Development of functional and molecular correlates of vaccine-induced protection for a model intracellular pathogen, F. tularensis LVS.
In contrast with common human infections for which vaccine efficacy can be evaluated directly in field studies, alternative strategies are needed to evaluate efficacy for slowly developing or sporadic diseases like tularemia. For diseases such as these caused by intracellular bacteria, serological m...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC3262015?pdf=render |
| _version_ | 1818039289373523968 |
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| author | Roberto De Pascalis Alicia Y Chou Catharine M Bosio Chiung-Yu Huang Dean A Follmann Karen L Elkins |
| author_facet | Roberto De Pascalis Alicia Y Chou Catharine M Bosio Chiung-Yu Huang Dean A Follmann Karen L Elkins |
| author_sort | Roberto De Pascalis |
| collection | DOAJ |
| description | In contrast with common human infections for which vaccine efficacy can be evaluated directly in field studies, alternative strategies are needed to evaluate efficacy for slowly developing or sporadic diseases like tularemia. For diseases such as these caused by intracellular bacteria, serological measures of antibodies are generally not predictive. Here, we used vaccines varying in efficacy to explore development of clinically useful correlates of protection for intracellular bacteria, using Francisella tularensis as an experimental model. F. tularensis is an intracellular bacterium classified as Category A bioterrorism agent which causes tularemia. The primary vaccine candidate in the U.S., called Live Vaccine Strain (LVS), has been the subject of ongoing clinical studies; however, safety and efficacy are not well established, and LVS is not licensed by the U.S. FDA. Using a mouse model, we compared the in vivo efficacy of a panel of qualitatively different Francisella vaccine candidates, the in vitro functional activity of immune lymphocytes derived from vaccinated mice, and relative gene expression in immune lymphocytes. Integrated analyses showed that the hierarchy of protection in vivo engendered by qualitatively different vaccines was reflected by the degree of lymphocytes' in vitro activity in controlling the intramacrophage growth of Francisella. Thus, this assay may be a functional correlate. Further, the strength of protection was significantly related to the degree of up-regulation of expression of a panel of genes in cells recovered from the assay. These included IFN-γ, IL-6, IL-12Rβ2, T-bet, SOCS-1, and IL-18bp. Taken together, the results indicate that an in vitro assay that detects control of bacterial growth, and/or a selected panel of mediators, may ultimately be developed to predict the outcome of vaccine efficacy and to complement clinical trials. The overall approach may be applicable to intracellular pathogens in general. |
| first_indexed | 2024-12-10T07:56:16Z |
| format | Article |
| id | doaj.art-8ec97ec5a78249b8855c2bfbca479214 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-10T07:56:16Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Pathogens |
| spelling | doaj.art-8ec97ec5a78249b8855c2bfbca4792142022-12-22T01:56:53ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742012-01-0181e100249410.1371/journal.ppat.1002494Development of functional and molecular correlates of vaccine-induced protection for a model intracellular pathogen, F. tularensis LVS.Roberto De PascalisAlicia Y ChouCatharine M BosioChiung-Yu HuangDean A FollmannKaren L ElkinsIn contrast with common human infections for which vaccine efficacy can be evaluated directly in field studies, alternative strategies are needed to evaluate efficacy for slowly developing or sporadic diseases like tularemia. For diseases such as these caused by intracellular bacteria, serological measures of antibodies are generally not predictive. Here, we used vaccines varying in efficacy to explore development of clinically useful correlates of protection for intracellular bacteria, using Francisella tularensis as an experimental model. F. tularensis is an intracellular bacterium classified as Category A bioterrorism agent which causes tularemia. The primary vaccine candidate in the U.S., called Live Vaccine Strain (LVS), has been the subject of ongoing clinical studies; however, safety and efficacy are not well established, and LVS is not licensed by the U.S. FDA. Using a mouse model, we compared the in vivo efficacy of a panel of qualitatively different Francisella vaccine candidates, the in vitro functional activity of immune lymphocytes derived from vaccinated mice, and relative gene expression in immune lymphocytes. Integrated analyses showed that the hierarchy of protection in vivo engendered by qualitatively different vaccines was reflected by the degree of lymphocytes' in vitro activity in controlling the intramacrophage growth of Francisella. Thus, this assay may be a functional correlate. Further, the strength of protection was significantly related to the degree of up-regulation of expression of a panel of genes in cells recovered from the assay. These included IFN-γ, IL-6, IL-12Rβ2, T-bet, SOCS-1, and IL-18bp. Taken together, the results indicate that an in vitro assay that detects control of bacterial growth, and/or a selected panel of mediators, may ultimately be developed to predict the outcome of vaccine efficacy and to complement clinical trials. The overall approach may be applicable to intracellular pathogens in general.http://europepmc.org/articles/PMC3262015?pdf=render |
| spellingShingle | Roberto De Pascalis Alicia Y Chou Catharine M Bosio Chiung-Yu Huang Dean A Follmann Karen L Elkins Development of functional and molecular correlates of vaccine-induced protection for a model intracellular pathogen, F. tularensis LVS. PLoS Pathogens |
| title | Development of functional and molecular correlates of vaccine-induced protection for a model intracellular pathogen, F. tularensis LVS. |
| title_full | Development of functional and molecular correlates of vaccine-induced protection for a model intracellular pathogen, F. tularensis LVS. |
| title_fullStr | Development of functional and molecular correlates of vaccine-induced protection for a model intracellular pathogen, F. tularensis LVS. |
| title_full_unstemmed | Development of functional and molecular correlates of vaccine-induced protection for a model intracellular pathogen, F. tularensis LVS. |
| title_short | Development of functional and molecular correlates of vaccine-induced protection for a model intracellular pathogen, F. tularensis LVS. |
| title_sort | development of functional and molecular correlates of vaccine induced protection for a model intracellular pathogen f tularensis lvs |
| url | http://europepmc.org/articles/PMC3262015?pdf=render |
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