital antibiotics may explain lower pneumococcal carriage prevalence among those hospitalized compared to healthy. However, pre-hospital antibiotics have not selected for penicillin resistance.

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BIOMASS SMOKE EXPOSURE AND INFLAMMATION ARE ASSOCIATED WITH PNEUMOCOCCAL CARRIAGE AMONG PCV13 VACCINATED INFANTS (ID 983)

Session Name
Basic Sciences - Immunology, Pathogenesis, and Host-pathogen Interactions
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Abstract

Background

Despite widespread use of PCV13, pneumococcal carriage remains high among Gambian infants. We investigated the role of biomass smoke exposure and inflammation in modulating pneumococcal carriage in The Gambia.

Methods

Rural Gambian children (n=120) were followed up at regular intervals from birth to two years of age. All infants received PCV13. Pneumococcal carriage was determined by quantitative PCR and inflammation by measuring plasma alpha-1 glycoprotein (AGP). Smoke exposure was self-reported by the mothers. Adjusted random effects regression models were applied to investigate the relationships between pneumococcal carriage, smoke exposure, and inflammation.

Results

Exposure to biomass smoke was significantly associated with a nearly 3-fold increase in the odds of pneumococcal carriage (OR 2.9, 95% CI: 1.13 - 7.5) and, in independent models, a 1/3-log10 increase in pneumococcal load (Coefficient 0.35, 95% CI: 0.11 - 0.59), compared to non-exposure. Inflammation (AGP) was significantly associated with an increased pneumococcal load (Coefficient 0.22, 95% CI: 0.03 - 0.41) in a model unadjusted for smoke exposure. Mediation analysis suggests that there are age, inflammation and smoke exposure interactions that may modify the effects of smoke exposure on pneumococcal carriage.

Conclusions

Biomass smoke exposure may be an important environmental factor driving pneumococcal carriage and loads among PCV-vaccinated Gambian children.

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NUTRITIONAL AND ENVIRONMENTAL REGULATION OF PNEUMOCOCCAL CENTRAL CARBON METABOLISM RELEVANT TO THE COMMENSAL-PATHOGEN INTERFACE. (ID 483)

Session Name
Basic Sciences - Immunology, Pathogenesis, and Host-pathogen Interactions
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MODELLING POST-PCV13 SEROTYPE-SPECIFIC ANTI-CAPSULAR AND ANTI-PROTEIN IGG RESPONSES IN BLANTYRE, MALAWI. (ID 989)

Session Name
Population Sciences - Epidemiology, Economics, and Mathematical Modelling
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RAPID WANING OF VACCINE-INDUCED IMMUNITY AMONG PCV13-VACCINATED CHILDREN UNDER 5 YEARS OLD IN MALAWI WITH SUBSEQUENT ACQUISITION OF NATURAL ANTIBODY THROUGH NATURAL EXPOSURE (ID 267)

Session Name
Basic Sciences - Immunology, Pathogenesis, and Host-pathogen Interactions
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Authors

HIGH LEVELS OF LUNG PNEUMOCOCCAL CAPSULAR-SPECIFIC IGG TO MOST VACCINE-TYPE SEROTYPES, BUT SEROTYPE 3, IN ADULTS VACCINATED WITH PCV13 (ID 577)

Session Name
Basic Sciences - Immunology, Pathogenesis, and Host-pathogen Interactions
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Authors

ACQUISITION AND CLEARANCE OF PNEUMOCOCCAL SEROTYPES IN NATURALLY-COLONISED PCV-EXPOSED GAMBIAN INFANTS (ID 990)

Session Name
Basic Sciences - Conventional and Molecular Microbiology
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Authors

Abstract

Background

Pneumococcal carriage influences population-wide strain dynamics, but limited data exist on serotype-specific temporal carriage patterns among PCV-vaccinated West African infants.

Methods

Pneumococcus was cultured from nasopharyngeal swabs (n=1, 595) collected from 102 PCV7-exposed infants followed up from birth to 12 months. Serotyping was performed by whole genome sequencing and sweep-latex agglutination. Parametric survival models with constant hazard rates were fitted to estimate carriage dynamics (duration, clearance and acquisition).

Results

The infants were naturally colonised with 60 pneumococcal serotypes with a mean of 7 (range:2-11) serotypes per infant. Carriage dynamics estimates for serotypes 5, 7F, 39, 9A, and 12F are provided here for the first time in infants. There was no correlation between time to first acquisition and carriage duration (ρ=0.06, P=0.709). Serotype prevalence showed a weak correlation with initial acquisition (ρ=0.07, P=0.706), carriage duration (ρ=0.219, P=0.194), and reacquisition times (ρ=0.09, P=0.730). Onset of initial acquisition was longer than the time taken to reacquire serotypes (median: 136.23 vs 26.15 days, P=7.63×10-6). Overall, serotype-specific carriage durations after initial acquisition and reacquisition were significantly different (P=0.020), varying by serotype.

carriage_duration.png

Conclusions

Pneumococcal carriage dynamics among Gambian infants are complex and highly variable by serotype which may have important implications for transmission and invasive disease.

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INCREASE IN FREQUENCY OF PNEUMOCOCCAL METABOLIC GENOTYPES CHARACTERISED BY ANTIMICROBIAL RESISTANCE AND ADAPTATIONS FOR COLONIZATION AFTER PCV13 INTRODUCTION IN BLANTYRE, MALAWI. (ID 416)

Session Name
Vaccines - Impact of Vaccine programs and Serotype Replacement
Presenter
Authors

Abstract

Background

Streptococcus pneumoniae naturally undergoes fluctuations in genotype. We previously showed a high residual prevalence of vaccine serotype (VT) pneumococci (18% in under 5’s) 7 years after PCV13 introduction in Malawi. In this context, we hypothesised the emergence and fixation of S. pneumoniae lineages with genetic traits conveying a competitive advantage in the nasopharyngeal niche.

Methods

1826 S. pneumoniae genomes were analysed from isolates collected during rolling cross-sectional carriage surveys in Blantyre, 4-7 years after PCV13 introduction. The metabolic core-genome includes 175 discrete metabolic genotypic profiles (metabolic types, MTs). Relative fitness was assessed by in-vitro growth and adhesive potential evaluated using Detroit 562 nasopharyngeal epithelial cells.

Results

High residual pneumococcal carriage is characterised by persistent MTs in VT (e.g. 3 and 23F) and emerging new MTs in non-VT (NVT; 38 and 23B). Increase in AMR MTs among 38 and 23B was observed. Emerging MTs show characteristic sequences of virulence genes and are characterised phenotypically by higher growth potential and propensity for better adherence to NP cell. We identified convergent evolution between MTs isolated in different countries, result of genetic bottlenecks.

Conclusions

This shift in metabolic genotypes, antimicrobial resistance and colonization adaptations may facilitate vaccine escape.

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THE EMERGENCE OF A STREPTOCOCCUS PNEUMONIAE SEROTYPE 3 VARIANT CARRIAGE IN THE 8 YEARS FOLLOWING POST-PCV13 INTRODUCTION IN BLANTYRE, MALAWI. (ID 606)

Session Name
Basic Sciences - Genomics and Transmission
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Authors

Abstract

Background

Several studies have demonstrated limited PCV13 efficacy against carriage of serotype 3 Streptococcus pneumoniae. In Blantyre, no direct vaccine effect was identified on serotype 3 carriage 8 years after PCV13 introduction, and population-based serology showed limited induction of serotype 3-specific antibodies by vaccine or natural exposure. We hypothesised that sequence variability of the CPS locus could at least partly explain these observations.

Methods

CPS loci of 540 serotype 3 isolates (from Africa, Asia, Europe and America) were analysed. ML-phylogeny, antimicrobial resistance (tetM, mefA, ermB, cat gene presence and pbpX allelic profiles) and MLST were calculated. Colony morphology was assessed in microaerophilic and anaerobic conditions.

Results

We identified a serotype 3 CPS locus variant in 82% of Blantyre isolates (2015-2019), characterized by an 8-gene cluster deletion but unchanged colony morphology. This variant appeared independently in at least 3 distinct phylogenetic clusters, including ST700 and ST3214. These strains are characterised by the presence of AMR genes and higher MIC to penicillin. The missing CPS genes have hypothetical protein annotation.

Conclusions

This CPS variant segregated with an AMR genotype, which may have contributed to its emergence. Whether this CPS variation will influence immunogenicity remains to be determined.

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