PROJECT SUMMARY/ABSTRACT
There is renewed international momentum to develop vaccines to prevent infections caused by the highly
adapted, human-restricted bacterial pathogen Group A Streptococcus (GAS). However, the lack of a known
correlate of human immune protection against GAS infection and the limitations of current in vitro assays and
preclinical models have impeded development of promising preclinical vaccine candidates and threatens future
investment in GAS vaccine discovery and design. To overcome this roadblock, we will undertake a cross-
disciplinary collaborative research program, drawing on highly relevant human samples and developing a new
human ex vivo tissue model, to discover broadly applicable potential human correlates of protection that will
inform design of practical immunoassays fit for deployment in clinical vaccine trials. Rather than adhering to the
constraints of historical GAS immunoassays, we are explicitly targeting preferred characteristics for clinical
immunogenicity assays to support vaccine development, such as practicality, accuracy and broad application to
relevant syndromes and strains.
GAS naturally infects humans only, therefore we will take a human-centred approach, purposefully moving away
from animal models that do not adequately represent relevant complexities of the human immune response. We
will apply cutting edge immunology approaches to study diverse human samples from parallel research
programs, including from externally funded trials using our own GAS human challenge model to evaluate vaccine
protection against pharyngitis, the primary target indication for vaccine development efforts. Initial published
findings from the GAS pharyngitis human challenge model show that protection may be associated with robust
early mucosal and systemic Th1 inflammatory responses, in clear alignment with recent preclinical animal model
findings, and highlighting vaccine-induced antigen-specific Th1 responses as a correlate of protection for
multicomponent vaccines. We will characterize the transcriptomic basis for this immune response using our
existing human sample collection. We will draw on our experience with human whole blood stimulation assays
and tissue models to establish whole-blood and organotypic tonsil tissue models as our primary research tools.
This approach will allow us to interrogate ex vivo human immune responses to whole bacteria, culture
supernatant, and vaccine antigens to discover potential systemic and mucosal correlates of protection. These
broad-ranging efforts to identify immune pathways implicated in vaccine-induced protection will inform the design
of a practical, scalable, and strain-agnostic whole-blood in-tube assay (analogous to cytokine release assays),
and a high-throughput functional oral fluid mucosal assay to test in forthcoming clinical trials of novel GAS
vaccines.
