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C A Long - One of the best experts on this subject based on the ideXlab platform.

  • immunogenicity of a chimeric plasmodium falciparum Merozoite Surface Protein vaccine in aotus monkeys
    Malaria Journal, 2016
    Co-Authors: James M Burns, C A Long, Kazutoyo Miura, Joann S Sullivan, John W Barnwell
    Abstract:

    Background The production of properly folded, recombinant sub-unit Plasmodium falciparum malaria vaccine candidates in sufficient quantities is often a challenge. Success in vaccine immunogenicity studies in small animal models does not always predict immunogenicity in non-human primates and/or human subjects. The aim of this study was to assess the immunogenicity of a chimeric blood-stage malaria vaccine in Aotus monkeys. This vaccine candidate includes the neutralizing B cell epitopes of P. falciparum Merozoite Surface Protein 1 (rPfMSP119) genetically linked to a highly immunogenic, well-conserved P. falciparum Merozoite Surface Protein 8 (rPfMSP8 (ΔAsn/Asp)) partner.

  • a chimeric plasmodium falciparum Merozoite Surface Protein vaccine induces high titers of parasite growth inhibitory antibodies
    Infection and Immunity, 2013
    Co-Authors: C A Long, James R Alaro, Andrea T Partridge, Kazutoyo Miura, Ababacar Diouf, Ana M Lopez, Evelina Angov, James M Burns
    Abstract:

    The C-terminal 19-kDa domain of Plasmodium falciparum Merozoite Surface Protein 1 (PfMSP119) is an established target of protective antibodies. However, clinical trials of PfMSP142, a leading blood-stage vaccine candidate which contains the protective epitopes of PfMSP119, revealed suboptimal immunogenicity and efficacy. Based on proof-of-concept studies in the Plasmodium yoelii murine model, we produced a chimeric vaccine antigen containing recombinant PfMSP119 (rPfMSP119) fused to the N terminus of P. falciparum Merozoite Surface Protein 8 that lacked its low-complexity Asn/Asp-rich domain, rPfMSP8 (ΔAsn/Asp). Immunization of mice with the chimeric rPfMSP1/8 vaccine elicited strong T cell responses to conserved epitopes associated with the rPfMSP8 (ΔAsn/Asp) fusion partner. While specific for PfMSP8, this T cell response was adequate to provide help for the production of high titers of antibodies to both PfMSP119 and rPfMSP8 (ΔAsn/Asp) components. This occurred with formulations adjuvanted with either Quil A or with Montanide ISA 720 plus CpG oligodeoxynucleotide (ODN) and was observed in both inbred and outbred strains of mice. PfMSP1/8-induced antibodies were highly reactive with two major alleles of PfMSP119 (FVO and 3D7). Of particular interest, immunization with PfMSP1/8 elicited higher titers of PfMSP119-specific antibodies than a combined formulation of rPfMSP142 and rPfMSP8 (ΔAsn/Asp). As a measure of functionality, PfMSP1/8-specific rabbit IgG was shown to potently inhibit the in vitro growth of blood-stage parasites of the FVO and 3D7 strains of P. falciparum. These data support the further testing and evaluation of this chimeric PfMSP1/8 antigen as a component of a multivalent vaccine for P. falciparum malaria.

  • humoral and cellular immunity to plasmodium falciparum Merozoite Surface Protein 1 and protection from infection with blood stage parasites
    The Journal of Infectious Diseases, 2013
    Co-Authors: Ann M Moormann, Peter Odada Sumba, Kiprotich Chelimo, Hua Fang, Daniel J Tisch, Arlene E Dent, Chandy C John, C A Long
    Abstract:

    Background. Acquired immunity to malaria develops with increasing age and repeated infections. Understanding immune correlates of protection from malaria would facilitate vaccine development and identification of biomarkers that reflect changes in susceptibility resulting from ongoing malaria control efforts. Methods. The relationship between immunoglobulin G (IgG) antibody and both interferon γ (IFN-γ) and interleukin 10 (IL-10) responses to the 42-kD C-terminal fragment of Plasmodium falciparum Merozoite Surface Protein 1 (MSP142) and the risk of (re)infection were examined following drug-mediated clearance of parasitemia in 94 adults and 95 children in an area of holoendemicity of western Kenya. Results. Positive IFN-γ enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunosorbent spot assay (ELISPOT) responses to MSP142 3D7 were associated with delayed time to (re)infection, whereas high-titer IgG antibodies to MSP142 3D7 or FVO alleles were not independently predictive of the risk of (re)infection. When IFN-γ and IL-10 responses were both present, the protective effect of IFN-γ was abrogated. A Cox proportional hazard model including IFN-γ, IL-10, MSP142 3D7 IgG antibody responses, hemoglobin S genotype, age, and infection status at baseline showed that the time to blood-stage infection correlated positively with IFN-γ responses and negatively with IL-10 responses, younger age, and asymptomatic parasitemia. Conclusions. Evaluating combined allele-specific cellular and humoral immunity elicited by malaria provides a more informative measure of protection relative to evaluation of either measure alone.

  • evaluation of the immunogenicity and vaccine potential of recombinant plasmodium falciparum Merozoite Surface Protein 8
    Infection and Immunity, 2012
    Co-Authors: James R Alaro, C A Long, Evelina Angov, Ana Lopez, Hong Zhou, James M Burns
    Abstract:

    The C-terminal 19-kDa domain of Merozoite Surface Protein 1 (MSP119) is the target of protective antibodies but alone is poorly immunogenic. Previously, using the Plasmodium yoelii murine model, we fused P. yoelii MSP119 (PyMSP119) with full-length P. yoelii Merozoite Surface Protein 8 (MSP8). Upon immunization, the MSP8-restricted T cell response provided help for the production of high and sustained levels of protective PyMSP119- and PyMSP8-specific antibodies. Here, we assessed the vaccine potential of MSP8 of the human malaria parasite, Plasmodium falciparum. Distinct from PyMSP8, P. falciparum MSP8 (PfMSP8) contains an N-terminal asparagine and aspartic acid (Asn/Asp)-rich domain whose function is unknown. Comparative analysis of recombinant full-length PfMSP8 and a truncated version devoid of the Asn/Asp-rich domain, PfMSP8(ΔAsn/Asp), showed that both Proteins were immunogenic for T cells and B cells. All T cell epitopes utilized mapped within rPfMSP8(ΔAsn/Asp). The dominant B cell epitopes were conformational and common to both rPfMSP8 and rPfMSP8(ΔAsn/Asp). Analysis of native PfMSP8 expression revealed that PfMSP8 is present intracellularly in late schizonts and Merozoites. Following invasion, PfMSP8 is found distributed on the Surface of ring- and trophozoite-stage parasites. Consistent with a low and/or transient expression of PfMSP8 on the Surface of Merozoites, PfMSP8-specific rabbit IgG did not inhibit the in vitro growth of P. falciparum blood-stage parasites. These studies suggest that the further development of PfMSP8 as a malaria vaccine component should focus on the use of PfMSP8(ΔAsn/Asp) and its conserved, immunogenic T cell epitopes as a fusion partner for protective domains of poor immunogens, including PfMSP119.

  • age related differences in naturally acquired t cell memory to plasmodium falciparum Merozoite Surface Protein 1
    PLOS ONE, 2011
    Co-Authors: C A Long, Ann M Moormann, Peter Odada Sumba, Kiprotich Chelimo, Paula B Embury, John M Vulule, Ayub V Ofulla, James W Kazura
    Abstract:

    Naturally acquired immunity to Plasmodium falciparum malaria in malaria holoendemic areas is characterized by the gradual, age-related development of protection against high-density parasitemia and clinical malaria. Animal studies, and less commonly, observations of humans with malaria, suggest that T-cell responses are important in the development and maintenance of this immunity, which is mediated primarily by antibodies that slow repeated cycles of Merozoites through erythrocytes. To advance our rather limited knowledge on human T-cell immunity to blood stage malaria infection, we evaluated CD4 and CD8 T-cell effector memory subset responses to the 42 kDa C-terminal fragment of Merozoite Surface Protein 1 (MSP142), a malaria vaccine candidate, by 49 healthy 0.5 to $18 year old residents of a holoendemic area in western Kenya. The proportion of individuals with peripheral blood mononuclear cell MSP142 driven IFN-c ELISPOT responses increased from 20% (2/20) among 0.5–1 year old children to 90% (9/10) of adults $18 years (P = 0.01); parallel increases in the magnitude of IFN-c responses were observed across all age groups (0.5, 1, 2, 5 and $18 years, P = 0.001). Less than 1% of total CD4 and CD8 T-cells from both children and adults produced IFN-c in response to MSP142. However, adults had higher proportions of MSP142 driven IFN-c secreting CD4 and CD8 effector memory (CD45RA 2 CD62L 2 ) T-cells than children (CD4: 50.9% vs. 28.8%, P = 0.036; CD8: 52.1% vs. 18.3%, respectively P = 0.009). In contrast, MSP142 driven IFN-c secreting nao ¨ve-like, transitional (CD45RA + CD62L + ) CD4 and CD8 cells were the predominant T-cell subset among children with significantly fewer of these cells in adults (CD4: 34.9% vs. 5.1%, P = 0.002; CD8: 47.0% vs. 20.5%, respectively, P = 0.030). These data support the concept that meaningful age-related differences exist in the quality of T-cell immunity to malaria antigens such as MSP1.

Anthony A Holder - One of the best experts on this subject based on the ideXlab platform.

  • the carboxy terminus of Merozoite Surface Protein 1 structure specific antibodies and immunity to malaria
    Parasitology, 2009
    Co-Authors: Anthony A Holder
    Abstract:

    Over the last 30 years, evidence has been gathered suggesting that Merozoite Surface Protein 1 (MSP1) is a target of protective immunity against malaria. In a variety of experimental approaches using in vitro methodology, animal models and sero-epidemiological techniques, the importance of antibody against MSP1 has been established but we are still finding out what are the mechanisms involved. Now that clinical trials of MSP1 vaccines are underway and the early results have been disappointing, it is increasingly clear that we need to know more about the mechanisms of immunity, because a better understanding will highlight the limitations of our current assays and identify the improvements required. Understanding the structure of MSP1 will help us design and engineer better antigens that are more effective than the first generation of vaccine candidates. This review is focused on the carboxy-terminus of MSP1.

  • the fine specificity but not the invasion inhibitory activity of 19 kilodalton Merozoite Surface Protein 1 specific antibodies is associated with resistance to malarial parasitemia in a cross sectional survey in the gambia
    Infection and Immunity, 2004
    Co-Authors: Rebecca A Odonnell, Brendan S. Crabb, Patrick H Corran, Jim Todd, Chairat Uthaipibull, Anthony A Holder, Eleanor M Riley
    Abstract:

    ABSTRACT In a cross-sectional survey of 187 Gambian children and adults, we have analyzed prevalence, fine specificity, and 19-kilodalton Merozoite Surface Protein 1 (MSP-119)-specific erythrocyte invasion inhibitory activity of antibodies to MSP-119 but find no significant association between any of these parameters and prevalence or density of malarial parasitemia, except that, after correcting for total anti-MSP-119 antibody levels, individuals with anti-MSP-119 antibodies that compete with an invasion inhibitory monoclonal antibody (12.10) were significantly less likely to have malaria infections with densities of ≥1,000 parasites/μl than were individuals without such antibodies. This association persisted after correction for age and ethnic origin.

  • fine specificity of serum antibodies to plasmodium falciparum Merozoite Surface Protein pfmsp 119 predicts protection from malaria infection and high density parasitemia
    Infection and Immunity, 2004
    Co-Authors: Brenda A Okech, Patrick H Corran, Jim Todd, Chairat Uthaipibull, Anthony A Holder, Amy Joynsonhicks, Thomas G Egwang, Eleanor M Riley
    Abstract:

    Antibodies to the C terminus of the Plasmodium falciparum Merozoite Surface Protein, PfMSP-1(19), may inhibit Merozoite invasion or block the effects of inhibitory antibodies. Here, using a competition enzyme-linked immunosorbent assay and antibody binding to wild-type and mutated recombinant Proteins, we show that there are marked variations between individuals in the fine specificity of naturally acquired anti-MSP-1(19) antibodies. Furthermore, although neither the prevalence nor the concentration of total anti-MSP-1(19) antibodies was associated with resistance to malaria in African children, significant associations were observed between antibody fine specificity and subsequent risk of infection and high-density parasitemia during a follow-up period. Thus, the fine specificity of naturally acquired human anti-MSP-1(19) antibodies is crucial in determining their function. Future field studies, including the evaluation of PfMSP-1 vaccine trials, should include assays that explore antibody fine specificity as well as titer.

  • fine specificity of serum antibodies to plasmodium falciparum Merozoite Surface Protein pfmsp 1 19 predicts protection from malaria infection and high density parasitemia
    Infection and Immunity, 2004
    Co-Authors: Brenda A Okech, Patrick H Corran, Jim Todd, Chairat Uthaipibull, Anthony A Holder, Amy Joynsonhicks, Thomas G Egwang, Eleanor M Riley
    Abstract:

    Antibodies to the C terminus of the Plasmodium falciparum Merozoite Surface Protein, PfMSP-1(19), may inhibit Merozoite invasion or block the effects of inhibitory antibodies. Here, using a competition enzyme-linked immunosorbent assay and antibody binding to wild-type and mutated recombinant Proteins, we show that there are marked variations between individuals in the fine specificity of naturally acquired anti-MSP-1(19) antibodies. Furthermore, although neither the prevalence nor the concentration of total anti-MSP-1(19) antibodies was associated with resistance to malaria in African children, significant associations were observed between antibody fine specificity and subsequent risk of infection and high-density parasitemia during a follow-up period. Thus, the fine specificity of naturally acquired human anti-MSP-1(19) antibodies is crucial in determining their function. Future field studies, including the evaluation of PfMSP-1 vaccine trials, should include assays that explore antibody fine specificity as well as titer.

  • disulfide bonds in Merozoite Surface Protein 1 of the malaria parasite impede efficient antigen processing and affect the in vivo antibody response
    European Journal of Immunology, 2004
    Co-Authors: Meike Hensmann, Anthony A Holder, Solabomi A Ogun, Catherine X Moss, Viv Lindo, Fiona M Greer, Colin Watts, Jean Langhorne
    Abstract:

    The 19 kDa C-terminal fragment of the malaria parasite Merozoite Surface Protein 1 (MSP119) is a leading malaria vaccine candidate. In rodents, high antibody levels to this Protein confer protective immunity, and can be generated by immunization with the antigen in adjuvants. In natural human infections, however, MSP119-specific antibody responses can be short-lived andcomparatively low, despite repeated exposure to infection. The tightly folded structure of MSP119 is stabilized by five or six disulfide bonds. These bonds impede antigen processing and, thereby, may affect the generation of CD4+ T cells providing help for B cells. Asparagine endopeptidase could digest unfolded, but not native MSP119in vitro. Immunization with unfolded MSP119 resulted in a faster antibody response, and a combination of unfolded and native MSP119 increased antibody responses to the native form. Immunization with either form of the antigen activated similar numbers of CD4+ T cells, but, unlike the antibody response, CD4+ T cells immunized with one form of MSP119 were able to respond in vitro to the other form of the Protein. Although the reduced form of MSP119 does not induce protective antibodies, our data suggest that inclusion of unfolded Protein may improve the efficacy of MSP119 as a vaccine. See correction http://dx.doi.org/10.1002/eji.200490004

James M Burns - One of the best experts on this subject based on the ideXlab platform.

  • immunogenicity of a chimeric plasmodium falciparum Merozoite Surface Protein vaccine in aotus monkeys
    Malaria Journal, 2016
    Co-Authors: James M Burns, C A Long, Kazutoyo Miura, Joann S Sullivan, John W Barnwell
    Abstract:

    Background The production of properly folded, recombinant sub-unit Plasmodium falciparum malaria vaccine candidates in sufficient quantities is often a challenge. Success in vaccine immunogenicity studies in small animal models does not always predict immunogenicity in non-human primates and/or human subjects. The aim of this study was to assess the immunogenicity of a chimeric blood-stage malaria vaccine in Aotus monkeys. This vaccine candidate includes the neutralizing B cell epitopes of P. falciparum Merozoite Surface Protein 1 (rPfMSP119) genetically linked to a highly immunogenic, well-conserved P. falciparum Merozoite Surface Protein 8 (rPfMSP8 (ΔAsn/Asp)) partner.

  • a chimeric plasmodium falciparum Merozoite Surface Protein vaccine induces high titers of parasite growth inhibitory antibodies
    Infection and Immunity, 2013
    Co-Authors: C A Long, James R Alaro, Andrea T Partridge, Kazutoyo Miura, Ababacar Diouf, Ana M Lopez, Evelina Angov, James M Burns
    Abstract:

    The C-terminal 19-kDa domain of Plasmodium falciparum Merozoite Surface Protein 1 (PfMSP119) is an established target of protective antibodies. However, clinical trials of PfMSP142, a leading blood-stage vaccine candidate which contains the protective epitopes of PfMSP119, revealed suboptimal immunogenicity and efficacy. Based on proof-of-concept studies in the Plasmodium yoelii murine model, we produced a chimeric vaccine antigen containing recombinant PfMSP119 (rPfMSP119) fused to the N terminus of P. falciparum Merozoite Surface Protein 8 that lacked its low-complexity Asn/Asp-rich domain, rPfMSP8 (ΔAsn/Asp). Immunization of mice with the chimeric rPfMSP1/8 vaccine elicited strong T cell responses to conserved epitopes associated with the rPfMSP8 (ΔAsn/Asp) fusion partner. While specific for PfMSP8, this T cell response was adequate to provide help for the production of high titers of antibodies to both PfMSP119 and rPfMSP8 (ΔAsn/Asp) components. This occurred with formulations adjuvanted with either Quil A or with Montanide ISA 720 plus CpG oligodeoxynucleotide (ODN) and was observed in both inbred and outbred strains of mice. PfMSP1/8-induced antibodies were highly reactive with two major alleles of PfMSP119 (FVO and 3D7). Of particular interest, immunization with PfMSP1/8 elicited higher titers of PfMSP119-specific antibodies than a combined formulation of rPfMSP142 and rPfMSP8 (ΔAsn/Asp). As a measure of functionality, PfMSP1/8-specific rabbit IgG was shown to potently inhibit the in vitro growth of blood-stage parasites of the FVO and 3D7 strains of P. falciparum. These data support the further testing and evaluation of this chimeric PfMSP1/8 antigen as a component of a multivalent vaccine for P. falciparum malaria.

  • evaluation of the immunogenicity and vaccine potential of recombinant plasmodium falciparum Merozoite Surface Protein 8
    Infection and Immunity, 2012
    Co-Authors: James R Alaro, C A Long, Evelina Angov, Ana Lopez, Hong Zhou, James M Burns
    Abstract:

    The C-terminal 19-kDa domain of Merozoite Surface Protein 1 (MSP119) is the target of protective antibodies but alone is poorly immunogenic. Previously, using the Plasmodium yoelii murine model, we fused P. yoelii MSP119 (PyMSP119) with full-length P. yoelii Merozoite Surface Protein 8 (MSP8). Upon immunization, the MSP8-restricted T cell response provided help for the production of high and sustained levels of protective PyMSP119- and PyMSP8-specific antibodies. Here, we assessed the vaccine potential of MSP8 of the human malaria parasite, Plasmodium falciparum. Distinct from PyMSP8, P. falciparum MSP8 (PfMSP8) contains an N-terminal asparagine and aspartic acid (Asn/Asp)-rich domain whose function is unknown. Comparative analysis of recombinant full-length PfMSP8 and a truncated version devoid of the Asn/Asp-rich domain, PfMSP8(ΔAsn/Asp), showed that both Proteins were immunogenic for T cells and B cells. All T cell epitopes utilized mapped within rPfMSP8(ΔAsn/Asp). The dominant B cell epitopes were conformational and common to both rPfMSP8 and rPfMSP8(ΔAsn/Asp). Analysis of native PfMSP8 expression revealed that PfMSP8 is present intracellularly in late schizonts and Merozoites. Following invasion, PfMSP8 is found distributed on the Surface of ring- and trophozoite-stage parasites. Consistent with a low and/or transient expression of PfMSP8 on the Surface of Merozoites, PfMSP8-specific rabbit IgG did not inhibit the in vitro growth of P. falciparum blood-stage parasites. These studies suggest that the further development of PfMSP8 as a malaria vaccine component should focus on the use of PfMSP8(ΔAsn/Asp) and its conserved, immunogenic T cell epitopes as a fusion partner for protective domains of poor immunogens, including PfMSP119.

  • immunization against plasmodium chabaudi malaria using combined formulations of apical membrane antigen 1 and Merozoite Surface Protein 1
    Vaccine, 2003
    Co-Authors: James M Burns, William P Weidanz, Patrick R Flaherty, Margarita Romero
    Abstract:

    Abstract The control of Plasmodium falciparum malaria by vaccination will require immunization with multiple parasite antigens effectively formulated in combination. In this regard, Proteins expressed on the Surface of blood-stage Merozoites are attractive as vaccine targets given their functional importance in the invasion of erythrocytes and accessibility to serum antibodies. We have utilized a Plasmodium chabaudi vaccine model to begin to evaluate the efficacy of immunization with combined formulations of apical membrane antigen-1 (AMA-1) and Merozoite Surface Protein-1 (MSP-1). Using a pET/T7 RNA polymerase bacterial expression system, we have expressed, purified and refolded recombinant antigens representing the 54 kDa ectodomain of Pc AMA-1 and the 42 kDa C-terminus of Pc MSP-1. Immunization with recombinant Pc AMA-1+ Pc MSP-1 42 induced a high level of protection against P. chabaudi malaria with protective efficacy varying with antigen dose, choice of adjuvant, and immunization protocol. Based on the reduction of P. chabaudi parasitemia, Alum proved effective for use with the combination of Pc AMA-1 and Pc MSP-1 42 . The use of Quil A was similarly effective with single or combined antigen immunizations, particularly with low antigen dose. In general, serological analysis of prechallenge sera indicated a dominant IgG1 response. For a given formulation, immunization with the combination of Pc AMA-1 and Pc MSP-1 42 elicited IgG responses comparable to those observed following immunization with each antigen alone. However, prechallenge antibody titers alone were not predictive of protective efficacy. While Pc AMA-1 and Pc MSP-1 42 can be effectively formulated in combination, further study is needed to define measurable parameters of protective T cell and B cell responses induced by Pc AMA-1+ Pc MSP-1 42 that are predictive of vaccine efficacy.

Michael J Blackman - One of the best experts on this subject based on the ideXlab platform.

  • suramin and suramin analogues inhibit Merozoite Surface Protein 1 secondary processing and erythrocyte invasion by the malaria parasite plasmodium falciparum
    Journal of Biological Chemistry, 2003
    Co-Authors: S L Fleck, Evelina Angov, Stephen R Martin, William D Morgan, B Birdsall, J Feeney, Jeffrey J Babon, Anton R Dluzewski, Catherine A Kettleborough, Michael J Blackman
    Abstract:

    Malarial Merozoites invade erythrocytes; and as an essential step in this invasion process, the 42-kDa fragment of Plasmodium falciparum Merozoite Surface Protein-1 (MSP142) is further cleaved to a 33-kDa N-terminal polypeptide (MSP133) and an 19-kDa C-terminal fragment (MSP119) in a secondary processing step. Suramin was shown to inhibit both Merozoite invasion and MSP142 proteolytic cleavage. This polysulfonated naphthylurea bound directly to recombinant P. falciparum MSP142 (Kd = 0.2 microM) and to Plasmodium vivax MSP142 (Kd = 0.3 microM) as measured by fluorescence enhancement in the presence of the Protein and by isothermal titration calorimetry. Suramin bound only slightly less tightly to the P. vivax MSP133 (Kd = 1.5 microM) secondary processing product (fluorescence measurements), but very weakly to MSP119 (Kd approximately 15 mM) (NMR measurements). Several residues in MSP119 were implicated in the interaction with suramin using NMR measurements. A series of symmetrical suramin analogues that differ in the number of aromatic rings and substitution patterns of the terminal naphthylamine groups was examined in invasion and processing assays. Two classes of analogue with either two or four bridging rings were found to be active in both assays, whereas two other classes without bridging rings were inactive. We propose that suramin and related compounds inhibit erythrocyte invasion by binding to MSP1 and by preventing its cleavage by the secondary processing protease. The results indicate that enzymatic events during invasion are suitable targets for drug development and validate the novel concept of an inhibitor binding to a macromolecular substrate to prevent its proteolysis by a protease.

  • vaccine efficacy of recombinant plasmodium falciparum Merozoite Surface Protein 1 in malaria naive exposed and or rechallenged aotus vociferans monkeys
    Infection and Immunity, 2000
    Co-Authors: Andrea Egan, Michael J Blackman, David C. Kaslow
    Abstract:

    Protection against a lethal challenge infection of Plasmodium falciparum was elicited in malaria-naive Aotus vociferans monkeys by vaccination with the C terminus 19-kDa Protein of the major Merozoite Surface Protein (MSP-119) fused to tetanus toxoid universal T-cell epitopes P30 and P2. Three of four monkeys were protected against a 104-parasite challenge. Four monkeys were challenged with 105 parasites; one self-cured the infection, two were protected against high parasitemia (<2%) but were treated for severe anemia (hematocrit of <25%), and the fourth was not protected. In this model system, anemia appears to be a manifestation of incomplete protection (prolonged low-level parasitemia). Enzyme-linked immunosorbent assay (ELISA) antibody titers correlated with protection. Antibodies from some protected monkeys inhibited secondary processing of MSP-142 to MSP-133 and MSP-119. To mimic the repeated reinfections seen in regions where malaria is endemic, a second malaria parasite challenge was administered 4 months later. All P30P2MSP-119-vaccinated monkeys were protected; thus, a single challenge infection may underestimate vaccine efficacy. ELISA antibody titers correlated with protection against a second infection but had decreased compared to the first challenge. As most target populations for asexual blood-stage malaria vaccines will have been exposed to malaria parasites, a malaria parasite-exposed monkey was vaccinated with P30P2MSP-119. This monkey was completely protected, while a malaria parasite-naive P30P2MSP-119-vaccinated monkey self-cured a low-grade parasitemia. Prior malaria parasite infection primed the production of anti-native MSP-119 antibodies, which were boosted by vaccination with recombinant P30P2MSP-119. Preliminary data suggest that immunogenicity studies of vaccines designed for malaria parasite-exposed populations should also be conducted in malaria parasite-exposed subjects.

  • antibodies that inhibit malaria Merozoite Surface Protein 1 processing and erythrocyte invasion are blocked by naturally acquired human antibodies
    Journal of Experimental Medicine, 1997
    Co-Authors: Jose Guevara A Patino, Jana S Mcbride, Anthony A Holder, Michael J Blackman
    Abstract:

    Merozoite Surface Protein–1 (MSP-1) of the human malaria parasite Plasmodium falciparum undergoes at least two endoproteolytic cleavage events during Merozoite maturation and release, and erythrocyte invasion. We have previously demonstrated that mAbs which inhibit erythrocyte invasion and are specific for epitopes within a membrane-proximal, COOH-terminal domain of MSP-1 (MSP-119) prevent the critical secondary processing step which occurs on the Surface of the extracellular Merozoite at around the time of erythrocyte invasion. Certain other anti–MSP-119 mAbs, which themselves inhibit neither erythrocyte invasion nor MSP-1 secondary processing, block the processing-inhibitory activity of the first group of antibodies and are termed blocking antibodies. We have now directly quantitated antibody-mediated inhibition of MSP-1 secondary processing and invasion, and the effects on this of blocking antibodies. We show that blocking antibodies function by competing with the binding of processing-inhibitory antibodies to their epitopes on the Merozoite. Polyclonal rabbit antibodies specific for certain MSP-1 sequences outside of MSP-119 also act as blocking antibodies. Most significantly, affinity-purified, naturally acquired human antibodies specific for epitopes within the NH2-terminal 83-kD domain of MSP-1 very effectively block the processing-inhibitory activity of the anti-MSP-119 mAb 12.8. The presence of these blocking antibodies also completely abrogates the inhibitory effect of mAb 12.8 on erythrocyte invasion by the parasite in vitro. Blocking antibodies therefore (a) are part of the human response to malarial infection; (b) can be induced by MSP-1 structures unrelated to the MSP-119 target of processing-inhibitory antibodies; and (c) have the potential to abolish protection mediated by anti–MSP-119 antibodies. Our results suggest that an effective MSP-119–based falciparum malaria vaccine should aim to induce an antibody response that prevents MSP-1 processing on the Merozoite Surface.

  • antibodies inhibit the protease mediated processing of a malaria Merozoite Surface Protein
    Journal of Experimental Medicine, 1994
    Co-Authors: Michael J Blackman, Terry J Scottfinnigan, Shafrira Shai
    Abstract:

    When Merozoites of the malaria parasite Plasmodium falciparum are released from infected erythrocytes and invade new red cells, a component of a Protein complex derived from the Merozoite Surface Protein 1 (MSP-1) precursor undergoes a single proteolytic cleavage known as secondary processing. This releases the complex from the parasite Surface, except for a small membrane-bound fragment consisting of two epidermal growth factor (EGF)-like domains, which is the only part of MSP-1 to be carried into invaded erythrocytes. We report that, a group of monoclonal antibodies specific for epitopes within the EGF-like domains, some interfere with secondary processing whereas others do not. Those that most effectively inhibit processing have previously been shown to prevent invasion. Other antibodies, some of which can block this inhibition, not only do not prevent invasion but are carried into the host cell bound to the Merozoite Surface. These observations unequivocally demonstrate that the binding of antibody to the COOH-terminal region of MSP-1 on the Merozoite Surface may not be sufficient to prevent erythrocyte invasion, and show that the interaction of different antibodies with adjacent epitopes within the EGF-like domains of MSP-1 can have distinct biochemical effects on the molecule. Inhibition of MSP-1 processing on Merozoites may be a mechanism by which protective antibodies interrupt the asexual cycle of the malaria parasite.

  • chapter 11 purification of plasmodium falciparum Merozoites for analysis of the processing of Merozoite Surface Protein 1
    Methods in Cell Biology, 1994
    Co-Authors: Michael J Blackman
    Abstract:

    Publisher Summary This chapter describes the preparation of highly purified Merozoites of Plasmodium falciparum and the use of the isolated cells to study the proteolytic processing of a particularly well characterized Merozoite Surface Protein. Acrylic membrane sieves are used to deplete culture supernatants, containing naturally released Merozoites, of parasitized and uninfected erythrocytes. Merozoites are then recovered from the filtered medium by centrifugation. The method is simple, rapid, and efficient and yields Merozoite preparations completely free of erythrocyte contamination, although some contamination with hemozoin pigment is evident. Merozoites prepared in this way have been used for Surface radioiodination studies exploring the composition of the Merozoite Surface and the interactions between Proteins on it. They have also been used to demonstrate the presence of sphingomyelin synthase in the plasma membrane of extracellular Merozoites and to investigate and characterize proteolytic processing of the Merozoite Surface Protein-1 (MSP-I). All these studies have indicated that Merozoites produced using this method are morphologically intact at the level of light and electron microscopy and structurally intact at the molecular level.

Eleanor M Riley - One of the best experts on this subject based on the ideXlab platform.

  • the fine specificity but not the invasion inhibitory activity of 19 kilodalton Merozoite Surface Protein 1 specific antibodies is associated with resistance to malarial parasitemia in a cross sectional survey in the gambia
    Infection and Immunity, 2004
    Co-Authors: Rebecca A Odonnell, Brendan S. Crabb, Patrick H Corran, Jim Todd, Chairat Uthaipibull, Anthony A Holder, Eleanor M Riley
    Abstract:

    ABSTRACT In a cross-sectional survey of 187 Gambian children and adults, we have analyzed prevalence, fine specificity, and 19-kilodalton Merozoite Surface Protein 1 (MSP-119)-specific erythrocyte invasion inhibitory activity of antibodies to MSP-119 but find no significant association between any of these parameters and prevalence or density of malarial parasitemia, except that, after correcting for total anti-MSP-119 antibody levels, individuals with anti-MSP-119 antibodies that compete with an invasion inhibitory monoclonal antibody (12.10) were significantly less likely to have malaria infections with densities of ≥1,000 parasites/μl than were individuals without such antibodies. This association persisted after correction for age and ethnic origin.

  • fine specificity of serum antibodies to plasmodium falciparum Merozoite Surface Protein pfmsp 119 predicts protection from malaria infection and high density parasitemia
    Infection and Immunity, 2004
    Co-Authors: Brenda A Okech, Patrick H Corran, Jim Todd, Chairat Uthaipibull, Anthony A Holder, Amy Joynsonhicks, Thomas G Egwang, Eleanor M Riley
    Abstract:

    Antibodies to the C terminus of the Plasmodium falciparum Merozoite Surface Protein, PfMSP-1(19), may inhibit Merozoite invasion or block the effects of inhibitory antibodies. Here, using a competition enzyme-linked immunosorbent assay and antibody binding to wild-type and mutated recombinant Proteins, we show that there are marked variations between individuals in the fine specificity of naturally acquired anti-MSP-1(19) antibodies. Furthermore, although neither the prevalence nor the concentration of total anti-MSP-1(19) antibodies was associated with resistance to malaria in African children, significant associations were observed between antibody fine specificity and subsequent risk of infection and high-density parasitemia during a follow-up period. Thus, the fine specificity of naturally acquired human anti-MSP-1(19) antibodies is crucial in determining their function. Future field studies, including the evaluation of PfMSP-1 vaccine trials, should include assays that explore antibody fine specificity as well as titer.

  • fine specificity of serum antibodies to plasmodium falciparum Merozoite Surface Protein pfmsp 1 19 predicts protection from malaria infection and high density parasitemia
    Infection and Immunity, 2004
    Co-Authors: Brenda A Okech, Patrick H Corran, Jim Todd, Chairat Uthaipibull, Anthony A Holder, Amy Joynsonhicks, Thomas G Egwang, Eleanor M Riley
    Abstract:

    Antibodies to the C terminus of the Plasmodium falciparum Merozoite Surface Protein, PfMSP-1(19), may inhibit Merozoite invasion or block the effects of inhibitory antibodies. Here, using a competition enzyme-linked immunosorbent assay and antibody binding to wild-type and mutated recombinant Proteins, we show that there are marked variations between individuals in the fine specificity of naturally acquired anti-MSP-1(19) antibodies. Furthermore, although neither the prevalence nor the concentration of total anti-MSP-1(19) antibodies was associated with resistance to malaria in African children, significant associations were observed between antibody fine specificity and subsequent risk of infection and high-density parasitemia during a follow-up period. Thus, the fine specificity of naturally acquired human anti-MSP-1(19) antibodies is crucial in determining their function. Future field studies, including the evaluation of PfMSP-1 vaccine trials, should include assays that explore antibody fine specificity as well as titer.

  • igg3 antibodies to plasmodium falciparum Merozoite Surface Protein 2 msp2 increasing prevalence with age and association with clinical immunity to malaria
    American Journal of Tropical Medicine and Hygiene, 1998
    Co-Authors: Rachel R Taylor, B M Greenwood, Stephen Allen, Eleanor M Riley
    Abstract:

    In a cross-sectional survey carried out in west Africa (The Gambia), where Plasmodium falciparum malaria is endemic with seasonal transmission, 178 individuals 1-75 years of age were assessed for their antibody response to the malaria vaccine candidate, Merozoite Surface Protein 2 (MSP2). Total IgG to recombinant antigens representing full-length, repetitive, and group-specific domains of both allelic families of MSP2 was determined by ELISA. The IgG-subclass profile of IgG-positive sera was assessed. Antibody prevalence was age-dependent, reaching a peak during adolescence. In MSP2-seropositive individuals, there was a predominance of cytophilic antibodies (IgG1 and IgG3); IgG1 antibodies were prevalent in children less than 10 years of age, whereas in adolescents and adults MSP2-specific antibodies were predominantly IgG3. In parallel, we conducted a longitudinal study of children (3-8 years of age) from the same community; sera collected before the malaria transmission season were tested for the presence of anti-MSP2 antibodies. The subsequent susceptibility of these children to clinical malaria was monitored and the association between anti-MSP2 antibodies of different IgG subclasses and resistance to clinical malaria was tested. The presence of IgG3 antibodies to MSP2 serogroup A was negatively associated with the risk of clinical malaria whereas IgG1 antibodies to MSP2 serogroup B were associated with an increased risk of clinical infection. Our data suggest that age/exposure-related acquisition of IgG3 antibodies to MSP2 may contribute to the development of clinically protective immunity to malaria.

  • human antibody response to plasmodium falciparum Merozoite Surface Protein 2 is serogroup specific and predominantly of the immunoglobulin g3 subclass
    Infection and Immunity, 1995
    Co-Authors: Rachel R Taylor, V J Robinson, Jana S Mcbride, Donald B. Smith, Eleanor M Riley
    Abstract:

    MSP2 is a Merozoite Surface Protein of Plasmodium falciparum and, as such, is a potential component of a malaria vaccine. In this study, we have used a panel of recombinant MSP2 antigens in enzyme-linked immunosorbent assays to investigate the recognition of MSP2 by antibodies from malaria-immune human serum. These recombinant antigens include full-length Proteins of serogroups A and B and fragments representing the conserved, group-specific, or repeat regions of each serogroup. Ninety-five percent of the serum samples tested contained MSP2-specific antibodies: 81% of serum samples tested responded to serogroup A, and 86% responded to serogroup B. The antibody response is directed almost exclusively towards dimorphic and polymorphic regions of MSP2; the conserved regions are rarely recognized, and antibodies to serogroups A and B do not cross-react. Interestingly, the antibody response is predominately of the cytophilic and complement-fixing subclass immunoglobulin G3.