Molecular epidemiology of Group A Streptococcus in West Africa (acronym: MEGAS)

Summary

Group A streptococcus (GAS) causes a massive burden of disease (>500,000 deaths per year), mainly in low- and middle-income countries (LMICs) where Rheumatic Heart Disease (RHD) causes >34 million cases and > 350,000 deaths per year. In May 2018, the WHO passed a resolution on RHD stressing the urgent need to improve prevention strategies, including the development of an effective vaccine. The most advanced multivalent M protein-based vaccine, currently in early clinical development is based on GAS strains found mainly in Europe and USA. In Africa and according to limited information, GAS infections seem to have a much higher genetic diversity of than in high income countries, suggesting that the efficacy of the current 30-valent vaccine may be sub-optimal. However, a recent study in Mali indicated cross-protection between vaccine and non-vaccine serotypes, with a higher-than-expected potential coverage. In order to further inform potential vaccine coverage in Africa, additional information on local GAS strains is urgently needed. This project aims at generating pioneering data on the molecular epidemiology of GAS in West Africa, and at initiating GAS genomic surveillance. Two hundred clinical GAS isolates stored at the MRC Unit The Gambia (MRCG) and 100 prospectively collected samples in Senegal and Burkina Faso will be analysed using whole genome sequencing at the MRCG.  Results will provide invaluable data to further inform current GAS vaccine development, to monitor antimicrobial resistance and to set the scene for upcoming vaccine trials in Africa.

Project outcomes

This one-year pilot study funded by the BactiVac Network has achieved its main objective of characterizing the molecular epidemiology of GAS strains and initiate GAS genomic surveillance in West Africa. Indeed, through existing regional networks funded by WHO (Reference Laboratory (RL) for Invasive Bacterial Diseases (IBD)) or EDTCP (WANETAM) we could initiate the prospective collection of GAS clinical samples, respectively in Senegal (Hopital Albert Royer, Dakar) and Burkina Faso (Centre Muraz, Bobo Dioulasso).  

The GAS prevalence among prospectively collected samples was lower than expected (respectively 6% and 12% in Senegal and Burkina versus 20% expected) and this could unfortunately not be compensated by increasing the recruitment of patients given the short timelines. Therefore, 45 GAS isolates were collected, including 31 in Burkina and 14 in Senegal and, together with 306 retrospective GAS isolates from The Gambia (MRCG Biobank; total = 341), were subjected to analysis using by standard microbiology methods and Whole Genome Sequencing using Illumina MiSeq. 

A total of 177 GAS isolates, including a majority of wound- (36%), oropharyngeal carriage- (21%) and blood samples (18%), were successfully sequenced. A total of 65 different emm types were identified and some isolates carried new sub-types which will be submitted to the CDC database. No dominant emm type was found, the most common being emm147 (4.5%) followed by emm44 and emm95 (totalling 4%). Interestingly, emm1 the most dominant emm type found in high income countries (HICs) was not found. 

Multi-locus sequence typing (MLST) identified 86 different sequence types (STs) some of which represented new STs. The phylogenetic analysis of the first 70 complete genomes showed clustering of isolates by genotype. 

All 177 isolates were tested for the presence of antimicrobial resistance genes using abricate software with the NCBI database. Several antimicrobial resistance genes were identified (Imrc, tets, tet (L), tetM, dfrK, efrA, DFRe and dfrg) and analysis is still ongoing. 

Similarly, work is ongoing by a Gambian junior scientist further supported by MRCG to identify virulence factors and to evaluate theoretical vaccine coverage. 

Together with other PIs working on GAS at the MRCG we recently created a GAS Study Group to join forces in establishing a regional library of reference GAS isolates and genomic sequences from The Gambia and across West Africa. Moreover, with the experience and contacts acquired during the prospective study with Burkina and Senegal, we plan to further collaborate with the WHO GAS Vaccine R&D Working Group as well as other WHO stakeholders (EPI-, Maternal & Child Health) to extend the scope of work of the existing WHO regional networks (ie, RL for IBD and -Collaborating Centre for New Vaccines Surveillance) to GAS genomic surveillance. 

Such data are crucially needed to fill the current knowledge gap on molecular epidemiology of GAS strains in West Africa, inform the development of an effective GAS vaccine, and monitor the GAS population structure and transmission dynamics after the rollout of a vaccine.

Annette ErhartDr Annette Erhart
Clinical Epidemiologist
Disease Control & Elimination, MRC Unit The Gambia at LSHTM (The Gambia)

Collaborators:
Professor Martin Antonio, WHO Collaborating Centre for New Vaccines Surveillance , MRC Unit The Gambia at LSHTM (The Gambia)

Dr Thushan de Silva, Vaccines and Immunity Theme, MRC Unit The Gambia at LSHTM (The Gambia)

Dr Abdul Karim Sesay, Laboratory Service, MRC Unit The Gambia at LSHTM, (The Gambia)

Dr Claire Turner, University of Sheffield (UK)

Professor Pierre Smeesters, Université libre de Bruxelles (ULB) (Belgium)