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.
<h4>Background</h4>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 su...
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doaj-09a1bfbcaf43443593836d98e5b0ffa52021-03-04T11:17:43ZengPublic Library of Science (PLoS)PLoS ONE1932-62032020-01-01156e023384010.1371/journal.pone.0233840IMRAS-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.Bradley HickeyNimfa Teneza-MoraJoanne LumsdenSharina ReyesMartha SedegahLindsey GarverMichael R HollingdaleJo Glenna BananiaHarini GaneshanMegan DowlerAnatalio ReyesCindy TammingaAlexandra SingerAlicia SimmonsMaria BelmonteArnel BelmonteJun HuangSandra InoueRachel VelascoSteve AbotCarlos S VasquezIvelese GuzmanMimi WongPatrick TwomeyMariusz WojnarskiJames MoonYolanda AlcortaSantina MaiolatesiMichele SpringSilas DavidsonSidhartha ChaudhuryEileen VillasanteThomas L RichieJudith E Epstein<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.<h4>Trial registration</h4>ClinicalTrials.gov NCT01994525.https://doi.org/10.1371/journal.pone.0233840 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Bradley Hickey Nimfa Teneza-Mora Joanne Lumsden Sharina Reyes Martha Sedegah Lindsey Garver Michael R Hollingdale Jo Glenna Banania Harini Ganeshan Megan Dowler Anatalio Reyes Cindy Tamminga Alexandra Singer Alicia Simmons Maria Belmonte Arnel Belmonte Jun Huang Sandra Inoue Rachel Velasco Steve Abot Carlos S Vasquez Ivelese Guzman Mimi Wong Patrick Twomey Mariusz Wojnarski James Moon Yolanda Alcorta Santina Maiolatesi Michele Spring Silas Davidson Sidhartha Chaudhury Eileen Villasante Thomas L Richie Judith E Epstein |
spellingShingle |
Bradley Hickey Nimfa Teneza-Mora Joanne Lumsden Sharina Reyes Martha Sedegah Lindsey Garver Michael R Hollingdale Jo Glenna Banania Harini Ganeshan Megan Dowler Anatalio Reyes Cindy Tamminga Alexandra Singer Alicia Simmons Maria Belmonte Arnel Belmonte Jun Huang Sandra Inoue Rachel Velasco Steve Abot Carlos S Vasquez Ivelese Guzman Mimi Wong Patrick Twomey Mariusz Wojnarski James Moon Yolanda Alcorta Santina Maiolatesi Michele Spring Silas Davidson Sidhartha Chaudhury Eileen Villasante Thomas L Richie Judith E Epstein 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. PLoS ONE |
author_facet |
Bradley Hickey Nimfa Teneza-Mora Joanne Lumsden Sharina Reyes Martha Sedegah Lindsey Garver Michael R Hollingdale Jo Glenna Banania Harini Ganeshan Megan Dowler Anatalio Reyes Cindy Tamminga Alexandra Singer Alicia Simmons Maria Belmonte Arnel Belmonte Jun Huang Sandra Inoue Rachel Velasco Steve Abot Carlos S Vasquez Ivelese Guzman Mimi Wong Patrick Twomey Mariusz Wojnarski James Moon Yolanda Alcorta Santina Maiolatesi Michele Spring Silas Davidson Sidhartha Chaudhury Eileen Villasante Thomas L Richie Judith E Epstein |
author_sort |
Bradley Hickey |
title |
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. |
title_short |
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. |
title_full |
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. |
title_fullStr |
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. |
title_full_unstemmed |
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. |
title_sort |
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. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2020-01-01 |
description |
<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.<h4>Trial registration</h4>ClinicalTrials.gov NCT01994525. |
url |
https://doi.org/10.1371/journal.pone.0233840 |
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