scholarly journals A Prime-Boost Strategy Using the Novel Vaccine Candidate, LemA, Protects Hamsters against Leptospirosis

2013 ◽  
Vol 20 (5) ◽  
pp. 747-752 ◽  
Author(s):  
Daiane D. Hartwig ◽  
Karine M. Forster ◽  
Thaís L. Oliveira ◽  
Marta Amaral ◽  
Alan J. A. McBride ◽  
...  
Keyword(s):  
Immune Response ◽  
Antibody Response ◽  
Dna Vaccine ◽  
Subunit Vaccine ◽  
Vaccine Candidate ◽  
Virulent Strain ◽  
Effective Vaccine ◽  
Pairwise Identity ◽  
Content Type ◽  
Vaccine Preparation

ABSTRACTToward developing an effective vaccine capable of conferring heterologous protection, the putative lipoprotein LemA, which presents an M3 epitope similar to that ofListeria, was evaluated as a vaccine candidate in the hamster model of leptospirosis. LemA is conserved (>70% pairwise identity) among the pathogenicLeptospiraspp., indicating its potential in stimulating a cross-protective immune response. Using different vaccination strategies, including prime-boost, DNA vaccine, and a subunit preparation, recombinant LemA conferred different levels of protection in hamsters. Significant protection against mortality was observed for the prime-boost and the DNA vaccine strategies, which showed 87.5% (P< 0.01) and 62.5% (P< 0.05) efficacy, respectively. Although the subunit vaccine preparation protected 50.0% of immunized hamsters, the level of protection was not significant. None of the hamsters in the control groups survived challenge with a virulent strain ofLeptospira interrogansserogroup Icterohaemorrhagiae. Characterization of the immune response found that the strongest antibody response was stimulated by the subunit vaccine preparation, followed by the prime-boost strategy. The DNA vaccine failed to elicit an antibody response in immunized hamsters.

scholarly journals Xanthan Gum as an Adjuvant in a Subunit Vaccine Preparation against Leptospirosis

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Katia L. Bacelo ◽  
Daiane D. Hartwig ◽  
Fabiana K. Seixas ◽  
Rodrigo Schuch ◽  
Angelita da S. Moreira ◽  
...  
Keyword(s):  
Subunit Vaccine ◽  
Xanthan Gum ◽  
Vaccine Candidate ◽  
Virulent Strain ◽  
Chinese Hamster ◽  
Extracellular Polysaccharide ◽  
Vaccine Preparation ◽  
Ability To Act ◽  
A Subunit

Leptospiral immunoglobulin-like (Lig) proteins are of great interest due to their ability to act as mediators of pathogenesis, serodiagnostic antigens, and immunogens. Purified recombinant LigA protein is the most promising subunit vaccine candidate against leptospirosis reported to date, however, as purified proteins are weak immunogens the use of a potent adjuvant is essential for the success of LigA as a subunit vaccine. In the present study, we compared xanthan pv. pruni (strain 106), aluminium hydroxide (alhydrogel), and CpG ODN as adjuvants in a LigA subunit vaccine preparation. Xanthan gum is a high molecular weight extracellular polysaccharide produced by fermentation ofXanthomonasspp., a plant-pathogenic bacterium genus. Preparations containing xanthan induced a strong antibody response comparable to that observed when alhydrogel was used. Upon challenge with a virulent strain ofL. interrogansserovar Copenhageni, significant protection (Fisher test,P<0.05) was observed in 100%, 100%, and 67% of hamsters immunized with rLigANI-xanthan, LigA-CpG-xanthan, and rLigANI-alhydrogel, respectively. Furthermore, xanthan did not cause cytotoxicity in Chinese hamster ovary (CHO) cellsin vitro. The use of xanthan as an adjuvant is a novel alternative for enhancing the immunogenicity of vaccines against leptospirosis and possibly against other pathogens.

scholarly journals Cryo-EM structure of S-Trimer, a subunit vaccine candidate for COVID-19

2021 ◽  
Author(s):  
Jiahao Ma ◽  
Danmei Su ◽  
Yinyan Sun ◽  
Xueqin Huang ◽  
Ying Liang ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Receptor Binding ◽  
Subunit Vaccine ◽  
Vaccine Candidate ◽  
Phase 1 ◽  
Full Length ◽  
Effective Vaccine ◽  
S Protein ◽  
Closed Conformation ◽  
A Subunit

Within a year after its emergence, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 100 million people worldwide with a death toll over 2 million. Vaccination remains the best hope to ultimately put this pandemic to an end. Here, using Trimer-Tag technology, we produced both wild-type (WT) and furin site mutant (MT) S-Trimers for COVID-19 vaccine studies. Cryo-EM structures of the WT and MT S-Trimers, determined at 3.2 Å and 2.6 Å respectively, revealed that both antigens adopt a tightly closed conformation and their structures are essentially identical to that of the previously solved full-length WT S protein in detergent. The tightly closed conformation is stabilized by fatty acid and polysorbate 80 binding at the receptor binding domains (RBDs) and the N terminal domains (NTDs) respectively. Additionally, we identified an important pH switch in the WT S-Trimer that shows dramatic conformational change and accounts for its increased stability at lower pH. These results validate Trimer-Tag as a platform technology in production of metastable WT S-Trimer as a candidate for COVID-19 subunit vaccine. IMPORTANCE Effective vaccine against SARS-CoV-2 is critical to end the COVID-19 pandemic. Here, using Trimer-Tag technology, we are able to produce stable and large quantities of WT S-Trimer, a subunit vaccine candidate for COVID-19 with high safety and efficacy from animal and Phase 1 clinical trial studies. Cryo-EM structures of the S-Trimer subunit vaccine candidate show that it predominately adopts tightly closed pre-fusion state, and resembles that of the native and full-length spike in detergent, confirming its structural integrity. WT S-Trimer is currently being evaluated in global Phase 2/3 clinical trial. Combining with published structures of the S protein, we also propose a model to dissect the conformation change of the spike protein before receptor binding.

scholarly journals STAT1 Signaling within Macrophages Is Required for Antifungal Activity against Cryptococcus neoformans

2015 ◽  
Vol 83 (12) ◽  
pp. 4513-4527 ◽  
Author(s):  
Chrissy M. Leopold Wager ◽  
Camaron R. Hole ◽  
Karen L. Wozniak ◽  
Michal A. Olszewski ◽  
Mathias Mueller ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Immune Response ◽  
Cryptococcus Neoformans ◽  
Macrophage Activation ◽  
Virulent Strain ◽  
T Helper 1 ◽  
Pulmonary Tissue ◽  
Content Type ◽  
M1 Macrophage ◽  
Opportunistic Fungal Pathogen

Cryptococcus neoformans, the predominant etiological agent of cryptococcosis, is an opportunistic fungal pathogen that primarily affects AIDS patients and patients undergoing immunosuppressive therapy. In immunocompromised individuals,C. neoformanscan lead to life-threatening meningoencephalitis. Studies using a virulent strain ofC. neoformansengineered to produce gamma interferon (IFN-γ), denoted H99γ, demonstrated that protection against pulmonaryC. neoformansinfection is associated with the generation of a T helper 1 (Th1)-type immune response and signal transducer and activator of transcription 1 (STAT1)-mediated classical (M1) macrophage activation. However, the critical mechanism by which M1 macrophages mediate their anti-C. neoformansactivity remains unknown. The current studies demonstrate that infection withC. neoformansstrain H99γ in mice with macrophage-specific STAT1 ablation resulted in severely increased inflammation of the pulmonary tissue, a dysregulated Th1/Th2-type immune response, increased fungal burden, deficient M1 macrophage activation, and loss of protection. STAT1-deficient macrophages produced significantly less nitric oxide (NO) than STAT1-sufficient macrophages, correlating with an inability to control intracellular cryptococcal proliferation, even in the presence of reactive oxygen species (ROS). Furthermore, macrophages from inducible nitric oxide synthase knockout mice, which had intact ROS production, were deficient in anticryptococcal activity. These data indicate that STAT1 activation within macrophages is required for M1 macrophage activation and anti-C. neoformansactivity via the production of NO.

scholarly journals Simultaneous Immunization with Multivalent Norovirus VLPs Induces Better Protective Immune Responses to Norovirus than Sequential Immunization

Viruses ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1018
Author(s):  
Maria Malm ◽  
Timo Vesikari ◽  
Vesna Blazevic
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Antibody Response ◽  
Vaccine Candidate ◽  
Serum Antibodies ◽  
Blocking Antibody ◽  
Alternative Approach ◽  
Sequential Boost ◽  
Trivalent Vaccine ◽  
Rotavirus Vp6

Human noroviruses (NoVs) are a genetically diverse, constantly evolving group of viruses. Here, we studied the effect of NoV pre-existing immunity on the success of NoV vaccinations with genetically close and distant genotypes. A sequential immunization as an alternative approach to multivalent NoV virus-like particles (VLPs) vaccine was investigated. Mice were immunized with NoV GI.3, GII.4-1999, GII.17, and GII.4 Sydney as monovalent VLPs or as a single tetravalent mixture combined with rotavirus VP6-protein. Sequentially immunized mice were primed with a trivalent vaccine candidate (GI.3 + GII.4-1999 + VP6) and boosted, first with GII.17 and then with GII.4 Sydney VLPs. NoV serum antibodies were analyzed. Similar NoV genotype-specific immune responses were induced with the monovalent and multivalent mixture immunizations, and no immunological interference was observed. Multivalent immunization with simultaneous mix was found to be superior to sequential immunization, as sequential boost induced strong blocking antibody response against the distant genotype (GII.17), but not against GII.4 Sydney, closely related to GII.4-1999, contained in the priming vaccine. Genetically close antigens may interfere with the immune response generation and thereby immune responses may be differently formed depending on the degree of NoV VLP genotype identity.

scholarly journals Protection against Lethal Leptospirosis after Vaccination with LipL32 Coupled or Coadministered with the B Subunit of Escherichia coli Heat-Labile Enterotoxin

2012 ◽  
Vol 19 (5) ◽  
pp. 740-745 ◽  
Author(s):  
André A. Grassmann ◽  
Samuel R. Félix ◽  
Carolina Ximendes dos Santos ◽  
Marta G. Amaral ◽  
Amilton C. P. Seixas Neto ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Immune Response ◽  
Subunit Vaccine ◽  
Lethal Dose ◽  
Control Group ◽  
Hamster Model ◽  
Content Type ◽  
B Subunit ◽  
Heat Labile ◽  
A Subunit

ABSTRACTLeptospirosis, a worldwide zoonosis, lacks an effective, safe, and cross-protective vaccine. LipL32, the most abundant, immunogenic, and conserved surface lipoprotein present in all pathogenic species ofLeptospira, is a promising antigen candidate for a recombinant vaccine. However, several studies have reported a lack of protection when this protein is used as a subunit vaccine. In an attempt to enhance the immune response, we used LipL32 coupled to or coadministered with the B subunit of theEscherichia coliheat-labile enterotoxin (LTB) in a hamster model of leptospirosis. After homologous challenge with 5× the 50% lethal dose (LD50) ofLeptospira interrogans, animals vaccinated with LipL32 coadministered with LTB and LTB::LipL32 had significantly higher survival rates (P< 0.05) than animals from the control group. This is the first report of a protective immune response afforded by a subunit vaccine using LipL32 and represents an important contribution toward the development of improved leptospirosis vaccines.

Intradermally administered enterotoxigenic E. coli vaccine candidate MecVax induces functional serum IgG antibodies against seven adhesins (CFA/I, CS1-CS6) and both toxins (STa, LT)

2021 ◽  
Author(s):  
Carolina Y Garcia ◽  
Hyesuk Seo ◽  
David A Sack ◽  
Weiping Zhang
Keyword(s):  
Escherichia Coli ◽  
Neutralizing Antibodies ◽  
Subunit Vaccine ◽  
Vaccine Candidate ◽  
Effective Vaccine ◽  
Protein Antigens ◽  
E Coli ◽  
Administration Routes ◽  
Heat Stable ◽  
Functional Antibodies

There are no vaccines licensed for enterotoxigenic Escherichia coli (ETEC), a leading bacterial cause of children’s diarrhea and travelers’ diarrhea. MecVax, a multivalent E. coli vaccine candidate composed of two epitope- and structure-based polyvalent proteins (toxoid fusion 3xSTa N12S -mnLT R192G/L211A and CFA/I/II/IV MEFA), is to induce broad anti-adhesin and antitoxin antibodies against heterogeneous ETEC pathovars. Administered intraperitoneally (IP) or intramuscularly (IM), MecVax was shown to induce antibodies against seven ETEC adhesins (CFA/I, CS1-CS6), which are produced by ETEC pathovars causing over 60% of ETEC-associated diarrheal cases and the moderate-to-severe cases, and both toxins (heat-labile toxin - LT and heat-stable toxin - STa) expressed by all ETEC strains. To further characterize immunogenicity of this protein-based injectable subunit vaccine candidate and to explore other parenteral administration routes for the product, in this study, we intradermally (ID) immunized mice with MecVax and measured antigen-specific antibody responses and further antibody functional activities against the adhesins and toxins targeted by the vaccine. Data showed that mice ID immunized with MecVax developed robust anti-CFA/I, -CS1, -CS2, -CS3, -CS4, -CS5, -CS6, -LT and anti-STa IgG responses. Furthermore, antibodies derived from MecVax via ID route inhibited adherence of ETEC or E. coli strains expressing any of the seven target adhesins (CFA/I, CS1-CS6) and neutralized enterotoxicity of LT and STa toxins. These results confirmed broad immunogenicity of MecVax and suggested that this multivalent ETEC subunit vaccine candidate can be effectively delivered via ID route. IMPORTANCE Enterotoxigenic Escherichia coli (ETEC) is a leading bacterial cause of diarrhea in children living in developing countries and international travelers. Developing an effective vaccine for ETEC diarrhea has been hampered because of challenges of virulence heterogeneity and difficulties of inducing neutralizing antibodies against the key STa toxin. MecVax, a subunit vaccine candidate carrying two polyvalent protein antigens for the first time induces functional antibodies against the most important ETEC adhesins which are associated with a majority of diarrheal cases and the moderate-to-severe cases but also against enterotoxicity of LT and more importantly STa toxin which plays a key role in children’s diarrhea and travelers’ diarrhea, potentially leading to development of a truly effective ETEC vaccine. Data from this study may also indicated that this ETEC subunit vaccine can be administered effectively via ID route, expanding clinical administration options for this vaccine product.

scholarly journals Induction of Multifunctional Broadly Reactive T Cell Responses by a Plasmodium vivax Circumsporozoite Protein Recombinant Chimera

2015 ◽  
Vol 83 (9) ◽  
pp. 3749-3761 ◽  
Author(s):  
Monica Cabrera-Mora ◽  
Jairo Andres Fonseca ◽  
Balwan Singh ◽  
Joseli Oliveira-Ferreira ◽  
Josué da Costa Lima-Junior ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Immune Responses ◽  
Plasmodium Vivax ◽  
Vaccine Candidate ◽  
Chimeric Protein ◽  
Plasmodium Yoelii ◽  
Circumsporozoite Protein ◽  
Soluble Form ◽  
Content Type

Plasmodium vivaxis the most widespread species ofPlasmodium, causing up to 50% of the malaria cases occurring outside sub-Saharan Africa. An effective vaccine is essential for successful control and potential eradication. A well-characterized vaccine candidate is the circumsporozoite protein (CSP). Preclinical and clinical trials have shown that both antibodies and cellular immune responses have been correlated with protection induced by immunization with CSP. On the basis of our reported approach of developing chimericPlasmodium yoeliiproteins to enhance protective efficacy, we designed PvRMC-CSP, a recombinant chimeric protein based on theP. vivaxCSP (PvCSP). In this engineered protein, regions of the PvCSP predicted to contain human T cell epitopes were genetically fused to an immunodominant B cell epitope derived from the N-terminal region I and to repeat sequences representing the two types of PvCSP repeats. The chimeric protein was expressed in soluble form with high yield. As the immune response to PvCSP has been reported to be genetically restricted in the murine model, we tested the immunogenicity of PvRMC-CSP in groups of six inbred strains of mice. PvRMC-CSP was able to induce robust antibody responses in all the mouse strains tested. Synthetic peptides representing the allelic forms of theP. vivaxCSP were also recognized to a similar extent regardless of the mouse strain. Furthermore, the immunization regimen induced high frequencies of multifunctional CD4+and CD8+PvRMC-CSP-specific T cells. The depth and breadth of the immune responses elicited suggest that immunization with PvRMC-CSP can circumvent the genetic restriction of the immune response toP. vivaxCSP. Interestingly, PvRMC-CSP was also recognized by naturally acquired antibodies from individuals living in areas where malaria is endemic. These features make PvRMC-CSP a promising vaccine candidate for further development.

scholarly journals Adjuvant-dependent immune response to malarial transmission-blocking vaccine candidate antigens.

1992 ◽  
Vol 176 (5) ◽  
pp. 1483-1487 ◽  
Author(s):  
D J Rawlings ◽  
D C Kaslow
Keyword(s):  
Immune Response ◽  
Recombinant Protein ◽  
Antibody Response ◽  
Vaccine Candidate ◽  
Congenic Mouse ◽  
Mouse Strains ◽  
Transmission Blocking ◽  
Freund's Adjuvant ◽  
Congenic Mouse Strains ◽  
Transmission Blocking Vaccine

Immune responses in major histocompatibility complex (MHC)-disparate congenic mouse strains immunized with sexual stage malaria parasites or purified recombinant protein were adjuvant dependent. Whereas mice exhibited a limited antibody response to immunization with newly emerged Plasmodium falciparum gametes in Freund's adjuvant, all five congenic mouse strains responded to several transmission-blocking vaccine candidate antigens, when parasites were emulsified in a monophosphoryl lipid A (MPL) and trehalose dimycolate (TDM) adjuvant. The humoral response in those animals immunized with the antigen in a MPL/TDM adjuvant was helper T cell dependent, as evident by boosting of the antibody response after a second immunization. If the immunogen consisted of purified recombinant protein, then the immune response was not MHC class II limited in mice immunized with either complete Freund's adjuvant or TDM/MPL. The potential role of adjuvants in overcoming apparent immune nonresponsiveness and the implications for development of a malaria transmission-blocking vaccine are discussed.

scholarly journals Preclinical Efficacy of a Lipooligosaccharide Peptide Mimic Candidate Gonococcal Vaccine

mBio ◽  
2019 ◽  
Vol 10 (6) ◽  
Author(s):  
Sunita Gulati ◽  
Michael W. Pennington ◽  
Andrzej Czerwinski ◽  
Darrick Carter ◽  
Bo Zheng ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Neisseria Gonorrhoeae ◽  
Vaccine Candidate ◽  
Peptide Vaccine ◽  
Human Infection ◽  
Effective Vaccine ◽  
Infection Model ◽  
Content Type ◽  
Peptide Mimic

ABSTRACT The global spread of multidrug-resistant strains of Neisseria gonorrhoeae constitutes a public health emergency. With limited antibiotic treatment options, there is an urgent need for development of a safe and effective vaccine against gonorrhea. Previously, we constructed a prototype vaccine candidate comprising a peptide mimic (mimitope) of a glycan epitope on gonococcal lipooligosaccharide (LOS), recognized by monoclonal antibody 2C7. The 2C7 epitope is (i) broadly expressed as a gonococcal antigenic target in human infection, (ii) a critical requirement for gonococcal colonization in the experimental setting, and (iii) a virulence determinant that is maintained and expressed by gonococci. Here, we have synthesized to >95% purity through a relatively facile and economical process a tetrapeptide derivative of the mimitope that was cyclized through a nonreducible thioether bond, thereby rendering the compound homogeneous and stable. This vaccine candidate, called TMCP2, when administered at 0, 3, and 6 weeks to BALB/c mice at either 50, 100 or 200 μg/dose in combination with glucopyranosyl lipid A-stable oil-in-water nanoemulsion (GLA-SE; a Toll-like receptor 4 and TH1-promoting adjuvant), elicited bactericidal IgG and reduced colonization levels of gonococci in experimentally infected mice while accelerating clearance by each of two different gonococcal strains. Similarly, a 3-dose biweekly schedule (50 μg TMCP2/dose) was also effective in mice. We have developed a gonococcal vaccine candidate that can be scaled up and produced economically to a high degree of purity. The candidate elicits bactericidal antibodies and is efficacious in a preclinical experimental infection model. IMPORTANCE Neisseria gonorrhoeae has become resistant to most antibiotics. The incidence of gonorrhea is also sharply increasing. A safe and effective antigonococcal vaccine is urgently needed. Lipooligosaccharide (LOS), the most abundant outer membrane molecule, is indispensable for gonococcal pathogenesis. A glycan epitope on LOS that is recognized by monoclonal antibody (MAb) 2C7 (called the 2C7 epitope) is expressed almost universally by gonococci in vivo. Previously, we identified a peptide mimic (mimitope) of the 2C7 epitope, which when configured as an octamer and used as an immunogen, attenuated colonization of mice by gonococci. Here, a homogenous, stable tetrameric derivative of the mimitope, when combined with a TH1-promoting adjuvant and used as an immunogen, also effectively attenuates gonococcal colonization of mice. This candidate peptide vaccine can be produced economically, an important consideration for gonorrhea, which affects socioeconomically underprivileged populations disproportionately, and represents an important advance in the development of a gonorrhea vaccine.

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