Correlates of immunity to Group A Streptococcus: a pathway to vaccine development

Abstract

Understanding immunity in humans to Group A Streptococcus (Strep A) is critical for the development of successful vaccines to prevent the morbidity and mortality attributed to Strep A infections. Despite decades of effort, no licensed vaccine against Strep A exists and immune correlates of protection are lacking; a major impediment to vaccine development. In the absence of a vaccine, we can take cues from the development of natural immunity to Strep A in humans to identify immune correlates of protection. The age stratification of incidence of acute Strep A infections, peaking in young children and waning in early adulthood, coincides with the development of specific immune responses. Therefore, understanding the immune mechanisms involved in natural protection from acute Strep A infection is critical to identifying immune correlates to inform vaccine development. This perspective summarises the findings from natural infection studies, existing assays of immunity to Strep A, and highlights the gaps in knowledge to guide the development of Strep A vaccines and associated correlates of protection.

Fig. 1. Proposed spectrum of antibody-derived immunity in oropharynx to explain the range of phenotypes observed in children.

In humans resistant to Strep A pharyngeal acquisition (first column), antibodies may inhibit adhesion and encourage opsonophagocytosis of bacteria before colonisation is established. In this situation antibodies targeting bacterial virulence factors and toxins may or may not be present. Colonised humans likely do not block adhesion with antibodies but, at least for some time, can limit the proliferation of bacteria. Shedders often have heavy colonisation but may inhibit symptomatic infection by controlling bacterial virulence factors. In most cases, pharyngitis is superficial and self-limiting, but can also develop into systemic illness including Scarlet fever (final column), which has been linked to toxins including superantigens. The antibody symbols (blue) indicate where antibodies inhibit bacterial function, the crosses (red) where antibodies are lacking and no symbol where there is no requirement for antibodies. Created with Biorender.com.

Fig. 2. Correlation between titres of type-specific antibodies and opsonophagocytic killing (OPK) for four different Strep A strains following vaccination with the 30-valent vaccine candidate StreptAnova^TM that included M1, M3, M5, M12.

A clear correlation is seen between OPK titre and antibody fold changes for M5 (green; R² = 0.82), which is not apparent for the other strains. Data are from Pastural et al..