Open AccessIMRAS—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
Author(s) -
Bradley Hickey,
Nimfa Teneza-Mora,
Joanne M. Lumsden,
Sharina Reyes,
Martha Sedegah,
Lindsey S. Garver,
Michael R. Hollingdale,
Jo Glenna Banania,
Harini Ganeshan,
Megan Dowler,
Anatalio Reyes,
Cindy Tamminga,
Alexandra Singer,
Alicia Simmons,
María Belmonte,
Arnel Belmonte,
Jun Huang,
Sandra Inoue,
Rachel Velasco,
Steve Abot,
Carlos Vásquez,
Ivelese Guzman,
Mimi Wong,
Patrick Twomey,
Mariusz Wojnarski,
James Moon,
Yolanda Alcorta,
Santina Maiolatesi,
Michele Spring,
Silas A. Davidson,
Sidhartha Chaudhury,
Eileen Villasante,
Thomas L. Richie,
Judith E. Epstein
Publication year - 2020
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0233840
Subject(s) - immunization , malaria , immunology , medicine , malaria vaccine , cohort , plasmodium falciparum , vaccination , virology , antigen , biology
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 .