학술논문
IMRAS-Immunization with radiation-attenuated Plasmodium falciparum sporozoites by mosquito bite: Cellular immunity to sporozoites, CSP, AMA1, TRAP and CelTOS.
Document Type
Academic Journal
Author
Sedegah M; Malaria Department, Naval Medical Research Center, Silver Spring, Maryland, United States of America.; Hollingdale MR; Malaria Department, Naval Medical Research Center, Silver Spring, Maryland, United States of America.; Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.; Ganeshan H; Malaria Department, Naval Medical Research Center, Silver Spring, Maryland, United States of America.; Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.; Belmonte M; Malaria Department, Naval Medical Research Center, Silver Spring, Maryland, United States of America.; Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.; Huang J; Malaria Department, Naval Medical Research Center, Silver Spring, Maryland, United States of America.; Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.; Belmonte A; Malaria Department, Naval Medical Research Center, Silver Spring, Maryland, United States of America.; Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.; Inoue S; Malaria Department, Naval Medical Research Center, Silver Spring, Maryland, United States of America.; Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.; Velasco R; Malaria Department, Naval Medical Research Center, Silver Spring, Maryland, United States of America.; Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.; Hickey B; Malaria Department, Naval Medical Research Center, Silver Spring, Maryland, United States of America.; Teneza-Mora N; Malaria Department, Naval Medical Research Center, Silver Spring, Maryland, United States of America.; Lumsden J; Malaria Department, Naval Medical Research Center, Silver Spring, Maryland, United States of America.; Reyes S; Malaria Department, Naval Medical Research Center, Silver Spring, Maryland, United States of America.; Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.; Banania JG; Malaria Department, Naval Medical Research Center, Silver Spring, Maryland, United States of America.; Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.; Reyes A; Malaria Department, Naval Medical Research Center, Silver Spring, Maryland, United States of America.; Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.; Guzman I; Malaria Department, Naval Medical Research Center, Silver Spring, Maryland, United States of America.; Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.; Richie TL; Malaria Department, Naval Medical Research Center, Silver Spring, Maryland, United States of America.; Epstein JE; Malaria Department, Naval Medical Research Center, Silver Spring, Maryland, United States of America.; Villasante E; Malaria Department, Naval Medical Research Center, Silver Spring, Maryland, United States of America.
Source
Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
Subject
Language
English
Abstract
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
Trial Registration: ClinicalTrials.gov NCT01994525.
Competing Interests: The authors have read the journal’s policy and have the following competing interests: JL, SR, and JCB are paid employees of The Bill & Melinda Gates Foundation. TLR is a paid employee of Sanaria, Inc. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Methods: 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.
Results: 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.
Conclusions: 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.
Trial Registration: ClinicalTrials.gov NCT01994525.
Competing Interests: The authors have read the journal’s policy and have the following competing interests: JL, SR, and JCB are paid employees of The Bill & Melinda Gates Foundation. TLR is a paid employee of Sanaria, Inc. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.