IMRAS-A clinical trial of mosquito-bite immunization with live, radiation-attenuated P. falciparum sporozoites: Impact of immunization parameters on protective efficacy and generation of a repository of immunologic reagents.

Autor: Hickey B; Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America., Teneza-Mora N; Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America., Lumsden J; Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America.; Henry M. Jackson Foundation, Bethesda, MD, United States of America., Reyes S; Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America.; Henry M. Jackson Foundation, Bethesda, MD, United States of America., Sedegah M; Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America., Garver L; Walter Reed Army Institute of Research, Silver Spring, MD, United States of America., Hollingdale MR; Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America.; Henry M. Jackson Foundation, Bethesda, MD, United States of America., Banania JG; Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America.; Henry M. Jackson Foundation, Bethesda, MD, United States of America., Ganeshan H; Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America.; Henry M. Jackson Foundation, Bethesda, MD, United States of America., Dowler M; Walter Reed Army Institute of Research, Silver Spring, MD, United States of America., Reyes A; Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America.; Henry M. Jackson Foundation, Bethesda, MD, United States of America., Tamminga C; Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America., Singer A; Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America., Simmons A; Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America.; Henry M. Jackson Foundation, Bethesda, MD, United States of America., Belmonte M; Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America.; Henry M. Jackson Foundation, Bethesda, MD, United States of America., Belmonte A; Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America.; Henry M. Jackson Foundation, Bethesda, MD, United States of America., Huang J; Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America.; Henry M. Jackson Foundation, Bethesda, MD, United States of America., Inoue S; Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America.; Henry M. Jackson Foundation, Bethesda, MD, United States of America., Velasco R; Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America.; Henry M. Jackson Foundation, Bethesda, MD, United States of America., Abot S; Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America.; Henry M. Jackson Foundation, Bethesda, MD, United States of America., Vasquez CS; Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America.; Henry M. Jackson Foundation, Bethesda, MD, United States of America., Guzman I; Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America.; Henry M. Jackson Foundation, Bethesda, MD, United States of America., Wong M; Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America.; Henry M. Jackson Foundation, Bethesda, MD, United States of America., Twomey P; Walter Reed Army Institute of Research, Silver Spring, MD, United States of America., Wojnarski M; Walter Reed Army Institute of Research, Silver Spring, MD, United States of America., Moon J; Walter Reed Army Institute of Research, Silver Spring, MD, United States of America., Alcorta Y; Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America.; Henry M. Jackson Foundation, Bethesda, MD, United States of America., Maiolatesi S; Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America.; Henry M. Jackson Foundation, Bethesda, MD, United States of America., Spring M; Henry M. Jackson Foundation, Bethesda, MD, United States of America.; Walter Reed Army Institute of Research, Silver Spring, MD, United States of America., Davidson S; Walter Reed Army Institute of Research, Silver Spring, MD, United States of America., Chaudhury S; Walter Reed Army Institute of Research, Silver Spring, MD, United States of America.; Biotechnology HPC Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Frederick, MD, United States of America., Villasante E; Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America., Richie TL; Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America.; Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America., Epstein JE; Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2020 Jun 17; Vol. 15 (6), pp. e0233840. Date of Electronic Publication: 2020 Jun 17 (Print Publication: 2020).
DOI: 10.1371/journal.pone.0233840
Abstrakt: Background: Immunization with radiation-attenuated sporozoites (RAS) by mosquito bite provides >90% sterile protection against Plasmodium falciparum (Pf) malaria in humans. RAS invade hepatocytes but do not replicate. CD8+ T cells recognizing parasite-derived peptides on the surface of infected hepatocytes are likely the primary protective mechanism. We conducted a randomized clinical trial of RAS immunization to assess safety, to achieve 50% vaccine efficacy (VE) against controlled human malaria infection (CHMI), and to generate reagents from protected and non-protected subjects for future identification of protective immune mechanisms and antigens.
Methods: Two cohorts (Cohort 1 and Cohort 2) of healthy, malaria-naïve, non-pregnant adults age 18-50 received five monthly immunizations with infected (true-immunized, n = 21) or non-infected (mock-immunized, n = 5) mosquito bites and underwent homologous CHMI at 3 weeks. Immunization parameters were selected for 50% protection based on prior clinical data. Leukapheresis was done to collect plasma and peripheral blood mononuclear cells.
Results: Adverse event rates were similar in true- and mock-immunized subjects. Two true- and two mock-immunized subjects developed large local reactions likely caused by mosquito salivary gland antigens. In Cohort 1, 11 subjects received 810-1235 infected bites; 6/11 (55%) were protected against CHMI vs. 0/3 mock-immunized and 0/6 infectivity controls (VE 55%). In Cohort 2, 10 subjects received 839-1131 infected bites with a higher first dose and a reduced fifth dose; 9/10 (90%) were protected vs. 0/2 mock-immunized and 0/6 controls (VE 90%). Three/3 (100%) protected subjects administered three booster immunizations were protected against repeat CHMI vs. 0/6 controls (VE 100%). Cohort 2 uniquely showed a significant rise in IFN-γ responses after the third and fifth immunizations and higher antibody responses to CSP.
Conclusions: PfRAS were generally safe and well tolerated. Cohort 2 had a higher first dose, reduced final dose, higher antibody responses to CSP and significant rise of IFN-γ responses after the third and fifth immunizations. Whether any of these factors contributed to increased protection in Cohort 2 requires further investigation. A cryobank of sera and cells from protected and non-protected individuals was generated for future immunological studies and antigen discovery.
Trial Registration: ClinicalTrials.gov NCT01994525.
Competing Interests: The authors have read the journal's policy and have the following competing interests: TLR is a full time salaried employee of Sanaria Inc. This affiliation does not alter our adherence to PLOS One Policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.
Databáze: MEDLINE
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