Differing Efficacies of Lead Group A Streptococcal Vaccine Candidates and Full-Length M Protein in Cutaneous and Invasive Disease Models.

Tania Rivera-Hernandez,Mark J Walker,Jason Cole,Nicholas P West,Anna Henningham,Victor Nizet,Khairunnisa Abdul Ghaffar,Michael R Batzloff,Michael F Good,Amanda J Cork,Manisha Pandey,Istvan Toth,Christine M Gillen,Biswa Choudhury,Peter M Moyle,Guido Silvestri

doi:10.1128/mbio.00618-16

Abstract

ABSTRACTGroup A Streptococcus (GAS) is an important human pathogen responsible for both superficial infections and invasive diseases. Autoimmune sequelae may occur upon repeated infection. For this reason, development of a vaccine against GAS represents a major challenge, since certain GAS components may trigger autoimmunity. We formulated three combination vaccines containing the following: (i) streptolysin O (SLO), interleukin 8 (IL-8) protease (Streptococcus pyogenes cell envelope proteinase [SpyCEP]), group A streptococcal C5a peptidase (SCPA), arginine deiminase (ADI), and trigger factor (TF); (ii) the conserved M-protein-derived J8 peptide conjugated to ADI; and (iii) group A carbohydrate lacking the N-acetylglucosamine side chain conjugated to ADI. We compared these combination vaccines to a “gold standard” for immunogenicity, full-length M1 protein. Vaccines were adjuvanted with alum, and mice were immunized on days 0, 21, and 28. On day 42, mice were challenged via cutaneous or subcutaneous routes. High-titer antigen-specific antibody responses with bactericidal activity were detected in mouse serum samples for all vaccine candidates. In comparison with sham-immunized mice, all vaccines afforded protection against cutaneous challenge. However, only full-length M1 protein provided protection in the subcutaneous invasive disease model.

Highlights

Group A Streptococcus (GAS) causes numerous human disease manifestations from mild infections of the skin and throat to more serious and life-threatening conditions, such as necrotizing fasciitis or toxic shock syndrome, to poststreptococcal autoimmune complications, including rheumatic heart disease and poststreptococcal glomerulonephritis
We evaluated the immunogenicity and efficacy of vaccine candidates in mice using a superficial skin infection model and invasive disease model upon challenge with M1 GAS, allowing parallel comparison between the different experimental vaccine formulations
The immune response to each vaccine component was assessed by enzyme-linked immunosorbent assay (ELISA) following immunization with M1 protein, the five-component streptolysin O (SLO), Streptococcus pyogenes cell envelope proteinase (SpyCEP), streptococcal C5a peptidase (SCPA), arginine deiminase (ADI), and trigger factor (TF) vaccine, and the conjugate J8-ADI and ⌬GAC-ADI vaccines

Summary

Introduction

Group A Streptococcus (GAS) causes numerous human disease manifestations from mild infections of the skin and throat to more serious and life-threatening conditions, such as necrotizing fasciitis or toxic shock syndrome, to poststreptococcal autoimmune complications, including rheumatic heart disease and poststreptococcal glomerulonephritis. More than 30 years ago, a ban on the administration of GAS and its components into humans was enforced by the U.S Food and Drug Administration (FDA), after children vaccinated with GAS M protein developed rheumatic fever [4]. While precluded as a human vaccine candidate due to safety concerns, full-length M protein from the homologous GAS challenge strain is effective at preventing infection in a variety of animal models and is regularly used as a positive control for GAS vaccine studies [7,8,9]. We evaluated the immunogenicity and efficacy of vaccine candidates in mice using a superficial skin infection model and invasive disease model upon challenge with M1 GAS, allowing parallel comparison between the different experimental vaccine formulations

Methods

Results

Conclusion