Human Antibody Responses to Group A Streptococcus Infection: A Systematic Review

Group A Streptococcus (GAS) is a leading global cause of infectious disease morbidity and mortality. A major barrier to GAS vaccine development is our incomplete understanding of human immunity. We undertook, to our knowledge, the first systematic review describing human antibody responses following GAS infection.

Eligible studies were publications reporting human antibody responses to any GAS antigen in individuals with microbiologically confirmed GAS infection. Case reports and studies primarily describing post-streptococcal autoimmune complications were excluded. Databases were last searched on 15th November 2025. Risk of bias was assessed using the relevant tools from the Joanna Briggs Institute. Results are presented in narrative form as meta-analysis was not appropriate.

A total of 143 studies spanning 1948-2025 met inclusion criteria. Most studies (83%) were conducted in the Global North and focused on tonsillopharyngitis (79·4%). Antibody responses were measured in serum (99·3%) and/or saliva (2·1%), targeting 116 distinct GAS antigens. The proportion of individuals exhibiting an antibody response to five antigens (SLO, DNase B, GAC, M protein and Streptokinase) was significantly greater in cases when compared with healthy controls. In longitudinal studies, the peak antibody titres were detected at a median of 28 days post-infection. Higher pre-infection titres of some antibodies (M protein, SpyCEP, SpyAD, SLO, DNase B, SpnA, T25, K4S2) correlated with subsequent protection from GAS infection or reduced severity of disease in three separate studies. Heterogeneity across studies prevented clear conclusions regarding how post-infection antibody responses vary by GAS serotype, participant age, infection site, or disease severity.

This review synthesizes 77 years of heterogenous studies describing antibody responses to GAS infection. Limitations of this review arise from the heterogeneity between studies and study risk of bias. Despite this, we identify major gaps in our understanding of the magnitude, kinetics, and protective role of antibody responses. Our synthesis uncovers information that will support GAS vaccine development including: guidance on sampling time points and the identification of antibodies that may be associated with protection from disease, as well as the need for standardisation of laboratory methodology and minimally-biased antigen discovery approaches.