Evaluating Human Immune Responses for Vaccine Development in a Novel Human Spleen Cell-Engrafted NOD-SCID-IL2rγNull Mouse Model
The lack of preclinical models able to faithfully predict the immune responses which are later obtained in the clinic is a major hurdle for vaccines development as it increases markedly the delays and the costs required to perform clinical studies. We developed and evaluated the relevance to human i...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2018.00601/full |
| _version_ | 1818558929721884672 |
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| author | Stéphanie Ghosn Stéphanie Ghosn Soulaima Chamat Soulaima Chamat Eric Prieur Antoine Stephan Pierre Druilhe Hasnaa Bouharoun-Tayoun |
| author_facet | Stéphanie Ghosn Stéphanie Ghosn Soulaima Chamat Soulaima Chamat Eric Prieur Antoine Stephan Pierre Druilhe Hasnaa Bouharoun-Tayoun |
| author_sort | Stéphanie Ghosn |
| collection | DOAJ |
| description | The lack of preclinical models able to faithfully predict the immune responses which are later obtained in the clinic is a major hurdle for vaccines development as it increases markedly the delays and the costs required to perform clinical studies. We developed and evaluated the relevance to human immune responses of a novel humanized mouse model, humanized-spleen cells-NOD-SCID-gamma null (Hu-SPL-NSG), in which we grafted human spleen cells in immunodeficient NOD-SCID-IL-2rγnull (NSG) mice. We selected the malaria vaccine candidate, Liver Stage Antigen 3-Full Length, because we had previously observed a major discrepancy between preclinical and clinical results, and compared its immunogenicity with that of a shorter form of the molecule, LSA3-729. NSG mice engrafted with human spleen lymphocytes were immunized with either LSA3-FL or LSA3-729, both adjuvanted with montanide ISA720. We found that the shorter LSA3-729 triggered the production of human antibodies and a T-helper-type 1 cellular immune response associated with protection whereas LSA3-FL did not. Results were consistent in five groups receiving lymphocytes from five distinct human donors. We identified antigenic regions in the full-length molecule, but not in the shorter version, which induced T-regulatory type of cellular responses. These regions had failed to be predicted by previous preclinical experiments in a wide range of animal models, including primates. Results were reproducible using spleen cells from all five human donors. The findings in the Hu-SPL-NSG model were similar to the results obtained using LSA3-FL in the clinic and hence could have been used to predict them. The model does not present graft versus host reaction, low survival of engrafted B lymphocytes and difficulty to raise primary immune responses, all limitations previously reported in humanized immune-compromised mice. Results also point to the shorter construct, LSA3-729 as a more efficient vaccine candidate. In summary, our findings indicate that the Hu-SPL-NSG model could be a relevant and cost-saving choice for early selection of vaccine candidates before clinical development, and deserves being further evaluated. |
| first_indexed | 2024-12-14T00:18:42Z |
| format | Article |
| id | doaj.art-84f760b932b4463aa9e0a48622d4c8dc |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-14T00:18:42Z |
| publishDate | 2018-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-84f760b932b4463aa9e0a48622d4c8dc2022-12-21T23:25:21ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-03-01910.3389/fimmu.2018.00601326494Evaluating Human Immune Responses for Vaccine Development in a Novel Human Spleen Cell-Engrafted NOD-SCID-IL2rγNull Mouse ModelStéphanie Ghosn0Stéphanie Ghosn1Soulaima Chamat2Soulaima Chamat3Eric Prieur4Antoine Stephan5Pierre Druilhe6Hasnaa Bouharoun-Tayoun7Laboratory of Immunology and Vector Born Diseases, Faculty of Public Health-Fanar, Lebanese University, Beirut, LebanonVac4All Initiative, Paris, FranceLaboratory of Immunology and Vector Born Diseases, Faculty of Public Health-Fanar, Lebanese University, Beirut, LebanonFaculty of Medicine, Lebanese University, Hadath, LebanonVac4All Initiative, Paris, FranceNational Organization for Organ and Tissues Donation and Transplantation (NOOTDT), Beirut, LebanonVac4All Initiative, Paris, FranceLaboratory of Immunology and Vector Born Diseases, Faculty of Public Health-Fanar, Lebanese University, Beirut, LebanonThe lack of preclinical models able to faithfully predict the immune responses which are later obtained in the clinic is a major hurdle for vaccines development as it increases markedly the delays and the costs required to perform clinical studies. We developed and evaluated the relevance to human immune responses of a novel humanized mouse model, humanized-spleen cells-NOD-SCID-gamma null (Hu-SPL-NSG), in which we grafted human spleen cells in immunodeficient NOD-SCID-IL-2rγnull (NSG) mice. We selected the malaria vaccine candidate, Liver Stage Antigen 3-Full Length, because we had previously observed a major discrepancy between preclinical and clinical results, and compared its immunogenicity with that of a shorter form of the molecule, LSA3-729. NSG mice engrafted with human spleen lymphocytes were immunized with either LSA3-FL or LSA3-729, both adjuvanted with montanide ISA720. We found that the shorter LSA3-729 triggered the production of human antibodies and a T-helper-type 1 cellular immune response associated with protection whereas LSA3-FL did not. Results were consistent in five groups receiving lymphocytes from five distinct human donors. We identified antigenic regions in the full-length molecule, but not in the shorter version, which induced T-regulatory type of cellular responses. These regions had failed to be predicted by previous preclinical experiments in a wide range of animal models, including primates. Results were reproducible using spleen cells from all five human donors. The findings in the Hu-SPL-NSG model were similar to the results obtained using LSA3-FL in the clinic and hence could have been used to predict them. The model does not present graft versus host reaction, low survival of engrafted B lymphocytes and difficulty to raise primary immune responses, all limitations previously reported in humanized immune-compromised mice. Results also point to the shorter construct, LSA3-729 as a more efficient vaccine candidate. In summary, our findings indicate that the Hu-SPL-NSG model could be a relevant and cost-saving choice for early selection of vaccine candidates before clinical development, and deserves being further evaluated.http://journal.frontiersin.org/article/10.3389/fimmu.2018.00601/fullhumanized mouse modelvaccine developmentPlasmodium falciparumhuman spleen cellsmalariaimmunogenicity |
| spellingShingle | Stéphanie Ghosn Stéphanie Ghosn Soulaima Chamat Soulaima Chamat Eric Prieur Antoine Stephan Pierre Druilhe Hasnaa Bouharoun-Tayoun Evaluating Human Immune Responses for Vaccine Development in a Novel Human Spleen Cell-Engrafted NOD-SCID-IL2rγNull Mouse Model Frontiers in Immunology humanized mouse model vaccine development Plasmodium falciparum human spleen cells malaria immunogenicity |
| title | Evaluating Human Immune Responses for Vaccine Development in a Novel Human Spleen Cell-Engrafted NOD-SCID-IL2rγNull Mouse Model |
| title_full | Evaluating Human Immune Responses for Vaccine Development in a Novel Human Spleen Cell-Engrafted NOD-SCID-IL2rγNull Mouse Model |
| title_fullStr | Evaluating Human Immune Responses for Vaccine Development in a Novel Human Spleen Cell-Engrafted NOD-SCID-IL2rγNull Mouse Model |
| title_full_unstemmed | Evaluating Human Immune Responses for Vaccine Development in a Novel Human Spleen Cell-Engrafted NOD-SCID-IL2rγNull Mouse Model |
| title_short | Evaluating Human Immune Responses for Vaccine Development in a Novel Human Spleen Cell-Engrafted NOD-SCID-IL2rγNull Mouse Model |
| title_sort | evaluating human immune responses for vaccine development in a novel human spleen cell engrafted nod scid il2rγnull mouse model |
| topic | humanized mouse model vaccine development Plasmodium falciparum human spleen cells malaria immunogenicity |
| url | http://journal.frontiersin.org/article/10.3389/fimmu.2018.00601/full |
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