IMRAS-Immunization with radiation-attenuated Plasmodium falciparum sporozoites by mosquito bite: Cellular immunity to sporozoites, CSP, AMA1, TRAP and CelTOS.
<h4>Background</h4>Immunization with radiation-attenuated sporozoites (RAS) by mosquito bites provides >90% sterile protection against Plasmodium falciparum malaria in humans. We conducted a clinical trial based on data from previous RAS clinical trials that suggested that 800-1200 in...
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2021-01-01
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| author | Martha Sedegah Michael R Hollingdale Harini Ganeshan Maria Belmonte Jun Huang Arnel Belmonte Sandra Inoue Rachel Velasco Bradley Hickey Nimfa Teneza-Mora Joanne Lumsden Sharina Reyes Jo Glenna Banania Anatalio Reyes Ivelese Guzman Thomas L Richie Judith E Epstein Eileen Villasante |
| author_facet | Martha Sedegah Michael R Hollingdale Harini Ganeshan Maria Belmonte Jun Huang Arnel Belmonte Sandra Inoue Rachel Velasco Bradley Hickey Nimfa Teneza-Mora Joanne Lumsden Sharina Reyes Jo Glenna Banania Anatalio Reyes Ivelese Guzman Thomas L Richie Judith E Epstein Eileen Villasante |
| author_sort | Martha Sedegah |
| collection | DOAJ |
| description | <h4>Background</h4>Immunization with radiation-attenuated sporozoites (RAS) by mosquito bites provides >90% sterile protection against Plasmodium falciparum malaria in humans. We conducted a clinical trial based on data from previous RAS clinical trials that suggested that 800-1200 infected bites should induce ~50% protective vaccine efficacy (VE) against controlled human malaria infection (CHMI) administered three weeks after the final immunization. Two cohorts were immunized separately. VE was 55% in Cohort 1 but 90% in Cohort 2, the cohort that received a higher first dose and a reduced (fractional) fifth dose. Immune responses were better boosted by the fractional fifth dose in Cohort 2 and suggested the importance of the fractional fifth dose for increased protection in Cohort 2 responses. Three protected subjects were later boosted and were protected suggesting that protection could be extended to at least 67 weeks.<h4>Methods</h4>The ex vivo FluoroSpot assay was used to measure peripheral IFN-γ, IL2, and IFN-γ+IL2 responses to PfNF54 sporozoites and malaria antigens CSP, AMA1, TRAP, and CelTOS using pools of synthetic overlapping 15mer peptides spanning each antigen.<h4>Results</h4>There was no correlation between IFN-γ, IL2, and IFN-γ+IL2 responses to sporozoites and protection, but fold-increases between post-4th and post-5th responses greater than 1.0 occurred mostly in protected subjects. IFN-γ and IL2 responses to TRAP, CelTOS and CSP occurred only in protected subjects. Peripheral IFN-γ, IL2, and IFN-γ+IL2 responses were short-lived and low by 27 weeks post-CHMI but were restored by boosting.<h4>Conclusions</h4>These studies highlight the importance of vaccine dose and schedule for vaccine efficacy, and suggest that CSP, TRAP, AMA1 and CelTOS may be targets of protective immunity. The correlation between fold-increases in responses and protection should be explored in other vaccine trials.<h4>Trial registration</h4>ClinicalTrials.gov NCT01994525. |
| format | Article |
| id | doaj-art-976cc23ed31b4e119cfee358be5ef4ee |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2021-01-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj-art-976cc23ed31b4e119cfee358be5ef4ee2025-01-18T05:31:05ZengPublic Library of Science (PLoS)PLoS ONE1932-62032021-01-01168e025639610.1371/journal.pone.0256396IMRAS-Immunization with radiation-attenuated Plasmodium falciparum sporozoites by mosquito bite: Cellular immunity to sporozoites, CSP, AMA1, TRAP and CelTOS.Martha SedegahMichael R HollingdaleHarini GaneshanMaria BelmonteJun HuangArnel BelmonteSandra InoueRachel VelascoBradley HickeyNimfa Teneza-MoraJoanne LumsdenSharina ReyesJo Glenna BananiaAnatalio ReyesIvelese GuzmanThomas L RichieJudith E EpsteinEileen Villasante<h4>Background</h4>Immunization with radiation-attenuated sporozoites (RAS) by mosquito bites provides >90% sterile protection against Plasmodium falciparum malaria in humans. We conducted a clinical trial based on data from previous RAS clinical trials that suggested that 800-1200 infected bites should induce ~50% protective vaccine efficacy (VE) against controlled human malaria infection (CHMI) administered three weeks after the final immunization. Two cohorts were immunized separately. VE was 55% in Cohort 1 but 90% in Cohort 2, the cohort that received a higher first dose and a reduced (fractional) fifth dose. Immune responses were better boosted by the fractional fifth dose in Cohort 2 and suggested the importance of the fractional fifth dose for increased protection in Cohort 2 responses. Three protected subjects were later boosted and were protected suggesting that protection could be extended to at least 67 weeks.<h4>Methods</h4>The ex vivo FluoroSpot assay was used to measure peripheral IFN-γ, IL2, and IFN-γ+IL2 responses to PfNF54 sporozoites and malaria antigens CSP, AMA1, TRAP, and CelTOS using pools of synthetic overlapping 15mer peptides spanning each antigen.<h4>Results</h4>There was no correlation between IFN-γ, IL2, and IFN-γ+IL2 responses to sporozoites and protection, but fold-increases between post-4th and post-5th responses greater than 1.0 occurred mostly in protected subjects. IFN-γ and IL2 responses to TRAP, CelTOS and CSP occurred only in protected subjects. Peripheral IFN-γ, IL2, and IFN-γ+IL2 responses were short-lived and low by 27 weeks post-CHMI but were restored by boosting.<h4>Conclusions</h4>These studies highlight the importance of vaccine dose and schedule for vaccine efficacy, and suggest that CSP, TRAP, AMA1 and CelTOS may be targets of protective immunity. The correlation between fold-increases in responses and protection should be explored in other vaccine trials.<h4>Trial registration</h4>ClinicalTrials.gov NCT01994525.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0256396&type=printable |
| spellingShingle | Martha Sedegah Michael R Hollingdale Harini Ganeshan Maria Belmonte Jun Huang Arnel Belmonte Sandra Inoue Rachel Velasco Bradley Hickey Nimfa Teneza-Mora Joanne Lumsden Sharina Reyes Jo Glenna Banania Anatalio Reyes Ivelese Guzman Thomas L Richie Judith E Epstein Eileen Villasante IMRAS-Immunization with radiation-attenuated Plasmodium falciparum sporozoites by mosquito bite: Cellular immunity to sporozoites, CSP, AMA1, TRAP and CelTOS. PLoS ONE |
| title | IMRAS-Immunization with radiation-attenuated Plasmodium falciparum sporozoites by mosquito bite: Cellular immunity to sporozoites, CSP, AMA1, TRAP and CelTOS. |
| title_full | IMRAS-Immunization with radiation-attenuated Plasmodium falciparum sporozoites by mosquito bite: Cellular immunity to sporozoites, CSP, AMA1, TRAP and CelTOS. |
| title_fullStr | IMRAS-Immunization with radiation-attenuated Plasmodium falciparum sporozoites by mosquito bite: Cellular immunity to sporozoites, CSP, AMA1, TRAP and CelTOS. |
| title_full_unstemmed | IMRAS-Immunization with radiation-attenuated Plasmodium falciparum sporozoites by mosquito bite: Cellular immunity to sporozoites, CSP, AMA1, TRAP and CelTOS. |
| title_short | IMRAS-Immunization with radiation-attenuated Plasmodium falciparum sporozoites by mosquito bite: Cellular immunity to sporozoites, CSP, AMA1, TRAP and CelTOS. |
| title_sort | imras immunization with radiation attenuated plasmodium falciparum sporozoites by mosquito bite cellular immunity to sporozoites csp ama1 trap and celtos |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0256396&type=printable |
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