Development of a TLR7/8 agonist adjuvant formulation to overcome early life hyporesponsiveness to DTaP vaccination
Abstract Infection is the most common cause of mortality early in life, yet the broad potential of immunization is not fully realized in this vulnerable population. Most vaccines are administered during infancy and childhood, but in some cases the full benefit of vaccination is not realized in-part....
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-10-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-20346-w |
| _version_ | 1811336325909970944 |
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| author | David J. Dowling Soumik Barman Alyson J. Smith Francesco Borriello Danielle Chaney Spencer E. Brightman Gandolina Melhem Byron Brook Manisha Menon Dheeraj Soni Simone Schüller Karthik Siram Etsuro Nanishi Hélène G. Bazin David J. Burkhart Ofer Levy Jay T. Evans |
| author_facet | David J. Dowling Soumik Barman Alyson J. Smith Francesco Borriello Danielle Chaney Spencer E. Brightman Gandolina Melhem Byron Brook Manisha Menon Dheeraj Soni Simone Schüller Karthik Siram Etsuro Nanishi Hélène G. Bazin David J. Burkhart Ofer Levy Jay T. Evans |
| author_sort | David J. Dowling |
| collection | DOAJ |
| description | Abstract Infection is the most common cause of mortality early in life, yet the broad potential of immunization is not fully realized in this vulnerable population. Most vaccines are administered during infancy and childhood, but in some cases the full benefit of vaccination is not realized in-part. New adjuvants are cardinal to further optimize current immunization approaches for early life. However, only a few classes of adjuvants are presently incorporated in vaccines approved for human use. Recent advances in the discovery and delivery of Toll-like receptor (TLR) agonist adjuvants have provided a new toolbox for vaccinologists. Prominent among these candidate adjuvants are synthetic small molecule TLR7/8 agonists. The development of an effective infant Bordetella pertussis vaccine is urgently required because of the resurgence of pertussis in many countries, contemporaneous to the switch from whole cell to acellular vaccines. In this context, TLR7/8 adjuvant based vaccine formulation strategies may be a promising tool to enhance and accelerate early life immunity by acellular B. pertussis vaccines. In the present study, we optimized (a) the formulation delivery system, (b) structure, and (c) immunologic activity of novel small molecule imidazoquinoline TLR7/8 adjuvants towards human infant leukocytes, including dendritic cells. Upon immunization of neonatal mice, this TLR7/8 adjuvant overcame neonatal hyporesponsiveness to acellular pertussis vaccination by driving a T helper (Th)1/Th17 biased T cell- and IgG2c-skewed humoral response to a licensed acellular vaccine (DTaP). This potent immunization strategy may represent a new paradigm for effective immunization against pertussis and other pathogens in early life. |
| first_indexed | 2024-04-13T17:37:47Z |
| format | Article |
| id | doaj.art-664c1c1f13a04a379a816fa55d3b47b1 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-13T17:37:47Z |
| publishDate | 2022-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-664c1c1f13a04a379a816fa55d3b47b12022-12-22T02:37:17ZengNature PortfolioScientific Reports2045-23222022-10-0112111710.1038/s41598-022-20346-wDevelopment of a TLR7/8 agonist adjuvant formulation to overcome early life hyporesponsiveness to DTaP vaccinationDavid J. Dowling0Soumik Barman1Alyson J. Smith2Francesco Borriello3Danielle Chaney4Spencer E. Brightman5Gandolina Melhem6Byron Brook7Manisha Menon8Dheeraj Soni9Simone Schüller10Karthik Siram11Etsuro Nanishi12Hélène G. Bazin13David J. Burkhart14Ofer Levy15Jay T. Evans16Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Harvard Institutes of MedicinePrecision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Harvard Institutes of MedicineCenter for Translational Medicine, University of MontanaPrecision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Harvard Institutes of MedicinePrecision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Harvard Institutes of MedicinePrecision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Harvard Institutes of MedicinePrecision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Harvard Institutes of MedicinePrecision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Harvard Institutes of MedicinePrecision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Harvard Institutes of MedicinePrecision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Harvard Institutes of MedicinePrecision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Harvard Institutes of MedicineDepartment of Biomedical and Pharmaceutical Sciences, University of MontanaPrecision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Harvard Institutes of MedicineCenter for Translational Medicine, University of MontanaCenter for Translational Medicine, University of MontanaPrecision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Harvard Institutes of MedicineCenter for Translational Medicine, University of MontanaAbstract Infection is the most common cause of mortality early in life, yet the broad potential of immunization is not fully realized in this vulnerable population. Most vaccines are administered during infancy and childhood, but in some cases the full benefit of vaccination is not realized in-part. New adjuvants are cardinal to further optimize current immunization approaches for early life. However, only a few classes of adjuvants are presently incorporated in vaccines approved for human use. Recent advances in the discovery and delivery of Toll-like receptor (TLR) agonist adjuvants have provided a new toolbox for vaccinologists. Prominent among these candidate adjuvants are synthetic small molecule TLR7/8 agonists. The development of an effective infant Bordetella pertussis vaccine is urgently required because of the resurgence of pertussis in many countries, contemporaneous to the switch from whole cell to acellular vaccines. In this context, TLR7/8 adjuvant based vaccine formulation strategies may be a promising tool to enhance and accelerate early life immunity by acellular B. pertussis vaccines. In the present study, we optimized (a) the formulation delivery system, (b) structure, and (c) immunologic activity of novel small molecule imidazoquinoline TLR7/8 adjuvants towards human infant leukocytes, including dendritic cells. Upon immunization of neonatal mice, this TLR7/8 adjuvant overcame neonatal hyporesponsiveness to acellular pertussis vaccination by driving a T helper (Th)1/Th17 biased T cell- and IgG2c-skewed humoral response to a licensed acellular vaccine (DTaP). This potent immunization strategy may represent a new paradigm for effective immunization against pertussis and other pathogens in early life.https://doi.org/10.1038/s41598-022-20346-w |
| spellingShingle | David J. Dowling Soumik Barman Alyson J. Smith Francesco Borriello Danielle Chaney Spencer E. Brightman Gandolina Melhem Byron Brook Manisha Menon Dheeraj Soni Simone Schüller Karthik Siram Etsuro Nanishi Hélène G. Bazin David J. Burkhart Ofer Levy Jay T. Evans Development of a TLR7/8 agonist adjuvant formulation to overcome early life hyporesponsiveness to DTaP vaccination Scientific Reports |
| title | Development of a TLR7/8 agonist adjuvant formulation to overcome early life hyporesponsiveness to DTaP vaccination |
| title_full | Development of a TLR7/8 agonist adjuvant formulation to overcome early life hyporesponsiveness to DTaP vaccination |
| title_fullStr | Development of a TLR7/8 agonist adjuvant formulation to overcome early life hyporesponsiveness to DTaP vaccination |
| title_full_unstemmed | Development of a TLR7/8 agonist adjuvant formulation to overcome early life hyporesponsiveness to DTaP vaccination |
| title_short | Development of a TLR7/8 agonist adjuvant formulation to overcome early life hyporesponsiveness to DTaP vaccination |
| title_sort | development of a tlr7 8 agonist adjuvant formulation to overcome early life hyporesponsiveness to dtap vaccination |
| url | https://doi.org/10.1038/s41598-022-20346-w |
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