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Novel structurally designed vaccine for S. aureus α-hemolysin: protection against bacteremia and pneumonia.

Adhikari RP, Karauzum H, Sarwar J, Abaandou L, Mahmoudieh M, Boroun AR, Vu H, Nguyen T, Devi VS, Shulenin S, Warfield KL, Aman MJ - PLoS ONE (2012)

Bottom Line: Efforts to develop effective vaccines against S. aureus have been largely unsuccessful, in part due to the variety of virulence factors produced by this organism.Our Hla-based vaccine is the first to be reported to reduce bacterial dissemination and to provide protection in a sepsis model of S. aureus infection.AT62-IgG and sera from vaccinated mice effectively neutralized the toxin in vitro and AT62-IgG inhibited the formation of Hla heptamers, suggesting antibody-mediated neutralization as the primary mechanism of action.

View Article: PubMed Central - PubMed

Affiliation: Integrated Biotherapeutics Inc., Gaithersburg, Maryland, United States of America.

ABSTRACT
Staphylococcus aureus (S. aureus) is a human pathogen associated with skin and soft tissue infections (SSTI) and life threatening sepsis and pneumonia. Efforts to develop effective vaccines against S. aureus have been largely unsuccessful, in part due to the variety of virulence factors produced by this organism. S. aureus alpha-hemolysin (Hla) is a pore-forming toxin expressed by most S. aureus strains and reported to play a key role in the pathogenesis of SSTI and pneumonia. Here we report a novel recombinant subunit vaccine candidate for Hla, rationally designed based on the heptameric crystal structure. This vaccine candidate, denoted AT-62aa, was tested in pneumonia and bacteremia infection models using S. aureus strain Newman and the pandemic strain USA300 (LAC). Significant protection from lethal bacteremia/sepsis and pneumonia was observed upon vaccination with AT-62aa along with a Glucopyranosyl Lipid Adjuvant-Stable Emulsion (GLA-SE) that is currently in clinical trials. Passive transfer of rabbit immunoglobulin against AT-62aa (AT62-IgG) protected mice against intraperitoneal and intranasal challenge with USA300 and produced significant reduction in bacterial burden in blood, spleen, kidney, and lungs. Our Hla-based vaccine is the first to be reported to reduce bacterial dissemination and to provide protection in a sepsis model of S. aureus infection. AT62-IgG and sera from vaccinated mice effectively neutralized the toxin in vitro and AT62-IgG inhibited the formation of Hla heptamers, suggesting antibody-mediated neutralization as the primary mechanism of action. This remarkable efficacy makes this Hla-based vaccine a prime candidate for inclusion in future multivalent S. aureus vaccine. Furthermore, identification of protective epitopes within AT-62aa could lead to novel immunotherapy for S. aureus infection.

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Related in: MedlinePlus

Comparative efficacy study of vaccine candidates in S. aureus bacteremia and pneumonia infection models.Survival of mice vaccinated with the three vaccine candidates and control mice after IP challenge with 5×104 CFU of USA300 along with Hog Mucin (A) or IN challenge with 6×107 CFU of S. aureus strain Newman (B). Survival of mice vaccinated with AT-62aa and challenged IN with 1.5×108 CFU of S. aureus USA300 (C). Symbol key: AT-50aa (open circle), AT-62aa (black square), AT-79aa (open triangles) and mock-immunized mice (grey diamond). Statistical analysis was performed using Log-Rank (Mantel-Cox) test.
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pone-0038567-g004: Comparative efficacy study of vaccine candidates in S. aureus bacteremia and pneumonia infection models.Survival of mice vaccinated with the three vaccine candidates and control mice after IP challenge with 5×104 CFU of USA300 along with Hog Mucin (A) or IN challenge with 6×107 CFU of S. aureus strain Newman (B). Survival of mice vaccinated with AT-62aa and challenged IN with 1.5×108 CFU of S. aureus USA300 (C). Symbol key: AT-50aa (open circle), AT-62aa (black square), AT-79aa (open triangles) and mock-immunized mice (grey diamond). Statistical analysis was performed using Log-Rank (Mantel-Cox) test.

Mentions: Groups of ten vaccinated or five control mice were challenged on day 42 by IP administration of 5×104 CFU of S. aureus strain USA300 along with 3% Hog Mucin. Mice were observed for signs of mortality and morbidity for 7 days. While 100% of mice vaccinated with AT-62aa or AT-79aa and 70% of mice vaccinated with AT-50aa survived the challenge, only one out of five control mice survived (Figure 4A). Maximal median weight loss of surviving mice in immunized groups was 6% of body weight. All surviving mice re-gained weight and had a healthy appearance (smooth fur, active) by day 7.


Novel structurally designed vaccine for S. aureus α-hemolysin: protection against bacteremia and pneumonia.

Adhikari RP, Karauzum H, Sarwar J, Abaandou L, Mahmoudieh M, Boroun AR, Vu H, Nguyen T, Devi VS, Shulenin S, Warfield KL, Aman MJ - PLoS ONE (2012)

Comparative efficacy study of vaccine candidates in S. aureus bacteremia and pneumonia infection models.Survival of mice vaccinated with the three vaccine candidates and control mice after IP challenge with 5×104 CFU of USA300 along with Hog Mucin (A) or IN challenge with 6×107 CFU of S. aureus strain Newman (B). Survival of mice vaccinated with AT-62aa and challenged IN with 1.5×108 CFU of S. aureus USA300 (C). Symbol key: AT-50aa (open circle), AT-62aa (black square), AT-79aa (open triangles) and mock-immunized mice (grey diamond). Statistical analysis was performed using Log-Rank (Mantel-Cox) test.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368876&req=5

pone-0038567-g004: Comparative efficacy study of vaccine candidates in S. aureus bacteremia and pneumonia infection models.Survival of mice vaccinated with the three vaccine candidates and control mice after IP challenge with 5×104 CFU of USA300 along with Hog Mucin (A) or IN challenge with 6×107 CFU of S. aureus strain Newman (B). Survival of mice vaccinated with AT-62aa and challenged IN with 1.5×108 CFU of S. aureus USA300 (C). Symbol key: AT-50aa (open circle), AT-62aa (black square), AT-79aa (open triangles) and mock-immunized mice (grey diamond). Statistical analysis was performed using Log-Rank (Mantel-Cox) test.
Mentions: Groups of ten vaccinated or five control mice were challenged on day 42 by IP administration of 5×104 CFU of S. aureus strain USA300 along with 3% Hog Mucin. Mice were observed for signs of mortality and morbidity for 7 days. While 100% of mice vaccinated with AT-62aa or AT-79aa and 70% of mice vaccinated with AT-50aa survived the challenge, only one out of five control mice survived (Figure 4A). Maximal median weight loss of surviving mice in immunized groups was 6% of body weight. All surviving mice re-gained weight and had a healthy appearance (smooth fur, active) by day 7.

Bottom Line: Efforts to develop effective vaccines against S. aureus have been largely unsuccessful, in part due to the variety of virulence factors produced by this organism.Our Hla-based vaccine is the first to be reported to reduce bacterial dissemination and to provide protection in a sepsis model of S. aureus infection.AT62-IgG and sera from vaccinated mice effectively neutralized the toxin in vitro and AT62-IgG inhibited the formation of Hla heptamers, suggesting antibody-mediated neutralization as the primary mechanism of action.

View Article: PubMed Central - PubMed

Affiliation: Integrated Biotherapeutics Inc., Gaithersburg, Maryland, United States of America.

ABSTRACT
Staphylococcus aureus (S. aureus) is a human pathogen associated with skin and soft tissue infections (SSTI) and life threatening sepsis and pneumonia. Efforts to develop effective vaccines against S. aureus have been largely unsuccessful, in part due to the variety of virulence factors produced by this organism. S. aureus alpha-hemolysin (Hla) is a pore-forming toxin expressed by most S. aureus strains and reported to play a key role in the pathogenesis of SSTI and pneumonia. Here we report a novel recombinant subunit vaccine candidate for Hla, rationally designed based on the heptameric crystal structure. This vaccine candidate, denoted AT-62aa, was tested in pneumonia and bacteremia infection models using S. aureus strain Newman and the pandemic strain USA300 (LAC). Significant protection from lethal bacteremia/sepsis and pneumonia was observed upon vaccination with AT-62aa along with a Glucopyranosyl Lipid Adjuvant-Stable Emulsion (GLA-SE) that is currently in clinical trials. Passive transfer of rabbit immunoglobulin against AT-62aa (AT62-IgG) protected mice against intraperitoneal and intranasal challenge with USA300 and produced significant reduction in bacterial burden in blood, spleen, kidney, and lungs. Our Hla-based vaccine is the first to be reported to reduce bacterial dissemination and to provide protection in a sepsis model of S. aureus infection. AT62-IgG and sera from vaccinated mice effectively neutralized the toxin in vitro and AT62-IgG inhibited the formation of Hla heptamers, suggesting antibody-mediated neutralization as the primary mechanism of action. This remarkable efficacy makes this Hla-based vaccine a prime candidate for inclusion in future multivalent S. aureus vaccine. Furthermore, identification of protective epitopes within AT-62aa could lead to novel immunotherapy for S. aureus infection.

Show MeSH
Related in: MedlinePlus