Background The concept that a minority of group A streptococcus (GAS) emm types are more “rheumatogenic” than others has been widely disseminated. We aimed to provide a comprehensive list of acute rheumatic fever–associated GAS isolates and assess the presence of associated rheumatogenic motifs. Methods Articles reporting GAS emm-type or emm-type–specific antibody responses associated with rheumatic fever were identified from 1 January 1944 to 31 July 2018. The revised Jones criteria were used to define rheumatic fever with a maximum period of 4 weeks between disease onset and microbiological characterization. A database of 175 representative M-protein sequences was used to analyze the protein diversity of rheumatic fever–associated strains in a phylogenetic tree and to identify the presence of 10 previously recognized rheumatogenic motifs. Results We included 411 cases of rheumatic fever, for which microbiological characterization identified 73 different emm types associated with the disease. The classic rheumatogenic emm types represented only 12.3% of the 73 emm types and were responsible for 31.6% of the 411 clinical cases. Rheumatic fever–associated emm types were disseminated throughout the phylogeny, suggesting they belong to various genetic backgrounds. Rheumatic fever–associated motifs were present in only 15.1% of the rheumatic fever–associated emm types and only 24.8% of clinical cases. Conclusions The concept of rheumatogenicity should be extended to include strains other than those classically described. Our results highlight significant knowledge gaps in the understanding of rheumatic fever pathogenesis and suggest that a GAS vaccine candidate should offer broad coverage against a variety of GAS genetic variants in order to protect against this serious sequela.

Background Immunity to Streptococcus pyogenes in high burden settings is poorly understood. We explored S. pyogenes nasopharyngeal colonization after intranasal live attenuated influenza vaccine (LAIV) among Gambian children aged 24-59 months, and resulting serological response to 7 antigens. Methods A post-hoc analysis was performed in 320 children randomized to receive LAIV at baseline (LAIV group) or not (control). S. pyogenes colonization was determined by quantitative Polymerase Chain Reaction (qPCR) on nasopharyngeal swabs from baseline (D0), day 7 (D7) and day 21 (D21). Anti-streptococcal IgG was quantified, including a subset with paired serum pre/post S. pyogenes acquisition. Results The point prevalence of S. pyogenes colonization ranged from 7-13%. In children negative at D0, S. pyogenes was detected at D7 or D21 in 18% of LAIV group and 11% of control group participants (p=0.12). The odds ratio (OR) for colonization over time was significantly increased in the LAIV group (D21 vs D0 OR 3.18, p=0.003) but not in the control group (OR 0.86, p=0.79). The highest IgG increases following asymptomatic colonization were seen for M1 and SpyCEP proteins. Conclusions Asymptomatic S. pyogenes colonization appears modestly increased by LAIV, and may be immunologically significant. LAIV could be used to study influenza-S. pyogenes interactions.

Background: Immunity toStreptococcus pyogenesin high burden settings is poorly understood. We exploredS. pyogenesnasopharyngeal colonization after intranasal live attenuated influenza vaccine (LAIV) among Gambian children aged 24-59 months, and resulting serological response to 7 antigens. Methods: A post-hoc analysis was performed in 320 children randomized to receive LAIV at baseline (LAIV group) or not (control).S. pyogenescolonization was determined by quantitative Polymerase Chain Reaction (qPCR) on nasopharyngeal swabs from baseline (D0), day 7 (D7) and day 21 (D21). Anti-streptococcal IgG was quantified, including a subset with paired serum pre/post S. pyogenes acquisition. Results: The point prevalence ofS. pyogenescolonization ranged from 7-13%. In children negative at D0,S. pyogeneswas detected at D7 or D21 in 18% of LAIV group and 11% of control group participants (p=0.12). The odds ratio (OR) for colonization over time was significantly increased in the LAIV group (D21 vs D0 OR 3.18, p=0.003) but not in the control group (OR 0.86, p=0.79). The highest IgG increases following asymptomatic colonization were seen for M1 and SpyCEP proteins. Conclusions: AsymptomaticS. pyogenescolonization appears modestly increased by LAIV, and may be immunologically significant. LAIV could be used to study influenza-S. pyogenesinteractions.