Recombinant Liver Stage Antigen-1 (LSA-1) formulated with AS01 or AS02 is safe, elicits high titer antibody and induces IFN-γ/IL-2 CD4+ T cells but does not protect against experimental Plasmodium falciparum infection

Cummings, James F.; Spring, Michele; Schwenk, Robert; Ockenhouse, Christian F.; Kester, Kent E.; Polhemus, Mark E.; Walsh, Douglas S.; Yoon, In-Kyu; Prosperi, Christine; Juompan, Laure; Lanar, David E.; Krzych, Urszula; Hall, Barry; Ware, Lisa A.; Stewart, V. Ann; Williams, Jack; Dowler, Megan; Nielsen, Robin; Hillier, Collette J.; Giersing, Birgitte; Dubovsky, Filip; Malkin, Elissa; Tucker, Kathryn; Dubois, Marie‐Claude; Cohen, Joe; Ballou, W. Ripley; Heppner, D. Gray

doi:10.1016/j.vaccine.2009.08.046

Cited by 83 publications

(59 citation statements)

References 33 publications

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“…Abs to P. falciparum antigens that we observed to correlate with protection from symptomatic malaria include both those considered previously as vaccine candidates (eg, MSP1, MSP2, LSA1, and LSA3) [25][26][27][28] and less studied proteins involved in erythrocyte invasion by merozoites (MSP10 and MSP7) [24,29] and trafficking of P. falciparum proteins from the parasite to the surface of the infected erythrocyte (PfEMP1, PF70, PHIST, and MSP7) [30][31][32][33][34][35].…”

Section: Discussionmentioning

confidence: 86%

Plasmodium falciparumProtein Microarray Antibody Profiles Correlate With Protection From Symptomatic Malaria in Kenya

Dent¹,

Nakajima²,

Liang³

et al. 2015

J Infect Dis.

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Background. Immunoglobulin G antibodies (Abs) to Plasmodium falciparum antigens have been associated with naturally acquired immunity to symptomatic malaria.Methods. We probed protein microarrays covering 824 unique P. falciparum protein features with plasma from residents of a community in Kenya monitored for 12 weeks for (re)infection and symptomatic malaria after administration of antimalarial drugs. P. falciparum proteins recognized by Abs from 88 children (aged 1-14 years) and 86 adults (aged ≥18 years), measured at the beginning of the observation period, were ranked by Ab signal intensity.Results. Abs from immune adults reacted with a total 163 of 824 P. falciparum proteins. Children gradually acquired Abs to the full repertoire of antigens recognized by adults. Abs to some antigens showed high seroconversion rates, reaching maximal levels early in childhood, whereas others did not reach adult levels until adolescence. No correlation between Ab signal intensity and time to (re)infection was observed. In contrast, Ab levels to 106 antigens were significantly higher in children who were protected from symptomatic malaria compared with those who were not. Abs to antigens predictive of protection included P. falciparum erythrocyte membrane protein 1, merozoite surface protein (MSP) 10, MSP2, liver-stage antigen 3, PF70, MSP7, and Plasmodium helical interspersed subtelomeric domain protein.Conclusions. Protein microarrays may be useful in the search for malaria antigens associated with protective immunity.

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Section: Discussionmentioning

confidence: 86%

Plasmodium falciparumProtein Microarray Antibody Profiles Correlate With Protection From Symptomatic Malaria in Kenya

Dent¹,

Nakajima²,

Liang³

et al. 2015

J Infect Dis.

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“…TRAP and LSA1 have also been evaluated in clinical trials. The viral-vectored ME-TRAP, a string of multiple PE antigen epitopes fused to the full-length TRAP antigen, demonstrated partial protection in efficacy trials (20,21), while an adjuvanted recombinant LSA1 vaccine (FMP-011) did not protect against P. falciparum challenge (22). However, the latter did not drive CD8 ϩ T cell responses.…”

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confidence: 99%

Inducing Humoral and Cellular Responses to Multiple Sporozoite and Liver-Stage Malaria Antigens Using Exogenous Plasmid DNA

et al. 2013

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A vaccine candidate that elicits humoral and cellular responses to multiple sporozoite and liver-stage antigens may be able to confer protection against Plasmodium falciparum malaria; however, a technology for formulating and delivering such a vaccine has remained elusive. Here, we report the preclinical assessment of an optimized DNA vaccine approach that targets four P. falciparum antigens: circumsporozoite protein (CSP), liver stage antigen 1 (LSA1), thrombospondin-related anonymous protein (TRAP), and cell-traversal protein for ookinetes and sporozoites (CelTOS). Synthetic DNA sequences were designed for each antigen with modifications to improve expression and were delivered using in vivo electroporation (EP). Immunogenicity was evaluated in mice and nonhuman primates (NHPs) and assessed by enzyme-linked immunosorbent assay (ELISA), gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assay, and flow cytometry. In mice, DNA with EP delivery induced antigen-specific IFN-γ production, as measured by ELISpot assay and IgG seroconversion against all antigens. Sustained production of IFN-γ, interleukin-2, and tumor necrosis factor alpha was elicited in both the CD4(+) and CD8(+) T cell compartments. Furthermore, hepatic CD8(+) lymphocytes produced LSA1-specific IFN-γ. The immune responses conferred to mice by this approach translated to the NHP model, which showed cellular responses by ELISpot assay and intracellular cytokine staining. Notably, antigen-specific CD8(+) granzyme B(+) T cells were observed in NHPs. Collectively, the data demonstrate that delivery of gene sequences by DNA/EP encoding malaria parasite antigens is immunogenic in animal models and can harness both the humoral and cellular arms of the immune system.

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“…It has been administered in different concentrations, together with the most potent adjuvants described to date: ASO1 or ASO2. Although clinically safe, this construct has elicited high antibody titres against the construct itself (as assessed by ELISA) and induced IF /IL-2 CD4+ T cells; however, it has NOT induced protection against experimental P. falciparum infection [182,183] suggesting, once more, that modified molecules must be used as vaccine components to ensure that protective immunity is effectively induced.…”

Section: Salsa (Genbank Accessionmentioning

confidence: 99%

Functional, Immunological and Three-Dimensional Analysis of Chemically Synthesised Sporozoite Peptides as Components of a Fully-Effective Antimalarial Vaccine

Curtidor¹,

Vanegas

Alba

et al. 2011

CMC

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Our ongoing search for a fully-effective vaccine against the Plasmodium falciparum parasite (causing the most lethal form of human malaria) has been focused on identifying and characterising proteins' amino acid sequences (high activity binding peptides or HABPs) involved in parasite invasion of red blood cells (RBC) by the merozoite and hepatocytes by the sporozoite. Many such merozoite HABPs have been recognised and molecularly and structurally characterised; however, native HABPs are immunologically silent since they do not induce any immune response or protection against P. falciparum malaria infection and they have to be structurally modified to allow them to fit perfectly into immune system molecules. A deeply structural analysis of these conserved merozoite HABPs and their modified analogues has led to rules or principles becoming recognised for constructing a logical and rational methodology for a minimal subunit-based, multi-epitope, multi-stage, chemically-synthesised vaccine. The same in-depth analysis of the most relevant sporozoite proteins involved in sporozoite cell-traversal and hepatocyte invasion as well as the hepatic stage is shown here. Specifically modifying these HABPs has resulted in a new set of potential pre-erythrocyte targets which are able to induce high, longlasting antibody titres in Aotus monkeys, against their corresponding recombinant proteins and the complete parasite native molecules. This review shows how these rules may be applied against the first stage of parasite invasion (i.e. the sporozoite) to mount the first line of defence against the malarial parasite, which may indeed be the most effective one. Our results strongly support including some of these modified sporozoite HABPs in combination with the previously-described modified merozoite HABPs for obtaining the aforementioned fully-protective, multiepitope, multi-stage, minimal subunit-based, chemically-synthesized, antimalarial vaccine.

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Recombinant Liver Stage Antigen-1 (LSA-1) formulated with AS01 or AS02 is safe, elicits high titer antibody and induces IFN-γ/IL-2 CD4+ T cells but does not protect against experimental Plasmodium falciparum infection

Cited by 83 publications

References 33 publications

Plasmodium falciparumProtein Microarray Antibody Profiles Correlate With Protection From Symptomatic Malaria in Kenya

Plasmodium falciparumProtein Microarray Antibody Profiles Correlate With Protection From Symptomatic Malaria in Kenya

Inducing Humoral and Cellular Responses to Multiple Sporozoite and Liver-Stage Malaria Antigens Using Exogenous Plasmid DNA

Functional, Immunological and Three-Dimensional Analysis of Chemically Synthesised Sporozoite Peptides as Components of a Fully-Effective Antimalarial Vaccine

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