Journal articles on the topic 'Stage-specific vaccine candidates'
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Jan Kristoff. "Malaria Stage-Specific Vaccine Candidates." Current Pharmaceutical Design 13, no. 19 (July 1, 2007): 1989–99. http://dx.doi.org/10.2174/138161207781039805.
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Ntumngia, Francis B., Jesse Schloegel, Samantha J. Barnes, Amy M. McHenry, Sanjay Singh, Christopher L. King, and John H. Adams. "Conserved and Variant Epitopes of Plasmodium vivax Duffy Binding Protein as Targets of Inhibitory Monoclonal Antibodies." Infection and Immunity 80, no. 3 (January 3, 2012): 1203–8. http://dx.doi.org/10.1128/iai.05924-11.
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The Duffy binding protein (DBP) is a vital ligand forPlasmodium vivaxblood-stage merozoite invasion, making the molecule an attractive vaccine candidate against vivax malaria. Similar to other blood-stage vaccine candidates, DBP allelic variation eliciting a strain-specific immunity may be a major challenge for development of a broadly effective vaccine against vivax malaria. To understand whether conserved epitopes can be the target of neutralizing anti-DBP inhibition, we generated a set of monoclonal antibodies to DBP and functionally analyzed their reactivity to a panel of allelic variants. Quantitative analysis by enzyme-linked immunosorbent assay (ELISA) determined that some monoclonal antibodies reacted strongly with epitopes conserved on all DBP variants tested, while reactivity of others was allele specific. Qualitative analysis characterized by anti-DBP functional inhibition using anin vitroerythrocyte binding inhibition assay indicated that there was no consistent correlation between the endpoint titers and functional inhibition. Some monoclonal antibodies were broadly inhibitory while inhibition of others varied significantly by target allele. These data demonstrate a potential for vaccine-elicited immunization to target conserved epitopes but optimization of DBP epitope target specificity and immunogenicity may be necessary for protection against diverseP. vivaxstrains.
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Scott, Connor A. P., Alberto A. Amarilla, Summa Bibby, Natalee D. Newton, Roy A. Hall, Jody Hobson-Peters, David A. Muller, et al. "Implications of Dengue Virus Maturation on Vaccine Induced Humoral Immunity in Mice." Viruses 13, no. 9 (September 15, 2021): 1843. http://dx.doi.org/10.3390/v13091843.
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The use of dengue virus (DENV) vaccines has been hindered by the complexities of antibody dependent enhancement (ADE). Current late-stage vaccine candidates utilize attenuated and chimeric DENVs that produce particles of varying maturities. Antibodies that are elicited by preferentially exposed epitopes on immature virions have been linked to increased ADE. We aimed to further understand the humoral immunity promoted by DENV particles of varying maturities in an AG129 mouse model using a chimeric insect specific vaccine candidate, bDENV-2. We immunized mice with mature, partially mature, and immature bDENV-2 and found that immunization with partially mature bDENV-2 produced more robust and cross-neutralizing immune responses than immunization with immature or mature bDENV-2. Upon challenge with mouse adapted DENV-2 (D220), we observed 80% protection for mature bDENV-2 vaccinated mice and 100% for immature and partially mature vaccinated mice, suggesting that protection to homotypic challenge is not dependent on maturation. Finally, we found reduced in vitro ADE at subneutralising serum concentrations for mice immunized with mature bDENV-2. These results suggest that both immature and mature DENV particles play a role in homotypic protection; however, the increased risk of in vitro ADE from immature particles indicates potential safety benefits from mature DENV-based vaccines.
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Li, Yike, Xiaofen Huang, Zhigang Zhang, Shaowei Li, Jun Zhang, Ningshao Xia, and Qinjian Zhao. "Prophylactic Hepatitis E Vaccines: Antigenic Analysis and Serological Evaluation." Viruses 12, no. 1 (January 16, 2020): 109. http://dx.doi.org/10.3390/v12010109.
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Hepatitis E virus (HEV) infection causes sporadic outbreaks of acute hepatitis worldwide. HEV was previously considered to be restricted to resource-limited countries with poor sanitary conditions, but increasing evidence implies that HEV is also a public health problem in developed countries and regions. Fortunately, several vaccine candidates based on virus-like particles (VLPs) have progressed into the clinical development stage, and one of them has been approved in China. This review provides an overview of the current HEV vaccine pipeline and future development with the emphasis on defining the critical quality attributes for the well-characterized vaccines. The presence of clinically relevant epitopes on the VLP surface is critical for eliciting functional antibodies against HEV infection, which is the key to the mechanism of action of the prophylactic vaccines against viral infections. Therefore, the epitope-specific immunochemical assays based on monoclonal antibodies (mAbs) for HEV vaccine antigen are critical methods in the toolbox for epitope characterization and for in vitro potency assessment. Moreover, serological evaluation methods after immunization are also discussed as biomarkers for clinical performance. The vaccine efficacy surrogate assays are critical in the preclinical and clinical stages of VLP-based vaccine development.
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Tripathi, Abhai K., Miranda S. Oakley, Nitin Verma, Godfree Mlambo, Hong Zheng, Scott M. Meredith, Edward Essuman, et al. "Plasmodium falciparum Pf77 and male development gene 1 as vaccine antigens that induce potent transmission-reducing antibodies." Science Translational Medicine 13, no. 597 (June 9, 2021): eabg2112. http://dx.doi.org/10.1126/scitranslmed.abg2112.
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Malaria vaccines that disrupt the Plasmodium life cycle in mosquitoes and reduce parasite transmission in endemic areas are termed transmission-blocking vaccines (TBVs). Despite decades of research, there are only a few Plasmodium falciparum antigens that indisputably and reproducibly demonstrate transmission-blocking immunity. So far, only two TBV candidates have advanced to phase 1/2 clinical testing with limited success. By applying an unbiased transcriptomics-based approach, we have identified Pf77 and male development gene 1 (PfMDV-1) as two P. falciparum TBV antigens that, upon immunization, induced antibodies that caused reductions in oocyst counts in Anopheles mosquito midguts in a standard membrane feeding assay. In-depth studies were performed to characterize the genetic diversity of, stage-specific expression by, and natural immunity to these two molecules to evaluate their suitability as TBV candidates. Pf77 and PfMDV-1 display limited antigenic polymorphism, are pan-developmentally expressed within the parasite, and induce naturally occurring antibodies in Ghanaian adults, which raises the prospect of natural boosting of vaccine-induced immune response in endemic regions. Together, these biological properties suggest that Pf77 and PfMDV-1 may warrant further investigation as TBV candidates.
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Bustamante, Leyla Y., Gareth T. Powell, Yen-Chun Lin, Michael D. Macklin, Nadia Cross, Alison Kemp, Paula Cawkill, et al. "Synergistic malaria vaccine combinations identified by systematic antigen screening." Proceedings of the National Academy of Sciences 114, no. 45 (October 23, 2017): 12045–50. http://dx.doi.org/10.1073/pnas.1702944114.
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A highly effective vaccine would be a valuable weapon in the drive toward malaria elimination. No such vaccine currently exists, and only a handful of the hundreds of potential candidates in the parasite genome have been evaluated. In this study, we systematically evaluated 29 antigens likely to be involved in erythrocyte invasion, an essential developmental stage during which the malaria parasite is vulnerable to antibody-mediated inhibition. Testing antigens alone and in combination identified several strain-transcending targets that had synergistic combinatorial effects in vitro, while studies in an endemic population revealed that combinations of the same antigens were associated with protection from febrile malaria. Video microscopy established that the most effective combinations targeted multiple discrete stages of invasion, suggesting a mechanistic explanation for synergy. Overall, this study both identifies specific antigen combinations for high-priority clinical testing and establishes a generalizable approach that is more likely to produce effective vaccines.
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Gregory, William F., Agnes K. Atmadja, Judith E. Allen, and Rick M. Maizels. "The Abundant Larval Transcript-1 and -2 Genes ofBrugia malayi Encode Stage-Specific Candidate Vaccine Antigens for Filariasis." Infection and Immunity 68, no. 7 (July 1, 2000): 4174–79. http://dx.doi.org/10.1128/iai.68.7.4174-4179.2000.
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ABSTRACT Lymphatic filariasis is a major tropical disease caused by the mosquito-borne nematodes Brugia and Wuchereria. About 120 million people are infected and at risk of lymphatic pathology such as acute lymphangitis and elephantiasis. Vaccines against filariasis must generate immunity to the infective mosquito-derived third-stage larva (L3) without accentuating immunopathogenic responses to lymphatic-dwelling adult parasites. We have identified two highly expressed genes, designated abundant larval transcript-1 and -2 (alt-1 and alt-2), from each of which mRNAs account for >1% of L3 cDNAs. ALT-1 and ALT-2 share 79% amino acid identity across 125 residues, including a putative signal sequence and a prominent acidic tract. Expression ofalt-1 and alt-2 is initiated midway through development in the mosquito, peaking in the infective larva and declining sharply following entry into the host. Humans exposed toBrugia malayi show a high frequency of immunoglobulin G1 (IgG1) and IgG3 antibodies to ALT-1 and -2, distinguishing them from adult-stage antigens, which are targeted by the IgG4 isotype. Immunization of susceptible rodents (jirds) with ALT-1 elicited a 76% reduction in parasite survival, the highest reported for a single antigen from any filarial parasite. ALT-1 and the closely related ALT-2 are therefore strong candidates for a future vaccine against human filariasis.
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Song, Xingju, Xu Yang, Taotao Zhang, Jing Liu, and Qun Liu. "A Novel Rhoptry Protein as Candidate Vaccine against Eimeria tenella Infection." Vaccines 8, no. 3 (August 12, 2020): 452. http://dx.doi.org/10.3390/vaccines8030452.
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Eimeria tenella (E. tenella) is a highly pathogenic and prevalent species of Eimeria that infects chickens, and it causes a considerable disease burden worldwide. The secreted proteins and surface antigens of E. tenella at the sporozoite stage play an essential role in the host–parasite interaction, which involves attachment and invasion, and these interactions are considered vaccine candidates based on the strategy of cutting off the invasion pathway to interrupt infection. We selected two highly expressed surface antigens (SAGs; Et-SAG13 and Et-SAG) and two highly expressed secreted antigens (rhoptry kinases Eten5-A, Et-ROPK-Eten5-A and dense granule 12, Et-GRA12) at the sporozoite stage. Et-ROPK-Eten5-A and Et-GRA12 were two unexplored proteins. Et-ROPK-Eten5-A was an E. tenella-specific rhoptry (ROP) protein and distributed in the apical pole of sporozoites and merozoites. Et-GRA12 was scattered in granular form at the sporozoite stage. To evaluate the potential of rEt-ROPK-Eten5-A, rEt-GRA12, rEt-SAG13 and rEt-SAG proteins as a coccidiosis vaccine, the protective efficacy was examined based on survival rate, lesion score, body weight gain, relative body weight gain and oocyst output. The survival rate was significantly improved in rEt-ROPK-Eten5-A (100%) and rEt-GRA12 (100%) immune chickens compared to the challenged control group (40%). The average body weight gains of rEt-ROPK-Eten5-A, rEt-GRA12, rEt-SAG13 and rEt-SAG immunized chickens were significantly higher than those of unimmunized chickens. The mean lesion score and oocyst output of the rEt-ROPK-Eten5-A immunized chickens were significantly reduced compared to unimmunized challenged chickens. These results suggest that the rEt-ROPK-Eten5-A protein effectively triggered protection against E. tenella in chickens and provides a useful foundation for future work developing anticoccidial vaccines.
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Weiss, Richard, Wolfgang W. Leitner, Sandra Scheiblhofer, Defeng Chen, Andrea Bernhaupt, Sven Mostböck, Josef Thalhamer, and Jeffrey A. Lyon. "Genetic Vaccination against Malaria Infection by Intradermal and Epidermal Injections of a Plasmid Containing the Gene Encoding thePlasmodium berghei Circumsporozoite Protein." Infection and Immunity 68, no. 10 (October 1, 2000): 5914–19. http://dx.doi.org/10.1128/iai.68.10.5914-5919.2000.
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ABSTRACT The circumsporozoite protein (CSP) from the surface of sporozoite stage Plasmodium sp. malaria parasites is among the most important of the malaria vaccine candidates. Gene gun injection of genetic vaccines encoding Plasmodium berghei CSP induces a significant protective effect against sporozoite challenge; however, intramuscular injection does not. In the present study we compared the immune responses and protective effects induced by P. berghei CSP genetic vaccines delivered intradermally with a needle or epidermally with a gene gun. Mice were immunized three times at 4-week intervals and challenged by a single infectious mosquito bite. Although 50 times more DNA was administered by needle than by gene gun, the latter method induced significantly greater protection against infection. Intradermal injection of the CSP genetic vaccine induced a strong Th1-type immune response characterized by a dominant CSP-specific immunoglobulin G2a (IgG2a) humoral response and high levels of gamma interferon produced by splenic T cells. Gene gun injection induced a predominantly Th2-type immune response characterized by a high IgG1/IgG2a ratio and significant IgE production. Neither method generated measurable cytotoxic T lymphocyte activity. The results indicate that a gene gun-mediated CS-specific Th2-type response may be best for protecting against malarial sporozoite infection when the route of parasite entry is via mosquito bite.
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Porter, Michael D., Jennifer Nicki, Christopher D. Pool, Margot DeBot, Ratish M. Illam, Clara Brando, Brooke Bozick, et al. "Transgenic Parasites Stably Expressing Full-Length Plasmodium falciparum Circumsporozoite Protein as a Model for Vaccine Down-Selection in Mice Using Sterile Protection as an Endpoint." Clinical and Vaccine Immunology 20, no. 6 (March 27, 2013): 803–10. http://dx.doi.org/10.1128/cvi.00066-13.
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ABSTRACTCircumsporozoite protein (CSP) ofPlasmodium falciparumis a protective human malaria vaccine candidate. There is an urgent need for models that can rapidly down-select novel CSP-based vaccine candidates. In the present study, the mouse-mosquito transmission cycle of a transgenicPlasmodium bergheimalaria parasite stably expressing a functional full-lengthP. falciparumCSP was optimized to consistently produce infective sporozoites for protection studies. A minimal sporozoite challenge dose was established, and protection was defined as the absence of blood-stage parasites 14 days after intravenous challenge. The specificity of protection was confirmed by vaccinating mice with multiple CSP constructs of differing lengths and compositions. Constructs that induced high NANP repeat-specific antibody titers in enzyme-linked immunosorbent assays were protective, and the degree of protection was dependent on the antigen dose. There was a positive correlation between antibody avidity and protection. The antibodies in the protected mice recognized the native CSP on the parasites and showed sporozoite invasion inhibitory activity. Passive transfer of anti-CSP antibodies into naive mice also induced protection. Thus, we have demonstrated the utility of a mouse efficacy model to down-select human CSP-based vaccine formulations.
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Lizotte-Waniewski, Michelle, Wilson Tawe, David B. Guiliano, Wenhong Lu, Jing Liu, Steven A. Williams, and Sara Lustigman. "Identification of Potential Vaccine and Drug Target Candidates by Expressed Sequence Tag Analysis and Immunoscreening of Onchocerca volvulus Larval cDNA Libraries." Infection and Immunity 68, no. 6 (June 1, 2000): 3491–501. http://dx.doi.org/10.1128/iai.68.6.3491-3501.2000.
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ABSTRACT The search for appropriate vaccine candidates and drug targets against onchocerciasis has so far been confronted with several limitations due to the unavailability of biological material, appropriate molecular resources, and knowledge of the parasite biology. To identify targets for vaccine or chemotherapy development we have undertaken two approaches. First, cDNA expression libraries were constructed from life cycle stages that are critical for establishment of Onchocerca volvulus infection, the third-stage larvae (L3) and the molting L3. A gene discovery effort was then initiated by random expressed sequence tag analysis of 5,506 cDNA clones. Cluster analyses showed that many of the transcripts were up-regulated and/or stage specific in either one or both of the cDNA libraries when compared to the microfilariae, L2, and both adult stages of the parasite. Homology searches against the GenBank database facilitated the identification of several genes of interest, such as proteinases, proteinase inhibitors, antioxidant or detoxification enzymes, and neurotransmitter receptors, as well as structural and housekeeping genes. Other O. volvulus genes showed homology only to predicted genes from the free-living nematode Caenorhabditis elegans or were entirely novel. Some of the novel proteins contain potential secretory leaders. Secondly, by immunoscreening the molting L3 cDNA library with a pool of human sera from putatively immune individuals, we identified six novel immunogenic proteins that otherwise would not have been identified as potential vaccinogens using the gene discovery effort. This study lays a solid foundation for a better understanding of the biology of O. volvulus as well as for the identification of novel targets for filaricidal agents and/or vaccines against onchocerciasis based on immunological and rational hypothesis-driven research.
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Murhandarwati, E. Elsa Herdiana, Lina Wang, Harini D. de Silva, Charles Ma, Magdalena Plebanski, Casilda G. Black, and Ross L. Coppel. "Growth-Inhibitory Antibodies Are Not Necessary for Protective Immunity to Malaria Infection." Infection and Immunity 78, no. 2 (November 16, 2009): 680–87. http://dx.doi.org/10.1128/iai.00939-09.
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ABSTRACT The absence of a validated surrogate marker for the immune state has complicated the design of a subunit vaccine against asexual stages of Plasmodium falciparum. In particular, it is not known whether the capacity to induce antibodies that inhibit parasite growth in vitro is an important criterion for selection of P. falciparum proteins to be assessed in human vaccine trials. We examined this issue in the Plasmodium yoelii rodent malaria model using the 19-kDa C-terminal fragment of merozoite surface protein 1 (MSP119). To examine the relationship between inhibitory antibodies in immunized mice and the immune state, as indicated by resistance to a blood-stage challenge, we used an allelic replacement strategy to generate a transgenic P. falciparum line that expresses MSP119 from P. yoelii. We show that MSP119 is functionally conserved across these two divergent Plasmodium species, and replacing PfMSP119 with PyMSP119 has no detectable effect on parasite growth in vitro. By comparing growth rates of this transgenic line with a matched transgenic line that expresses the endogenous PfMSP119, we developed an assay to measure the specific growth-inhibitory activity directed exclusively to the PyMSP119 protein in the sera from vaccinated animals. To validate this assay, sera from rabbits immunized with recombinant PyMSP119 were tested and showed specific inhibitory activity in a concentration-dependent manner. In mice that were immunized with recombinant PyMSP119, the levels of PyMSP119-specific inhibitory activity did not correlate with the total antibody levels measured by enzyme-linked immunosorbent assay. Furthermore, they did not correlate with resistance to subsequent blood-stage infection, and some mice with complete protection showed no detectable inhibitory activity in their prechallenge sera. These data indicated that growth-inhibitory activity measured in vitro was not a reliable predictor of immune status in vivo, and the reliance on this criterion to select vaccine candidates for human clinical trials may be misplaced. The transgenic lines further offer useful tools for comparing the efficacy of MSP119-based vaccines that utilize different immunization regimens and antigen formulations.
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Miura, Kazutoyo, Hong Zhou, Olga V. Muratova, Andrew C. Orcutt, Birgitte Giersing, Louis H. Miller, and Carole A. Long. "In Immunization with Plasmodium falciparum Apical Membrane Antigen 1, the Specificity of Antibodies Depends on the Species Immunized." Infection and Immunity 75, no. 12 (October 8, 2007): 5827–36. http://dx.doi.org/10.1128/iai.00593-07.
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ABSTRACT At least a million people, mainly African children under 5 years old, still die yearly from malaria, and the burden of disease and death has increased. Plasmodium falciparum apical membrane antigen 1 (PfAMA1) is one of the most promising blood-stage malarial vaccine candidates. However, the allelic polymorphism observed in this protein is a potential stumbling block for vaccine development. To overcome the polymorphism- and strain-specific growth inhibition in vitro, we previously showed in a rabbit model that vaccination with a mixture of two allelic forms of PfAMA1 induced parasite growth-inhibitory antisera against both strains of P. falciparum parasites in vitro. In the present study, we have established that, in contrast to a single-allele protein, the antigen mixture elicits primarily antibodies recognizing antigenic determinants common to the two antigens, as judged by an antigen reversal growth inhibition assay (GIA). We also show that a similar reactivity pattern occurs after immunization of mice. By contrast, sera from rhesus monkeys do not distinguish the two alleles when tested by an enzyme-linked immunosorbent assay or by GIA, regardless of whether the immunogen is a single AMA1 protein or the mixture. This is the first report that a malarial vaccine candidate induced different specificities of functional antibodies depending on the animal species immunized. These observations, as well as data available on human immune responses in areas of endemicity, suggest that polymorphism in the AMA1 protein may not be as formidable a problem for vaccine development as anticipated from studies with rabbits and mice.
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Smit, Cornelis H., Christiaan L. Kies, Hamish E. G. McWilliam, Els N. T. Meeusen, Cornelis H. Hokke, and Angela van Diepen. "Local Antiglycan Antibody Responses to Skin Stage and Migratory Schistosomula of Schistosoma japonicum." Infection and Immunity 84, no. 1 (October 12, 2015): 21–33. http://dx.doi.org/10.1128/iai.00954-15.
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Schistosomiasis is a tropical disease affecting over 230 million people worldwide. Although effective drug treatment is available, reinfections are common, and development of immunity is slow. Most antibodies raised during schistosome infection are directed against glycans, some of which are thought to be protective. Developing schistosomula are considered most vulnerable to immune attack, and better understanding of local antibody responses raised against glycans expressed by this life stage might reveal possible glycan vaccine candidates for future vaccine research. We used antibody-secreting cell (ASC) probes to characterize local antiglycan antibody responses against migratingSchistosoma japonicumschistosomula in different tissues of rats. Analysis by shotgunSchistosomaglycan microarray resulted in the identification of antiglycan antibody response patterns that reflected the migratory pathway of schistosomula. Antibodies raised by skin lymph node (LN) ASC probes mainly targeted N-glycans with terminal mannose residues, Galβ1-4GlcNAc (LacNAc) and Galβ1-4(Fucα1-3)GlcNAc (LeX). Also, responses to antigenic and schistosome-specific glycosphingolipid (GSL) glycans containing highly fucosylated GalNAcβ1-4(GlcNAcβ1)nstretches that are believed to be present at the parasite's surface constitutively upon transformation were found. Antibody targets recognized by lung LN ASC probes were mainly N-glycans presenting GalNAcβ1-4GlcNAc (LDN) and GlcNAc motifs. Surprisingly, antibodies against highly antigenic multifucosylated motifs of GSL glycans were not observed in lung LN ASC probes, indicating that these antigens are not expressed in lung stage schistosomula or are not appropriately exposed to induce immune responses locally. The local antiglycan responses observed in this study highlight the stage- and tissue-specific expression of antigenic parasite glycans and provide insights into glycan targets possibly involved in resistance toS. japonicuminfection.
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McCarthy, James S., Moira Wieseman, Joe Tropea, David Kaslow, David Abraham, Sara Lustigman, Rocky Tuan, Ronald H. Guderian, and Thomas B. Nutman. "Onchocerca volvulus Glycolytic Enzyme Fructose-1,6-Bisphosphate Aldolase as a Target for a Protective Immune Response in Humans." Infection and Immunity 70, no. 2 (February 2002): 851–58. http://dx.doi.org/10.1128/iai.70.2.851-858.2002.
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ABSTRACT To identify potential vaccine candidates for the prevention of infection with the filarial nematode Onchocerca volvulus, we screened an O. volvulus L3 stage cDNA library with sera from putatively immune (PI) subjects, and a prominent immunogenic clone of 1,184 nucleotides was identified. It contained an open reading frame of 363 amino acids encoding the glycolytic enzyme fructose 1,6 bisphosphate aldolase (Ov-fba-1). Immunolocalization experiments demonstrated that the protein was most abundantly expressed in metabolically active tissues, including body wall muscle and the reproductive tract of adult female worms. Immunoelectron microscopy of L3 demonstrated binding in the region where the cuticle separates during molting, in the channels connecting the esophagus to the cuticle, and in the basal lamina surrounding the esophagus and the body cavity. Among subjects from areas where this organism is endemic specific humoral and cellular immune responses to recombinant protein were observed in both PI and infected subjects, whereas responses were not observed among subjects who had not been exposed to O. volvulus. Despite the absence of differential responsiveness in parasite-exposed human populations, when the recombinant was tested for protective efficacy in a mouse chamber model, a reduction in survival of larvae by ca. 50% was seen. This observation provides support for the further study of this parasite enzyme as a vaccine candidate in larger animal models.
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Sakthivel, Dhanasekaran, Jaclyn Swan, Sarah Preston, MD Shakif-Azam, Pierre Faou, Yaqing Jiao, Rachael Downs, et al. "Proteomic identification of galectin-11 and 14 ligands fromHaemonchus contortus." PeerJ 6 (March 19, 2018): e4510. http://dx.doi.org/10.7717/peerj.4510.
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Haemonchus contortusis the most pathogenic nematode of small ruminants. Infection in sheep and goats results in anaemia that decreases animal productivity and can ultimately cause death. The involvement of ruminant-specific galectin-11 (LGALS-11) and galectin-14 (LGALS-14) has been postulated to play important roles in protective immune responses against parasitic infection; however, their ligands are unknown. In the current study, LGALS-11 and LGALS-14 ligands inH. contortuswere identified from larval (L4) and adult parasitic stages extracts using immobilised LGALS-11 and LGALS-14 affinity column chromatography and mass spectrometry. Both LGALS-11 and LGALS-14 bound more putative protein targets in the adult stage ofH. contortus(43 proteins) when compared to the larval stage (two proteins). Of the 43 proteins identified in the adult stage, 34 and 35 proteins were bound by LGALS-11 and LGALS-14, respectively, with 26 proteins binding to both galectins. Interestingly, hematophagous stage-specific sperm-coating protein and zinc metalloprotease (M13), which are known vaccine candidates, were identified as putative ligands of both LGALS-11 and LGALS-14. The identification of glycoproteins ofH. contortusby LGALS-11 and LGALS-14 provide new insights into host-parasite interactions and the potential for developing new interventions.
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Sack, Brandon K., Jessica L. Miller, Ashley M. Vaughan, Alyse Douglass, Alexis Kaushansky, Sebastian Mikolajczak, Alida Coppi, et al. "Model forIn VivoAssessment of Humoral Protection against Malaria Sporozoite Challenge by Passive Transfer of Monoclonal Antibodies and Immune Serum." Infection and Immunity 82, no. 2 (December 9, 2013): 808–17. http://dx.doi.org/10.1128/iai.01249-13.
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ABSTRACTEvidence from clinical trials of malaria vaccine candidates suggests that both cell-mediated and humoral immunity to pre-erythrocytic parasite stages can provide protection against infection. Novel pre-erythrocytic antibody (Ab) targets could be key to improving vaccine formulations, which are currently based on targeting antigens such as the circumsporozoite protein (CSP). However, methods to assess the effects of sporozoite-specific Abs on pre-erythrocytic infectionin vivoremain underdeveloped. Here, we combined passive transfer of monoclonal Abs (MAbs) or immune serum with a luciferase-expressingPlasmodium yoeliisporozoite challenge to assess Ab-mediated inhibition of liver infection in mice. Passive transfer of aP. yoeliiCSP MAb showed inhibition of liver infection when mice were challenged with sporozoites either intravenously or by infectious mosquito bite. However, inhibition was most potent for the mosquito bite challenge, leading to a more significant reduction of liver-stage burden and even a lack of progression to blood-stage parasitemia. This suggests that Abs provide effective protection against a natural infection. Inhibition of liver infection was also achieved by passive transfer of immune serum from whole-parasite-immunized mice. Furthermore, we demonstrated that passive transfer of a MAb againstP. falciparumCSP inhibited liver-stage infection in a humanized mouse/P. falciparumchallenge model. Together, these models constitute unique and sensitivein vivomethods to assess serum-transferable protection againstPlasmodiumsporozoite challenge.
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Haase, Silvia, Ana Cabrera, Christine Langer, Moritz Treeck, Nicole Struck, Susann Herrmann, Pascal W. Jansen, et al. "Characterization of a Conserved Rhoptry-Associated Leucine Zipper-Like Protein in the Malaria Parasite Plasmodium falciparum." Infection and Immunity 76, no. 3 (January 3, 2008): 879–87. http://dx.doi.org/10.1128/iai.00144-07.
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ABSTRACT One of the key processes in the pathobiology of the malaria parasite is the invasion and subsequent modification of the human erythrocyte. In this complex process, an unknown number of parasite proteins are involved, some of which are leading vaccine candidates. The majority of the proteins that play pivotal roles in invasion are either stored in the apical secretory organelles or located on the surface of the merozoite, the invasive stage of the parasite. Using transcriptional and structural features of these known proteins, we performed a genomewide search that identified 49 hypothetical proteins with a high probability of being located on the surface of the merozoite or in the secretory organelles. Of these candidates, we characterized a novel leucine zipper-like protein in Plasmodium falciparum that is conserved in Plasmodium spp. This protein is expressed in late blood stages and localizes to the rhoptries of the parasite. We demonstrate that this Plasmodium sp.-specific protein has a high degree of conservation within field isolates and that it is refractory to gene knockout attempts and thus might play an important role in invasion.
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Zhang, Guoquan, Katalin Kiss, Rekha Seshadri, Laura R. Hendrix, and James E. Samuel. "Identification and Cloning of Immunodominant Antigens of Coxiella burnetii." Infection and Immunity 72, no. 2 (February 2004): 844–52. http://dx.doi.org/10.1128/iai.72.2.844-852.2004.
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ABSTRACT A sublethal-challenge model was established in BALB/c mice by using protection from the development of severe splenomegaly as an indicator of vaccinogenic activity for evaluation of the protective efficacies of vaccine candidates. To determine the immunodominant antigens as defined by reaction to an infection-derived antibody, mouse sera from different stages of experimental infection with various doses of Coxiella burnetii were tested by immunoblotting. Proteins with molecular masses of 14, 16, 21, 28, 32, 45 to 50, 57, and 60 kDa were recognized as immunodominant antigens. Antibody responses in whole-cell antigen (WCA)-vaccinated mice were compared with those in unvaccinated mice by immunoblotting using two-dimensional gel-separated C. burnetii antigens. The results indicated that there were significantly different antibody responses during different stages of vaccination and challenge, suggesting that several specific immunogenic antigens may play critical roles in the protection of mice against challenge. To clone these immunogenic antigens, a genomic DNA library of Nine Mile phase I was screened with convalescent-phase antisera from mice. Eighteen novel immunoreactive proteins with molecular masses ranging from ∼14 to 67 kDa were cloned and identified. Interestingly, several recombinant proteins reacted with sera from both early-stage infected and WCA-vaccinated prechallenged mice. These results suggest that these proteins may play critical roles in the development of protective immunity and that they are logical candidates for vaccine and serodiagnostic reagents.
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SCHOLZEN, ANJA, and ROBERT W. SAUERWEIN. "Immune activation and induction of memory: lessons learned from controlled human malaria infection with Plasmodium falciparum." Parasitology 143, no. 2 (January 7, 2016): 224–35. http://dx.doi.org/10.1017/s0031182015000761.
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SUMMARYControlled human malaria infections (CHMIs) are a powerful tool to assess the efficacy of drugs and/or vaccine candidates, but also to study anti-malarial immune responses at well-defined time points after infection. In this review, we discuss the insights that CHMI trials have provided into early immune activation and regulation during acute infection, and the capacity to induce and maintain immunological memory. Importantly, these studies show that a single infection is sufficient to induce long-lasting parasite-specific T- and B-cell memory responses, and suggest that blood-stage induced regulatory responses can limit inflammation both in ongoing and potentially future infections. As future perspective of investigation in CHMIs, we discuss the role of innate cell subsets, the interplay between innate and adaptive immune activation and the potential modulation of these responses after natural pre-exposure.
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Gozar, Mary Margaret G., Virginia L. Price, and David C. Kaslow. "Saccharomyces cerevisiae-Secreted Fusion Proteins Pfs25 and Pfs28 Elicit Potent Plasmodium falciparum Transmission-Blocking Antibodies in Mice." Infection and Immunity 66, no. 1 (January 1, 1998): 59–64. http://dx.doi.org/10.1128/iai.66.1.59-64.1998.
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ABSTRACT Transmission-blocking vaccines based on sexual-stage surface antigens of Plasmodium falciparum may assist in the control of this lethal form of human malaria. Two vaccine candidates, Pfs25 and Pfs28, were produced as single recombinant fusion proteins. The 39-kDa chimeric proteins, having a C-terminal His6 tag, were secreted by Saccharomyces cerevisiae, using the prepro-α-factor leader sequence. Pfs25-28 fusion proteins were significantly more potent than either Pfs25 or Pfs28 alone in eliciting antibodies in mice that blocked oocyst development in Anopheles freeborni mosquitoes: complete inhibition of oocyst development in the mosquito midgut was achieved with fewer vaccinations, at a lower dose, and for a longer duration than with either Pfs25 or Pfs28 alone. Increased antigen-specific immunoglobulin G titers and highly significant lymphoproliferative stimulation by Pfs28-containing antigens suggest the presence of an immunodominant helper T-cell epitope in the Pfs28 portion of the fusion proteins. This epitope may be responsible for the enhanced humoral response to both Pfs25 and Pfs28 antigens. Protein production of the fusion protein was improved 12-fold by converting Pfs28 codons to yeast-preferred codons (TBV28), using a modified ADH 2 promoter and incorporating a (Glu-Ala)2 repeat after the Kex2 cleavage site.
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Darko, Christian A., Evelina Angov, William E. Collins, Elke S. Bergmann-Leitner, Autumn S. Girouard, Stacy L. Hitt, Jana S. McBride, et al. "The Clinical-Grade 42-Kilodalton Fragment of Merozoite Surface Protein 1 of Plasmodium falciparum Strain FVO Expressed in Escherichia coli Protects Aotus nancymai against Challenge with Homologous Erythrocytic-Stage Parasites." Infection and Immunity 73, no. 1 (January 2005): 287–97. http://dx.doi.org/10.1128/iai.73.1.287-297.2005.
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ABSTRACT A 42-kDa fragment from the C terminus of major merozoite surface protein 1 (MSP1) is among the leading malaria vaccine candidates that target infection by asexual erythrocytic-stage malaria parasites. The MSP142 gene fragment from the Vietnam-Oak Knoll (FVO) strain of Plasmodium falciparum was expressed as a soluble protein in Escherichia coli and purified according to good manufacturing practices. This clinical-grade recombinant protein retained some important elements of correct structure, as it was reactive with several functional, conformation-dependent monoclonal antibodies raised against P. falciparum malaria parasites, it induced antibodies (Abs) that were reactive to parasites in immunofluorescent Ab tests, and it induced strong growth and invasion inhibitory antisera in New Zealand White rabbits. The antigen quality was further evaluated by vaccinating Aotus nancymai monkeys and challenging them with homologous P. falciparum FVO erythrocytic-stage malaria parasites. The trial included two control groups, one vaccinated with the sexual-stage-specific antigen of Plasmodium vivax, Pvs25, as a negative control, and the other vaccinated with baculovirus-expressed MSP142 (FVO) as a positive control. Enzyme-linked immunosorbent assay (ELISA) Ab titers induced by E. coli MSP142 were significantly higher than those induced by the baculovirus-expressed antigen. None of the six monkeys that were vaccinated with the E. coli MSP142 antigen required treatment for uncontrolled parasitemia, but two required treatment for anemia. Protective immunity in these monkeys correlated with the ELISA Ab titer against the p19 fragment and the epidermal growth factor (EGF)-like domain 2 fragment of MSP142, but not the MSP142 protein itself or the EGF-like domain 1 fragment. Soluble MSP142 (FVO) expressed in E. coli offers excellent promise as a component of a vaccine against erythrocytic-stage falciparum malaria.
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Gupta, Puneet K., Paushali Mukherjee, Shikha Dhawan, Alok K. Pandey, Suman Mazumdar, Deepak Gaur, S. K. Jain, and Virander S. Chauhan. "Production and Preclinical Evaluation of Plasmodium falciparum MSP-119and MSP-311Chimeric Protein, PfMSP-Fu24." Clinical and Vaccine Immunology 21, no. 6 (April 30, 2014): 886–97. http://dx.doi.org/10.1128/cvi.00179-14.
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ABSTRACTAPlasmodium falciparumchimeric protein, PfMSP-Fu24, was constructed by genetically coupling immunodominant, conserved regions of two merozoite surface proteins, the 19-kDa region C-terminal region of merozoite surface protein 1 (PfMSP-119) and an 11-kDa conserved region of merozoite surface protein 3 (PfMSP-311), to augment the immunogenicity potential of these blood-stage malaria vaccine candidates. Here we describe an improved, efficient, and scalable process to produce high-quality PfMSP-Fu24. The chimeric protein was produced inEscherichia coliSHuffle T7 ExpresslysYcells that express disulfide isomerase DsbC. A two-step purification process comprising metal affinity followed by cation exchange chromatography was developed, and we were able to obtain PfMSP-Fu24with purity above 99% and with a considerable yield of 23 mg/liter. Immunogenicity of PfMSP-Fu24formulated with several adjuvants, including Adjuplex, Alhydrogel, Adjuphos, Alhydrogel plus glucopyranosyl lipid adjuvant, aqueous (GLA-AF), Adjuphos+GLA-AF, glucopyranosyl lipid adjuvant-stable emulsion (GLA-SE), and Freund's adjuvant, was evaluated. PfMSP-Fu24formulated with GLA-SE and Freund's adjuvant in mice and with Alhydrogel and Freund's adjuvant in rabbits produced high titers of PfMSP-119and PfMSP-311-specific functional antibodies. Some of the adjuvant formulations induced inhibitory antibody responses and inhibitedin vitrogrowth ofP. falciparumparasites in the presence as well as in the absence of human monocytes. These results suggest that PfMSP-Fu24can form a constituent of a multistage malaria vaccine.
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Pradel, Gabriele, Karen Hayton, L. Aravind, Lakshminarayan M. Iyer, Mitchell S. Abrahamsen, Annemarie Bonawitz, Cesar Mejia, and Thomas J. Templeton. "A Multidomain Adhesion Protein Family Expressed in Plasmodium falciparum Is Essential for Transmission to the Mosquito." Journal of Experimental Medicine 199, no. 11 (June 7, 2004): 1533–44. http://dx.doi.org/10.1084/jem.20031274.
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The recent sequencing of several apicomplexan genomes has provided the opportunity to characterize novel antigens essential for the parasite life cycle that might lead to the development of new diagnostic and therapeutic markers. Here we have screened the Plasmodium falciparum genome sequence for genes encoding extracellular multidomain putative adhesive proteins. Three of these identified genes, named PfCCp1, PfCCp2, and PfCCp3, have multiple adhesive modules including a common Limulus coagulation factor C domain also found in two additional Plasmodium genes. Orthologues were identified in the Cryptosporidium parvum genome sequence, indicating an evolutionary conserved function. Transcript and protein expression analysis shows sexual stage–specific expression of PfCCp1, PfCCp2, and PfCCp3, and cellular localization studies revealed plasma membrane–associated expression in mature gametocytes. During gametogenesis, PfCCps are released and localize surrounding complexes of newly emerged microgametes and macrogametes. PfCCp expression markedly decreased after formation of zygotes. To begin to address PfCCp function, the PfCCp2 and PfCCp3 gene loci were disrupted by homologous recombination, resulting in parasites capable of forming oocyst sporozoites but blocked in the salivary gland transition. Our results describe members of a conserved apicomplexan protein family expressed in sexual stage Plasmodium parasites that may represent candidates for subunits of a transmission-blocking vaccine.
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Coley, A. M., K. Parisi, R. Masciantonio, J. Hoeck, J. L. Casey, V. J. Murphy, K. S. Harris, A. H. Batchelor, R. F. Anders, and M. Foley. "The Most Polymorphic Residue on Plasmodium falciparum Apical Membrane Antigen 1 Determines Binding of an Invasion-Inhibitory Antibody." Infection and Immunity 74, no. 5 (May 2006): 2628–36. http://dx.doi.org/10.1128/iai.74.5.2628-2636.2006.
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ABSTRACT Apical membrane antigen 1 (AMA1) is currently one of the leading malarial vaccine candidates. Anti-AMA1 antibodies can inhibit the invasion of erythrocytes by Plasmodium merozoites and prevent the multiplication of blood-stage parasites. Here we describe an anti-AMA1 monoclonal antibody (MAb 1F9) that inhibits the invasion of Plasmodium falciparum parasites in vitro. We show that both reactivity of MAb 1F9 with AMA1 and MAb 1F9-mediated invasion inhibition were strain specific. Site-directed mutagenesis of a fragment of AMA1 displayed on M13 bacteriophage identified a single polymorphic residue in domain I of AMA1 that is critical for MAb 1F9 binding. The identities of all other polymorphic residues investigated in this domain had little effect on the binding of the antibody. Examination of the P. falciparum AMA1 crystal structure localized this residue to a surface-exposed α-helix at the apex of the polypeptide. This description of a polymorphic inhibitory epitope on AMA1 adds supporting evidence to the hypothesis that immune pressure is responsible for the polymorphisms seen in this molecule.
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Amici, Carla, Maria Gabriella Donà, Barbara Chirullo, Paola Di Bonito, and Luisa Accardi. "Epitope Mapping and Computational Analysis of Anti-HPV16 E6 and E7 Antibodies in Single-Chain Format for Clinical Development as Antitumor Drugs." Cancers 12, no. 7 (July 6, 2020): 1803. http://dx.doi.org/10.3390/cancers12071803.
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Human Papillomavirus 16-associated cancer, affecting primarily the uterine cervix but, increasingly, other body districts, including the head–neck area, will long be a public health problem, despite there being a vaccine. Since the virus oncogenic activity is fully ascribed to the viral E6 and E7 oncoproteins, one of the therapeutic approaches for HPV16 cancer is based on specific antibodies in single-chain format targeting the E6/E7 activity. We analyzed the Complementarity Determining Regions, repositories of antigen-binding activity, of four anti-HPV16 E6 and -HPV16 E7 scFvs, to highlight possible conformity to biophysical properties, recognized to be advantageous for therapeutic use. By epitope mapping, using E7 mutants with amino acid deletions or variations, we investigated differences among the anti-16E7 scFvs in terms of antigen-binding capacity. We also performed computational analyses to determine whether length, total net charge, surface hydrophobicity, polarity and charge distribution conformed well to those of the antibodies that had already reached clinical use, through the application of developability guidelines derived from recent literature on clinical-stage antibodies, and the Therapeutic Antibodies Profiler software. Overall, our findings show that the scFvs investigated may represent valid candidates to be developed as therapeutic molecules for clinical use, and highlight characteristics that could be improved by molecular engineering.
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Berger, Imre, Christine Tölzer, and Kapil Gupta. "The MultiBac system: a perspective." Emerging Topics in Life Sciences 3, no. 5 (September 4, 2019): 477–82. http://dx.doi.org/10.1042/etls20190084.
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Baculovirus expression is a time-tested technique to produce proteins in insect cells, in high quality and quantity for a range of applications. MultiBac is a baculovirus expression system we developed originally for producing multiprotein complexes comprising many subunits, for structural and mechanistic studies. First introduced in 2004, MultiBac is now in use in many laboratories worldwide, accelerating research programmes in academia and industry. We have continuously optimized our MultiBac system, providing customized reagents and standard operating protocols to facilitate its use also by non-specialists. More recently, we have generated MultiBac genomes tailored for specific purposes, for example, to produce humanized glycoproteins, high-value pharmaceutical targets including kinases, viral polymerases, and virus-like particles (VLPs) as promising vaccine candidates. By altering the host tropism of the baculovirion, we created MultiBacMam, a heterologous DNA delivery toolkit to target mammalian cells, tissues and organisms. Introducing CRISPR/Cas modalities, we set the stage for large-scale genomic engineering applications utilizing this high-capacity DNA delivery tool. Exploiting synthetic biology approaches and bottom-up design, we engage in optimizing the properties of our baculoviral genome, also to improve manufacturing at scale. Here we provide a perspective of our MultiBac system and its developments, past, present and future.
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Aka, Peter, Maria Vila, Amar Jariwala, Francis Nkrumah, Benjamin Emmanuel, Masanory Yagi, Nirianne Palacpac, et al. "Risk of Burkitt Lymphoma Correlates with Breadth and Strength of Antibody Response to Plasmodium Falciparum Malaria Stage-Specific Antigens." Blood 120, no. 21 (November 16, 2012): LBA—3—LBA—3. http://dx.doi.org/10.1182/blood.v120.21.lba-3.lba-3.
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Abstract Abstract LBA-3 The incidence of endemic Burkitt lymphoma (eBL) is high in areas where Plasmodium falciparum (Pf) malaria is endemic, which suggests a role of malaria in eBL etiology. Previous data suggest that children with eBL are 5–12 times more likely to have elevated antibody titers to the whole schizont extract, a surrogate of exposure to malaria, compared to controls of comparable age and sex without eBL. However, the corollary studies to understand the role of protective malarial antibodies in eBL have not been conducted. We hypothesized that the risk for eBL might be different according to the breadth and strength of protective immunity to clinical malaria in children exposed to Pf malaria parasites. We investigated this hypothesis in children with and without eBL cases using samples from the National Cancer Institutes (NCI) Ghana Burkitt Lymphoma Study. Cases were children aged 0–15 years enrolled at the Korle-Bu Teaching Hospital, Accra, Ghana, during 1965–1994. Controls were children enrolled contemporaneously from the same villages as the cases or children who were referred to Korle-Bu as BL but diagnosed with benign or a non-hematologic malignancy. Antibodies to recombinant Pf serine repeat antigen 36 (SE 36) and merozoite surface protein-1 (MSP-1), which are blood stage vaccine candidates, and antibodies to histidine-rich protein-II (HRP-II), an exposure antigen expressed during the blood stage, and the peptide 6NANP, which is a circumsporozoite protein (CSP) expressed in the pre-hepatic stage, were measured using sub-class-specific enzyme-linked absorbent immunoassays (ELISAs). Antibodies to tetanus toxoid were measured as an irrelevant antigen control. Markers were included if the within (W)- and between (B)-plate coefficients of variation for the sub-class-specific IgG results was <30% (Figure 1). The independent association of each malaria marker with eBL was determined by calculating the odds ratio (ORs) and 95% confidence intervals (95% CIs) using unconditional multivariable logistic regression adjusted for sex, age, calendar year, and for all the other malaria markers, which were hypothesized to be contributory. In adjusted results, eBL was inversely associated with IgG1 seropositivity to SE36 (OR 0.54 [95% CI 0.34–0.86], p=0.01) and positively associated with HRPII (OR 1.47 [95% CI 1.06–2.02], p=0.019). The ORs for eBL were significantly decreased for low, medium, and high titers, but without a trend (0.44, 0.47, and 0.58 for low, medium, and high, respectively [ptrend=0.216]) (Figure 2: Odds ratios and 95% confidence intervals of association of eBL with different malaria markers). They increased significantly with increasing titers of IgG3 antibodies to HRPII (ORs 1.83, 1.91, to 2.25 for low, medium, and high titers, respectively [ptrend<0.002]) and showed a trend. Having antibodies to 6NANP was associated with eBL (OR 1.48 [95% CI 0.90–2.43]), but among the positives, having medium and high IgG3 antibodies to 6NANP as opposed to being sero-negative was associated with decreased risk of BL (ORs 0.79 and OR 0.60, respectively [ptrend=0.002]). Models with three markers (IgG1 to SE36, IgG3 to HRP-II, and IgG3 to 6NANP) predicted eBL better than models with just one of the markers. These data suggest children with eBL in Ghana had decreased SE36 IgG1 and increased HRPII IgG3 antibodies compared to children without eBL from the same Pf endemic areas. These results fit with the hypothesis that eBL risk increases with greater exposure to Pf malaria parasites. They also provide the first confirmation of the hypothesis that antibodies elicited by antigens targeted by protective immunity might be protective for eBL. However, they also highlight that the relationship between eBL and Pf antibodies is complex as it appears to depend on whether the antibodies reflect exposure, protection, or both. A better understanding of the specific contribution of immune response to malaria in eBL risk should be the priority of efforts to discover a biomarker profile for eBL. Disclosures: No relevant conflicts of interest to declare.
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SCHICHT, SABINE, WEIHONG QI, LUCY POVEDA, and CHRISTINA STRUBE. "Whole transcriptome analysis of the poultry red mite Dermanyssus gallinae (De Geer, 1778)." Parasitology 141, no. 3 (October 18, 2013): 336–46. http://dx.doi.org/10.1017/s0031182013001467.
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SUMMARYAlthough the poultry red mite Dermanyssus gallinae (De Geer, 1778) is the major parasitic pest in poultry farming causing substantial economic losses every year, nucleotide data are rare in the public databases. Therefore, de novo sequencing covering the transcriptome of D. gallinae was carried out resulting in a dataset of 232 097 singletons and 42 130 contiguous sequences (contigs) which were subsequently clustered into 24 140 isogroups consisting of 35 788 isotigs. After removal of sequences possibly originating from bacteria or the chicken host, 267 464 sequences (231 657 singletons, 56 contigs and 35 751 isotigs) remained, of which 10·3% showed homology to proteins derived from other organisms. The most significant Blast top-hit species was the mite Metaseiulus occidentalis followed by the tick Ixodes scapularis. To gain functional knowledge of D. gallinae transcripts, sequences were mapped to Gene Ontology terms, Kyoto Encyclopedia of Gene and Genomes (KEGG) pathways and parsed to InterProScan. The transcriptome dataset provides new insights in general mite genetics and lays a foundation for future studies on stage-specific transcriptomics as well as genomic, proteomic, and metabolomic explorations and might provide new perspectives to control this parasitic mite by identifying possible drug targets or vaccine candidates. It is also worth noting that in different tested species of the class Arachnida no 28S rRNA was detectable in the rRNA profile, indicating that 28S rRNA might consists of two separate, hydrogen-bonded fragments, whose (heat-induced) disruption may led to co-migration with 18S rRNA.
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Dejon-Agobe, Jean Claude, Ulysse Ateba-Ngoa, Albert Lalremruata, Andreas Homoet, Julie Engelhorn, Odilon Paterne Nouatin, Jean Ronald Edoa, et al. "Controlled Human Malaria Infection of Healthy Adults With Lifelong Malaria Exposure to Assess Safety, Immunogenicity, and Efficacy of the Asexual Blood Stage Malaria Vaccine Candidate GMZ2." Clinical Infectious Diseases 69, no. 8 (December 18, 2018): 1377–84. http://dx.doi.org/10.1093/cid/ciy1087.
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AbstractBackgroundGMZ2 is a recombinant malaria vaccine inducing immune responses against Plasmodium falciparum (Pf) merozoite surface protein-3 and glutamate-rich protein. We used standardized controlled human malaria infection (CHMI) to assess the efficacy of this asexual blood-stage vaccine.MethodsWe vaccinated 50 healthy, adult volunteers with lifelong exposure to Pf 3 times, at 4-week intervals, with 30 or 100 µg GMZ2 formulated in CAF01, a liposome-based adjuvant; 100 µg GMZ2, formulated in Alhydrogel; or a control vaccine (Verorab). Approximately 13 weeks after the last vaccination, 35/50 volunteers underwent CHMI by direct venous inoculation of 3200 Pf sporozoites (Sanaria® PfSPZ Challenge).ResultsAdverse events were similarly distributed between GMZ2 and control vaccinees. Baseline-corrected anti-GMZ2 antibody concentrations 4 weeks after the last vaccination were higher in all 3 GMZ2-vaccinated arms, compared to the control group. All GMZ2 formulations induced similar antibody levels. CHMI resulted in 29/34 (85%) volunteers with Pf parasitemia and 15/34 (44%) with malaria (parasitemia and symptoms). The proportion of participants with malaria (2/5 control, 6/10 GMZ2-Alhydrogel, 2/8 30 µg GMZ2-CAF01, and 5/11 100 µg GMZ2-CAF01) and the time it took them to develop malaria were similar in all groups. Baseline, vaccine-specific antibody concentrations were associated with protection against malaria.ConclusionsGMZ2 is well tolerated and immunogenic in lifelong–Pf-exposed adults from Gabon, with similar antibody responses regardless of formulation. CHMI showed no protective effect of prior vaccination with GMZ2, although baseline, vaccine-specific antibody concentrations were associated with protection. CHMI with the PfSPZ Challenge is a potent new tool to validate asexual, blood-stage malaria vaccines in Africa.Clinical Trials RegistrationPan-African Clinical Trials: PACTR201503001038304
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Williamson, K. C., H. Fujioka, M. Aikawa, and D. C. Kaslow. "Stage-specific processing of Pfs230, a Plasmodium falciparum transmission-blocking vaccine candidate." Molecular and Biochemical Parasitology 78, no. 1-2 (June 1996): 161–69. http://dx.doi.org/10.1016/s0166-6851(96)02621-7.
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Burns, James M., Patrick R. Flaherty, Payal Nanavati, and William P. Weidanz. "Protection against Plasmodium chabaudi Malaria Induced by Immunization with Apical Membrane Antigen 1 and Merozoite Surface Protein 1 in the Absence of Gamma Interferon or Interleukin-4." Infection and Immunity 72, no. 10 (October 2004): 5605–12. http://dx.doi.org/10.1128/iai.72.10.5605-5612.2004.
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ABSTRACT Strategies to optimize formulations of multisubunit malaria vaccines require a basic knowledge of underlying protective immune mechanisms induced by each vaccine component. In the present study, we evaluated the contribution of antibody-mediated and cell-mediated immune mechanisms to the protection induced by immunization with two blood-stage malaria vaccine candidate antigens, apical membrane antigen 1 (AMA-1) and merozoite surface protein 1 (MSP-1). Immunologically intact or selected immunologic knockout mice were immunized with purified recombinant Plasmodium chabaudi AMA-1 (PcAMA-1) and/or the 42-kDa C-terminal processing fragment of P. chabaudi MSP-1 (MSP-142). The efficacy of immunization in each animal model was measured as protection against blood-stage P. chabaudi malaria. Immunization of B-cell-deficient JH −/− mice indicated that PcAMA-1 vaccine-induced immunity is largely antibody dependent. In contrast, JH −/− mice immunized with PcMSP-142 were partially protected against P. chabaudi malaria, indicating a role for protective antibody-dependent and antibody-independent mechanisms of immunity. The involvement of γδ T cells in vaccine-induced PcAMA-1 and/or PcMSP-142 protection was minor. Analysis of the isotypic profile of antigen-specific antibodies induced by immunization of immunologically intact mice revealed a dominant IgG1 response. However, neither interleukin-4 and the production of IgG1 antibodies nor gamma interferon and the production of IgG2a/c antibodies were essential for PcAMA-1 and/or PcMSP-142 vaccine-induced protection. Therefore, for protective antibody-mediated immunity, vaccine adjuvants and delivery systems for AMA-1- and MSP-1-based vaccines can be selected for their ability to maximize responses irrespective of IgG isotype or any Th1 versus Th2 bias in the CD4+-T-cell response.
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Negahdaripour, Manica, Navid Nezafat, Reza Heidari, Nasrollah Erfani, Nasim Hajighahramani, Mohammad B. Ghoshoon, Eskandar Shoolian, et al. "Production and Preliminary In Vivo Evaluations of a Novel in silico-designed L2-based Potential HPV Vaccine." Current Pharmaceutical Biotechnology 21, no. 4 (March 25, 2020): 316–24. http://dx.doi.org/10.2174/1389201020666191114104850.
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Background: L2-based Human Papillomavirus (HPV) prophylactic vaccines, containing epitopes from HPV minor capsid proteins, are under investigation as second-generation HPV vaccines. No such vaccine has passed clinical trials yet, mainly due to the low immunogenicity of peptide vaccines; so efforts are being continued. A candidate vaccine composed of two HPV16 L2 epitopes, flagellin and a Toll-Like Receptor (TLR) 4 agonist (RS09) as adjuvants, and two universal T-helper epitopes was designed in silico in our previous researches. Methods: The designed vaccine construct was expressed in E. coli BL21 (DE3) and purified through metal affinity chromatography. Following mice vaccination, blood samples underwent ELISA and flow cytometry analyses for the detection of IgG and seven Th1 and Th2 cytokines. Results: Following immunization, Th1 (IFN-γ, IL-2) and Th2 (IL-4, IL-5, IL-10) type cytokines, as well as IgG, were induced significantly compared with the PBS group. Significant increases in IFN-γ, IL-2, and IL-5 levels were observed in the vaccinated group versus Freund’s adjuvant group. Conclusion: The obtained cytokine induction profile implied both cellular and humoral responses, with a more Th-1 favored trend. However, an analysis of specific antibodies against L2 is required to confirm humoral responses. No significant elevation in inflammatory cytokines, (IL-6 and TNF-α), suggested a lack of unwanted inflammatory side effects despite using a combination of two TLR agonists. The designed construct might be capable of inducing adaptive and innate immunity; nevertheless, comprehensive immune tests were not conducted at this stage and will be a matter of future work.
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Malkin, Elissa M., David J. Diemert, Julie H. McArthur, John R. Perreault, Aaron P. Miles, Birgitte K. Giersing, Gregory E. Mullen, et al. "Phase 1 Clinical Trial of Apical Membrane Antigen 1: an Asexual Blood-Stage Vaccine for Plasmodium falciparum Malaria." Infection and Immunity 73, no. 6 (June 2005): 3677–85. http://dx.doi.org/10.1128/iai.73.6.3677-3685.2005.
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ABSTRACT Apical membrane antigen 1 (AMA1), a polymorphic merozoite surface protein, is a leading blood-stage malaria vaccine candidate. A phase 1 trial was conducted with 30 malaria-naïve volunteers to assess the safety and immunogenicity of the AMA1-C1 malaria vaccine. AMA1-C1 contains an equal mixture of recombinant proteins based on sequences from the FVO and 3D7 clones of Plasmodium falciparum. The proteins were expressed in Pichia pastoris and adsorbed on Alhydrogel. Ten volunteers in each of three dose groups (5 μg, 20 μg, and 80 μg) were vaccinated in an open-label study at 0, 28, and 180 days. The vaccine was well tolerated, with pain at the injection site being the most commonly observed reaction. Anti-AMA1 immunoglobulin G (IgG) was detected by enzyme-linked immunosorbent assay (ELISA) in 15/28 (54%) volunteers after the second immunization and in 23/25 (92%) after the third immunization, with equal reactivity to both AMA1-FVO and AMA1-3D7 vaccine components. A significant dose-response relationship between antigen dose and antibody response by ELISA was observed, and the antibodies were predominantly of the IgG1 isotype. Confocal microscopic evaluation of sera from vaccinated volunteers demonstrated reactivity with P. falciparum schizonts in a pattern similar to native parasite AMA1. Antigen-specific in vitro inhibition of both FVO and 3D7 parasites was achieved with IgG purified from sera of vaccinees, demonstrating biological activity of the antibodies. To our knowledge, this is the first AMA1 vaccine candidate to elicit functional immune responses in malaria-naïve humans, and our results support the further development of this vaccine.
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Aidoo, Michael, Ajit Lalvani, Sarah C. Gilbert, Jiang Ting Hu, Pierre Daubersies, Nicole Hurt, Hilton C. Whittle, Pierre Druihle, and Adrian V. S. Hill. "Cytotoxic T-Lymphocyte Epitopes for HLA-B53 and Other HLA Types in the Malaria Vaccine Candidate Liver-Stage Antigen 3." Infection and Immunity 68, no. 1 (January 1, 2000): 227–32. http://dx.doi.org/10.1128/iai.68.1.227-232.2000.
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ABSTRACT The development of an effective preerythrocytic vaccine againstPlasmodium falciparum malaria is likely to require inclusion of components from several preerythrocytic antigens. The association of HLA-B53 with resistance to severe malaria in West Africa provided evidence that HLA class I-restricted CD8+ T-cell responses play a role in protective immunity in African children, supporting data from rodent models of malaria. Previously, a single epitope from liver-stage-specific antigen 1 (LSA-1) has been shown to be recognized by HLA-B53-specific cytotoxic T lymphocytes (CTL), but HLA-B53 epitopes were not found in four other antigens. In this study we measured CTL responses to peptides from the recently sequenced antigen liver-stage antigen 3 (LSA-3) and identified in it a new epitope restricted by HLA-B53. Several CTL epitopes restricted by other class I types were also identified within LSA-3 in studies in The Gambia and Tanzania. CTL were also identified to an additional P. falciparum antigen, exported protein 1 (Exp-1), the homologue of which is a protective antigen in a rodent model of malaria. These findings emphasize the diversity of P. falciparum antigens recognized by CD8+ T cells in humans and support the inclusion of components from several antigens in new CTL-inducing vaccines against malaria.
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Arnot, David E., David R. Cavanagh, Edmond J. Remarque, Alison M. Creasey, Mercy P. K. Sowa, William D. Morgan, Anthony A. Holder, Shirley Longacre, and Alan W. Thomas. "Comparative Testing of Six Antigen-Based Malaria Vaccine Candidates Directed Toward Merozoite-Stage Plasmodium falciparum." Clinical and Vaccine Immunology 15, no. 9 (June 11, 2008): 1345–55. http://dx.doi.org/10.1128/cvi.00172-08.
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ABSTRACT Immunogenicity testing of Plasmodium falciparum antigens being considered as malaria vaccine candidates was undertaken in rabbits. The antigens compared were recombinant baculovirus MSP-119 and five Pichia pastoris candidates, including two versions of MSP-119, AMA-1 (domains I and II), AMA-1+MSP-119, and fused AMA-1/MSP-119). Animals were immunized with equimolar amounts of each antigen, formulated in Montanide ISA720. The specificities and titers of antibodies were compared using immunofluorescence assays and enzyme-linked immunosorbent assay (ELISA). The antiparasite activity of immunoglobulin G (IgG) in in vitro cultures was determined by growth inhibition assay, flow cytometry, lactate dehydrogenase assay, and microscopy. Baculovirus MSP-119 immunizations produced the highest parasite-specific antibody titers in immunofluorescence assays. In ELISAs, baculovirus-produced MSP-119 induced more antibodies than any other single MSP-119 immunogen and three times more MSP-119 specific antibodies than the AMA-1/MSP-119 fusion. Antibodies induced by baculovirus MSP-119 gave the highest levels of growth inhibition in HB3 and 3D7 parasite cultures, followed by AMA-1+MSP-119 and the AMA-1/MSP-119 fusion. With the FCR3 isolate (homologous to the AMA-1 construct), antibodies to the three AMA-1-containing candidates gave the highest levels of growth inhibition at high IgG concentrations, but antibodies to baculovirus MSP-119 inhibited as well or better at lower IgG concentrations. The two P. pastoris-produced MSP-119-induced IgGs conferred the lowest growth inhibition. Comparative analysis of immunogenicity of vaccine antigens can be used to prioritize candidates before moving to expensive GMP production and clinical testing. The assays used have given discriminating readouts but it is not known whether any of them accurately reflect clinical protection.
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Akpogheneta, Onome J., Nancy O. Duah, Kevin K. A. Tetteh, Samuel Dunyo, David E. Lanar, Margaret Pinder, and David J. Conway. "Duration of Naturally Acquired Antibody Responses to Blood-Stage Plasmodium falciparum Is Age Dependent and Antigen Specific." Infection and Immunity 76, no. 4 (January 22, 2008): 1748–55. http://dx.doi.org/10.1128/iai.01333-07.
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ABSTRACT Naturally acquired antibody responses provide partial protection from clinical malaria, and blood-stage parasite vaccines under development aim to prime such responses. To investigate the determinants of antibody response longevity, immunoglobulin G (IgG) antibodies to several blood-stage vaccine candidate antigens in the sera of two cohorts of children of up to 6 years of age during the dry seasons of 2003 and 2004 in The Gambia were examined. The first cohort showed that most antibodies were lost within less than 4 months of the first sampling if a persistent infection was not present, so the study of the second-year cohort involved collecting samples from individuals every 2 weeks over a 3-month period. Antibody responses in the second cohort were also influenced by persistent malaria infection, so analysis focused particularly on children in whom parasites were not detected after the first time point. Antibodies to most antigens declined more slowly in children in the oldest age group (>5 years old) and more rapidly in children in the youngest group (<3 years old). However, antibodies to merozoite surface protein 2 were shorter lived than antibodies to other antigens and were not more persistent in older children. The age-specific and antigen-specific differences were not explained by different IgG subclass response profiles, indicating the probable importance of differential longevities of plasma cell populations rather than antibody molecules. It is likely that young children mostly have short-lived plasma cells and thus experience rapid declines in antibody levels but that older children have longer-lasting antibody responses that depend on long-lived plasma cells.
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Stubbs, Janine, Sope Olugbile, Balam Saidou, Jacques Simpore, Giampietro Corradin, and Antonio Lanzavecchia. "Strain-Transcending Fc-Dependent Killing ofPlasmodium falciparumby Merozoite Surface Protein 2 Allele-Specific Human Antibodies." Infection and Immunity 79, no. 3 (December 28, 2010): 1143–52. http://dx.doi.org/10.1128/iai.01034-10.
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ABSTRACTIt is widely accepted that antibody responses against the human parasitic pathogenPlasmodium falciparumprotect the host from the rigors of severe malaria and death. However, there is a continuing need for the development ofin vitrocorrelate assays of immune protection. To this end, the capacity of human monoclonal and polyclonal antibodies in eliciting phagocytosis and parasite growth inhibition via Fcγ receptor-dependent mechanisms was explored. In examining the extent to which sequence diversity in merozoite surface protein 2 (MSP2) results in the evasion of antibody responses, an unexpectedly high level of heterologous function was measured for allele-specific human antibodies. The dependence on Fcγ receptors for opsonic phagocytosis and monocyte-mediated antibody-dependent parasite inhibition was demonstrated by the mutation of the Fc domain of monoclonal antibodies against both MSP2 and a novel vaccine candidate, peptide 27 from the genePFF0165c. The described flow cytometry-based functional assays are expected to be useful for assessing immunity in naturally infected and vaccinated individuals and for prioritizing among blood-stage antigens for inclusion in blood-stage vaccines.
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Kawabata, Yuko, Heiichiro Udono, Kiri Honma, Masakatsu Ueda, Hiroshi Mukae, Jun-ichi Kadota, Shigeru Kohno, and Katsuyuki Yui. "Merozoite Surface Protein 1-Specific Immune Response Is Protective against Exoerythrocytic Forms of Plasmodium yoelii." Infection and Immunity 70, no. 11 (November 2002): 6075–82. http://dx.doi.org/10.1128/iai.70.11.6075-6082.2002.
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ABSTRACT One of the difficulties in developing an effective malaria vaccine is the antigenic change of the parasite during the life cycle. It is desirable that vaccine-induced protective immunity be effective at different stages of parasite development. Merozoite surface protein 1 (MSP1) is a candidate vaccine antigen against blood-stage malaria, but it is also expressed in the exoerythrocytic forms. It was not known, however, whether the anti-MSP1 immune response is effective against the liver-stage malaria parasite. We generated a recombinant protein of MSP1 fused to heat-shock cognate protein 70 (hsc70) and studied its vaccination effect. When C57BL/6 mice were immunized with the fusion protein prior to challenge infection with Plasmodium yoelii sporozoites, the onset of parasitemia was delayed or no parasitemia was observed. To determine whether this was due to the protective immunity against liver-stage parasites, P. yoelii-specific rRNA in the infected liver was quantitated by real-time reverse transcription-PCR analysis. The level of parasite-specific rRNA was reduced in mice immunized with the fusion protein of MSP1 and hsc70 but not with hsc70 alone, indicating that MSP1-specific immunity can be protective against the exoerythrocytic form of the parasite. Furthermore, the adoptive transfer experiments of immune lymphocytes and serum into naive mice suggested that the protective immunity was dependent on cellular and not humoral immunity. Finally, the vaccine-induced protection was also observed in A/J, C3H, and BALB/c mice, suggesting that MSP1-specific protective immunity at the exoerythrocytic stage can be induced in animals over a wide range of genetic backgrounds.
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Jing, Ran, Rama Rao Vunnam, Yuhong Yang, Adam Karevoll, and Srinivas Rao Vunnam. "Current Status of Treatment Options, Clinical Trials, and Vaccine Development for SARS-CoV-2 Infection." Journal of Pure and Applied Microbiology 14, suppl 1 (May 23, 2020): 733–40. http://dx.doi.org/10.22207/jpam.14.spl1.10.
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The severe acute respiratory syndrome virus (SARS-CoV-2), a novel coronavirus first discovered in Wuhan, China in December 2019 causes the Coronavirus Disease 19 (COVID-19), which presents with a wide range of clinical symptoms from mild or moderate to severe and critical illnesses. With the continuing transmission of the virus worldwide and the rapidly evolving situation globally, the World Health Organization (WHO) declared the COVID-19 outbreak a pandemic in March. Currently, there is no proven specific treatment for this potentially deadly disease beyond supportive care. However, a massive effort has been put globally into the investigation of medications and other interventional measures to fight COVID-19. Convalescent plasma therapy from recovered patients has recently drawn considerable interest. Several alternative medical treatments, although evidence of their efficacy still lacking, have also gained popularity, especially in countries with such traditions such as India and China. Rapid repurposing of drugs for COVID-19 has revealed a few promising candidate antiviral agents, but further research, especially high quality randomized controlled trials, will be needed to prove their efficacy and safety in the clinical use to treat COVID-19. Vaccine development has been the imperative task in the battle against SARS-CoV-2. While clinical trials have been launched for several candidate vaccines, research on COVID-19 vaccines is still at an early stage. So far, optimized supportive care remains the best practice against COVID-19.
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Tambornino, Lisa, and Dirk Lanzerath. "COVID-19 human challenge trials – what research ethics committees need to consider." Research Ethics 16, no. 3-4 (July 2020): 1–11. http://dx.doi.org/10.1177/1747016120943635.
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To reduce the global burden of the COVID-19 pandemic, there is an urgent need to develop a safe vaccine. Vaccine development usually takes many years as it goes through several different phases. To hasten COVID-19 vaccine development, it has been suggested that the final stage could be replaced with a human challenge trial (HCT). Volunteers would be intentionally infected with SARS-CoV-2 to see how the vaccine candidate works. To intentionally infect a healthy human being with a potentially deadly virus is contrary to the highest ethical standards in medical research. This article highlights the benefits and risks of COVID-19 HCTs and summarises what research ethics committees (RECs) need to consider during the ethical assessment of such trials including risk reduction, strict containment measures, specific informed consent measures and avoiding high monetary inducements.
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Reddy, K. Sony, Alok K. Pandey, Hina Singh, Tajali Sahar, Amlabu Emmanuel, Chetan E. Chitnis, Virander S. Chauhan, and Deepak Gaur. "Bacterially Expressed Full-Length Recombinant Plasmodium falciparum RH5 Protein Binds Erythrocytes and Elicits Potent Strain-Transcending Parasite-Neutralizing Antibodies." Infection and Immunity 82, no. 1 (October 14, 2013): 152–64. http://dx.doi.org/10.1128/iai.00970-13.
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ABSTRACTPlasmodium falciparumreticulocyte binding-like homologous protein 5 (PfRH5) is an essential merozoite ligand that binds with its erythrocyte receptor, basigin. PfRH5 is an attractive malaria vaccine candidate, as it is expressed by a wide number ofP. falciparumstrains, cannot be genetically disrupted, and exhibits limited sequence polymorphisms. Viral vector-induced PfRH5 antibodies potently inhibited erythrocyte invasion. However, it has been a challenge to generate full-length recombinant PfRH5 in a bacterial-cell-based expression system. In this study, we have produced full-length recombinant PfRH5 inEscherichia colithat exhibits specific erythrocyte binding similar to that of the native PfRH5 parasite protein and also, importantly, elicits potent invasion-inhibitory antibodies against a number ofP. falciparumstrains. Antibasigin antibodies blocked the erythrocyte binding of both native and recombinant PfRH5, further confirming that they bind with basigin. We have thus successfully produced full-length PfRH5 as a functionally active erythrocyte binding recombinant protein with a conformational integrity that mimics that of the native parasite protein and elicits potent strain-transcending parasite-neutralizing antibodies.P. falciparumhas the capability to develop immune escape mechanisms, and thus, blood-stage malaria vaccines that target multiple antigens or pathways may prove to be highly efficacious. In this regard, antibody combinations targeting PfRH5 and other key merozoite antigens produced potent additive inhibition against multiple worldwideP. falciparumstrains. PfRH5 was immunogenic when immunized with other antigens, eliciting potent invasion-inhibitory antibody responses with no immune interference. Our results strongly support the development of PfRH5 as a component of a combination blood-stage malaria vaccine.
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Chootong, Patchanee, Francis B. Ntumngia, Kelley M. VanBuskirk, Jia Xainli, Jennifer L. Cole-Tobian, Christopher O. Campbell, Tresa S. Fraser, Christopher L. King, and John H. Adams. "Mapping Epitopes of the Plasmodium vivax Duffy Binding Protein with Naturally Acquired Inhibitory Antibodies." Infection and Immunity 78, no. 3 (December 14, 2009): 1089–95. http://dx.doi.org/10.1128/iai.01036-09.
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ABSTRACT Plasmodium vivax Duffy binding protein (DBP) is a merozoite microneme ligand vital for blood-stage infection, which makes it an important candidate vaccine for antibody-mediated immunity against vivax malaria. A differential screen with a linear peptide array compared the reactivities of noninhibitory and inhibitory high-titer human immune sera to identify target epitopes associated with protective immunity. Naturally acquired anti-DBP-specific serologic responses observed in the residents of a region of Papua New Guinea where P. vivax is highly endemic exhibited significant changes in DBP-specific titers over time. The anti-DBP functional inhibition for each serum ranged from complete inhibition to no inhibition even for high-titer responders to the DBP, indicating that epitope specificity is important. Inhibitory immune human antibodies identified specific B-cell linear epitopes on the DBP (SalI) ligand domain that showed significant correlations with inhibitory responses. Affinity-purified naturally acquired antibodies on these epitopes inhibited the DBP erythrocyte binding function greatly, confirming the protective value of specific epitopes. These results represent an important advance in our understanding of part of blood-stage immunity to P. vivax and some of the specific targets for vaccine-elicited antibody protection.
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Heal, Karen G., and Andrew W. Taylor-Robinson. "Tomatine Adjuvantation of Protective Immunity to a Major Pre-erythrocytic Vaccine Candidate of Malaria is Mediated viaCD8+T Cell Release of IFN-γ." Journal of Biomedicine and Biotechnology 2010 (2010): 1–7. http://dx.doi.org/10.1155/2010/834326.
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The glycoalkaloid tomatine, derived from the wild tomato, can act as a powerful adjuvant to elicit an antigen-specific cell-mediated immune response to the circumsporozoite (CS) protein, a major pre-erythrocytic stage malaria vaccine candidate antigen. Using a defined MHC-class-I-restricted CS epitope in aPlasmodium bergheirodent model, antigen-specific cytotoxic T lymphocyte activity and IFN-γsecretion ex vivo were both significantly enhanced compared to responses detected from similarly stimulated splenocytes from naive and tomatine-saline-immunized mice. Further, through lymphocyte depletion it is demonstrated that antigen-specific IFN-γis produced exclusively by theCD8+T cell subset. We conclude that the processing of theP. bergheiCS peptide as an exogenous antigen and its presentation via MHC class I molecules toCD8+T cells leads to an immune response that is an in vitro correlate of protection against pre-erythrocytic malaria. Further characterization of tomatine as an adjuvant in malaria vaccine development is indicated.
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Luo, Xuenong, Yadong Zheng, Junling Hou, Shaohua Zhang, and Xuepeng Cai. "Protection against Asiatic Taenia solium Induced by a Recombinant 45W-4B Protein." Clinical and Vaccine Immunology 16, no. 2 (December 17, 2008): 230–32. http://dx.doi.org/10.1128/cvi.00367-08.
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ABSTRACT Taenia solium is a great threat not only to human health but also to the pig-raising industry. Oncospheral stage-specific 45W proteins are good candidates for the development of anticysticercosis vaccines. In this study, a recombinant 45W-4B protein was highly produced and used for vaccination. Two animal trials resulted in a significant reduction in parasite burden induced by the definite protein against Asiatic T. solium, up to 97.0% and 98.4%, respectively. These provide informative results for the development of effective 45W-4B vaccines against cysticercosis caused by both Chinese and Mexican T. solium isolates and even by other isolates.
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Alaro, James R., Andrea Partridge, Kazutoyo Miura, Ababacar Diouf, Ana M. Lopez, Evelina Angov, Carole A. Long, and James M. Burns. "A Chimeric Plasmodium falciparum Merozoite Surface Protein Vaccine Induces High Titers of Parasite Growth Inhibitory Antibodies." Infection and Immunity 81, no. 10 (July 29, 2013): 3843–54. http://dx.doi.org/10.1128/iai.00522-13.
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ABSTRACTThe C-terminal 19-kDa domain ofPlasmodium falciparummerozoite surface protein 1 (PfMSP119) is an established target of protective antibodies. However, clinical trials ofPfMSP142, a leading blood-stage vaccine candidate which contains the protective epitopes ofPfMSP119, revealed suboptimal immunogenicity and efficacy. Based on proof-of-concept studies in thePlasmodium yoeliimurine model, we produced a chimeric vaccine antigen containing recombinantPfMSP119(rPfMSP119) fused to the N terminus ofP. falciparummerozoite 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 forPfMSP8, this T cell response was adequate to provide help for the production of high titers of antibodies to bothPfMSP119and 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 ofPfMSP119(FVO and 3D7). Of particular interest, immunization withPfMSP1/8 elicited higher titers ofPfMSP119-specific antibodies than a combined formulation of rPfMSP142and rPfMSP8 (ΔAsn/Asp). As a measure of functionality,PfMSP1/8-specific rabbit IgG was shown to potently inhibit thein vitrogrowth of blood-stage parasites of the FVO and 3D7 strains ofP. falciparum. These data support the further testing and evaluation of this chimericPfMSP1/8 antigen as a component of a multivalent vaccine forP. falciparummalaria.
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Wieczorek, Lindsay, Shelly J. Krebs, Vaniambadi Kalyanaraman, Stephen Whitney, Sodsai Tovanabutra, Carlos G. Moscoso, Eric Sanders-Buell, et al. "Comparable Antigenicity and Immunogenicity of Oligomeric Forms of a Novel, Acute HIV-1 Subtype C gp145 Envelope for Use in Preclinical and Clinical Vaccine Research." Journal of Virology 89, no. 15 (May 13, 2015): 7478–93. http://dx.doi.org/10.1128/jvi.00412-15.
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ABSTRACTEliciting broadly reactive functional antibodies remains a challenge in human immunodeficiency virus type 1 (HIV-1) vaccine development that is complicated by variations in envelope (Env) subtype and structure. The majority of new global HIV-1 infections are subtype C, and novel antigenic properties have been described for subtype C Env proteins. Thus, an HIV-1 subtype C Env protein (CO6980v0c22) from an infected person in the acute phase (Fiebig stage I/II) was developed as a research reagent and candidate immunogen. The gp145 envelope is a novel immunogen with a fully intact membrane-proximal external region (MPER), extended by a polylysine tail. Soluble gp145 was enriched for trimers that yielded the expected “fan blade” motifs when visualized by cryoelectron microscopy. CO6980v0c22 gp145 reacts with the 4E10, PG9, PG16, and VRC01 HIV-1 neutralizing monoclonal antibodies (MAbs), as well as the V1/V2-specific PGT121, 697, 2158, and 2297 MAbs. Different gp145 oligomers were tested for immunogenicity in rabbits, and purified dimers, trimers, and larger multimers elicited similar levels of cross-subtype binding and neutralizing antibodies to tier 1 and some tier 2 viruses. Immunized rabbit sera did not neutralize the highly resistant CO6980v0c22 pseudovirus but did inhibit the homologous infectious molecular clone in a peripheral blood mononuclear cell (PBMC) assay. This Env is currently in good manufacturing practice (GMP) production to be made available for use as a clinical research tool and further evaluation as a candidate vaccine.IMPORTANCEAt present, the product pipeline for HIV vaccines is insufficient and is limited by inadequate capacity to produce large quantities of vaccine to standards required for human clinical trials. Such products are required to evaluate critical questions of vaccine formulation, route, dosing, and schedule, as well as to establish vaccine efficacy. The gp145 Env protein presented in this study forms physical trimers, binds to many of the well-characterized broad neutralizing MAbs that target conserved Env epitopes, and induce cross-subtype neutralizing antibodies as measured in both cell line and primary cell assays. This subtype C Env gp145 protein is currently undergoing good manufacturing practice production for use as a reagent for preclinical studies and for human clinical research. This product will serve as a reagent for comparative studies and may represent a next-generation candidate HIV immunogen.
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Shi, Qifang, Michelle M. Lynch, Margarita Romero, and James M. Burns. "Enhanced Protection against Malaria by a Chimeric Merozoite Surface Protein Vaccine." Infection and Immunity 75, no. 3 (December 11, 2006): 1349–58. http://dx.doi.org/10.1128/iai.01467-06.
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ABSTRACTThe 42-kDa processed fragment ofPlasmodium falciparummerozoite surface protein 1 (MSP-142) is a prime candidate for a blood-stage malaria vaccine. Merozoite surface protein 8 contains two C-terminal epidermal growth factor (EGF)-like domains that may function similarly to those of MSP-142. Immunization with either MSP-1 or MSP-8 induces protection that is mediated primarily by antibodies against conformation-dependent epitopes. In a series of comparative immunogenicity and efficacy studies using thePlasmodium yoeliirodent model, we tested the ability of recombinantP. yoeliiMSP-8 (rPyMSP-8) to complement rPyMSP-1-based vaccines. Unlike MSP-1, PyMSP-8-dependent protection required immunization with the full-length protein and was not induced with recombinant antigens that contained only the C-terminal EGF-like domains. Unlike PyMSP-8, the immunogenicity of the PyMSP-1 EGF-like domains was low when present as part of the rPyMSP-142antigen. Immunization with a mixture of rPyMSP-142and rPyMSP-8 further inhibited the antibody response to protective epitopes of rPyMSP-142and did not improve vaccine efficacy. To improve PyMSP-1 immunogenicity, we produced a chimeric antigen containing the EGF-like domains of PyMSP-1 fused to the N terminus of PyMSP-8. Immunization with the chimeric rPyMSP-1/8 antigen induced high and comparable antibody responses against the EGF-like domains of both PyMSP-1 and PyMSP-8. This enhanced MSP-1-specific antibody response and the concurrent targeting of MSP-1 and MSP-8 resulted in improved, nearly complete protection against lethalP. yoelii17XL malaria. Unexpectedly, immunization with rPyMSP-1/8 failed to protect against challenge infection with reticulocyte-restrictedP. yoelii17X parasites. Overall, these data establish an effective strategy to improve the efficacy ofP. falciparumMSP-based vaccines.
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Yan, Ming, Xiaoxia Cui, Qiping Zhao, Shunhai Zhu, Bing Huang, Lu Wang, Huanzhi Zhao, et al. "Molecular characterization and protective efficacy of the microneme 2 protein from Eimeria tenella." Parasite 25 (2018): 60. http://dx.doi.org/10.1051/parasite/2018061.
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Microneme proteins play an important role in the adherence of apicomplexan parasites to host cells during the invasion process. In this study, the microneme 2 protein from the protozoan parasite Eimeria tenella (EtMIC2) was cloned, characterized, and its protective efficacy as a DNA vaccine investigated. The EtMIC2 gene, which codes for a 35.07 kDa protein in E. tenella sporulated oocysts, was cloned and recombinant EtMIC2 protein (rEtMIC2) was produced in an Escherichia coli expression system. Immunostaining with an anti-rEtMIC2 antibody showed that the EtMIC2 protein mainly localized in the anterior region and membrane of sporozoites, in the cytoplasm of first- and second-generation merozoites, and was strongly expressed during first-stage schizogony. In addition, incubation with specific antibodies against EtMIC2 was found to efficiently reduce the ability of E. tenella sporozoites to invade host cells. Furthermore, animal-challenge experiments demonstrated that immunization with pcDNA3.1(+)-EtMIC2 significantly increased average body weight gain, while decreasing the mean lesion score and oocyst output in chickens. Taken together, these results suggest that EtMIC2 plays an important role in parasite cell invasion and may be a viable candidate for the development of new vaccines against E. tenella infection in chickens.
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Schussek, Sophie, Angela Trieu, Simon H. Apte, John Sidney, Alessandro Sette, and Denise L. Doolan. "Immunization with Apical Membrane Antigen 1 Confers Sterile Infection-Blocking Immunity against Plasmodium Sporozoite Challenge in a Rodent Model." Infection and Immunity 81, no. 10 (July 8, 2013): 3586–99. http://dx.doi.org/10.1128/iai.00544-13.
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ABSTRACTApical membrane antigen 1 (AMA-1) is a leading blood-stage malaria vaccine candidate. Consistent with a key role in erythrocytic invasion, AMA-1-specific antibodies have been implicated in AMA-1-induced protective immunity. AMA-1 is also expressed in sporozoites and in mature liver schizonts where it may be a target of protective cell-mediated immunity. Here, we demonstrate for the first time that immunization with AMA-1 can induce sterile infection-blocking immunity againstPlasmodiumsporozoite challenge in 80% of immunized mice. Significantly higher levels of gamma interferon (IFN-γ)/interleukin-2 (IL-2)/tumor necrosis factor (TNF) multifunctional T cells were noted in immunized mice than in control mice. We also report the first identification of minimal CD8+and CD4+T cell epitopes onPlasmodium yoeliiAMA-1. These data establish AMA-1 as a target of both preerythrocytic- and erythrocytic-stage protective immune responses and validate vaccine approaches designed to induce both cellular and humoral immunity.