Safety and Immunogenicity of a 4-Component Toxoid-Based Staphylococcus aureus Vaccine in Rhesus Macaques
| Autor: | Rajan P. Adhikari, Dean J. Kobs, Hatice Karauzum, Daniel L. Barber, Eunice Cho, M. Javad Aman, Tom Kort, Grant C. Liao, Keith D. Kauffman, Arundhathi Venkatasubramaniam, Frederick W. Holtsberg, Nickiana E. Lora, Karen E. Elsass, Thomas L. Rudge |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
CD4-Positive T-Lymphocytes
Methicillin-Resistant Staphylococcus aureus 0301 basic medicine safety lcsh:Immunologic diseases. Allergy Staphylococcal Toxoid multi-component 030106 microbiology Immunology immunogenicity toxoid Immunity Heterologous Lymphocyte Activation medicine.disease_cause staphylococcal 03 medical and health sciences Immunogenicity Vaccine Immune system Antigen CD4 T cells response Superantigen medicine Animals Immunology and Allergy neutralizing antibodies Original Research Superantigens biology business.industry Immunogenicity Vaccination Toxoid Staphylococcal Vaccines Staphylococcal Infections Antibodies Bacterial Macaca mulatta 030104 developmental biology Antibody Formation biology.protein Antibody business lcsh:RC581-607 Broadly Neutralizing Antibodies Exotoxin |
| Zdroj: | Frontiers in Immunology, Vol 12 (2021) Frontiers in Immunology |
| ISSN: | 1664-3224 |
| DOI: | 10.3389/fimmu.2021.621754/full |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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