Title
Safety, toxicity and immunogenicity of a malaria vaccine based on the circumsporozoite protein (FMP013) with the adjuvant army liposome formulation containing QS21 (ALFQ)
Date Issued
27 June 2019
Access level
open access
Resource Type
research article
Author(s)
Cawlfield A.
Genito C.J.
Beck Z.
Bergmann-Leitner E.S.
Bitzer A.A.
Soto K.
Zou X.
Hadiwidjojo S.H.
Mullins A.B.
Noe A.
Waters N.C.
Alving C.R.
Matyas G.R.
Dutta S.
Naval Medical Research Center
Abstract
Antibodies to Circumsporozoite protein (CSP) confer protection against controlled human malaria infection (CHMI) caused by the parasite Plasmodium falciparum. Although CSP is highly immunogenic, it does not induce long lasting protection and efforts to improve CSP-specific immunological memory and duration of protection are underway. We have previously reported that the clinical grade CSP vaccine FMP013 was immunogenic and protective against malaria challenge in mice when combined with the Army Liposomal Formulation adjuvant containing immune modulators 3D-PHAD™ and QS21 (ALFQ). To move forward with clinical evaluation, we now report the safety, toxicity and immunogenicity of clinical grade FMP013 and ALFQ in Rhesus macaques. Three groups of Rhesus (n = 6) received half or full human dose of FMP013 + ALFQ on a 0-1-2 month schedule, which showed mild local site reactions with no hematologic derangements in red blood cell homeostasis, liver function or kidney function. Immunization induced a transient systemic inflammatory response, including elevated white blood cell counts, mild fever, and a few incidences of elevated creatine kinase, receding to normal range by day 7 post vaccination. Optimal immunogenicity in Rhesus was observed using a 1 mL ALFQ + 20 µg FMP013 dose. Doubling the FMP013 antigen dose to 40 µg had no effect while halving the ALFQ adjuvant dose to 0.5 mL lowered immunogenicity. Similar to data generated in mice, FMP013 + ALFQ induced serum antibodies that reacted to all regions of the CSP molecule and a Th1-biased cytokine response in Rhesus. Rhesus antibody response to FMP013 + ALFQ was found to be non-inferior to historical benchmarks including that of RTS,S + AS01 in humans. A four-dose GLP toxicity study in rabbits confirmed no local site reactions and transient systemic inflammation associated with ALFQ adjuvant administration. These safety and immunogenicity data support the clinical progression and testing of FMP013 + ALFQ in a CHMI trial in the near future.
Start page
3793
End page
3803
Volume
37
Issue
29
Language
English
OCDE Knowledge area
Enfermedades infecciosas
Scopus EID
2-s2.0-85066121624
PubMed ID
Source
Vaccine
ISSN of the container
0264410X
Sponsor(s)
The funding for this work was provided by the USAID Malaria Vaccine Development Program and the Department of the Army. The work of ZB, CRA and GRM was supported through a Cooperative Agreement Award (no. W81XWH-07-2-067 ) between the Henry M. Jackson Foundation for the Advancement of Military Medicine and the U.S. Army Medical Research and Materiel Command (MRMC). The funding bodies had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. We thank COL Viseth Ngauy, WRAIR, for comments on the manuscript. We thank Lisa Dlugosz and Tanisha Robinson for Rhesus sample processing and data collection. We thank Dawn Wolf and Marcia Caputo for their diligent work with Rhesus handling and sample collection. We thank Lorraine Soisson and Carter Diggs, USAID, for their advice on trial design. Material has been reviewed by the Walter Reed Army Institute of Research and the US Agency for International Development. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the author, and are not to be construed as official, or as reflecting true views of the Department of the Army, the Department of Defense, or the US Agency for International Development. Research was conducted under an approved animal use protocol in an AAALACi accredited facility in compliance with the Animal Welfare Act and other federal statutes and regulations relating to animals and experiments involving animals and adheres to principles stated in the Guide for the Care and Use of Laboratory Animals, NRC Publication, 2011 edition. The funding for this work was provided by the USAID Malaria Vaccine Development Program and the Department of the Army. The work of ZB, CRA and GRM was supported through a Cooperative Agreement Award (no. W81XWH-07-2-067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine and the U.S. Army Medical Research and Materiel Command (MRMC). The funding bodies had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. SD and the US Army hold the patent on FMP013 antigen. SD, ZB and CA have filed for a patent on FMP013 + ALFQ formulation.
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