Journal Article

Immunity to Staphylococcus aureus secreted proteins protects rabbits from serious illnesses

Schlievert, Patrick M., Spaulding, Adam R., Lin, Ying-Chi, Brosnahan, Amanda J., Merriman, Joseph A., Peterson, Marnie L.

2012

Overview

► Vaccination against Staphylococcus aureus is achieved with toxoids. ► Toxoids are >107 inactivated and stimulate immunity to S. aureus. ► Superantigen toxoids exhibit adjuvant activity dependent on immune co-stimulatory molecule CD40 binding activity. ► Protective neutralizing antibodies are produced in rabbits to toxic shock syndrome toxin-1. Staphylococcus aureus causes significant illnesses throughout the world, including toxic shock syndrome (TSS), pneumonia, and infective endocarditis. Major contributors to S. aureus illnesses are secreted virulence factors it produces, including superantigens and cytolysins. This study investigates the use of superantigens and cytolysins as staphylococcal vaccine candidates. Importantly, 20% of humans and 50% of rabbits in our TSS model cannot generate antibody responses to native superantigens. We generated three TSST-1 mutants; G31S/S32P, H135A, and Q136A. All rabbits administered these TSST-1 toxoids generated strong antibody responses (titers>10,000) that neutralized native TSST-1 in TSS models, both in vitro and in vivo. These TSST-1 mutants lacked detectable residual toxicity. Additionally, the TSST-1 mutants exhibited intrinsic adjuvant activity, increasing antibody responses to a second staphylococcal antigen (β-toxin). This effect may be due to TSST-1 mutants binding to the immune co-stimulatory molecule CD40. The superantigens TSST-1 and SEC and the cytolysin α-toxin are known to contribute to staphylococcal pneumonia. Immunization of rabbits against these secreted toxins provided complete protection from highly lethal challenge with a USA200 S. aureus strain producing all three exotoxins; USA200 strains are common causes of staphylococcal infections. The same three exotoxins plus the cytolysins β-toxin and γ-toxin contribute to infective endocarditis and sepsis caused by USA200 strains. Immunization against these five exotoxins protected rabbits from infective endocarditis and lethal sepsis. These data suggest that immunization against toxoid proteins of S. aureus exotoxins protects from serious illnesses, and concurrently superantigen toxoid mutants provide endogenous adjuvant activity.

• Publisher: Elsevier Ltd
• Subject: Adjuvants, Immunologic - administration & dosage / Allergy and Immunology / Animals / Antibodies, Bacterial - blood / Antibodies, Bacterial - immunology / Antibody Formation / Bacterial Proteins - immunology / Bacterial Toxins - administration & dosage / Bacterial Toxins - immunology / CD40 Antigens - immunology / Cell Line / Cytolysin / Cytotoxins - administration & dosage / Cytotoxins - immunology / endocarditis / Endocarditis, Bacterial - immunology / Endocarditis, Bacterial - microbiology / Endocarditis, Bacterial - therapy / exotoxins / Exotoxins - immunology / Female / Hemolysin Proteins - administration & dosage / Hemolysin Proteins - immunology / Humans / immunity / immunization / Male / mutants / neutralization / Neutralization Tests / pneumonia / Pneumonia, Staphylococcal - immunology / Pneumonia, Staphylococcal - microbiology / Pneumonia, Staphylococcal - therapy / proteins / Rabbit Model / rabbits / Rabbits - immunology / Rabbits - microbiology / septic shock / Shock, Septic - immunology / Shock, Septic - microbiology / Shock, Septic - therapy / Staphylococcal Infections - immunology / Staphylococcal Infections - microbiology / Staphylococcal Infections - therapy / Staphylococcal Toxoid - administration & dosage / Staphylococcal Toxoid - immunology / Staphylococcal Vaccines - immunology / Staphylococcus aureus / Staphylococcus aureus - immunology / Staphylococcus aureus - pathogenicity / Superantigen / superantigens / Superantigens - administration & dosage / Superantigens - immunology / toxicity / toxoids / Vaccination / Vaccine / vaccines / virulence