scholarly journals Improving Our Understanding of Salmonella enterica Serovar Paratyphi B through the Engineering and Testing of a Live Attenuated Vaccine Strain

mSphere ◽  
2018 ◽  
Vol 3 (6) ◽  
Author(s):  
Ellen E. Higginson ◽  
Girish Ramachandran ◽  
Tracy H. Hazen ◽  
Dane A. Kania ◽  
David A. Rasko ◽  
...  
Keyword(s):  
Vaccine Strain ◽  
Salmonella Enterica ◽  
Enteric Fever ◽  
Sensu Stricto ◽  
Live Attenuated Vaccine ◽  
Content Type ◽  
Heterologous Challenge ◽  
Paratyphi B ◽  
Homologous Challenge ◽  
Ideal Vaccine

ABSTRACT Enteric fever is caused by three Salmonella enterica serovars: Typhi, Paratyphi A, and Paratyphi B sensu stricto. Although vaccines against two of these serovars are licensed (Typhi) or in clinical development (Paratyphi A), as yet there are no candidates for S. Paratyphi B. To gain genomic insight into these serovars, we sequenced 38 enteric fever-associated strains from Chile and compared these with reference genomes. Each of the serovars was separated genomically based on the core genome. Genomic comparisons identified loci that were aberrant between serovars Paratyphi B sensu stricto and Paratyphi B Java, which is typically associated with gastroenteritis; however, the majority of these were annotated as hypothetical or phage related and thus were not ideal vaccine candidates. With the genomic information in hand, we engineered a live attenuated S. Paratyphi B sensu stricto vaccine strain, CVD 2005, which was capable of protecting mice from both homologous challenge and heterologous challenge with S. Paratyphi B Java. These findings extend our understanding of S. Paratyphi B and provide a viable vaccine option for inclusion in a trivalent live attenuated enteric fever vaccine formulation. IMPORTANCE We developed a live attenuated Salmonella enterica serovar Paratyphi B vaccine that conferred protection in mice against challenge with S. Paratyphi B sensu stricto and S. Paratyphi B Java, which are the causes of enteric fever and gastroenteritis, respectively. Currently, the incidence of invasive S. Paratyphi B sensu stricto infections is low; however, the development of new conjugate vaccines against other enteric fever serovars could lead to the emergence of S. Paratyphi B to fill the niche left by these other pathogens. As such, an effective S. Paratyphi B vaccine would be a useful tool in the armamentarium against Salmonella infections. Comparative genomics confirmed the serovar-specific groupings of these isolates and revealed that there are a limited number of genetic differences between the sensu stricto and Java strains, which are mostly hypothetical and phage-encoded proteins. The observed level of genomic similarity likely explains why we observe some cross-protection.

scholarly journals Genome-wide analysis provides a deeper understanding of the population structure of the Salmonella enterica serotype Paratyphi B complex in Bangladesh

2021 ◽  
Vol 7 (9) ◽  
Author(s):  
Sadia Isfat Ara Rahman ◽  
Alyce Taylor-Brown ◽  
Farhana Khanam ◽  
Ashraful Islam Khan ◽  
Gal Horesh ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Disease Surveillance ◽  
Sensu Stricto ◽  
Enteric Disease ◽  
Content Type ◽  
Link Type ◽  
Genome Wide ◽  
Wide Range ◽  
Paratyphi B ◽  
Paratyphoid Fever

The Salmonella enterica serotype Paratyphi B complex causes a wide range of diseases, from gastroenteritis to paratyphoid fever, depending on the biotypes Java and sensu stricto. The burden of Paratyphi B biotypes in Bangladesh is still unknown, as these are indistinguishable by Salmonella serotyping. Here, we conducted the first whole-genome sequencing (WGS) study on 79 Salmonella isolates serotyped as Paratyphi B that were collected from 10 nationwide enteric disease surveillance sites in Bangladesh. Placing these in a global genetic context revealed that these are biotype Java, and the addition of these genomes expanded the previously described PG4 clade containing Bangladeshi and UK isolates. Importantly, antimicrobial resistance (AMR) genes were scarce amongst Bangladeshi S. Java isolates, somewhat surprisingly given the widespread availability of antibiotics without prescription. This genomic information provides important insights into the significance of S. Paratyphi B biotypes in enteric disease and their implications for public health.

scholarly journals Infection with Conditionally Virulent Streptococcus pneumoniae ΔpabStrains Induces Antibody to Conserved Protein Antigens but Does Not Protect against Systemic Infection with Heterologous Strains

2011 ◽  
Vol 79 (12) ◽  
pp. 4965-4976 ◽  
Author(s):  
Suneeta Chimalapati ◽  
Jonathan Cohen ◽  
Emilie Camberlein ◽  
Claire Durmort ◽  
Helen Baxendale ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Capsular Polysaccharide ◽  
Bacterial Pathogen ◽  
Systemic Infection ◽  
Complete Medium ◽  
Protein Antigens ◽  
Live Attenuated Vaccine ◽  
Content Type ◽  
Immunological Responses ◽  
Heterologous Challenge

ABSTRACTAvirulent strains of a bacterial pathogen could be useful tools for investigating immunological responses to infection and potentially effective vaccines. We have therefore constructed an auxotrophic TIGR4 Δpabstrain ofStreptococcus pneumoniaeby deleting thepabBgene Sp_0665. The TIGR4 Δpabstrain grew well in complete medium but was unable to grow in serum unless it was supplemented withpara-aminobenzoic acid (PABA). The TIGR4 Δpabstrain was markedly attenuated in virulence in mouse models ofS. pneumoniaenasopharyngeal colonization, pneumonia, and sepsis. Supplementing mouse drinking water with PABA largely restored the virulence of TIGR4 Δpab. An additional Δpabstrain constructed in the D39 capsular serotype 2 background was also avirulent in a sepsis model. Systemic inoculation of mice with TIGR4 Δpabinduced antibody responses toS. pneumoniaeprotein antigens, including PpmA, PsaA, pneumolysin, and CbpD, but not capsular polysaccharide. Flow cytometry demonstrated that IgG in sera from TIGR4 Δpab-vaccinated mice bound to the surface of TIGR4 and D39 bacteria but not to a capsular serotype 3 strain, strain 0100993. Mice vaccinated with the TIGR4 Δpabor D39 Δpabstrain by intraperitoneal inoculation were protected from developing septicemia when challenged with the homologousS. pneumoniaestrain. Vaccination with the TIGR4 Δpabstrain provided only weak or no protection against heterologous challenge with the D39 or 0100993 strain but did strongly protect against a TIGR4 capsular-switch strain expressing a serotype 2 capsule. The failure of cross-protection after systemic vaccination with Δpabbacteria suggests that parenteral administration of a live attenuated vaccine is not an attractive approach for preventingS. pneumoniaeinfection.

scholarly journals Live Oral Typhoid Vaccine Ty21a Induces Cross-Reactive Humoral Immune Responses against Salmonella enterica Serovar Paratyphi A andS. Paratyphi B in Humans

2012 ◽  
Vol 19 (6) ◽  
pp. 825-834 ◽  
Author(s):  
Rezwanul Wahid ◽  
Raphael Simon ◽  
Shah J. Zafar ◽  
Myron M. Levine ◽  
Marcelo B. Sztein
Keyword(s):  
Immune Responses ◽  
Salmonella Enterica ◽  
Outer Membrane Proteins ◽  
Serum Antibody ◽  
Significant Proportion ◽  
Field Trials ◽  
Content Type ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Paratyphi B

ABSTRACTEnteric fever caused bySalmonella entericaserovar Paratyphi A infection has emerged as an important public health problem. Recognizing that in randomized controlled field trials oral immunization with attenuatedS. entericaserovar Typhi live vaccine Ty21a conferred significant cross-protection againstS. Paratyphi B but notS. Paratyphi A disease, we undertook a clinical study to ascertain whether humoral immune responses could explain the field trial results. Ty21a immunization of adult residents of Maryland elicited predominantly IgA antibody-secreting cells (ASC) that recognizeS. Typhi lipopolysaccharide (LPS). Cross-reactivity toS. Paratyphi A LPS was significantly lower than that toS. Paratyphi B LPS. ASC producing IgG and IgA that bind LPS from each of theseSalmonellaserovars expressed CD27 and integrin α4β7 (gut homing), with a significant proportion coexpressing CD62L (secondary lymphoid tissue homing). No significant differences were observed in serum antibody against LPS of the different serovars. Levels of IgA B memory (BM) cells toS. Typhi LPS were significantly higher than those againstS. Paratyphi A or B LPS, with no differences observed betweenS. Paratyphi A and B. The response of IgA BMto outer membrane proteins (OMP) fromS. Typhi was significantly stronger than that to OMP ofS. Paratyphi A but similar to that to OMP ofS. Paratyphi B. The percentages of IgG or IgA BMresponders to LPS or OMP from theseSalmonellastrains were similar. Whereas cross-reactive humoral immune responses toS. Paratyphi A or B antigens are demonstrable following Ty21a immunization, they cannot explain the efficacy data gleaned from controlled field trials.

scholarly journals In vitro activity of azithromycin in Salmonella isolates from Pakistan

2011 ◽  
Vol 5 (05) ◽  
pp. 391-395 ◽  
Author(s):  
Farhana Butt ◽  
Faisal Sultan
Keyword(s):  
Salmonella Enterica ◽  
Enteric Fever ◽  
Therapeutic Option ◽  
Close Correlation ◽  
Salmonella Typhi ◽  
Public Health Issue ◽  
Disc Diffusion ◽  
Paratyphi B ◽  
High Level

Introduction: Enteric fever is caused by Salmonella enterica serovars Typhi and Paratyphi A, B and C. It is a significant public health issue in Pakistan, which is exacerbated by a high level of resistance some isolates display to drugs routinely used in treatment. Azithromycin may be a treatment option for such isolates. Methodology: We determined the minimum inhibitory concentrations (MICs) of Salmonella Typhi and Paratyphi isolates against azithromycin in an attempt to gauge its feasibility as a therapeutic option. The MICs were also compared with corresponding disc diffusion zone sizes to see if there was consistency between the two tests. We tested 45 Salmonella enterica isolates using E-tests for MIC detection and azithromycin discs with a concentration of 15µg/ml for disc diffusion testing. Results: Salmonella Typhi, Salmonella Paratyphi A, and Salmonella Paratyphi C isolates demonstrated MICs of 2-12mg/L against azithromycin, suggesting that the antibiotic could be used for therapeutic purposes. For Salmonella Paratyphi B, the MICs were 2-48 mg/L. The higher MIC indicates a need for caution when considering use of azithromycin for Salmonella Paratyphi B infections without first testing for the MIC. There was a close correlation between MICs and zone sizes which was statistically significant. Conclusions: Our results indicate azithromycin is a potential therapeutic option for enteric fever. Standardized laboratory testing methods and interpretation for azithromycin  against Salmonella enterica would allow laboratories to report upon this antibiotic with confidence.

scholarly journals Live Oral Salmonella enterica Serovar Typhi Vaccines Ty21a and CVD 909 Induce Opsonophagocytic Functional Antibodies in Humans That Cross-React withS. Paratyphi A andS. Paratyphi B

2014 ◽  
Vol 21 (3) ◽  
pp. 427-434 ◽  
Author(s):  
Rezwanul Wahid ◽  
Shah J. Zafar ◽  
Monica A. McArthur ◽  
Marcela F. Pasetti ◽  
Myron M. Levine ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Content Type ◽  
Before And After ◽  
Human Sera ◽  
Antibody Titers ◽  
Paratyphi B ◽  
Iga Antibody ◽  
Functional Antibodies ◽  
New Generation

ABSTRACTLive oralSalmonella entericaserovar Typhi vaccine Ty21a induces specific antibodies that cross-react againstSalmonella entericaserovar Paratyphi A andSalmonella entericaserovar Paratyphi B, although their functional role in clearance remains unknown. We utilized anin vitroassay with THP-1 macrophages to compare the phagocytosis and survival ofSalmonellaopsonized with heat-inactivated human sera obtained before and after vaccination with Ty21a or a live oralS. Typhi vaccine, CVD 909. Opsonization with postvaccination sera predominantly increased the phagocytosis ofS. Typhi relative to the corresponding prevaccination sera, and increases were also observed withS. Paratyphi A andS. Paratyphi B, albeit of lower magnitudes. Relative to prevaccination sera, opsonization with the postvaccination sera reduced the survival inside macrophages ofS. Typhi but not ofS. Paratyphi A orS. Paratyphi B. Higher anti-S. Typhi O antigen (lipopolysaccharide [LPS]) IgG, but not IgA, antibody titers correlated significantly with postvaccination increases in opsonophagocytosis. No differences were observed between immunization with four doses of Ty21a or one dose of CVD 909. Ty21a and CVD 909 induced cross-reactive functional antibodies, predominantly againstS. Typhi. IgG anti-LPS antibodies may be important in phagocytic clearance of these organisms. Therefore, measurement of functional antibodies might be important in assessing the immunogenicity of a new generation of typhoid and paratyphoid A vaccines. (The CVD 909 study has been registered at ClinicalTrials.gov under registration no. NCT00326443.)

scholarly journals Salmonella enterica Serovar Typhimurium trxA Mutants Are Protective against Virulent Challenge and Induce Less Inflammation than the Live-Attenuated Vaccine Strain SL3261

2009 ◽  
Vol 78 (1) ◽  
pp. 326-336 ◽  
Author(s):  
S. E. Peters ◽  
G. K. Paterson ◽  
E. S. D. Bandularatne ◽  
H. C. Northen ◽  
S. Pleasance ◽  
...  
Keyword(s):  
Vaccine Strain ◽  
Salmonella Enterica ◽  
Parent Strain ◽  
Reductase Activity ◽  
Gene Cassette ◽  
Kanamycin Resistance ◽  
Live Attenuated Vaccine ◽  
Attenuated Vaccine ◽  
Oxidative Stresses ◽  
Serovar Typhimurium

ABSTRACT In Salmonella enterica serovar Typhimurium, trxA encodes thioredoxin 1, a small, soluble protein with disulfide reductase activity, which catalyzes thiol disulfide redox reactions in a variety of substrate proteins. Thioredoxins are involved as antioxidants in defense against oxidative stresses, such as exposure to hydrogen peroxide and hydroxyl radicals. We have made a defined, complete deletion of trxA in the mouse-virulent S. Typhimurium strain SL1344 (SL1344 trxA), replacing the gene with a kanamycin resistance gene cassette. SL1344 trxA was attenuated for virulence in BALB/c mice by the oral and intravenous routes and when used in immunization experiments provided protection against challenge with the virulent parent strain. SL1344 trxA induced less inflammation in murine spleens and livers than SL3261, the aroA mutant, live attenuated vaccine strain. The reduced splenomegaly observed following infection with SL1344 trxA was partially attributed to a reduction in the number of both CD4+ and CD8+ T cells and B lymphocytes in the spleen and reduced infiltration by CD11b+ cells into the spleen compared with spleens from mice infected with SL3261. This less severe pathological response indicates that a trxA mutation might be used to reduce reactogenicity of live attenuated vaccine strains. We tested this by deleting trxA in SL3261. SL3261 trxA was also less inflammatory than SL3261 but was slightly less effective as a vaccine strain than either the SL3261 parent strain or SL1344 trxA.

Vaccination against Trichinella spiralis in mice using antigens from different isolates

Parasitology ◽  
1993 ◽  
Vol 107 (3) ◽  
pp. 311-317 ◽  
Author(s):  
P. K. Goyal ◽  
D. Wakelin
Keyword(s):  
Adult Worm ◽  
Trichinella Spiralis ◽  
Female Worm ◽  
Sensu Stricto ◽  
Cross Reactivity ◽  
Antibody Responses ◽  
Heterologous Challenge ◽  
Worm Recovery ◽  
Before And After ◽  
Homologous Challenge

SummaryAntigen preparations from three isolates of Trichinella spiralis (sensu-stricto) have been tested for their ability to immunize mice against homologous and heterologous challenge infections. Immunization was measured by accelerated expulsion of adult worms, reduction in female worm fecundity, stunting of growth, and level of antibody responses before and after challenge. Antigens of two isolates, from London (L) and Poland (P), immunized effectively against homologous challenge, adult worm recoveries being reduced by 64% and 51% respectively within 6 days. Antigen from a Spanish(S) isolate gave no homologous protection in terms of worm recovery at day 6 and only 43% reduction at day 8. L- and P-isolate antigens immunized well against heterologous challenge (day 6 worm recoveries reduced by 66% and 59%) but similar protection against S-isolate challenge was not seen until day 8. Immunization with S antigen gave better protection at day 6 against L-isolate challenge (77%) than against challenge with P-isolate (37%). These results imply considerable, but not complete, antigen cross-reactivity between the isolates and this was reflected in antibody responses. These variations in immunogenicity and immunization potential are discussed in terms of constraints on the use of vaccines against parasites that are widely distributed geographically.

scholarly journals Clinically and Microbiologically Derived Azithromycin Susceptibility Breakpoints for Salmonella enterica Serovars Typhi and Paratyphi A

2015 ◽  
Vol 59 (5) ◽  
pp. 2756-2764 ◽  
Author(s):  
Christopher M. Parry ◽  
Nga Tran Vu Thieu ◽  
Christiane Dolecek ◽  
Abhilasha Karkey ◽  
Ruchi Gupta ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Enteric Fever ◽  
Inhibition Zone ◽  
Antimicrobial Treatment ◽  
Response To Treatment ◽  
Zone Size ◽  
Content Type ◽  
Fever Clearance Time ◽  
Significant Difference ◽  
The Relationship

ABSTRACTAzithromycin is an effective treatment for uncomplicated infections withSalmonella entericaserovar Typhi and serovar Paratyphi A (enteric fever), but there are no clinically validated MIC and disk zone size interpretative guidelines. We studied individual patient data from three randomized controlled trials (RCTs) of antimicrobial treatment in enteric fever in Vietnam, with azithromycin used in one treatment arm, to determine the relationship between azithromycin treatment response and the azithromycin MIC of the infecting isolate. We additionally compared the azithromycin MIC and the disk susceptibility zone sizes of 1,640S. Typhi andS. Paratyphi A clinical isolates collected from seven Asian countries. In the RCTs, 214 patients who were treated with azithromycin at a dose of 10 to 20 mg/ml for 5 to 7 days were analyzed. Treatment was successful in 195 of 214 (91%) patients, with no significant difference in response (cure rate, fever clearance time) with MICs ranging from 4 to 16 μg/ml. The proportion of Asian enteric fever isolates with an MIC of ≤16 μg/ml was 1,452/1,460 (99.5%; 95% confidence interval [CI], 98.9 to 99.7) forS. Typhi and 207/240 (86.3%; 95% CI, 81.2 to 90.3) (P< 0.001) forS. Paratyphi A. A zone size of ≥13 mm to a 5-μg azithromycin disk identifiedS. Typhi isolates with an MIC of ≤16 μg/ml with a sensitivity of 99.7%. An azithromycin MIC of ≤16 μg/ml or disk inhibition zone size of ≥13 mm enabled the detection of susceptibleS. Typhi isolates that respond to azithromycin treatment. Further work is needed to define the response to treatment inS. Typhi isolates with an azithromycin MIC of >16 μg/ml and to determine MIC and disk breakpoints forS. Paratyphi A.

scholarly journals Development of a Simple, Peripheral-Blood-Based Lateral-Flow Dipstick Assay for Accurate Detection of Patients with Enteric Fever

2016 ◽  
Vol 23 (5) ◽  
pp. 403-409 ◽  
Author(s):  
Iqbal Hassan Khan ◽  
M. Abu Sayeed ◽  
Nishat Sultana ◽  
Kamrul Islam ◽  
Jakia Amin ◽  
...  
Keyword(s):  
Blood Culture ◽  
Salmonella Enterica ◽  
Enteric Fever ◽  
Systemic Infection ◽  
Lymphocyte Culture ◽  
Lateral Flow ◽  
True Negative ◽  
Content Type ◽  
Mortality And Morbidity ◽  
Resource Limited

ABSTRACTEnteric fever is a systemic infection caused by typhoidal strains ofSalmonella entericaand is a significant cause of mortality and morbidity in many parts of the world, especially in resource-limited areas. Unfortunately, currently available diagnostic tests for enteric fever lack sensitivity and/or specificity. No true clinically practical gold standard for diagnosing patients with enteric fever exists. Unfortunately, microbiologic culturing of blood is only 30 to 70% sensitive although 100% specific. Here, we report the development of a lateral-flow immunochromatographic dipstick assay based on the detection ofSalmonella entericaserovar Typhi (S. Typhi) lipopolysaccharide (LPS)-specific IgG in lymphocyte culture secretion. We tested the assay using samples from 142 clinically suspected enteric fever patients, 28 healthy individuals residing in a zone where enteric fever is endemic, and 35 patients with other febrile illnesses. In our analysis, the dipstick detected all blood culture-confirmedS. Typhi cases (48/48) and 5 of 6Salmonella entericaserovar Paratyphi A blood cultured-confirmed cases. The test was negative in all 35 individuals febrile with other illnesses and all 28 healthy controls from the zone of endemicity. The test was positive in 19 of 88 individuals with suspected enteric fever but with negative blood cultures. Thus, the dipstick had a sensitivity of 98% compared to blood culture results and a specificity that ranged from 78 to 100% (95% confidence interval [CI], 70 to 100%), depending on the definition of a true negative. These results suggest that this dipstick assay can be very useful for the detection of enteric fever patients especially in regions of endemicity.

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