Abstract
Staphylococcus aureus causes a wide range of diseases from skin infections to life threatening invasive diseases such as bacteremia, endocarditis, pneumonia, surgical site infections, and osteomyelitis. Skin infections such as furuncles, carbuncles, folliculitis, erysipelas, and cellulitis constitute a large majority of infections caused by S. aureus (SA). These infections cause significant morbidity, healthcare costs, and represent a breeding ground for antimicrobial resistance. Furthermore, skin infection with SA is a major risk factor for invasive disease. Here we describe the pre-clinical efficacy of a multicomponent toxoid vaccine (IBT-V02) for prevention of S. aureus acute skin infections and recurrence. IBT-V02 targets six SA toxins including the pore-forming toxins alpha hemolysin (Hla), Panton-Valentine leukocidin (PVL), leukocidin AB (LukAB), and the superantigens toxic shock syndrome toxin-1 and staphylococcal enterotoxins A and B. Immunization of mice and rabbits with IBT-V02 generated antibodies with strong neutralizing activity against toxins included in the vaccine, as well as cross-neutralizing activity against multiple related toxins, and protected against skin infections by several clinically relevant SA strains of USA100, USA300, and USA1000 clones. Efficacy of the vaccine was also shown in non-naïve mice pre-exposed to S. aureus. Furthermore, vaccination with IBT-V02 not only protected mice from a primary infection but also demonstrated lasting efficacy against a secondary infection, while prior challenge with the bacteria alone was unable to protect against recurrence. Serum transfer studies in a primary infection model showed that antibodies are primarily responsible for the protective response.
Highlights
Staphylococcus aureus (SA) is an opportunistic pathogen responsible for a wide range of clinical infections, ranging from superficial skin lesions, deep-seated abscesses, and osteomyelitis to life threatening sepsis, endocarditis and pneumonia [1, 2]
IBT-V02 consists of rationally designed toxoid formulations representative of pore-forming and superantigenic toxins: Hla, Panton-Valentine leukocidin (PVL), leukocidin AB (LukAB), SEA, SEB, as well as toxic shock syndrome toxin-1 (TSST-1)
LukABmut50 is a dimeric toxoid form of LukAB with mutations introduced in LukA (D39A) and LukB (R23E) that render the protein unable to form a pore in the plasma membrane of target cells [25]
Summary
Staphylococcus aureus (SA) is an opportunistic pathogen responsible for a wide range of clinical infections, ranging from superficial skin lesions, deep-seated abscesses, and osteomyelitis to life threatening sepsis, endocarditis and pneumonia [1, 2]. In the case of one of these vaccine candidates, the single component vaccine consisting of the iron-regulated protein IsdB (V710, Merck), the trial was stopped due to safety concerns after ∼8,000 patients undergoing cardiothoracic surgery were recruited Among those patients who developed a SA infection, a higher number of multi-organ failures and death occurred in the vaccine arm compared to placebo [11]. A follow up study in a subset of these patients suggested that a combination of immunization with IsdB, SA infection, and the immunological status of the host (reflected in low or undetectable serum IL-2 and IL-17 at the time of vaccination) contributed to the catastrophic outcome [12] Both studies in mice [13] and rabbits [14] showed a vaccination induced disease enhancement when whole cell vaccine or crude surface antigens were used for immunization, raising the potential for induction of a deleterious immune response by cell associated antigens
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