Use of a small molecule integrin activator as a systemically administered vaccine adjuvant in controlling Chagas disease
Abstract The development of suitable safe adjuvants to enhance appropriate antigen-driven immune responses remains a challenge. Here we describe the adjuvant properties of a small molecule activator of the integrins αLβ2 and α4β1, named 7HP349, which can be safely delivered systemically independent...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2021-09-01
|
| Series: | npj Vaccines |
| Online Access: | https://doi.org/10.1038/s41541-021-00378-5 |
| _version_ | 1797641316497096704 |
|---|---|
| author | Nandadeva Lokugamage Imran H. Chowdhury Ronald J. Biediger Robert V. Market Sayadeth Khounlo Navin D. Warier Shen-An Hwang Jeffrey K. Actor Darren G. Woodside Upendra Marathi Peter Vanderslice Nisha Jain Garg |
| author_facet | Nandadeva Lokugamage Imran H. Chowdhury Ronald J. Biediger Robert V. Market Sayadeth Khounlo Navin D. Warier Shen-An Hwang Jeffrey K. Actor Darren G. Woodside Upendra Marathi Peter Vanderslice Nisha Jain Garg |
| author_sort | Nandadeva Lokugamage |
| collection | DOAJ |
| description | Abstract The development of suitable safe adjuvants to enhance appropriate antigen-driven immune responses remains a challenge. Here we describe the adjuvant properties of a small molecule activator of the integrins αLβ2 and α4β1, named 7HP349, which can be safely delivered systemically independent of antigen. 7HP349 directly activates integrin cell adhesion receptors crucial for the generation of an immune response. When delivered systemically in a model of Chagas disease following immunization with a DNA subunit vaccine encoding candidate T. cruzi antigens, TcG2 and TcG4, 7HP349 enhanced the vaccine efficacy in both prophylactic and therapeutic settings. In a prophylactic setting, mice immunized with 7HP349 adjuvanted vaccine exhibited significantly improved control of acute parasite burden in cardiac and skeletal muscle as compared to vaccination alone. When administered with vaccine therapeutically, parasite burden was again decreased, with the greatest adjuvant effect of 7HP349 being noted in skeletal muscle. In both settings, adjuvantation with 7HP349 was effective in decreasing pathological inflammatory infiltrate, improving the integrity of tissue, and controlling tissue fibrosis in the heart and skeletal muscle of acutely and chronically infected Chagas mice. The positive effects correlated with increased splenic frequencies of CD8+T effector cells and an increase in the production of IFN-γ and cytolytic molecules (perforin and granzyme) by the CD4+ and CD8+ effector and central memory subsets in response to challenge infection. This demonstrates that 7HP349 can serve as a systemically administered adjuvant to enhance T cell-mediated immune responses to vaccines. This approach could be applied to numerous vaccines with no reformulation of existing stockpiles. |
| first_indexed | 2024-03-11T13:43:52Z |
| format | Article |
| id | doaj.art-fa56993f549b4cbda0b8eb8236c01b18 |
| institution | Directory Open Access Journal |
| issn | 2059-0105 |
| language | English |
| last_indexed | 2024-03-11T13:43:52Z |
| publishDate | 2021-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Vaccines |
| spelling | doaj.art-fa56993f549b4cbda0b8eb8236c01b182023-11-02T11:18:56ZengNature Portfolionpj Vaccines2059-01052021-09-016111410.1038/s41541-021-00378-5Use of a small molecule integrin activator as a systemically administered vaccine adjuvant in controlling Chagas diseaseNandadeva Lokugamage0Imran H. Chowdhury1Ronald J. Biediger2Robert V. Market3Sayadeth Khounlo4Navin D. Warier5Shen-An Hwang6Jeffrey K. Actor7Darren G. Woodside8Upendra Marathi9Peter Vanderslice10Nisha Jain Garg11Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB)Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB)Department of Molecular Cardiology, Texas Heart InstituteDepartment of Molecular Cardiology, Texas Heart InstituteDepartment of Molecular Cardiology, Texas Heart InstituteDepartment of Molecular Cardiology, Texas Heart InstituteDepartment of Pathology and Laboratory Medicine, UTHealth McGovern Medical SchoolDepartment of Pathology and Laboratory Medicine, UTHealth McGovern Medical SchoolDepartment of Molecular Cardiology, Texas Heart Institute7 Hills Pharma LLC, 2450 Holcombe Blvd, Suite JDepartment of Molecular Cardiology, Texas Heart InstituteDepartment of Microbiology and Immunology, University of Texas Medical Branch (UTMB)Abstract The development of suitable safe adjuvants to enhance appropriate antigen-driven immune responses remains a challenge. Here we describe the adjuvant properties of a small molecule activator of the integrins αLβ2 and α4β1, named 7HP349, which can be safely delivered systemically independent of antigen. 7HP349 directly activates integrin cell adhesion receptors crucial for the generation of an immune response. When delivered systemically in a model of Chagas disease following immunization with a DNA subunit vaccine encoding candidate T. cruzi antigens, TcG2 and TcG4, 7HP349 enhanced the vaccine efficacy in both prophylactic and therapeutic settings. In a prophylactic setting, mice immunized with 7HP349 adjuvanted vaccine exhibited significantly improved control of acute parasite burden in cardiac and skeletal muscle as compared to vaccination alone. When administered with vaccine therapeutically, parasite burden was again decreased, with the greatest adjuvant effect of 7HP349 being noted in skeletal muscle. In both settings, adjuvantation with 7HP349 was effective in decreasing pathological inflammatory infiltrate, improving the integrity of tissue, and controlling tissue fibrosis in the heart and skeletal muscle of acutely and chronically infected Chagas mice. The positive effects correlated with increased splenic frequencies of CD8+T effector cells and an increase in the production of IFN-γ and cytolytic molecules (perforin and granzyme) by the CD4+ and CD8+ effector and central memory subsets in response to challenge infection. This demonstrates that 7HP349 can serve as a systemically administered adjuvant to enhance T cell-mediated immune responses to vaccines. This approach could be applied to numerous vaccines with no reformulation of existing stockpiles.https://doi.org/10.1038/s41541-021-00378-5 |
| spellingShingle | Nandadeva Lokugamage Imran H. Chowdhury Ronald J. Biediger Robert V. Market Sayadeth Khounlo Navin D. Warier Shen-An Hwang Jeffrey K. Actor Darren G. Woodside Upendra Marathi Peter Vanderslice Nisha Jain Garg Use of a small molecule integrin activator as a systemically administered vaccine adjuvant in controlling Chagas disease npj Vaccines |
| title | Use of a small molecule integrin activator as a systemically administered vaccine adjuvant in controlling Chagas disease |
| title_full | Use of a small molecule integrin activator as a systemically administered vaccine adjuvant in controlling Chagas disease |
| title_fullStr | Use of a small molecule integrin activator as a systemically administered vaccine adjuvant in controlling Chagas disease |
| title_full_unstemmed | Use of a small molecule integrin activator as a systemically administered vaccine adjuvant in controlling Chagas disease |
| title_short | Use of a small molecule integrin activator as a systemically administered vaccine adjuvant in controlling Chagas disease |
| title_sort | use of a small molecule integrin activator as a systemically administered vaccine adjuvant in controlling chagas disease |
| url | https://doi.org/10.1038/s41541-021-00378-5 |
| work_keys_str_mv | AT nandadevalokugamage useofasmallmoleculeintegrinactivatorasasystemicallyadministeredvaccineadjuvantincontrollingchagasdisease AT imranhchowdhury useofasmallmoleculeintegrinactivatorasasystemicallyadministeredvaccineadjuvantincontrollingchagasdisease AT ronaldjbiediger useofasmallmoleculeintegrinactivatorasasystemicallyadministeredvaccineadjuvantincontrollingchagasdisease AT robertvmarket useofasmallmoleculeintegrinactivatorasasystemicallyadministeredvaccineadjuvantincontrollingchagasdisease AT sayadethkhounlo useofasmallmoleculeintegrinactivatorasasystemicallyadministeredvaccineadjuvantincontrollingchagasdisease AT navindwarier useofasmallmoleculeintegrinactivatorasasystemicallyadministeredvaccineadjuvantincontrollingchagasdisease AT shenanhwang useofasmallmoleculeintegrinactivatorasasystemicallyadministeredvaccineadjuvantincontrollingchagasdisease AT jeffreykactor useofasmallmoleculeintegrinactivatorasasystemicallyadministeredvaccineadjuvantincontrollingchagasdisease AT darrengwoodside useofasmallmoleculeintegrinactivatorasasystemicallyadministeredvaccineadjuvantincontrollingchagasdisease AT upendramarathi useofasmallmoleculeintegrinactivatorasasystemicallyadministeredvaccineadjuvantincontrollingchagasdisease AT petervanderslice useofasmallmoleculeintegrinactivatorasasystemicallyadministeredvaccineadjuvantincontrollingchagasdisease AT nishajaingarg useofasmallmoleculeintegrinactivatorasasystemicallyadministeredvaccineadjuvantincontrollingchagasdisease |