title: Recombinant Liver Stage Antigen-1 (LSA-1) formulated with AS01 or AS02 is safe, elicits high titer antibody and induces IFN-gamma/IL-2 CD4+ T cells but does not protect against experimental Plasmodium falciparum infection.
abstract: Plasmodium falciparum Liver Stage Antigen 1 (LSA-1) is a pre-erythrocytic stage antigen. Our LSA-1 vaccine candidate is a recombinant protein with full-length C- and N-terminal flanking domains and two of the 17 amino acid repeats from the central repeat region termed "LSA-NRC." We describe the first Phase I/II study of this recombinant LSA-NRC protein formulated with either the AS01 or AS02 adjuvant system. We conducted an open-label Phase I/II study. Thirty-six healthy malaria-naïve adults received one of four formulations by intra-deltoid injection on a 0 and 1 month schedule; low dose (LD) LSA-NRC/AS01:10microg LSA-NRC/0.5ml AS01 (n=5), high dose (HD) LSA-NRC/AS01: 50microg LSA-NRC/0.5ml AS01 (n=13); LD LSA-NRC/AS02: 10microg LSA-NRC/0.5ml AS02 (n=5) and HD LSA-NRC/AS02: 50microg LSA-NRC/0.5ml AS02 (n=13). Two weeks post-second immunization, the high dose vaccinees and 6 non-immunized infectivity controls underwent experimental malaria sporozoite challenge. The vaccines showed a reassuring safety profile but were moderately reactogenic. There were no serious adverse events. All subjects seroconverted after the first immunization. Following the second immunization, LSA-1-specific CD4+ T cells producing two cytokines (IL-2 and IFN-gamma) were found by intra-cellular staining in all subjects in the LD LSA-NRC/AS01B group and in 3 of 5 subjects in the LD LSA-NRC/AS02 group. In contrast, the HD LSA-NRC/AS01 and HD LSA-NRC/AS02 group subjects had fewer LSA-1-specific CD4+ T cells, and minimal to no IFN-gamma responses. There was no increase in LSA-1-specific CD8+ T cells found in any group. Per protocol, 22 high dose vaccinees, but no low dose vaccinees, underwent P. falciparum homologous malaria challenge (3D7 clone). All vaccinees became parasitemic and there was no delay in their pre-patent period versus controls (p=0.95). LSA-NRC/AS01 and LSA-NRC/AS02 elicited antigen-specific antibody and CD4+ T cell responses, but elicited no protective immunity. Although the optimal antigen dose of LSA-NRC may not have been selected for the challenge portion of the protocol, further vaccine development based upon LSA-1 should not be excluded and should include alternative vaccine platforms able to elicit additional effector mechanisms such as CD8+ T cells.
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA. james.cummings@us.army.mil
authors.forename: James F
authors.initials: JF
authors.lastname: Cummings
authors.forename: Michele D
authors.initials: MD
authors.lastname: Spring
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schwenk
authors.forename: Christian F
authors.initials: CF
authors.lastname: Ockenhouse
authors.forename: Kent E
authors.initials: KE
authors.lastname: Kester
authors.forename: Mark E
authors.initials: ME
authors.lastname: Polhemus
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Walsh
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Yoon
authors.forename: Christine
authors.initials: C
authors.lastname: Prosperi
authors.forename: Laure Y
authors.initials: LY
authors.lastname: Juompan
authors.forename: David E
authors.initials: DE
authors.lastname: Lanar
authors.forename: Urszula
authors.initials: U
authors.lastname: Krzych
authors.forename: B Ted
authors.initials: BT
authors.lastname: Hall
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Ware
authors.forename: V Ann
authors.initials: VA
authors.lastname: Stewart
authors.forename: Jack
authors.initials: J
authors.lastname: Williams
authors.forename: Megan
authors.initials: M
authors.lastname: Dowler
authors.forename: Robin K
authors.initials: RK
authors.lastname: Nielsen
authors.forename: Collette J
authors.initials: CJ
authors.lastname: Hillier
authors.forename: Birgitte K
authors.initials: BK
authors.lastname: Giersing
authors.forename: Filip
authors.initials: F
authors.lastname: Dubovsky
authors.forename: Elissa
authors.initials: E
authors.lastname: Malkin
authors.forename: Kathryn
authors.initials: K
authors.lastname: Tucker
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Dubois
authors.forename: Joe D
authors.initials: JD
authors.lastname: Cohen
authors.forename: W Ripley
authors.initials: WR
authors.lastname: Ballou
authors.forename: D Gray
authors.initials: DG
authors.lastname: Heppner
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000328:Adult; D000913:Antibodies, Protozoan / Q000097:blood; D000917:Antibody Formation; D000953:Antigens, Protozoan / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D006801:Humans; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D007115:Immunization Schedule; D007117:Immunization, Secondary; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D016778:Malaria, Falciparum / Q000276:immunology / Q000517:prevention & control*; D008297:Male; D018512:Parasitemia / Q000276:immunology; D010963:Plasmodium falciparum / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology; D034101:Sporozoites / Q000276:immunology; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; C508594:IL2 protein, human; D007376:Interleukin-2; D017780:Malaria Vaccines; D011994:Recombinant Proteins; C067302:liver stage-specific antigen, Plasmodium; D007371:Interferon-gamma