Effective Treatment of Staphylococcal Enterotoxin B Aerosol Intoxication in Rhesus Macaques by Using Two Parenterally Administered High-Affinity Monoclonal Antibodies

Verreault, Daniel; Ennis, Jane; Whaley, Kevin J.; Killeen, Stephanie Z.; Karaüzüm, Hatice; Aman, M. Javad; Holtsberg, Rick; Doyle-Meyers, Lara A.; Didier, Peter J.; Zeitlin, Larry; Roy, Chad J.

doi:10.1128/aac.02049-18

Cited by 18 publications

(14 citation statements)

References 39 publications

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“…Three control animals received an IV injection of an anti-SEB IgG 1 (Ig121), kindly provided by Dr. Javad Aman (Integrated Biotherapeutics). 18 The serum concentrations of huPB10-LS IgG1 in the experimental animals on the day of challenge ranged between 113 and 315 μg/ml and are consistent with expected dosing regimen ( Table 1).…”

Section: Recombinant Hupb10 Igg Variants With Extended Serum Half-livsupporting

confidence: 73%

Passive immunization with an extended half-life monoclonal antibody protects Rhesus macaques against aerosolized ricin toxin

et al. 2020

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Inhalation of ricin toxin (RT), a Category B biothreat agent, provokes an acute respiratory distress syndrome marked by proinflammatory cytokine and chemokine production, neutrophilic exudate, and pulmonary edema. The severity of RT exposure is attributed to the tropism of the toxin's B subunit (RTB) for alveolar macrophages and airway epithelial cells, coupled with the extraordinarily potent ribosome-inactivating properties of the toxin's enzymatic subunit (RTA). While there are currently no vaccines or treatments approved to prevent RT intoxication, we recently described a humanized anti-RTA IgG 1 MAb, huPB10, that was able to rescue non-human primates (NHPs) from lethal dose RT aerosol challenge if administered by intravenous (IV) infusion within hours of toxin exposure. We have now engineered an extended serum half-life variant of that MAb, huPB10-LS, and evaluated it as a pre-exposure prophylactic. Five Rhesus macaques that received a single intravenous infusion (25 mg/kg) of huPB10-LS survived a lethal dose aerosol RT challenge 28 days later, whereas three control animals succumbed to RT intoxication within 48 h. The huPB10-LS treated animals remained clinically normal in the hours and days following toxin insult, suggesting that pre-existing antibody levels were sufficient to neutralize RT locally. Moreover, pro-inflammatory markers in sera and BAL fluids collected 24 h following RT challenge were significantly dampened in huPB10-LS treated animals, as compared to controls. Finally, we found that all five surviving animals, within days after RT exposure, had anti-RT serum IgG titers against epitopes other than huPB10-LS, indicative of active immunization by residual RT and/or RT-immune complexes.

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Section: Recombinant Hupb10 Igg Variants With Extended Serum Half-livsupporting

confidence: 73%

Passive immunization with an extended half-life monoclonal antibody protects Rhesus macaques against aerosolized ricin toxin

et al. 2020

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“…Biofilm formation is regulated by the quorumsensing (QS) system [11], and the hld gene is regarded as the most effective molecule in the Staphylococcal QS system [12]. The biofilm formation increases MRSA resistance to antibiotics by 10-10,000 times and is also the cause of many chronic MRSA infections [13]. Therefore, ideal antibacterial agents could inhibit biofilm formation.…”

Section: Introductionmentioning

confidence: 99%

Bisdemethoxycurcumin Reduces Methicillin-Resistant Staphylococcus aureus Expression of Virulence-Related Exoproteins and Inhibits the Biofilm Formation

Wang

Kang

Kwon

2021

Toxins

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Methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen of nosocomial infection, which is resistant to most antibiotics. Presently, anti-virulence therapy and anti-biofilm therapy are considered to be promising alternatives. In the current work, we investigated the influence of bisdemethoxycurcumin (BDMC) on the virulence-related exoproteins and the biofilm formation using a reference strain and clinic isolated strains. Western blotting, quantitative RT-PCR, and tumor necrosis factor (TNF) release assay were performed to assess the efficacy of BDMC in reducing the expression of Staphylococcus enterotoxin-related exoproteins (enterotoxin A, enterotoxin B) and α-toxin in MRSA. The anti-biofilm activity of BDMC was evaluated through a biofilm inhibition assay. The study suggests that sub-inhibitory concentrations of BDMC significantly inhibited the expression of sea, seb, and hla at the mRNA level in MRSA. Moreover, the expression of virulence-related exoproteins was significantly decreased by down-regulating accessory gene regulator agr, and the inhibition of biofilms formation was demonstrated by BDMC at sub-inhibitory concentrations. Consequently, the study suggests that BDMC may be a potential natural antibacterial agent to release the pressure brought by antibiotic resistance.

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“…For example, the affinity of all SAgs for human MHC class II molecules, the primary receptor for all SAgs, is far greater than for the mouse counterparts leading to poor response of mice to SAgs (27). Here we elected to evaluate the safety and immunogenicity of a four-component toxoid vaccine candidate in rhesus macaques, known to be highly sensitive to SAgs and multiple cytolytic toxins of S. aureus (14)(15)(16). This study shows that the vaccine is safe, well tolerated, and highly immunogenic inducing neutralizing antibodies and specific memory T cell responses in macaques.…”

Section: Discussionmentioning

confidence: 99%

“…In comparison to mice which are the typical animal model used to study SA vaccines due to their easy availability, nonhuman primates are more susceptible than mice to a majority of human-adapted pathogens. They are closest to humans in terms of anatomy and immune responses and highly sensitive to staphylococcal toxins such as superantigens and Hla and hence remain an important disease model for translating the discovery of treatments and vaccines into potential clinical outcomes (13)(14)(15)(16). Hence, in the present study, we chose NHPs as the model of choice for our vaccine safety and immunogenicity study described in this article.…”

Section: Introductionmentioning

confidence: 99%

Safety and Immunogenicity of a 4-Component Toxoid-Based Staphylococcus aureus Vaccine in Rhesus Macaques

et al. 2021

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Staphylococcus aureus is a leading cause of significant morbidity and mortality and an enormous economic burden to public health worldwide. Infections caused by methicillin-resistant S. aureus (MRSA) pose a major threat as MRSA strains are becoming increasingly prevalent and multi-drug resistant. To this date, vaccines targeting surface-bound antigens demonstrated promising results in preclinical testing but have failed in clinical trials. S. aureus pathogenesis is in large part driven by immune destructive and immune modulating toxins and thus represent promising vaccine targets. Hence, the objective of this study was to evaluate the safety and immunogenicity of a staphylococcal 4-component vaccine targeting secreted bi-component pore-forming toxins (BCPFTs) and superantigens (SAgs) in non-human primates (NHPs). The 4-component vaccine proved to be safe, even when repeated vaccinations were given at a dose that is 5 to 10- fold higher than the proposed human dose. Vaccinated rhesus macaques did not exhibit clinical signs, weight loss, or changes in hematology or serum chemistry parameters related to the administration of the vaccine. No acute, vaccine-related elevation of serum cytokine levels was observed after vaccine administration, confirming the toxoid components lacked superantigenicity. Immunized animals demonstrated high level of toxin-specific total and neutralizing antibodies toward target antigens of the 4-component vaccine as well as cross-neutralizing activity toward staphylococcal BCPFTs and SAgs that are not direct targets of the vaccine. Cross-neutralization was also observed toward the heterologous streptococcal pyogenic exotoxin B. Ex vivo stimulation of PBMCs with individual vaccine components demonstrated an overall increase in several T cell cytokines measured in supernatants. Immunophenotyping of CD4 T cells ex vivo showed an increase in Ag-specific polyfunctional CD4 T cells in response to antigen stimulation. Taken together, we demonstrate that the 4-component vaccine is well-tolerated and immunogenic in NHPs generating both humoral and cellular immune responses. Targeting secreted toxin antigens could be the next-generation vaccine approach for staphylococcal vaccines if also proven to provide efficacy in humans.

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Effective Treatment of Staphylococcal Enterotoxin B Aerosol Intoxication in Rhesus Macaques by Using Two Parenterally Administered High-Affinity Monoclonal Antibodies

Cited by 18 publications

References 39 publications

Passive immunization with an extended half-life monoclonal antibody protects Rhesus macaques against aerosolized ricin toxin

Passive immunization with an extended half-life monoclonal antibody protects Rhesus macaques against aerosolized ricin toxin

Bisdemethoxycurcumin Reduces Methicillin-Resistant Staphylococcus aureus Expression of Virulence-Related Exoproteins and Inhibits the Biofilm Formation

Safety and Immunogenicity of a 4-Component Toxoid-Based Staphylococcus aureus Vaccine in Rhesus Macaques

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