Enhanced Anti-Mycobacterium tuberculosis Immunity over Time with Combined Drug and Immunotherapy Treatment
It is estimated that one third of the world’s population is infected with Mycobacterium tuberculosis (Mtb). This astounding statistic, in combination with costly and lengthy treatment regimens make the development of therapeutic vaccines paramount for controlling the global burden of tuber...
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| Format: | Article |
| Language: | English |
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MDPI AG
2018-05-01
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| Series: | Vaccines |
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| Online Access: | http://www.mdpi.com/2076-393X/6/2/30 |
| _version_ | 1798040246740320256 |
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| author | Sasha E. Larsen Susan L. Baldwin Mark T. Orr Valerie A. Reese Tiffany Pecor Brian Granger Natasha Dubois Cauwelaert Brendan K. Podell Rhea N. Coler |
| author_facet | Sasha E. Larsen Susan L. Baldwin Mark T. Orr Valerie A. Reese Tiffany Pecor Brian Granger Natasha Dubois Cauwelaert Brendan K. Podell Rhea N. Coler |
| author_sort | Sasha E. Larsen |
| collection | DOAJ |
| description | It is estimated that one third of the world’s population is infected with Mycobacterium tuberculosis (Mtb). This astounding statistic, in combination with costly and lengthy treatment regimens make the development of therapeutic vaccines paramount for controlling the global burden of tuberculosis. Unlike prophylactic vaccination, therapeutic immunization relies on the natural pulmonary infection with Mtb as the mucosal prime that directs boost responses back to the lung. The purpose of this work was to determine the protection and safety profile over time following therapeutic administration of our lead Mtb vaccine candidate, ID93 with a synthetic TLR4 agonist (glucopyranosyl lipid adjuvant in a stable emulsion (GLA-SE)), in combination with rifampicin, isoniazid, and pyrazinamide (RHZ) drug treatment. We assessed the host inflammatory immune responses and lung pathology 7–22 weeks post infection, and determined the therapeutic efficacy of combined treatment by enumeration of the bacterial load and survival in the SWR/J mouse model. We show that drug treatment alone, or with immunotherapy, tempered the inflammatory responses measured in brochoalveolar lavage fluid and plasma compared to untreated cohorts. RHZ combined with therapeutic immunizations significantly enhanced TH1-type cytokine responses in the lung over time, corresponding to decreased pulmonary pathology evidenced by a significant decrease in the percentage of lung lesions and destructive lung inflammation. These data suggest that bacterial burden assessment alone may miss important correlates of lung architecture that directly contribute to therapeutic vaccine efficacy in the preclinical mouse model. We also confirmed our previous finding that in combination with antibiotics therapeutic immunizations provide an additive survival advantage. Moreover, therapeutic immunizations with ID93/GLA-SE induced differential T cell immune responses over the course of infection that correlated with periods of enhanced bacterial control over that of drug treatment alone. Here we advance the immunotherapy model and investigate reliable correlates of protection and Mtb control. |
| first_indexed | 2024-04-11T22:04:49Z |
| format | Article |
| id | doaj.art-1bd3c591d0f5443787e2a0d1fccfca66 |
| institution | Directory Open Access Journal |
| issn | 2076-393X |
| language | English |
| last_indexed | 2024-04-11T22:04:49Z |
| publishDate | 2018-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Vaccines |
| spelling | doaj.art-1bd3c591d0f5443787e2a0d1fccfca662022-12-22T04:00:46ZengMDPI AGVaccines2076-393X2018-05-01623010.3390/vaccines6020030vaccines6020030Enhanced Anti-Mycobacterium tuberculosis Immunity over Time with Combined Drug and Immunotherapy TreatmentSasha E. Larsen0Susan L. Baldwin1Mark T. Orr2Valerie A. Reese3Tiffany Pecor4Brian Granger5Natasha Dubois Cauwelaert6Brendan K. Podell7Rhea N. Coler8Infectious Disease Research Institute, Seattle, WA 98102, USAInfectious Disease Research Institute, Seattle, WA 98102, USAInfectious Disease Research Institute, Seattle, WA 98102, USAInfectious Disease Research Institute, Seattle, WA 98102, USAInfectious Disease Research Institute, Seattle, WA 98102, USAInfectious Disease Research Institute, Seattle, WA 98102, USAInfectious Disease Research Institute, Seattle, WA 98102, USADepartment of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USAInfectious Disease Research Institute, Seattle, WA 98102, USAIt is estimated that one third of the world’s population is infected with Mycobacterium tuberculosis (Mtb). This astounding statistic, in combination with costly and lengthy treatment regimens make the development of therapeutic vaccines paramount for controlling the global burden of tuberculosis. Unlike prophylactic vaccination, therapeutic immunization relies on the natural pulmonary infection with Mtb as the mucosal prime that directs boost responses back to the lung. The purpose of this work was to determine the protection and safety profile over time following therapeutic administration of our lead Mtb vaccine candidate, ID93 with a synthetic TLR4 agonist (glucopyranosyl lipid adjuvant in a stable emulsion (GLA-SE)), in combination with rifampicin, isoniazid, and pyrazinamide (RHZ) drug treatment. We assessed the host inflammatory immune responses and lung pathology 7–22 weeks post infection, and determined the therapeutic efficacy of combined treatment by enumeration of the bacterial load and survival in the SWR/J mouse model. We show that drug treatment alone, or with immunotherapy, tempered the inflammatory responses measured in brochoalveolar lavage fluid and plasma compared to untreated cohorts. RHZ combined with therapeutic immunizations significantly enhanced TH1-type cytokine responses in the lung over time, corresponding to decreased pulmonary pathology evidenced by a significant decrease in the percentage of lung lesions and destructive lung inflammation. These data suggest that bacterial burden assessment alone may miss important correlates of lung architecture that directly contribute to therapeutic vaccine efficacy in the preclinical mouse model. We also confirmed our previous finding that in combination with antibiotics therapeutic immunizations provide an additive survival advantage. Moreover, therapeutic immunizations with ID93/GLA-SE induced differential T cell immune responses over the course of infection that correlated with periods of enhanced bacterial control over that of drug treatment alone. Here we advance the immunotherapy model and investigate reliable correlates of protection and Mtb control.http://www.mdpi.com/2076-393X/6/2/30therapeutic vaccineMycobacterium tuberculosistuberculosisimmunotherapyadjuvantGLA-SEID93 |
| spellingShingle | Sasha E. Larsen Susan L. Baldwin Mark T. Orr Valerie A. Reese Tiffany Pecor Brian Granger Natasha Dubois Cauwelaert Brendan K. Podell Rhea N. Coler Enhanced Anti-Mycobacterium tuberculosis Immunity over Time with Combined Drug and Immunotherapy Treatment Vaccines therapeutic vaccine Mycobacterium tuberculosis tuberculosis immunotherapy adjuvant GLA-SE ID93 |
| title | Enhanced Anti-Mycobacterium tuberculosis Immunity over Time with Combined Drug and Immunotherapy Treatment |
| title_full | Enhanced Anti-Mycobacterium tuberculosis Immunity over Time with Combined Drug and Immunotherapy Treatment |
| title_fullStr | Enhanced Anti-Mycobacterium tuberculosis Immunity over Time with Combined Drug and Immunotherapy Treatment |
| title_full_unstemmed | Enhanced Anti-Mycobacterium tuberculosis Immunity over Time with Combined Drug and Immunotherapy Treatment |
| title_short | Enhanced Anti-Mycobacterium tuberculosis Immunity over Time with Combined Drug and Immunotherapy Treatment |
| title_sort | enhanced anti mycobacterium tuberculosis immunity over time with combined drug and immunotherapy treatment |
| topic | therapeutic vaccine Mycobacterium tuberculosis tuberculosis immunotherapy adjuvant GLA-SE ID93 |
| url | http://www.mdpi.com/2076-393X/6/2/30 |
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