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Poultry Science Nov 2010Attenuated Salmonella Enteriditis (ΔSE) recombinant vaccine vectors incorporating a Salmonella flagellar filament protein (fliC) subunit, a putative cell-mediated...
Attenuated Salmonella Enteriditis (ΔSE) recombinant vaccine vectors incorporating a Salmonella flagellar filament protein (fliC) subunit, a putative cell-mediated epitope, for expression of the lamB gene (encoding a maltose outer membrane porin), with or without co-expression of a putative immune-enhancing CD154 oligopeptide, were developed and compared with wild-type Salmonella Enteriditis (experiments 1 and 2) or the attenuated ΔSE empty vector (experiment 3) as initial vaccine candidates against Salmonella infection. A total of 3 experiments were performed to assess the infection and clearance rate of each of these constructs. Each construct or Salmonella Enteriditis was orally administered to broiler chicks at day of hatch by oral gavage (~10(8) cfu/chick). In experiments 1 to 3, liver-spleen and cecal tonsils were removed aseptically for recovery of wild-type Salmonella Enteriditis or ΔSE mutants. These experiments suggested that cell surface expression of fliC alone markedly increased the clearance rate of the vector at or before 21d postvaccination in all 3 experiments. In a fourth experiment, broilers were vaccinated with one of the vaccine constructs or the ΔSE empty vector and then challenged with wild-type Salmonella Typhimurium. At 19 d posthatch, 16 d postinfection, neither candidate protected against challenge significantly better than the ΔSE empty vector, although there was significantly less Salmonella recovered from vaccinated chickens as compared with nonvaccinated controls. These experiments indicate that these experimental vaccines did not protect against heterologous challenge or enhance clearance after Salmonella Typhimurium challenge; as such, their value as vaccines is limited. The increased clearance of the candidate vaccines, particularly the vector expressing fliC alone, may have value in that the fliC epitope may decrease the clearance time of other recombinant vectored Salmonella vaccines.
Topics: Animals; Enteritis; Genetic Vectors; Hypersensitivity, Delayed; Recombinant Proteins; Salmonella; Salmonella Infections, Animal; Salmonella Vaccines; Salmonella typhimurium; United States
PubMed: 20952699
DOI: 10.3382/ps.2010-00702 -
Frontiers in Cellular and Infection... 2017Non-typhoidal includes thousands of serovars that are leading causes of foodborne diarrheal illness worldwide. In this study, we constructed three bivalent vaccines for...
Non-typhoidal includes thousands of serovars that are leading causes of foodborne diarrheal illness worldwide. In this study, we constructed three bivalent vaccines for preventing both Typhimurium and Newport infections by using the aspartate semialdehyde dehydrogenase (Asd)-based balanced-lethal vector-host system. The constructed Asd plasmid pCZ11 carrying a subset of the Newport O-antigen gene cluster including the genes was introduced into three Typhimurium mutants: SLT19 (Δ) with a smooth LPS phenotype, SLT20 (Δ Δ) with a rough LPS phenotype, and SLT22 (Δ Δ Δ P) with a smooth LPS phenotype when grown with arabinose. Immunoblotting demonstrated that SLT19 harboring pCZ11 [termed SLT19 (pCZ11)] co-expressed the homologous and heterologous O-antigens; SLT20 (pCZ11) exclusively expressed the heterologous O-antigen; and when arabinose was available, SLT22 (pCZ11) expressed both types of O-antigens, while in the absence of arabinose, SLT22 (pCZ11) expressed only the heterologous O-antigen. Exclusive expression of the heterologous O-antigen in Typhimurium decreased the swimming ability of the bacterium and its susceptibility to polymyxin B. Next, the gene was deleted from the three recombinant strains for attenuation purposes, generating the three bivalent vaccine strains SLT25 (pCZ11), SLT26 (pCZ11), and SLT27 (pCZ11), respectively. Groups of BALB/c mice (12 mice/group) were orally immunized with 10 CFU of each vaccine strain twice at an interval of 4 weeks. Compared with a mock immunization, immunization with all three vaccine strains induced significant serum IgG responses against both Typhimurium and Newport LPS. The bacterial loads in the mouse tissues were significantly lower in the three vaccine-strain-immunized groups than in the mock group after either Typhimurium or Newport lethal challenge. All of the mice in the three vaccine-immunized groups survived the lethal Typhimurium challenge. In contrast, SLT26 (pCZ11) and SLT27 (pCZ11) conferred full protection against lethal Newport challenge, but SLT25 (pCZ11) provided only 50% heterologous protection. Thus, we developed two novel bivalent vaccines, SLT26 (pCZ11) and SLT27 (pCZ11), suggesting that the delivery of a heterologous O-antigen in attenuated strains is a prospective approach for developing vaccines with broad serovar coverage.
Topics: Animals; Arabinose; Disease Models, Animal; Female; Immunization; Mice; Mice, Inbred BALB C; Mutation; O Antigens; Plasmids; Salmonella Infections; Salmonella Vaccines; Salmonella typhimurium; Serogroup; Vaccines, Attenuated; Virulence
PubMed: 28929089
DOI: 10.3389/fcimb.2017.00391 -
Clinical Infectious Diseases : An... Jul 2020Typhoid fever has been endemic on the island nation of Samoa (2016 population, 195 979) since the 1960s and has persisted through 2019, despite economic development...
BACKGROUND
Typhoid fever has been endemic on the island nation of Samoa (2016 population, 195 979) since the 1960s and has persisted through 2019, despite economic development and improvements in water supply and sanitation.
METHODS
Salmonella enterica serovar Typhi isolates from the 2 hospitals with blood culture capability and matched patient demographic and clinical data from January 2008 through December 2019 were analyzed. Denominators to calculate incidence by island, region, and district came from 2011 and 2016 censuses and from 2017-2019 projections from Samoa's Bureau of Statistics. Data were analyzed to describe typhoid case burden and incidence from 2008 to 2019 by time, place, and person.
RESULTS
In sum, 53-193 blood culture-confirmed typhoid cases occurred annually from 2008 to 2019, without apparent seasonality. Typhoid incidence was low among children age < 48 months (17.6-27.8/105), rose progressively in ages 5-9 years (54.0/105), 10-19 years (60.7-63.4/105), and 20-34 years (61.0-79.3/105), and then tapered off; 93.6% of cases occurred among Samoans < 50 years of age. Most typhoid cases and the highest incidence occurred in Northwest Upolu, but Apia Urban Area (served by treated water supplies) also exhibited moderate incidence. The proportion of cases from short-cycle versus long-cycle transmission is unknown. Samoan S. Typhi are pansusceptible to traditional first-line antibiotics. Nevertheless, enhanced surveillance in 2019 detected 4 (2.9%) deaths among 140 cases.
CONCLUSIONS
Typhoid has been endemic in Samoa in the period 2008-2019. Interventions, including mass vaccination with a Vi-conjugate vaccine coadministered with measles vaccine are planned.
Topics: Child; Child, Preschool; Humans; Infant; Salmonella typhi; Samoa; Typhoid Fever; Typhoid-Paratyphoid Vaccines; Vaccines, Conjugate
PubMed: 32725232
DOI: 10.1093/cid/ciaa314 -
Vaccine Jul 2014Contemporary vaccine development relies less on empirical methods of vaccine construction, and now employs a powerful array of precise engineering strategies to... (Review)
Review
Contemporary vaccine development relies less on empirical methods of vaccine construction, and now employs a powerful array of precise engineering strategies to construct immunogenic live vaccines. In this review, we will survey various engineering techniques used to create attenuated vaccines, with an emphasis on recent advances and insights. We will further explore the adaptation of attenuated strains to create multivalent vaccine platforms for immunization against multiple unrelated pathogens. These carrier vaccines are engineered to deliver sufficient levels of protective antigens to appropriate lymphoid inductive sites to elicit both carrier-specific and foreign antigen-specific immunity. Although many of these technologies were originally developed for use in Salmonella vaccines, application of the essential logic of these approaches will be extended to development of other enteric vaccines where possible. A central theme driving our discussion will stress that the ultimate success of an engineered vaccine rests on achieving the proper balance between attenuation and immunogenicity. Achieving this balance will avoid over-activation of inflammatory responses, which results in unacceptable reactogenicity, but will retain sufficient metabolic fitness to enable the live vaccine to reach deep tissue inductive sites and trigger protective immunity. The breadth of examples presented herein will clearly demonstrate that genetic engineering offers the potential for rapidly propelling vaccine development forward into novel applications and therapies which will significantly expand the role of vaccines in public health.
Topics: Drug Discovery; Genetic Engineering; Humans; Salmonella Vaccines; Technology, Pharmaceutical; Vaccines, Attenuated; Vaccines, Synthetic
PubMed: 24370705
DOI: 10.1016/j.vaccine.2013.12.026 -
Clinical Infectious Diseases : An... Jul 2020Enteric fever remains a major cause of morbidity in developing countries with poor sanitation conditions that enable fecal contamination of water distribution systems.... (Review)
Review
Enteric fever remains a major cause of morbidity in developing countries with poor sanitation conditions that enable fecal contamination of water distribution systems. Historical evidence has shown that contamination of water systems used for household consumption or agriculture are key transmission routes for Salmonella Typhi and Salmonella Paratyphi A. The World Health Organization now recommends that typhoid conjugate vaccines (TCV) be used in settings with high typhoid incidence; consequently, governments face a challenge regarding how to prioritize typhoid against other emerging diseases. A key issue is the lack of typhoid burden data in many low- and middle-income countries where TCV could be deployed. Here we present an argument for utilizing environmental sampling for the surveillance of enteric fever organisms to provide data on community-level typhoid risk. Such an approach could complement traditional blood culture-based surveillance or even replace it in settings where population-based clinical surveillance is not feasible. We review historical studies characterizing the transmission of enteric fever organisms through sewage and water, discuss recent advances in the molecular detection of typhoidal Salmonella in the environment, and outline challenges and knowledge gaps that need to be addressed to establish environmental sampling as a tool for generating actionable data that can inform public health responses to enteric fever.
Topics: Environmental Monitoring; Humans; Salmonella paratyphi A; Salmonella typhi; Typhoid Fever; Typhoid-Paratyphoid Vaccines
PubMed: 32725227
DOI: 10.1093/cid/ciaa513 -
Proceedings of the National Academy of... Jan 2021capsular polysaccharides (CPSs) are major determinants of bacterial pathogenicity. CPSs of different serotypes form the main components of the pneumococcal vaccines...
capsular polysaccharides (CPSs) are major determinants of bacterial pathogenicity. CPSs of different serotypes form the main components of the pneumococcal vaccines Pneumovax, Prevnar7, and Prevnar13, which substantially reduced the disease burden in developed countries. However, the laborious production processes of traditional polysaccharide-based vaccines have raised the cost of the vaccines and limited their impact in developing countries. The aim of this study is to develop a kind of low-cost live vaccine based on using the recombinant attenuated vaccine (RASV) system to protect against pneumococcal infections. We cloned genes for seven different serotypes of CPSs to be expressed by the RASV strain. Oral immunization of mice with the RASV-CPS strains elicited robust Th1 biased adaptive immune responses. All the CPS-specific antisera mediated opsonophagocytic killing of the corresponding serotype of in vitro. The RASV-CPS2 and RASV-CPS3 strains provided efficient protection of mice against challenge infections with either strain D39 or WU2. Synthesis and delivery of CPSs using the RASV strains provide an innovative strategy for low-cost pneumococcal vaccine development, production, and use.
Topics: Animals; Antibodies, Bacterial; Female; Immune Sera; Immunization; Immunoglobulin G; Mice; Mice, Inbred BALB C; Pneumococcal Infections; Pneumococcal Vaccines; Polysaccharides; Salmonella Vaccines; Serogroup; Streptococcus pneumoniae; Vaccines, Attenuated; Vaccines, Synthetic
PubMed: 33380455
DOI: 10.1073/pnas.2013350118 -
Research in Microbiology 1990In recent years there has been a resurgence of research to develop new and improved attenuated strains of Salmonella typhi to function as live oral vaccines against... (Clinical Trial)
Clinical Trial Comparative Study Review
In recent years there has been a resurgence of research to develop new and improved attenuated strains of Salmonella typhi to function as live oral vaccines against typhoid fever and to serve as "carrier" vaccines to express foreign antigens of other pathogens and deliver them to the immune system. Strain Ty21a has served as a prototype in clinical and field trials to identify the optimal formulations and dosage schedules for live vaccines and to quantitate the duration of protection that can be achieved. Clinical trials with three new attenuated S. typhi candidate vaccines, a Vi+ variant of Ty21a, an aroC,aroD double mutant recombinant strain and a cya,crp double mutant, are underway or will be initiated shortly.
Topics: Administration, Oral; Humans; Mutation; Salmonella typhi; Typhoid-Paratyphoid Vaccines; Vaccines, Attenuated; Vaccines, Synthetic
PubMed: 2101470
DOI: 10.1016/0923-2508(90)90114-6 -
Clinical and Vaccine Immunology : CVI May 2014Invasive Salmonella infections for which improved or new vaccines are being developed include enteric fever caused by Salmonella enterica serovars Typhi, Paratyphi A,...
Invasive Salmonella infections for which improved or new vaccines are being developed include enteric fever caused by Salmonella enterica serovars Typhi, Paratyphi A, and Paratyphi B and sepsis and meningitis in young children in sub-Saharan Africa caused by nontyphoidal Salmonella (NTS) serovars, particularly S. enterica serovars Typhimurium and Enteritidis. Assays are needed to measure functional antibodies elicited by the new vaccines to assess their immunogenicities and potential protective capacities. We developed in vitro assays to quantify serum bactericidal antibody (SBA) activity induced by S. Typhi, S. Paratyphi A, S. Typhimurium, and S. Enteritidis vaccines in preclinical studies. Complement from various sources was tested in assays designed to measure antibody-dependent complement-mediated killing. Serum from rabbits 3 to 4 weeks of age provided the best complement source compared to serum from pigs, goats, horses, bovine calves, or rabbits 8 to 12 weeks of age. For S. Enteritidis, S. Typhimurium, and S. Typhi SBA assays to be effective, bacteria had to be harvested at log phase. In contrast, S. Paratyphi A was equally susceptible to killing whether it was grown to the stationary or log phase. The typhoidal serovars were more susceptible to complement-mediated killing than were the nontyphoidal serovars. Lastly, the SBA endpoint titers correlated with serum IgG anti-lipopolysaccharide (LPS) titers in mice immunized with mucosally administered S. Typhimurium, S. Enteritidis, and S. Paratyphi A but not S. Typhi live attenuated vaccines. The SBA assay described here is a useful tool for measuring functional antibodies elicited by Salmonella vaccine candidates.
Topics: Animals; Antibodies, Bacterial; Blood Bactericidal Activity; Complement System Proteins; Humans; Immunoassay; Immunoglobulin G; Lipopolysaccharides; Meningitis, Bacterial; Salmonella Infections; Salmonella Vaccines; Sepsis; Typhoid Fever
PubMed: 24623629
DOI: 10.1128/CVI.00115-14 -
Trials Dec 2019Typhoidal Salmonella is a major global problem affecting more than 12 million people annually. Controlled human infection models (CHIMs) in high-resource settings have... (Comparative Study)
Comparative Study
Typhoidal Salmonella is a major global problem affecting more than 12 million people annually. Controlled human infection models (CHIMs) in high-resource settings have had an important role in accelerating the development of conjugate vaccines against Salmonella Typhi.The typhoidal Salmonella model has an established safety profile in over 2000 volunteers in high-income settings, and trial protocols, with modification, could be readily transferred to new study sites. To date, a typhoidal Salmonella CHIM has not been conducted in a low-resource setting, although it is being considered.Our article describes the challenges posed by a typhoidal Salmonella CHIM in the high-resource setting of Oxford and explores considerations for an endemic setting.Development of CHIMs in endemic settings is scientifically justifiable as it remains unclear whether findings from challenge studies performed in high-resource non-endemic settings can be extrapolated to endemic settings, where the burden of invasive Salmonella is highest. Volunteers are likely to differ across a range of important variables such as previous Salmonella exposure, diet, intestinal microbiota, and genetic profile. CHIMs in endemic settings arguably are ethically justifiable as affected communities are more likely to gain benefit from the study. Local training and research capacity may be bolstered.Safety was of primary importance in the Oxford model. Risk of harm to the individual was mitigated by careful inclusion and exclusion criteria; close monitoring with online diary and daily visits; 24/7 on-call staffing; and access to appropriate hospital facilities with capacity for in-patient admission. Risk of harm to the community was mitigated by exclusion of participants with contact with vulnerable persons; stringent hygiene and sanitation precautions; and demonstration of clearance of Salmonella infection from stool following antibiotic treatment.Safety measures should be more stringent in settings where health systems, transport networks, and sanitation are less robust.We compare the following issues between high- and low-resource settings: scientific justification, risk of harm to the individual and community, benefits to the individual and community, participant understanding, compensation, and regulatory requirements.We conclude that, with careful consideration of country-specific ethical and practical issues, a typhoidal Salmonella CHIM in an endemic setting is possible.
Topics: Developed Countries; Developing Countries; Health Resources; Healthy Volunteers; Humans; Research Design; Salmonella typhi; Therapeutic Human Experimentation; Typhoid Fever; Typhoid-Paratyphoid Vaccines
PubMed: 31852488
DOI: 10.1186/s13063-019-3844-z -
Clinical Infectious Diseases : An... Jul 2020In 1993, the International Task Force on Disease Eradication classified the political will for typhoid eradication as "none." Here we revisit the Task Force's assessment...
In 1993, the International Task Force on Disease Eradication classified the political will for typhoid eradication as "none." Here we revisit the Task Force's assessment in light of developments in typhoid vaccines and increasing antimicrobial resistance in Salmonella Typhi that have served to increase interest in typhoid elimination. Considering the requisite biological and technical factors for elimination, effective interventions exist for typhoid, and humans are the organism's only known reservoir. Improvements in water supply, sanitation, hygiene, and food safety are critical for robust long-term typhoid control, and the recent Strategic Advisory Group of Experts on Immunization recommendation and World Health Organization prequalification should make typhoid conjugate vaccine more accessible and affordable in low-income countries, which will allow the vaccine to offer a critical bridge to quickly reduce burden. While these developments are encouraging, all current typhoid diagnostics are inadequate, having either poor performance characteristics, limited scalability, or both. No clear solution exists, and this should be viewed as a critical challenge to any elimination effort. Moreover, asymptomatic carriers and limited data and surveillance remain major challenges, and countries considering elimination campaigns will need to develop strategies to identify high-risk populations and to monitor progress over time. Finally, policymakers must be realistic in planning, learn from the planning failures of previous elimination and eradication efforts, and expect unforeseeable shocks and setbacks. In the end, if we assume neither unanticipated breakthroughs in typhoid control nor any chaotic shocks, history suggests that we should expect typhoid elimination to take decades.
Topics: Feasibility Studies; Humans; Salmonella typhi; Typhoid Fever; Typhoid-Paratyphoid Vaccines; World Health Organization
PubMed: 32725226
DOI: 10.1093/cid/ciaa585