scholarly journals Identification of lipid A deacylase as a novel, highly conserved and protective antigen against enterohemorrhagic Escherichia coli

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Maricarmen Rojas-Lopez ◽  
Manuele Martinelli ◽  
Valentina Brandi ◽  
Grégory Jubelin ◽  
Fabio Polticelli ◽  
...  
Keyword(s):  
Lipid A ◽  
Vaccine Development ◽  
Protective Antigen ◽  
Vaccine Candidate ◽  
Bacterial Load ◽  
Enterohemorrhagic Escherichia Coli ◽  
Protein Antigens ◽  
E Coli ◽  
Epidemiology Data ◽  
Potential Vaccine

AbstractEnterohemorrhagic E. coli (EHEC) is a major cause of large outbreaks worldwide associated with hemorrhagic colitis and hemolytic uremic syndrome. While vaccine development is warranted, a licensed vaccine, specific for human use, against EHEC is not yet available. In this study, the reverse vaccinology approach combined with genomic, transcriptional and molecular epidemiology data was applied on the EHEC O157:H7 genome to select new potential vaccine candidates. Twenty-four potential protein antigens were identified and one of them (MC001) was successfully expressed onto Generalized Modules for Membrane Antigens (GMMA) delivery system. GMMA expressing this vaccine candidate was immunogenic, raising a specific antibody response. Immunization with the MC001 candidate was able to reduce the bacterial load of EHEC O157:H7 strain in feces, colon and caecum tissues after murine infection. MC001 is homologue to lipid A deacylase enzyme (LpxR), and to our knowledge, this is the first study describing it as a potential vaccine candidate. Gene distribution and sequence variability analysis showed that MC001 is present and conserved in EHEC and in enteropathogenic E. coli (EPEC) strains. Given the high genetic variability among and within E. coli pathotypes, the identification of such conserved antigen suggests that its inclusion in a vaccine might represent a solution against major intestinal pathogenic strains.

scholarly journals Moraxella catarrhalis Bacterium without Endotoxin, a Potential Vaccine Candidate

2005 ◽  
Vol 73 (11) ◽  
pp. 7569-7577 ◽  
Author(s):  
Daxin Peng ◽  
Wenzhou Hong ◽  
Biswa P. Choudhury ◽  
Russell W. Carlson ◽  
Xin-Xing Gu
Keyword(s):  
Moraxella Catarrhalis ◽  
Lipid A ◽  
Vaccine Candidate ◽  
Gene Encoding ◽  
Potential Vaccine Candidate ◽  
Whole Cells ◽  
Potential Vaccine ◽  
Major Surface ◽  
Membrane Components ◽  
Human Infections

ABSTRACT Lipooligosaccharide (LOS) is a major surface component of Moraxella catarrhalis and a possible virulence factor in the pathogenesis of human infections caused by this organism. The presence of LOS on the bacterium is an obstacle to the development of vaccines derived from whole cells or outer membrane components of the bacterium. An lpxA gene encoding UDP-N-acetylglucosamine acyltransferase responsible for the first step of lipid A biosynthesis was identified by the construction and characterization of an isogenic M. catarrhalis lpxA mutant in strain O35E. The resulting mutant was viable despite the complete loss of LOS. The mutant strain showed significantly decreased toxicity by the Limulus amebocyte lysate assay, reduced resistance to normal human serum, reduced adherence to human epithelial cells, and enhanced clearance in lungs and nasopharynx in a mouse aerosol challenge model. Importantly, the mutant elicited high levels of antibodies with bactericidal activity and provided protection against a challenge with the wild-type strain. These data suggest that the null LOS mutant is attenuated and may be a potential vaccine candidate against M. catarrhalis.

scholarly journals TheSiderophore Receptor IroN of Extraintestinal PathogenicEscherichia coli Is a Potential VaccineCandidate

2003 ◽  
Vol 71 (12) ◽  
pp. 7164-7169 ◽  
Author(s):  
Thomas A. Russo ◽  
Catherine D. McFadden ◽  
Ulrike B. Carlino-MacDonald ◽  
Janet M. Beanan ◽  
Ruth Olson ◽  
...  
Keyword(s):  
Vaccine Candidate ◽  
Outer Membrane Proteins ◽  
Specific Response ◽  
Specific Antibody Response ◽  
E Coli ◽  
Iga Response ◽  
Potential Vaccine ◽  
Subcutaneous Immunization

ABSTRACT It would be medically and economically desirable to prevent the millions of annual extraintestinal infections and the thousands of associated deaths due to Escherichia coli. Outer membrane proteins are potential vaccine candidates for the prevention of these infections. This study tested the hypotheses that the siderophore receptor IroN is antigenic and that an IroN-specific antibody response confers protection in vivo. Subcutaneous immunization with denatured IroN resulted in a significant IroN immunoglobulin G (IgG)-specific response in serum (P < 0.0001) but not a systemic or mucosal IroN-specific IgA response. In a mouse model of ascending urinary tract infection, subcutaneous immunization with denatured IroN conferred significant protection against renal (P = 0.0135 and 0.0095 in two independent experiments), but not bladder, infection. These data, together with the previously demonstrated role of IroN in virulence, its expression in human biologic fluids, and its prevalence among extraintestinal pathogenic E. coli strains, support further studies on the role of IroN as a vaccine candidate.

scholarly journals Preclinical characterization of immunogenicity and efficacy against diarrhea from MecVax, a multivalent enterotoxigenic E. coli vaccine candidate

2021 ◽  
Author(s):  
Hyesuk Seo ◽  
Carolina Garcia ◽  
Xiaosai Ruan ◽  
Qiangde Duan ◽  
David A Sack ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Developing Countries ◽  
Vaccine Development ◽  
Vaccine Candidate ◽  
Preclinical Study ◽  
Watery Diarrhea ◽  
E Coli ◽  
Heat Stable ◽  
Protective Antibodies

There are no vaccines licensed for enterotoxigenic Escherichia coli (ETEC), a leading cause of diarrhea for children in developing countries and international travelers. Virulence heterogeneity among strains and difficulties identifying safe antigens for protective antibodies against STa, a potent but poorly immunogenic heat-stable toxin which plays a key role in ETEC diarrhea, are challenges in ETEC vaccine development. To overcome these challenges, we applied toxoid fusion strategy and novel epitope- and structure-based multiepitope-fusion-antigen (MEFA) vaccinology platform to construct two chimeric multivalent proteins, toxoid fusion 3xSTaN12S-mnLTR192G/L211A and adhesin CFA/I/II/IV MEFA, and demonstrated that proteins induced protective antibodies against STa and heat-labile toxin (LT) produced by all ETEC strains or the seven most important ETEC adhesins (CFA/I, CS1 to CS6) expressed by the ETEC strains causing 60-70% diarrheal cases and moderate-to-severe cases. Combining two proteins, we prepared a protein-based multivalent ETEC vaccine, MecVax. MecVax was broadly immunogenic; mice and pigs intramuscularly immunized with MecVax developed no apparent adverse effects but robust antibody responses to the target toxins and adhesins. Importantly, MecVax-induced antibodies were broadly protective, demonstrated by significant adherence inhibition against E. coli bacteria producing any of the seven adhesins and neutralization of STa and CT enterotoxicity. Moreover, MecVax protected against watery diarrhea, and over 70% or 90% any diarrhea from an STa+ or an LT+ ETEC strain in a pig challenge model. These results indicated that MecVax induces broadly protective antibodies and prevents diarrhea preclinically, signifying MecVax potentially an effective injectable vaccine for ETEC. IMPORTANCE: Enterotoxigenic Escherichia coli (ETEC) bacteria are a top cause of children’s diarrhea and travelers’ diarrhea and are responsible for over 220 million diarrheal cases and more than 100,000 deaths annually. A safe and effective ETEC vaccine can significantly improve public health, particularly in developing countries. Data from this preclinical study showed that MecVax induces broadly protective anti-adhesin and antitoxin antibodies, becoming the first ETEC vaccine candidate to induce protective antibodies inhibiting adherence of the seven most important ETEC adhesins and neutralizing enterotoxicity of LT but also STa toxin. More importantly, MecVax is shown to protect against clinical diarrhea from STa+ or LT+ ETEC infection in a pig challenge model, recording protection from antibodies induced by protein-based injectable subunit vaccine MecVax against ETEC diarrhea and perhaps the possibility of IM administered protein vaccines for protection against intestinal mucosal infection.

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 Evaluation of Recombinant Lipidated P2086 Protein as a Vaccine Candidate for Group B Neisseria meningitidis in a Murine Nasal Challenge Model

2005 ◽  
Vol 73 (10) ◽  
pp. 6838-6845 ◽  
Author(s):  
Duzhang Zhu ◽  
Ying Zhang ◽  
Vicki Barniak ◽  
Liesel Bernfield ◽  
Alan Howell ◽  
...  
Keyword(s):  
Neisseria Meningitidis ◽  
Capsular Polysaccharide ◽  
Vaccine Development ◽  
Vaccine Candidate ◽  
Active Immunization ◽  
Human Beings ◽  
Nasal Tissue ◽  
Potential Vaccine ◽  
Group B ◽  
Different Strains

ABSTRACT Neisseria meningitidis is a major causative agent of bacterial meningitis in human beings, especially among young children (≤2 years of age). Prevention of group B meningococcal disease represents a particularly difficult challenge in vaccine development, due to the inadequate immune response elicited against type B capsular polysaccharide. We have established an adult mouse intranasal challenge model for group B N. meningitidis to evaluate potential vaccine candidates through active immunization. Swiss Webster mice were inoculated intranasally with meningococci, and bacteria were recovered from the noses for at least 3 days postchallenge. Iron dextran was required in the bacterial inoculum to ensure sufficient meningococcal recovery from nasal tissue postchallenge. This model has been utilized to evaluate the potential of a recombinant lipidated group B meningococcal outer membrane protein P2086 (rLP2086) as a vaccine candidate. In this study, mice were immunized subcutaneously with purified rLP2086 formulated with or without an attenuated cholera toxin as an adjuvant. The mice were then challenged intranasally with N. meningitidis strain H355 or M982, and the colonization of nasal tissue was determined by quantitative culture 24 h postchallenge. We demonstrated that immunization with rLP2086 significantly reduced nasal colonization of mice challenged with the two different strains of group B N. meningitidis. Mice immunized with rLP2086 produced a strong systemic immunoglobulin G response, and the serum antibodies were cross-reactive with heterologous strains of group B N. meningitidis. The antibodies have functional activity against heterologous N. meningitidis strain, as demonstrated via bactericidal and infant rat protection assays. These results suggest that rLP2086 is a potential vaccine candidate for group B N. meningitidis.

scholarly journals Structure ofStreptococcus agalactiaeglyceraldehyde-3-phosphate dehydrogenase holoenzyme reveals a novel surface

2014 ◽  
Vol 70 (10) ◽  
pp. 1333-1339 ◽  
Author(s):  
Chapelle A. Ayres ◽  
Norbert Schormann ◽  
Olga Senkovich ◽  
Alexandra Fry ◽  
Surajit Banerjee ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Amino Acid ◽  
Vaccine Development ◽  
Vaccine Candidate ◽  
Group B Streptococcus ◽  
Bacterial Pathogenesis ◽  
Bacterial Virulence ◽  
Significant Difference ◽  
Potential Vaccine ◽  
Group B

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a conserved cytosolic enzyme, which plays a key role in glycolysis. GAPDH catalyzes the oxidative phosphorylation of D-glyceraldehyde 3-phosphate using NAD or NADP as a cofactor. In addition, GAPDH localized on the surface of some bacteria is thought to be involved in macromolecular interactions and bacterial pathogenesis. GAPDH on the surface of group B streptococcus (GBS) enhances bacterial virulence and is a potential vaccine candidate. Here, the crystal structure of GBS GAPDH fromStreptococcus agalactiaein complex with NAD is reported at 2.46 Å resolution. Although the overall structure of GBS GAPDH is very similar to those of other GAPDHs, the crystal structure reveals a significant difference in the area spanning residues 294–307, which appears to be more acidic. The amino-acid sequence of this region of GBS GAPDH is also distinct compared with other GAPDHs. This region therefore may be of interest as an immunogen for vaccine development.

scholarly journals A dose-response study in mice of a tetravalent recombinant dengue envelope domain III protein secreted from insect cells

2020 ◽  
Author(s):  
Lijun Shao ◽  
Zheng Pang ◽  
Yu Bi ◽  
Zhenhua Li ◽  
Weiping Lin ◽  
...  
Keyword(s):  
Immune Responses ◽  
Humoral Immunity ◽  
Insect Cells ◽  
Vaccine Development ◽  
Vaccine Candidate ◽  
Potential Vaccine ◽  
Domain Iii ◽  
Dose Response Study ◽  
Development Methods ◽  
Medium Dose

Abstract Background: DENV is the most globally prevalent mosquito-transmitted virus. Induction of a broadly and potently immune response is desirable for dengue vaccine development. Methods: We constructed a secreted tetravalent EDⅢ protein from eukaryotic cells and established a MAC-ELISA method for DENV diagnosis. This work aimed to evaluate the immune responses in mice of several formulations of rEDIII containing different amounts of the tetravalent protein. Results: We demonstrated that the tetravalent protein induced humoral immunity against all four serotypes of DENV, even at the lowest dose assayed. Besides, cellular immunities against DENV-1 and DENV-2 were elicited by medium dose group. Importantly, the immune responses induced by the tetravalent formulation were functional in clearing DENV-2 in circulation of mice. Conclusions: We believe that the tetravalent formulation of secreted EDⅢ protein is a potential vaccine candidate against DENV and suggest further detailed studies of this formulation in nonhuman primates. Keywords: Dengue virus; Tetravalent; Humoral immunity; Cellular immunity; Vaccine

scholarly journals A Scalable Topical Vectored Vaccine Candidate Against SARS-CoV-2

2020 ◽  
Author(s):  
Mohammed A Rohaim ◽  
Muhammad Munir
Keyword(s):  
Vaccine Development ◽  
Protective Antigen ◽  
Vaccine Candidate ◽  
De Novo ◽  
Recombinant Vaccine ◽  
Avirulent Strain ◽  
Global Public Health ◽  
S Protein ◽  
Vectored Vaccine

AbstractThe severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) caused an ongoing unprecedented global public health crises of coronavirus disease in 2019 (CoVID-19). The precipitously increased death rates, its impact on livelihood and trembling economies warrant the urgent development of SARS-CoV-2 vaccine which would be safe, efficacious and scalable. Owing to unavailability of the vaccine, we propose a de novo synthesised avian orthoavulavirus 1 (AOaV-1)-based topical respiratory vaccine candidate against CoVID-19. Avirulent strain of Newcastle disease virus, proto-type virus of AOaV-1, was engineered to express full length spike (S) glycoprotein which is highly neutralizing and major protective antigen of the SARS-CoV-2. Broad-scale in vitro characterization of recombinant vaccine candidate demonstrated efficient co-expression of the hemagglutinin-neuraminidase (HN) of AOaV-1 and S protein of SARS-CoV-2, and comparable replication kinetics were observed in cell culture model. The recombinant vaccine candidate virus actively replicated and spread within cells independently of exogenous trypsin. Interestingly, incorporation of S protein of SARS-CoV-2 into the recombinant AOaV-1 particles attributed the sensitivity to anti-SARS-CoV-2 antiserum and more prominently to anti-AOaV-1 antiserum. Finally, our results demonstrated that the recombinant vaccine vector stably expressed S protein after multiple propagation in chicken embryonated eggs, and this expression did not significantly impact the in vitro growth characteristics of the recombinant. Taken together, the presented respiratory vaccine candidate is highly attenuated in primates per se, safe and lacking pre-existing immunity in human, and carries the potential for accelerated vaccine development against CoVID-19 for clinical studies.

scholarly journals A Scalable Topical Vectored Vaccine Candidate against SARS-CoV-2

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 472 ◽  
Author(s):  
Mohammed A. Rohaim ◽  
Muhammad Munir
Keyword(s):  
Vaccine Development ◽  
Protective Antigen ◽  
Vaccine Candidate ◽  
De Novo ◽  
Recombinant Vaccine ◽  
Avirulent Strain ◽  
Global Public Health ◽  
S Protein ◽  
Vectored Vaccine

The severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) caused an ongoing unprecedented global public health crises of coronavirus disease in 2019 (CoVID-19). The precipitously increased death rates, its impact on livelihood and trembling economies warrant the urgent development of a SARS-CoV-2 vaccine which would be safe, efficacious and scalable. Owing to unavailability of the vaccine, we propose a de novo synthesized avian orthoavulavirus 1 (AOaV-1)-based topical respiratory vaccine candidate against CoVID-19. Avirulent strain of AOaV-1 was engineered to express full length spike (S) glycoprotein which is highly neutralizing and a major protective antigen of the SARS-CoV-2. Broad-scale in vitro characterization of a recombinant vaccine candidate demonstrated efficient co-expression of the hemagglutinin-neuraminidase (HN) of AOaV-1 and S protein of SARS-CoV-2, and comparable replication kinetics were observed in a cell culture model. The recombinant vaccine candidate virus actively replicated and spread within cells independently of exogenous trypsin. Interestingly, incorporation of S protein of SARS-CoV-2 into the recombinant AOaV-1 particles attributed the sensitivity to anti-SARS-CoV-2 antiserum and more prominently to anti-AOaV-1 antiserum. Finally, our results demonstrated that the recombinant vaccine vector stably expressed S protein after multiple propagations in chicken embryonated eggs, and this expression did not significantly impact the in vitro growth characteristics of the recombinant. Taken together, the presented respiratory vaccine candidate is highly attenuated in primates per se, safe and lacking pre-existing immunity in human, and carries the potential for accelerated vaccine development against CoVID-19 for clinical studies.

scholarly journals Modular vaccine platform based on the norovirus-like particle

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Vili Lampinen ◽  
Suvi Heinimäki ◽  
Olli H. Laitinen ◽  
Marko Pesu ◽  
Minna M. Hankaniemi ◽  
...  
Keyword(s):  
Antibody Production ◽  
High Efficiency ◽  
Vaccine Development ◽  
Protein Antigens ◽  
Vaccine Platform ◽  
Adjuvant Effect ◽  
E Coli ◽  
Virus Like Particle ◽  
Scalable Methods ◽  
Conventional Vaccine

Abstract Background Virus-like particle (VLP) vaccines have recently emerged as a safe and effective alternative to conventional vaccine technologies. The strong immunogenic effects of VLPs can be harnessed for making vaccines against any pathogen by decorating VLPs with antigens from the pathogen. Producing the antigenic pathogen fragments and the VLP platform separately makes vaccine development rapid and convenient. Here we decorated the norovirus-like particle with two conserved influenza antigens and tested for the immunogenicity of the vaccine candidates in BALB/c mice. Results SpyTagged noro-VLP was expressed with high efficiency in insect cells and purified using industrially scalable methods. Like the native noro-VLP, SpyTagged noro-VLP is stable for months when refrigerated in a physiological buffer. The conserved influenza antigens were produced separately as SpyCatcher fusions in E. coli before covalent conjugation on the surface of noro-VLP. The noro-VLP had a high adjuvant effect, inducing high titers of antibody production against the antigens presented on its surface. Conclusions The modular noro-VLP vaccine platform presented here offers a rapid, convenient and safe method to present various soluble protein antigens to the immune system for vaccination and antibody production purposes.

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