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Vaccine Mar 2023The typhoid conjugate vaccine (TCV) ensures a long-lasting protective immune response, requires fewer doses and is fit for children under 2 years of age. From Phase I... (Randomized Controlled Trial)
Randomized Controlled Trial
A Phase II/III, Multicenter, Observer-blinded, Randomized, Non-inferiority and Safety, study of typhoid conjugate vaccine (EuTCV) compared to Typbar-TCV® in healthy 6 Months-45 years aged participants.
The typhoid conjugate vaccine (TCV) ensures a long-lasting protective immune response, requires fewer doses and is fit for children under 2 years of age. From Phase I study, EuTCV displayed considerable immunogenicity and reliable safety, thus endorsing further examination in Phase II/III trials. Therefore, a clinical Phase II/III study (NCT04830371) was conducted to evaluate its efficacy in healthy Filipino participants aged 6 months to 45 years through administration of the test vaccine (Arm A, B, and C) or comparator vaccine Typbar-TCV® (Arm D). Sera samples were collected pre-vaccination (Visit 1) and post-vaccination (Visit 4, Day 28) to assess the immunogenicity of EuTCV and Typbar-TCV®. During the study, participants were regularly monitored through scheduled visits to the clinic to report any adverse events associated with the vaccine. For vaccine safety, the proportion of solicited and unsolicited Treatment-Emergent Adverse Events was all comparable between EuTCV and Typbar-TCV® groups. A single dose of EuTCV produced seroconversion in 99.4% of treated participants, with seroconversion rates non-inferior to that of Typbar-TCV®. Batch-to-batch consistency was concluded based on the 90% Confidence Interval of the geometric mean ratio (EuTCV Arm A, B, and C) at Week 4, lying within the equivalence margin of 0.5 to 2.0 for all batches. Results from this Phase II/III clinical trial of EuTCV in healthy volunteers show comparable safety and considerable immunogenicity, compared to Typbar-TCV®, meeting the objectives of this pivotal study. ClinicalTrials.gov registration number: NCT04830371.
Topics: Child; Humans; Infant; Typhoid Fever; Typhoid-Paratyphoid Vaccines; Vaccines, Conjugate; Vaccination; Smallpox Vaccine; Immunogenicity, Vaccine
PubMed: 36774331
DOI: 10.1016/j.vaccine.2022.12.007 -
Microbial Genomics Jan 2023Typhi (. Typhi) and Paratyphi A (. Paratyphi A) are the causative agents of enteric fever, a systemic human disease with a burden of 300 000 cases per year in...
Typhi (. Typhi) and Paratyphi A (. Paratyphi A) are the causative agents of enteric fever, a systemic human disease with a burden of 300 000 cases per year in India. The majority of enteric fever cases are associated with . Typhi, resulting in a paucity of data regarding . Paratyphi A, specifically with respect to genomic surveillance and antimicrobial resistance (AMR). Here, we exploited whole-genome sequencing (WGS) to identify . Paratyphi A genotypes and AMR determinants associated with an outbreak of . Paratyphi A in Vadodara, India, from December 2018 to December 2019. In total 117 . Paratyphi A were isolated and genome sequenced, most were genotype 2.4.2 (72.6 % of all cases), which is the globally dominant genotype. The remainder were genotype 2.3 (25.6 %), while only two isolates belonged to genotype 2.4.1. A single base-pair mutation in , associated with reduced susceptibility to fluoroquinolones, was present in all of the outbreak isolates; with 74.35 % of isolates having a S83F substitution and the remainder having an S83Y substitution. Our surveillance study suggests that . Paratyphi A is an emergent pathogen in South Asia, which may become increasingly relevant with the introduction of Vi conjugate vaccines.
Topics: Humans; Typhoid Fever; Salmonella paratyphi A; Drug Resistance, Bacterial; Salmonella typhi; India; Disease Outbreaks; Genomics
PubMed: 36748526
DOI: 10.1099/mgen.0.000914 -
Scientific Reports Jan 2023Salmonella enterica serovar Typhi is the causative agent of typhoid fever restricted to humans and does not replicate in commonly used inbred mice. Genetic variation in...
Salmonella enterica serovar Typhi is the causative agent of typhoid fever restricted to humans and does not replicate in commonly used inbred mice. Genetic variation in humans is far greater and more complex than that in a single inbred strain of mice. The Collaborative Cross (CC) is a large panel of recombinant inbred strains which has a wider range of genetic diversity than laboratory inbred mouse strains. We found that the CC003/Unc and CC053/Unc strains are permissive to intraperitoneal but not oral route of S. Typhi infection and show histopathological changes characteristic of human typhoid. These CC strains are immunocompetent, and immunization induces antigen-specific responses that can kill S. Typhi in vitro and control S. Typhi in vivo. Our results indicate that CC003/Unc and CC053/Unc strains can help identify the genetic basis for typhoid susceptibility, S. Typhi virulence mechanism(s) in vivo, and serve as a preclinical mammalian model system to identify effective vaccines and therapeutics strategies.
Topics: Animals; Humans; Mice; Salmonella typhi; Typhoid Fever; Collaborative Cross Mice; Typhoid-Paratyphoid Vaccines; Mammals
PubMed: 36624251
DOI: 10.1038/s41598-023-27400-1 -
Journal of Family Medicine and Primary... Oct 2022Salmonella (. ) and Salmonella A (. A), together known as typhoidal Salmonella, are causal agents for an invasive, serious, and sometimes fatal disease of humans...
Salmonella (. ) and Salmonella A (. A), together known as typhoidal Salmonella, are causal agents for an invasive, serious, and sometimes fatal disease of humans called typhoid fever or paratyphoid fever (also known as enteric fever). S. Typhi, the lineage causing typhoid fever, is the main group; whereas S. Paratyphi A, the lineage causing paratyphoid fever, belongs to the second group, which comprises a set of three paratyphoid types (the other two being S. Paratyphi C and d-tartrate-negative S. Paratyphi B). All these lineages are adapted to humans, with S. Typhi and S. Paratyphi A being strictly restricted to growth in humans, and S. Paratyphi C being able to establish infections in experimental animals quite easily (at moderate infection doses); the host-restriction status of d-tartrate-negative S. Paratyphi B is so far unclear. The potential source of infection is the use of sewage-contaminated water in plants and vegetable irrigation and clinical presentation is varied, mainly presenting with fever, malaise, abdominal discomfort, and nonspecific symptoms often confused with other causes of the febrile syndrome. S. Paratyphi is usually a mild form of disease without any complication, but we report a complicated case of Paratyphi, who presented with fever and gastrointestinal symptoms complicated by multiorgan dysfunction needing mechanical ventilatory support, multiple hemodialysis, and blood transfusion. Fortunately, he recovered from all the insults and was discharged home in stable condition on the 26 day of hospitalization.
PubMed: 36618154
DOI: 10.4103/jfmpc.jfmpc_335_22 -
Vaccine Jan 2023Models are useful to inform policy decisions on typhoid conjugate vaccine (TCV) deployment in endemic settings. However, methodological choices can influence...
Models are useful to inform policy decisions on typhoid conjugate vaccine (TCV) deployment in endemic settings. However, methodological choices can influence model-predicted outcomes. To provide robust estimates for the potential public health impact of TCVs that account for structural model differences, we compared four dynamic and one static mathematical model of typhoid transmission and vaccine impact. All models were fitted to a common dataset of age-specific typhoid fever cases in Kolkata, India. We evaluated three TCV strategies: no vaccination, routine vaccination at 9 months of age, and routine vaccination at 9 months with a one-time catch-up campaign (ages 9 months to 15 years). The primary outcome was the predicted percent reduction in symptomatic typhoid cases over 10 years after vaccine introduction. For three models with economic analyses (Models A-C), we also compared the incremental cost-effectiveness ratios (ICERs), calculated as the incremental cost (US$) per disability-adjusted life-year (DALY) averted. Routine vaccination was predicted to reduce symptomatic cases by 10-46 % over a 10-year time horizon under an optimistic scenario (95 % initial vaccine efficacy and 19-year mean duration of protection), and by 2-16 % under a pessimistic scenario (82 % initial efficacy and 6-year mean protection). Adding a catch-up campaign predicted a reduction in incidence of 36-90 % and 6-35 % in the optimistic and pessimistic scenarios, respectively. Vaccine impact was predicted to decrease as the relative contribution of chronic carriers to transmission increased. Models A-C all predicted routine vaccination with or without a catch-up campaign to be cost-effective compared to no vaccination, with ICERs varying from $95-789 per DALY averted; two models predicted the ICER of routine vaccination alone to be greater than with the addition of catch-up campaign. Despite differences in model-predicted vaccine impact and cost-effectiveness, routine vaccination plus a catch-up campaign is likely to be impactful and cost-effective in high incidence settings such as Kolkata.
Topics: Humans; Public Health; Cost-Benefit Analysis; Vaccines, Conjugate; Typhoid-Paratyphoid Vaccines; Typhoid Fever
PubMed: 36586741
DOI: 10.1016/j.vaccine.2022.12.032 -
Nature Communications Dec 2022Salmonella Paratyphi A, the primary etiology of paratyphoid, is estimated to cause 3.4 million infections annually, worldwide. With rising antimicrobial resistance and...
Salmonella Paratyphi A, the primary etiology of paratyphoid, is estimated to cause 3.4 million infections annually, worldwide. With rising antimicrobial resistance and no licensed vaccines, genomic surveillance is key to track and monitor transmission, but there is currently no reliable genotyping framework for this pathogen. Here, we sequence 817 isolates from South Asia and add 562 publicly available genomes to build a global database representing 37 countries, covering 1917-2019. We develop a single nucleotide polymorphism-based genotyping scheme, Paratype, that segregates Salmonella Paratyphi A population into three primary and nine secondary clades, and 18 genotypes. Each genotype is assigned a unique allele definition located on an essential gene. Using Paratype, we identify spatiotemporal genomic variation and antimicrobial resistance markers. We release Paratype as an open-access tool that can use raw read files from both Illumina and Nanopore platforms, and thus can assist surveillance studies tracking Salmonella Paratyphi A across the globe.
Topics: Humans; Salmonella paratyphi A; Genotype; Paratyphoid Fever; Genomics; Anti-Infective Agents
PubMed: 36564386
DOI: 10.1038/s41467-022-35587-6 -
Disaster Medicine and Public Health... Dec 2022In 2016, an outbreak of paratyphoid fever occurred in 40 cases at Qingyang town, in China. A case-control study was carried out to determine the source of this outbreak....
In 2016, an outbreak of paratyphoid fever occurred in 40 cases at Qingyang town, in China. A case-control study was carried out to determine the source of this outbreak. Case-control study was conducted to identify the risk factors of this outbreak. The cases were identified as patients with isolation of , controls were confirmed cases' healthy classmates, colleagues or neighbors and matched by age (±5 y) and gender. Pulsed-field gel electrophoresis was performed to source tracking. Totally, 40 cases were reported: 24 cases were students, and 20 (20/24) of them were Qingyang High School students. For the case-control study, consuming Chinese egg pancakes was detected as a risk factor (OR = 5.000; 95% CI: 1.710-14.640), and hand-washing before meals was protective behavior compared with seldom hand-washing (OR = 23.256; 95% CI: 2.451-200.000). Paratyphi was cultured from a well water sample used for washing contents of the pancakes. Isolates from well water and paratyphoid cases showed the same PFGE patterns. Contaminated well water and Chinese egg pancakes were likely source and vehicle of this outbreak. Health education, especially handwashing, and food safety supervision should be promoted particularly in schools.
Topics: Humans; Paratyphoid Fever; Case-Control Studies; Disease Outbreaks; China; Water
PubMed: 36537008
DOI: 10.1017/dmp.2022.165 -
Human Vaccines & Immunotherapeutics Nov 2022Infectious diseases continue to disproportionately affect low- and middle-income countries (LMICs) and children aged <5 y. Developing vaccines against diseases endemic... (Review)
Review
Infectious diseases continue to disproportionately affect low- and middle-income countries (LMICs) and children aged <5 y. Developing vaccines against diseases endemic in LMICs relies mainly on strong public-private collaborations, but several challenges remain. We review the operating model of the GSK Vaccines Institute for Global Health (GVGH), which aims to address these challenges. The model involves i) selection of vaccine targets based on priority ranking for impact on global health; ii) development from design to clinical proof-of-concept; iii) transfer to an industrial partner, for further technical/clinical development, licensing, manufacturing, and distribution. Cost and risks associated with pre-clinical and early clinical development are assumed by GVGH, increasing the probability to make the vaccine more affordable in LMICs. A conjugate vaccine against typhoid fever, Vi-CRM, has recently obtained WHO prequalification, within a year from licensure in India, demonstrating the success of the GVGH model for development and delivery of global health vaccines.
Topics: Child; Humans; Typhoid-Paratyphoid Vaccines; Neglected Diseases; Sustainable Development; Typhoid Fever; Vaccines, Conjugate
PubMed: 36495000
DOI: 10.1080/21645515.2022.2136451 -
Microbial Pathogenesis Jan 2023Relentless emergence of antibiotic resistant Salmonella strains, coupled with the drawbacks associated with currently available vaccines against enteric fever, warrants...
Relentless emergence of antibiotic resistant Salmonella strains, coupled with the drawbacks associated with currently available vaccines against enteric fever, warrants an urgent need to look for new vaccine candidates. Out of the multiple virulence factors harbored by Salmonella, flagella are regarded as one of the most important targets of innate as well as adaptive immune response. Individual Salmonella serotypes alternate between expression of two different antigenic forms encoded by fliC and fljB genes, respectively thereby employing this as a strategy to escape the host immune response. In the present study, using various immunoinformatic approaches, a flagellin epitope, present in both antigenic forms of typhoidal Salmonellae has been targeted. Following B-cell epitope and B-cell derived T-cell epitope prediction and interaction studies with major histocompatibility complexes using molecular docking, a peptide epitope was selected. Further, it was screened for its presence in majority of typhoidal serovars along with other useful attributes, in silico. Thereafter, safety studies were performed with the synthesized peptide. Subsequently, immunization studies were carried out using S. Typhi as well as S. Paratyphi A induced murine peritonitis model. Active immunization with peptide-BSA conjugate resulted in 75% and 80% mice survival following lethal challenge with S. Typhi and S. Paratyphi A respectively, along with a significant IgG antibody titer, thereby highlighting its immunogenic potential. Reduced bacterial burden in vital organs along with improved histoarchitecture and cytokine levels further substantiated the protective efficacy of the proposed candidate. Passive immunization studies with the candidate verified the protective efficacy of the generated antibodies against lethal challenge of bacteria in mice. Given the endemic nature of enteric fever and the antigenic variability observed in Salmonella serotypes, present study highlights the importance of using a vaccine candidate, which, along with generating a strong immune response, also exhibits a broad coverage against both, S. Typhi as well as S. Paratyphi A strains.
Topics: Animals; Mice; Typhoid Fever; Flagellin; Epitopes; Molecular Docking Simulation; Typhoid-Paratyphoid Vaccines; Salmonella typhi
PubMed: 36494021
DOI: 10.1016/j.micpath.2022.105936 -
The Lancet. Global Health Jan 2023Typhoid conjugate vaccines are being introduced in low-income and middle-income countries to prevent typhoid illness in children. Vaccine effectiveness studies assess... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Typhoid conjugate vaccines are being introduced in low-income and middle-income countries to prevent typhoid illness in children. Vaccine effectiveness studies assess vaccine performance after introduction. The test-negative design is a commonly used method to estimate vaccine effectiveness that has not been applied to typhoid vaccines because of concerns over blood culture insensitivity. The overall aim of the study was to evaluate the appropriateness of using a test-negative design to assess typhoid Vi polysaccharide-tetanus toxoid conjugate vaccine (Vi-TT) effectiveness using a gold standard randomised controlled trial database.
METHODS
Using blood culture data from a randomised controlled trial of Vi-TT in Malawi, we simulated a test-negative design to derive vaccine effectiveness estimates using three different approaches and compared these to randomised trial efficacy results. In the randomised trial, 27 882 children aged 9 months to 12 years were randomly assigned (1:1) to receive a single dose of Vi-TT or meningococcal capsular group A conjugate vaccine between Feb 21 and Sept 27, 2018, and were followed up for blood culture-confirmed typhoid fever until Sept 30, 2021.
FINDINGS
For all three test-negative design approaches, vaccine effectiveness estimates (test-negative design A, 80·3% [95% CI 66·2 to 88·5] vs test-negative design B, 80·5% [66·5 to 88·6] vs test-negative design C, 80·4% [66·9 to 88·4]) were almost identical to the randomised trial results (80·4% [95% CI 66·4 to 88·5]). Receipt of Vi-TT did not affect the risk of non-typhoid fever (vaccine efficacy against non-typhoid fever -0·4% [95% CI -4·9 to 3·9] vs -1% [-5·6 to 3·3] vs -2·5% [-6·4 to 1·3] for test-negative design A, test-negative design B, and test-negative design C, respectively).
INTERPRETATION
This study validates the test-negative design core assumption for typhoid vaccine effectiveness estimation and shows the accuracy and precision of the estimates compared with the randomised controlled trial. These results show that the test-negative design is suitable for assessing typhoid conjugate vaccine effectiveness in post-introduction studies using blood culture surveillance.
FUNDING
Bill & Melinda Gates Foundation.
Topics: Child; Humans; Typhoid-Paratyphoid Vaccines; Vaccines, Conjugate; Vaccine Efficacy; Malawi; Salmonella typhi; Typhoid Fever
PubMed: 36442498
DOI: 10.1016/S2214-109X(22)00466-1