scholarly journals Toward the Rational Design of a Malaria Vaccine Construct Using the MSP3 Family as an Example: Contribution of Antigenicity Studies in Humans

2009 ◽  
Vol 78 (1) ◽  
pp. 486-494 ◽  
Author(s):  
Corine G. Demanga ◽  
Lena-Juliette Daher ◽  
Eric Prieur ◽  
Catherine Blanc ◽  
Jean-Louis Pérignon ◽  
...  
Keyword(s):  
Rational Design ◽  
Vaccine Development ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Native Proteins ◽  
Malaria Vaccines ◽  
Igg3 Subclass ◽  
And Function ◽  
The Village ◽  
Similar Organization

ABSTRACT Plasmodium falciparum merozoite surface protein (MSP3) is a main target of protective immunity against malaria that is currently undergoing vaccine development. It was shown recently to belong, together with MSP6, to a new multigene family whose C-terminal regions have a similar organization, contain both homologous and divergent regions, and are highly conserved across isolates. In an attempt to rationally design novel vaccine constructs, we extended the analysis of antigenicity and function of region-specific antibodies, previously performed with MSP3 and MSP6, to the remaining four proteins of the MSP3 family using four recombinant proteins and 24 synthetic peptides. Antibodies to each MSP3 family antigen were found to be highly prevalent among malaria-exposed individuals from the village of Dielmo (Senegal). Each of the 24 peptides was antigenic, defining at least one epitope mimicking that of the native proteins, with a distinct IgG isotype pattern for each, although with an overall predominance of the IgG3 subclass. Human antibodies affinity purified upon each of the 24 peptides exerted an antiparasite antibody-dependent cellular inhibition effect, which in most cases was as strong as that of IgG from protected African adults. The two regions with high homology were found to generate a broad network of cross-reactive antibodies with various avidities. A first multigenic construct was designed using these findings and those from related immunogenicity studies in mice and demonstrated valuable immunological properties. These results indicate that numerous regions from the MSP3 family play a role in protection and provide a rationale for the tailoring of new MSP3-derived malaria vaccines.

scholarly journals A malaria merozoite surface protein (MSP1)-structure, processing and function

1992 ◽  
Vol 87 (suppl 3) ◽  
pp. 37-42 ◽  
Author(s):  
Anthony A. Holder ◽  
Michael J. Blackman ◽  
Petra A. Burghaus ◽  
Jonathan A. Chappel ◽  
Irene T. Ling ◽  
...  
Keyword(s):  
Surface Protein ◽  
Merozoite Surface Protein ◽  
And Function

scholarly journals Immunoglobulin G Subclass-Specific Responses against Plasmodium falciparum Merozoite Antigens Are Associated with Control of Parasitemia and Protection from Symptomatic Illness

2009 ◽  
Vol 77 (3) ◽  
pp. 1165-1174 ◽  
Author(s):  
Danielle I. Stanisic ◽  
Jack S. Richards ◽  
Fiona J. McCallum ◽  
Pascal Michon ◽  
Christopher L. King ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Immunoglobulin G ◽  
Vaccine Development ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Igg Subclass ◽  
Apical Membrane Antigen 1 ◽  
Falciparum Merozoite ◽  
Merozoite Antigens

ABSTRACT Substantial evidence indicates that antibodies to Plasmodium falciparum merozoite antigens play a role in protection from malaria, although the precise targets and mechanisms mediating immunity remain unclear. Different malaria antigens induce distinct immunoglobulin G (IgG) subclass responses, but the importance of different responses in protective immunity from malaria is not known and the factors determining subclass responses in vivo are poorly understood. We examined IgG and IgG subclass responses to the merozoite antigens MSP1-19 (the 19-kDa C-terminal region of merozoite surface protein 1), MSP2 (merozoite surface protein 2), and AMA-1 (apical membrane antigen 1), including different polymorphic variants of these antigens, in a longitudinal cohort of children in Papua New Guinea. IgG1 and IgG3 were the predominant subclasses of antibodies to each antigen, and all antibody responses increased in association with age and exposure without evidence of increasing polarization toward one subclass. The profiles of IgG subclasses differed somewhat for different alleles of MSP2 but not for different variants of AMA-1. Individuals did not appear to have a propensity to make a specific subclass response irrespective of the antigen. Instead, data suggest that subclass responses to each antigen are generated independently among individuals and that antigen properties, rather than host factors, are the major determinants of IgG subclass responses. High levels of AMA-1-specific IgG3 and MSP1-19-specific IgG1 were strongly predictive of a reduced risk of symptomatic malaria and high-density P. falciparum infections. However, no antibody response was significantly associated with protection from parasitization per se. Our findings have major implications for understanding human immunity and for malaria vaccine development and evaluation.

scholarly journals Diversity Covering AMA1-MSP119Fusion Proteins as Malaria Vaccines

2013 ◽  
Vol 81 (5) ◽  
pp. 1479-1490 ◽  
Author(s):  
Bart W. Faber ◽  
Sumera Younis ◽  
Edmond J. Remarque ◽  
Roberto Rodriguez Garcia ◽  
Vanessa Riasat ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Fusion Proteins ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Immunological Study ◽  
Growth Inhibition Assay ◽  
Content Type ◽  
Apical Membrane Antigen 1 ◽  
Malaria Vaccines ◽  
Order Of Magnitude

ABSTRACTTo overcome polymorphism in the malaria vaccine candidatePlasmodium falciparumapical membrane antigen 1 (PfAMA1), fusion protein chimeras comprised of three diversity-covering (DiCo) PfAMA1 molecules (D1, D2, and D3) and two allelic variants of the C-terminal 19-kDa region of merozoite surface protein 1 (MSP119) (variants M1 and M2) were generated. A mixture of fusion proteins (D1M1/D2M2D3) and the D1M1D2M2D3 fusion were compared to a single-unit mixture (D1/D2/D3/M1) in an immunological study in groups of rabbits. Following immunization, titers of antibodies (Abs) against four naturally occurring PfAMA1 alleles were high for all groups, as were growth inhibition assay (GIA) levels against two antigenically distinct laboratory parasite strains. Fusion of AMA1 to MSP119did not suppress levels of antibodies against the AMA1 component. In addition, the breadth of antibody responses was unaffected. Anti-AMA1 antibodies were largely responsible for parasite growth inhibition, as shown in reversal-of-inhibition experiments by adding competing AMA1 antigen. For all groups, titration of the MSP119antigen into the GIA led to only a small decrease in parasite inhibition, although titers of antibodies against MSP119were increased 15-fold for the groups immunized with fusion proteins. GIA with affinity-purified anti-MSP119antibodies showed that the 50% inhibitory concentrations of the anti-MSP119antibody preparations were in the same order of magnitude for all animals tested, leading to the conclusion that fusing MSP119to PfAMA1 leads to a small but significant increase in functional antibody levels. This study shows that combination of multiple vaccine candidates in fusion proteins may lead to improved characteristics of the vaccine.

scholarly journals Humoral Responses to Plasmodium falciparum Blood-Stage Antigens and Association with Incidence of Clinical Malaria in Children Living in an Area of Seasonal Malaria Transmission in Burkina Faso, West Africa

2007 ◽  
Vol 76 (2) ◽  
pp. 759-766 ◽  
Author(s):  
Issa Nebie ◽  
Amidou Diarra ◽  
Alphonse Ouedraogo ◽  
Issiaka Soulama ◽  
Edith C. Bougouma ◽  
...  
Keyword(s):  
Malaria Transmission ◽  
Malaria Vaccine ◽  
Vaccine Development ◽  
Malaria Incidence ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Clinical Malaria ◽  
Blood Stage ◽  
Igg Subclass ◽  
Malaria Surveillance

ABSTRACT There is longstanding evidence that immunoglobulin G (IgG) has a role in protection against clinical malaria, and human antibodies of the cytophilic subclasses are thought to be particularly critical in this respect. In this cohort study, 286 Burkinabè children 6 months to 15 years old were kept under malaria surveillance in order to assess the protective role of antibody responses against four antigens which are currently being evaluated as vaccine candidates: apical membrane antigen 1 (AMA1), merozoite surface protein 1-19 (MSP1-19), MSP3, and glutamate-rich protein (GLURP). Total IgG, IgM, and IgG subclass responses were measured just before the malaria transmission season. The incidence of malaria was 2.4 episodes per child year of risk. After adjusting for the confounding effects of age, the level of total IgG to GLURP was strongly associated with reduced malaria incidence (incidence rate ratio associated with a doubling of total IgG, 0.79; 95% confidence interval, 0.66 to 0.94; P = 0.009.); there was a borderline statistically significant association between the level of total IgG to MSP3 and malaria incidence and no evidence of an association for total IgG to AMA1 and to MSP1-19. Of the IgG subclass responses studied, only IgG3 and IgG4 against GLURP and IgG1 against AMA1 were associated with reduced risk of clinical malaria. There was no evidence of an interaction between responses to AMA1 and baseline parasitemia in their effects on malaria incidence. Currently included in malaria vaccine formulations for clinical trials in humans, these blood-stage antigens, AMA1 and GLURP, offer good prospects for malaria vaccine development.

scholarly journals Antigenic Polymorphism and Naturally Acquired Antibodies to Plasmodium vivax Merozoite Surface Protein 1 in Rural Amazonians

2007 ◽  
Vol 14 (10) ◽  
pp. 1249-1259 ◽  
Author(s):  
Melissa S. Bastos ◽  
Mônica da Silva-Nunes ◽  
Rosely S. Malafronte ◽  
Erika Hellena E. Hoffmann ◽  
Gerhard Wunderlich ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Vaccine Development ◽  
Sequence Divergence ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Igg Antibodies ◽  
Antibody Recognition ◽  
Merozoite Surface Protein 1 ◽  
Relative Contribution ◽  
Repeated Infections

ABSTRACT Merozoite surface protein 1 of Plasmodium vivax (PvMSP-1), a major target for malaria vaccine development, contains six highly polymorphic domains interspersed with conserved sequences. Although there is evidence that the sequence divergence in PvMSP-1 has been maintained over 5 million years by balanced selection exerted by the host's acquired immunity, the variant specificity of naturally acquired antibodies to PvMSP-1 remains poorly investigated. Here, we show that 15 recombinant proteins corresponding to PvMSP-1 variants commonly found in local parasites were poorly recognized by 376 noninfected subjects aged 5 to 90 years exposed to malaria in rural Amazonia; less than one-third of them had detectable immunoglobulin G (IgG) antibodies to at least one variant of blocks 2, 6, and 10 that were expressed, although 54.3% recognized the invariant 19-kDa C-terminal domain PvMSP-119. Although the proportion of responders to PvMSP-1 variants increased substantially during subsequent acute P. vivax infections, the specificity of IgG antibodies did not necessarily match the PvMSP-1 variant(s) found in infecting parasites. We discuss the relative contribution of antigenic polymorphism, poor immunogenicity, and original antigenic sin (the skew in the specificity of antibodies elicited by exposure to new antigenic variants due to preexisting variant-specific responses) to the observed patterns of antibody recognition of PvMSP-1. We suggest that antibody responses to the repertoire of variable domains of PvMSP-1 to which subjects are continuously exposed are elicited only after several repeated infections and may require frequent boosting, with clear implications for the development of PvMSP-1-based subunit vaccines.

scholarly journals Genetic diversity and multiplicity of Plasmodium falciparum merozoite surface protein 2 in field isolates from Sudan

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1790 ◽  
Author(s):  
Shaza O. Mustafa ◽  
Muzamil M. Abdel Hamid ◽  
Mariam A. Aboud ◽  
Mutaz Amin ◽  
Mohamed S. Muneer ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Red Sea ◽  
Vaccine Development ◽  
Age Groups ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Multiplicity Of Infection ◽  
River Nile ◽  
Major Health Problem ◽  
Allelic Family

Background: Malaria  is a major health problem, with over one third of worldwide populations currently at risk.  Determining the genetic diversity of plasmodium parasites is essential for assessing the efficacy of antimalarial drugs and for future vaccine development. This study investigated the genetic diversity of P. falciparum merozoite surface protein 2 (MSP2), and multiplicity of infection (MOI) in different geographic regions in Sudan. Methods: A total of 271 patients with uncomplicated malaria were recruited from four ecological sites during malaria transmission season, 2011-2013. P. falciparum was confirmed using species specific primers targeting the rDNA gene. All P. falciparum positive samples were genotyped for the major MSP2 allelic families (IC1/3D7 and FC27 MSP2 allele) using nested PCR. Multiplicity of infection and allele frequencies were determined. Results: A total of 241 samples (88.9%) were confirmed positive for P. falciparum. The number of different MSP2 alleles were 14, 15, 13 and 12 in Khartoum, Gezira, River Nile and Red Sea states, respectively. The 3D7 allelic family was more prevalent in the states of Khartoum, Gezira, River Nile and Red Sea compared to the FC27 allelic family. Multiclonal infections were observed in 25.8% of patients, with a mean multiplicity of infection (MOI) of 1.45. MOIs were highest in the age group over 40, with an average of 2 and 1.68 in Khartoum and Gezira states, respectively, however MOIs in River Nile and Red Sea states were higher in age groups below 18, with an average of 1.37 and 1.33, respectively. Conclusions: MSP2 allelic genotyping revealed MOI and diversity of the Sudanese P. falciparum isolates. The results of our study are expected to influence current and future malaria control strategies, since the MOI predicts development of clinical malaria and subsequent efficacy of antimalarial treatment.

scholarly journals Multistage Multiantigen Heterologous Prime Boost Vaccine forPlasmodium knowlesi Malaria Provides Partial Protection in Rhesus Macaques

2001 ◽  
Vol 69 (9) ◽  
pp. 5565-5572 ◽  
Author(s):  
William O. Rogers ◽  
J. Kevin Baird ◽  
Anita Kumar ◽  
John A. Tine ◽  
Walter Weiss ◽  
...  
Keyword(s):  
Dna Vaccine ◽  
Vaccine Development ◽  
Plasmodium Knowlesi ◽  
Rhesus Macaques ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Antibody Responses ◽  
Primate Model ◽  
Boost Vaccine

ABSTRACT A nonhuman primate model for malaria vaccine development allowing reliable, stringent sporozoite challenge and evaluation of both cellular and antibody responses is needed. We therefore constructed a multicomponent, multistage DNA vaccine for the simian malaria species Plasmodium knowlesi including two preerythrocytic-stage antigens, the circumsporozoite protein (PkCSP) and sporozoite surface protein 2 (PkSSP2), and two blood stage antigens, apical merozoite antigen 1 (PkAMA1) and merozoite surface protein 1 (PkMSP1p42), as well as recombinant canarypox viruses encoding the four antigens (ALVAC-4). The DNA vaccine plasmids expressed the corresponding antigens in vitro and induced antiparasite antibodies in mice. Groups of four rhesus monkeys received three doses of a mixture of the four DNA vaccine plasmids and a plasmid encoding rhesus granulocyte-monocyte colony-stimulating factor, followed by boosting with a single dose of ALVAC-4. Three groups received the priming DNA doses by different routes, either by intramuscular needle injection, by intramuscular injection with a needleless injection device, the Biojector, or by a combination of intramuscular and intradermal routes by Biojector. Animals immunized by any route developed antibody responses against sporozoites and infected erythrocytes and against a recombinant PkCSP protein, as well as gamma interferon-secreting T-cell responses against peptides from PkCSP. Following challenge with 100 P. knowlesi sporozoites, 1 of 12 experimental monkeys was completely protected and the mean parasitemia in the remaining monkeys was significantly lower than that in 4 control monkeys. This model will be important in preclinical vaccine development.

scholarly journals Actinoporins: From the Structure and Function to the Generation of Biotechnological and Therapeutic Tools

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 539 ◽  
Author(s):  
Santos Ramírez-Carreto ◽  
Beatriz Miranda-Zaragoza ◽  
Claudia Rodríguez-Almazán
Keyword(s):  
Rational Design ◽  
Vaccine Development ◽  
Molecular Probes ◽  
Immunomodulatory Activity ◽  
Molecular Tools ◽  
Sea Anemones ◽  
Liposomal Formulations ◽  
Conformational Plasticity ◽  
Therapeutic Tools ◽  
And Function

Actinoporins (APs) are a family of pore-forming toxins (PFTs) from sea anemones. These biomolecules exhibit the ability to exist as soluble monomers within an aqueous medium or as constitutively open oligomers in biological membranes. Through their conformational plasticity, actinoporins are considered good candidate molecules to be included for the rational design of molecular tools, such as immunotoxins directed against tumor cells and stochastic biosensors based on nanopores to analyze unique DNA or protein molecules. Additionally, the ability of these proteins to bind to sphingomyelin (SM) facilitates their use for the design of molecular probes to identify SM in the cells. The immunomodulatory activity of actinoporins in liposomal formulations for vaccine development has also been evaluated. In this review, we describe the potential of actinoporins for use in the development of molecular tools that could be used for possible medical and biotechnological applications.

scholarly journals Familial Correlation of Immunoglobulin G Subclass Responses to Plasmodium falciparum Antigens in Burkina Faso

2001 ◽  
Vol 69 (2) ◽  
pp. 996-1001 ◽  
Author(s):  
Christophe Aucan ◽  
Yves Traoré ◽  
Francis Fumoux ◽  
Pascal Rihet
Keyword(s):  
Plasmodium Falciparum ◽  
Burkina Faso ◽  
Immunoglobulin G ◽  
Genetic Factors ◽  
Vaccine Development ◽  
Correlation Coefficients ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Blood Stage ◽  
Igg Subclass

ABSTRACT Host genes are thought to determine the immune response to malaria infection and the outcome. Cytophilic antibodies have been associated with protection, whereas noncytophilic antibodies against the same epitopes may block the protective activity of the protective ones. To assess the contribution of genetic factors to immunoglobulin G (IgG) subclass responses against conserved epitopes and Plasmodium falciparum blood-stage extracts, we analyzed the isotypic distribution of the IgG responses in 366 individuals living in two differently exposed areas in Burkina Faso. We used one-way analysis of variance and pairwise estimators to calculate sib-sib and parent-offspring correlation coefficients, respectively. Familial patterns of inheritance of IgG subclass responses to defined antigens and P. falciparum extracts appear to be similar in the two areas. We observed a sibling correlation for the IgG, IgG1, IgG2, IgG3, and IgG4 responses directed against ring-infected-erythrocyte surface antigen, merozoite surface protein 1 (MSP-1), MSP-2, andP. falciparum extract. Moreover, a parent-offspring correlation was found for several IgG subclass responses, including the IgG, IgG1, IgG2, IgG3, and IgG4 responses directed against conserved MSP-2 epitopes. Our results indicated that the IgG subclass responses against P. falciparum blood-stage antigens are partly influenced by host genetic factors. The localization and identification of these genes may have implications for immunoepidemiology and vaccine development.

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