Liposomes containing monophosphoryl lipid A and QS-21 serve as an effective adjuvant for soluble circumsporozoite protein malaria vaccine FMP013

Christopher J Genito; Zoltan Beck; Timothy W Phares; Fanta Kalle; Keith J Limbach; Maureen E Stefaniak; Noelle B Patterson; Elke S Bergmann-Leitner; Norman C Waters; Gary R Matyas; Carl R Alving; Sheetij Dutta

doi:10.1016/j.vaccine.2017.05.070

Liposomes containing monophosphoryl lipid A and QS-21 serve as an effective adjuvant for soluble circumsporozoite protein malaria vaccine FMP013

Vaccine. 2017 Jul 5;35(31):3865-3874. doi: 10.1016/j.vaccine.2017.05.070. Epub 2017 Jun 7.

Affiliations

¹ Laboratory of Structural Vaccinology, Malaria Vaccine Branch, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA.
² Laboratory of Adjuvant and Antigen Research, US Military HIV Research Program, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA.
³ Malaria Department, Naval Medical Research Center, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., 6720A Rockledge Drive, Suite 100, Bethesda, MD 20817, USA.
⁴ Flow Cytometry Center, Malaria Vaccine Branch, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA.
⁵ Malaria Vaccine Branch, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA.
⁶ Laboratory of Structural Vaccinology, Malaria Vaccine Branch, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA. Electronic address: sheetij.dutta.civ@mail.mil.

PMID: 28596090
DOI: 10.1016/j.vaccine.2017.05.070

Abstract

Malaria caused by Plasmodium falciparum continues to threaten millions of people living in the tropical parts of the world. A vaccine that confers sterile and life-long protection remains elusive despite more than 30years of effort and resources invested in solving this problem. Antibodies to a malaria vaccine candidate circumsporozoite protein (CSP) can block invasion and can protect humans against malaria. We have manufactured the Falciparum Malaria Protein-013 (FMP013) vaccine based on the nearly full-length P. falciparum CSP 3D7 strain sequence. We report here immunogenicity and challenge data on FMP013 antigen in C57BL/6 mice formulated with two novel adjuvants of the Army Liposome Formulation (ALF) series and a commercially available adjuvant Montanide ISA 720 (Montanide) as a control. ALF is a liposomal adjuvant containing a synthetic monophosphoryl lipid A (3D-PHAD®). In our study, FMP013 was adjuvanted with ALF alone, ALF containing aluminum hydroxide (ALFA) or ALF containing QS-21 (ALFQ). Adjuvants ALF and ALFA induced similar antibody titers and protection against transgenic parasite challenge that were comparable to Montanide. ALFQ was superior to the other three adjuvants as it induced higher antibody titers with improved boosting after the third immunization, higher serum IgG2c titers, and enhanced protection. FMP013+ALFQ also augmented the numbers of splenic germinal center-derived activated B-cells and antibody secreting cells compared to Montanide. Further, FMP013+ALFQ induced antigen-specific IFN-γ ELISPOT activity, CD4⁺ T-cells and a T_H1-biased cytokine profile. These results demonstrate that soluble CSP can induce a potent and sterile protective immune response when formulated with the QS-21 containing adjuvant ALFQ. Comparative mouse immunogenicity data presented here were used as the progression criteria for an ongoing non-human primate study and a regulatory toxicology study in preparation for a controlled human malaria infection (CHMI) trial.

Keywords: ALFQ; Adjuvant; Circumsporozoite protein; FMP013; Liposomes; Malaria; Monophosphoryl lipid A; Plasmodium falciparum; QS-21; Vaccine.

Published by Elsevier Ltd.

MeSH terms

Adjuvants, Immunologic / administration & dosage*
Animals
Antibodies, Protozoan / blood
B-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / immunology
Disease Models, Animal
Enzyme-Linked Immunospot Assay
Female
Interferon-gamma / metabolism
Lipid A / administration & dosage
Lipid A / analogs & derivatives*
Liposomes / administration & dosage*
Malaria Vaccines / administration & dosage
Malaria Vaccines / immunology*
Malaria, Falciparum / prevention & control*
Mice, Inbred C57BL
Protozoan Proteins / immunology*
Saponins / administration & dosage*

Substances

Adjuvants, Immunologic
Antibodies, Protozoan
Lipid A
Liposomes
Malaria Vaccines
Protozoan Proteins
Saponins
circumsporozoite protein, Protozoan
saponin QA-21V1
Interferon-gamma
monophosphoryl lipid A