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

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 a...

Full description

Saved in:
Bibliographic Details
Published in:PloS one 2020-06, Vol.15 (6), p.e0233840-e0233840
Main Authors: Hickey, Bradley, Teneza-Mora, Nimfa, Lumsden, Joanne, Reyes, Sharina, Sedegah, Martha, Garver, Lindsey, Hollingdale, Michael R, Banania, Jo Glenna, Ganeshan, Harini, Dowler, Megan, Reyes, Anatalio, Tamminga, Cindy, Singer, Alexandra, Simmons, Alicia, Belmonte, Maria, Belmonte, Arnel, Huang, Jun, Inoue, Sandra, Velasco, Rachel, Abot, Steve, Vasquez, Carlos S, Guzman, Ivelese, Wong, Mimi, Twomey, Patrick, Wojnarski, Mariusz, Moon, James, Alcorta, Yolanda, Maiolatesi, Santina, Spring, Michele, Davidson, Silas, Chaudhury, Sidhartha, Villasante, Eileen, Richie, Thomas L, Epstein, Judith E
Format: Article
Language:English
Subjects:
Antibodies
Antigens
Biology and Life Sciences
CD8 antigen
Clinical trials
Dose-response relationship
Health aspects
Hepatocytes
Homology
Immunization
Immunology
Infectivity
Leukapheresis
Leukocytes (mononuclear)
Liver
Lymphocytes
Lymphocytes T
Malaria
Medical research
Medicine and Health Sciences
Mosquitoes
Parameters
Parasites
Peptides
Peripheral blood mononuclear cells
Plasmodium falciparum
Prevention
R&D
Radiation
Reagents
Research & development
Research and Analysis Methods
Salivary gland
Salivary glands
Sporozoites
Testing
Vaccine efficacy
Vaccines
Vector-borne diseases
γ-Interferon
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. 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. 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-[gamma] responses after the third and fifth immunizations and higher antibody responses to CSP. 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-[gamma] 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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0233840