Multicomponent Vaccines against Group A Streptococcus Can Effectively Target Broad Disease Presentations

Helen A Shaw,Fatme Mawas,James Ozanne,Keira Burns

doi:10.3390/vaccines9091025

Helen A Shaw, Fatme Mawas + Show 2 more

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https://doi.org/10.3390/vaccines9091025

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Abstract

Group A Streptococcus (GAS) is an important global human pathogen, with a wide range of disease presentations, from mild mucosal infections like pharyngitis to invasive diseases such as toxic shock syndrome. The effect on health and mortality from GAS infections is substantial worldwide, particularly from autoimmune sequelae-like rheumatic heart disease (RHD), and there is currently no licenced vaccine. We investigated protein antigens targeting a broad range of GAS disease presentations as vaccine components in individual and combination formulations. The potency and functional immunity generated were evaluated and compared between groups. Antibodies against all components were found in pooled human IgG (IVIG) and an immune response generated following the subcutaneous immunisation of mice. A combination immunisation showed a reduction in IgG response for SpyCEP but an increase for Cpa and Mac-1 (IdeS). An opsonophagocytosis assay (OPA) showed the killing of GAS with immune sera against M protein and combination groups, with a lower killing activity observed for immune sera against other individual antigens. Specific antigen assays showed functional immunity against SpyCEP and Mac-1 from both individual and combination immunisations, with the activity correlating with antibody titres. However, efficient blocking of the binding activity of Cpa to collagen I and fibronectin could not be demonstrated with immune sera or purified IgG. Our data indicate that combination immunisations, while effective at covering a broader range of virulence factors, can also affect the immune response generated. Further, our results showed that an OPA alone is inadequate for understanding protection from vaccination, particularly when considering protection from immune evasion factors and evaluation of the colonisation leading to pharyngitis.

Highlights

Group A Streptococcus (GAS) is a global bacterial pathogen causing a wide range of disease presentations, from mild pharyngitis to potentially fatal invasive and toxinmediated diseases
While antibiotic treatment has proven effective in high-income countries at reducing the prevalence of rheumatic heart disease (RHD), it is still endemic in low- and middle-income countries (LMIC) [1], such that the WHO have highlighted the important need for a global vaccine against GAS [2]
Several multicomponent vaccines have been tested preclinically but have yet to enter clinical trials [7,8,9]. These have focussed on targets identified through reverse vaccinology, combining the sequence conservation, localisation and immunogenicity of conserved antigens, as shown with the Streptococcus pyogenes cell envelope protein (SpyCEP), S. pyogenes Adhesion and Division protein (SpyAD) and streptolysin O (SLO) [7] or by identifying antigens generating an immune response through natural infections from pooled human IgG (Spy7) [8]

Summary

Introduction

Group A Streptococcus (GAS) is a global bacterial pathogen causing a wide range of disease presentations, from mild pharyngitis to potentially fatal invasive and toxinmediated diseases. There is no licenced vaccine to prevent GAS infection, with few candidates undergoing clinical trials [3,4] These most progressed vaccines target the M-protein, either as a multivalent formulation against the variable N-terminal domain [3] or against the conserved C-terminal domain [4]. Several multicomponent vaccines have been tested preclinically but have yet to enter clinical trials [7,8,9] These have focussed on targets identified through reverse vaccinology, combining the sequence conservation, localisation and immunogenicity of conserved antigens, as shown with the Streptococcus pyogenes cell envelope protein (SpyCEP), S. pyogenes Adhesion and Division protein (SpyAD) and streptolysin O (SLO) [7] or by identifying antigens generating an immune response through natural infections from pooled human IgG (Spy7) [8]. Other multicomponent vaccine studies have combined individual promising candidates such as SLO, SpyCEP, C5a peptidase (SCPA), arginine deiminase (ADI) and trigger factor (TF)

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