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Human Vaccines & Immunotherapeutics Dec 2023Typhoid remains one of the major serious health concerns for children in developing countries. With extremely drug-resistant cases emerging, preventative measures like... (Randomized Controlled Trial)
Randomized Controlled Trial
A randomized, observer-blind, controlled phase III clinical trial assessing safety and immunological non-inferiority of Vi-diphtheria toxoid versus Vi-tetanus toxoid typhoid conjugate vaccine in healthy volunteers in eastern Nepal.
Typhoid remains one of the major serious health concerns for children in developing countries. With extremely drug-resistant cases emerging, preventative measures like sanitation and vaccination, including typhoid conjugate vaccines (TCV) remain the mainstay in its prevention and control. Different types of TCVs are being developed to meet the global demand. This report outlines the results from a study done to assess the immunogenicity and safety of Vi-Diphtheria toxoid (Vi-DT) TCV in Nepal. The study was a randomized, active-controlled, immunological non-inferiority and safety study. Eligible participants from Sunsari and Morang districts of eastern Nepal were randomized into 4 study groups (A-D) within 3 age strata (6 months to <2 years, 2 to <18 years, and 18 to 45 years). Groups A to C received a single dose (25 μg) of Vi-DT test vaccine from any of the 3 lots, while group D received the comparator, Typbar-TCV®, Vi-tetanus toxoid (Vi-TT) vaccine (25 μg) in 1:1:1:1 ratio and evaluated at 4 weeks postvaccination with 6 months follow-up. Amongst 400 randomized participants, anti-Vi-IgG seroconversion rates for all age strata in Vi-DT pooled groups (A+B+C) were 100.00% (97.5% CI 98.34-100.00) vs 98.99% (97.5% CI 93.99-99.85) in Vi-TT group (D) at 4 weeks. Comparable safety events were reported between the groups. Three serious adverse events (1 in Vi-DT; 2 in Vi-TT group) were reported during the 6 months follow-up, none being related to the investigational product. Thus, Vi-DT vaccine is safe, immunogenic, and immunologically non-inferior to Vi-TT when analyzed at 4 weeks postvaccination.
Topics: Child; Humans; Infant; Child, Preschool; Typhoid Fever; Vaccines, Conjugate; Tetanus Toxoid; Nepal; Healthy Volunteers; Diphtheria Toxoid; Typhoid-Paratyphoid Vaccines; Antibodies, Bacterial
PubMed: 37128723
DOI: 10.1080/21645515.2023.2203634 -
Clinical Infectious Diseases : An... Jul 2023
Topics: Child; Humans; Typhoid Fever; Vaccines, Conjugate; Typhoid-Paratyphoid Vaccines; Public Sector; India
PubMed: 36947122
DOI: 10.1093/cid/ciad134 -
Lancet (London, England) Feb 2024Randomised controlled trials of typhoid conjugate vaccines among children in Africa and Asia have shown high short-term efficacy. Data on the durability of protection...
BACKGROUND
Randomised controlled trials of typhoid conjugate vaccines among children in Africa and Asia have shown high short-term efficacy. Data on the durability of protection beyond 2 years are sparse. We present the final analysis of a randomised controlled trial in Malawi, encompassing more than 4 years of follow-up, with the aim of investigating vaccine efficacy over time and by age group.
METHODS
In this phase 3, double-blind, randomised controlled efficacy trial in Blantyre, Malawi, healthy children aged 9 months to 12 years were randomly assigned (1:1) by an unmasked statistician to receive a single dose of Vi polysaccharide conjugated to tetanus toxoid vaccine (Vi-TT) or meningococcal capsular group A conjugate (MenA) vaccine. Children had to have no previous history of typhoid vaccination and reside in the study areas for inclusion and were recruited from government schools and health centres. Participants, their parents or guardians, and the study team were masked to vaccine allocation. Nurses administering vaccines were unmasked. We did surveillance for febrile illness from vaccination until follow-up completion. The primary outcome was first occurrence of blood culture-confirmed typhoid fever. Eligible children who were randomly assigned and vaccinated were included in the intention-to-treat analyses. This trial is registered at ClinicalTrials.gov, NCT03299426.
FINDINGS
Between Feb 21, 2018, and Sept 27, 2018, 28 130 children were vaccinated; 14 069 were assigned to receive Vi-TT and 14 061 to receive MenA. After a median follow-up of 4·3 years (IQR 4·2-4·5), 24 (39·7 cases per 100 000 person-years) children in the Vi-TT group and 110 (182·7 cases per 100 000 person-years) children in the MenA group were diagnosed with a first episode of blood culture-confirmed typhoid fever. In the intention-to-treat population, efficacy of Vi-TT was 78·3% (95% CI 66·3-86·1), and 163 (129-222) children needed to be vaccinated to prevent one case. Efficacies by age group were 70·6% (6·4-93·0) for children aged 9 months to 2 years; 79·6% (45·8-93·9) for children aged 2-4 years; and 79·3% (63·5-89·0) for children aged 5-12 years.
INTERPRETATION
A single dose of Vi-TT is durably efficacious for at least 4 years among children aged 9 months to 12 years and shows efficacy in all age groups, including children younger than 2 years. These results support current WHO recommendations in typhoid-endemic areas for mass campaigns among children aged 9 months to 15 years, followed by routine introduction in the first 2 years of life.
FUNDING
Bill & Melinda Gates Foundation.
Topics: Child; Humans; Infant; Typhoid Fever; Salmonella typhi; Vaccines, Conjugate; Typhoid-Paratyphoid Vaccines; Malawi; Randomized Controlled Trials as Topic
PubMed: 38281499
DOI: 10.1016/S0140-6736(23)02031-7 -
Clinical Infectious Diseases : An... Jul 2023The World Health Organization recommends vaccines for prevention and control of typhoid fever, especially where antimicrobial-resistant typhoid circulates. In 2018, the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The World Health Organization recommends vaccines for prevention and control of typhoid fever, especially where antimicrobial-resistant typhoid circulates. In 2018, the Navi Mumbai Municipal Corporation (NMMC) implemented a typhoid conjugate vaccine (TCV) campaign. The campaign targeted all children aged 9 months through 14 years within NMMC boundaries (approximately 320 000 children) over 2 vaccination phases. The phase 1 campaign occurred from 14 July 2018 through 25 August 2018 (71% coverage, approximately 113 420 children). We evaluated the phase 1 campaign's programmatic effectiveness in reducing typhoid cases at the community level.
METHODS
We established prospective, blood culture-based surveillance at 6 hospitals in Navi Mumbai and offered blood cultures to children who presented with fever ≥3 days. We used a cluster-randomized (by administrative boundary) test-negative design to estimate the effectiveness of the vaccination campaign on pediatric typhoid cases. We matched test-positive, culture-confirmed typhoid cases with up to 3 test-negative, culture-negative controls by age and date of blood culture and assessed community vaccine campaign phase as an exposure using conditional logistic regression.
RESULTS
Between 1 September 2018 and 31 March 2021, we identified 81 typhoid cases and matched these with 238 controls. Cases were 0.44 times as likely to live in vaccine campaign communities (programmatic effectiveness, 56%; 95% confidence interval [CI], 25% to 74%; P = .002). Cases aged ≥5 years were 0.37 times as likely (95% CI, .19 to .70; P = .002) and cases during the first year of surveillance were 0.30 times as likely (95% CI, .14 to .64; P = .002) to live in vaccine campaign communities.
CONCLUSIONS
Our findings support the use of TCV mass vaccination campaigns as effective population-based tools to combat typhoid fever.
Topics: Adolescent; Child; Child, Preschool; Humans; Infant; Incidence; India; Prospective Studies; Typhoid Fever; Typhoid-Paratyphoid Vaccines; Vaccines, Attenuated; Vaccines, Conjugate
PubMed: 36947143
DOI: 10.1093/cid/ciad132 -
The Lancet. Microbe Mar 2024Ciprofloxacin is the first-line drug for treating typhoid fever in many countries in Africa with a high disease burden, but the emergence of non-susceptibility poses a... (Observational Study)
Observational Study
BACKGROUND
Ciprofloxacin is the first-line drug for treating typhoid fever in many countries in Africa with a high disease burden, but the emergence of non-susceptibility poses a challenge to public health programmes. Through enhanced surveillance as part of vaccine evaluation, we investigated the occurrence and potential determinants of ciprofloxacin non-susceptibility in Blantyre, Malawi.
METHODS
We conducted systematic surveillance of typhoid fever cases and antibiotic prescription in two health centres in Blantyre, Malawi, between Oct 1, 2016, and Oct 31, 2019, as part of the STRATAA and TyVAC studies. In addition, blood cultures were taken from eligible patients presenting at Queen Elizabeth Central Hospital, Blantyre, as part of routine diagnosis. Inclusion criteria were measured or reported fever, or clinical suspicion of sepsis. Microbiologically, we identified Salmonella enterica serotype Typhi (S Typhi) isolates with a ciprofloxacin non-susceptible phenotype from blood cultures, and used whole-genome sequencing to identify drug-resistance mutations and phylogenetic relationships. We constructed generalised linear regression models to investigate associations between the number of ciprofloxacin prescriptions given per month to study participants and the proportion of S Typhi isolates with quinolone resistance-determining region (QRDR) mutations in the following month.
FINDINGS
From 46 989 blood cultures from Queen Elizabeth Central Hospital, 502 S Typhi isolates were obtained, 30 (6%) of which had either decreased ciprofloxacin susceptibility, or ciprofloxacin resistance. From 11 295 blood cultures from STRATAA and TyVAC studies, 241 microbiologically confirmed cases of typhoid fever were identified, and 198 isolates from 195 participants sequenced (mean age 12·8 years [SD 10·2], 53% female, 47% male). Between Oct 1, 2016, and Aug 31, 2019, of 177 typhoid fever cases confirmed by whole-genome sequencing, four (2%) were caused by S Typhi with QRDR mutations, compared with six (33%) of 18 cases between Sept 1 and Oct 31, 2019. This increase was associated with a preceding spike in ciprofloxacin prescriptions. Every additional prescription of ciprofloxacin given to study participants in the preceding month was associated with a 4·2% increase (95% CI 1·8-7·0) in the relative risk of isolating S Typhi with a QRDR mutation (p=0·0008). Phylogenetic analysis showed that S Typhi isolates with QRDR mutations from September and October, 2019, belonged to two distinct subclades encoding two different QRDR mutations, and were closely related (4-10 single-nucleotide polymorphisms) to susceptible S Typhi endemic to Blantyre.
INTERPRETATION
We postulate a causal relationship between increased ciprofloxacin prescriptions and an increase in fluoroquinolone non-susceptibility in S Typhi. Decreasing ciprofloxacin use by improving typhoid diagnostics, and reducing typhoid fever cases through the use of an efficacious vaccine, could help to limit the emergence of resistance.
FUNDING
Wellcome Trust, Bill & Melinda Gates Foundation, and National Institute for Health and Care Research (UK).
Topics: Humans; Male; Female; Child; Salmonella typhi; Ciprofloxacin; Typhoid Fever; Malawi; Phylogeny; Typhoid-Paratyphoid Vaccines
PubMed: 38387472
DOI: 10.1016/S2666-5247(23)00327-0 -
MBio Apr 2024serovars Typhi and Paratyphi cause a prolonged illness known as enteric fever, whereas other serovars cause acute gastroenteritis. Mechanisms responsible for the...
UNLABELLED
serovars Typhi and Paratyphi cause a prolonged illness known as enteric fever, whereas other serovars cause acute gastroenteritis. Mechanisms responsible for the divergent clinical manifestations of nontyphoidal and enteric fever infections have remained elusive. Here, we show that . Typhi and . Paratyphi A can persist within human macrophages, whereas . Typhimurium rapidly induces apoptotic macrophage cell death that is dependent on pathogenicity island 2 (SPI2). . Typhi and . Paratyphi A lack 12 specific SPI2 effectors with pro-apoptotic functions, including nine that target nuclear factor κB (NF-κB). Pharmacologic inhibition of NF-κB or heterologous expression of the SPI2 effectors GogA or GtgA restores apoptosis of . Typhi-infected macrophages. In addition, the absence of the SPI2 effector SarA results in deficient signal transducer and activator of transcription 1 (STAT1) activation and interleukin 12 production, leading to impaired T1 responses in macrophages and humanized mice. The absence of specific nontyphoidal SPI2 effectors may allow . Typhi and . Paratyphi A to cause chronic infections.
IMPORTANCE
Salmonella enterica is a common cause of gastrointestinal infections worldwide. The serovars Typhi and Paratyphi A cause a distinctive systemic illness called enteric fever, whose pathogenesis is incompletely understood. Here, we show that enteric fever serovars lack 12 specific virulence factors possessed by nontyphoidal serovars, which allow the enteric fever serovars to persist within human macrophages. We propose that this fundamental difference in the interaction of with human macrophages is responsible for the chronicity of typhoid and paratyphoid fever, suggesting that targeting the nuclear factor κB (NF-κB) complex responsible for macrophage survival could facilitate the clearance of persistent bacterial infections.
Topics: Humans; Animals; Mice; Salmonella typhi; Typhoid Fever; NF-kappa B; Macrophages; Salmonella
PubMed: 38497655
DOI: 10.1128/mbio.00454-24 -
Diseases (Basel, Switzerland) Dec 2023The impact of the COVID-19 pandemic was very broad and substantial, affecting a variety of fields worldwide. In Japan, the infection began spreading in March 2020. At...
The impact of the COVID-19 pandemic was very broad and substantial, affecting a variety of fields worldwide. In Japan, the infection began spreading in March 2020. At that time, the government alerted people to cancel overseas travel, and encouraged wearing of masks, handwashing, sanitizing and keeping social distance. We sought to determine how COVID-19 infections affected other infectious diseases by investigating the trends in seven gastrointestinal infections that are listed among the 77 important infectious diseases designated by the National Institute of Infectious Diseases. We compared seven gastrointestinal infectious diseases, namely cholera, bacterial dysentery, enterohemorrhagic Escherichia coli, typhoid fever, paratyphoid fever, amoebic dysentery, and giardiasis, in terms of numbers of new cases before the COVID-19 pandemic (2012-2019) and during the pandemic (2020-2022). During the COVID-19 pandemic period (2020-2022), the incidence of the seven infections decreased significantly ( < 0.05) compared with before the pandemic (2012-2019). The sharp and significant decline in incidence of these seven infections in Japan during the COVID-19 pandemic period (2020-2022) appears to be due to restrictions on overseas travel and strict anti-infection measures, such as self-quarantine and encouragement of handwashing and sanitizing. The number of new cases of gastrointestinal infections in Japan is expected to increase in 2024 as these measures lapse. It is important for physicians to continue to monitor trends in gastrointestinal infections and educate people about proper infection prevention.
PubMed: 38275566
DOI: 10.3390/diseases12010004 -
Vaccine Sep 2023Typhoid and emerging paratyphoid fever are a severe enteric disease worldwide with high morbidity and mortality. Licensed typhoid vaccines are in the market, but no...
Typhoid and emerging paratyphoid fever are a severe enteric disease worldwide with high morbidity and mortality. Licensed typhoid vaccines are in the market, but no paratyphoid vaccine is currently available. In the present study we developed a bivalent vaccine against Salmonella Typhi and Paratyphi A using a bacterial ghost platform. Bacterial ghost cells (BGs) are bacteria-derived cell membranes without cytoplasmic contents that retain their cellular morphology, including all cell surface features. Furthermore, BGs have inherent adjuvant properties that promote an enhanced humoral and cellular immune reaction to the target antigen. Sodium hydroxide was used to prepare ghost cells of Salmonella Typhi and Paratyphi A. The bacterial ghost cells were characterised using electron microscopy. Then BALB/c mice were immunized three times (0, 14 and 28 day) with the bivalent typhoidal bacterial ghost cells. Haematological study of adult mice throughout immunization period reflected that the immunogen was safe to administer and does not affect the animals' health. After complete immunization, we found significant serum antibody titter against whole cell lysate, outer membrane protein and lipopolysaccharide of both bacteria, and cell-mediated immunity was observed in an ex-vivo experiment. CD4+, CD8a+ and CD19+ splenic cell populations were increased in immunized animals. Bivalent Typhoidal ghost cell immunized mice showed better survival, less bacterial colonization in systemic organs, and less inflammation and/or destruction of tissue in histopathological analysis than non-immunized control mice.Serum antibodies of immunized animals can significantly inhibit bacterial motility and mucin penetration ability with better killing properties against Salmonella Typhi and Paratyphi A. Furthermore, significant passive protection was observed through the adoptive transfer of serum antibody and lymphocytes of immunized animals to naïve animals after bacterial infection. In summary, Bivalent Typhoidal Bacterial Ghost cells (BTBGs) enhances immunogenic properties and serves as a safe and effective prevention strategy against Salmonella Typhi and Paratyphi A.
Topics: Mice; Animals; Salmonella typhi; Salmonella paratyphi A; Mice, Inbred BALB C; Typhoid Fever; Typhoid-Paratyphoid Vaccines
PubMed: 37625993
DOI: 10.1016/j.vaccine.2023.08.049 -
Vaccine Feb 2024As an innovative vaccine delivery technology, vaccine microarray patches could have a meaningful impact on routine immunization coverage in low- and middle-income... (Review)
Review
As an innovative vaccine delivery technology, vaccine microarray patches could have a meaningful impact on routine immunization coverage in low- and middle-income countries, and vaccine deployment during epidemics and pandemics. This review of the potential use cases for a subset of vaccine microarray patches in various stages of clinical development, including measles-rubella, measles-mumps-rubella, and typhoid conjugate, highlights the breadth of their applicability to support immunization service delivery and their potential scope of utilization within national immunization programs. Definition and assessment of the use cases for this novel vaccine presentation provide important insights for vaccine developers and policymakers into the strengths of the public health and commercial value propositions, and the preparatory requirements for public health systems for the future rollout of vaccine microarray patches. An in-depth understanding of use cases for vaccine microarray patches serves as a foundational input to overcoming the remaining technical, regulatory, and financial challenges. Additional efforts will help to realize the potential of vaccine microarray patches as part of the global effort to improve the coverage and equity of national immunization programs.
Topics: Humans; Infant; Mumps; Vaccines, Conjugate; Typhoid-Paratyphoid Vaccines; Typhoid Fever; Rubella; Measles; Rubella Vaccine; Mumps Vaccine; Vaccination; Measles-Mumps-Rubella Vaccine
PubMed: 38326130
DOI: 10.1016/j.vaccine.2023.12.047 -
Journal of Nepal Health Research Council Dec 2023Enteric fever is a major public health problem in developing and under developed countries. Case fatality rate without treatment is 10-30% and with appropriate treatment...
BACKGROUND
Enteric fever is a major public health problem in developing and under developed countries. Case fatality rate without treatment is 10-30% and with appropriate treatment is only 1-4%. Gold standard for diagnosis is isolation of Salmonella enterica from blood or bone marrow. Antibiotics resistance is skyrocketing with emergence of multidrug resistance S. typhi and extensively drug resistant S. typhi.
METHODS
The blood culture done in Kanti children hospital in last six years were taken from the data base and the culture positive cases were taken from which the salmonella species positive cases along with the drug sensitivity pattern were used in our study.
RESULTS
The culture positivity rate was 2.8% and 7.6% (n=136) among the culture positive cases were Salmonella species. Salmonella typhi (121; 88.9%) was the most frequently isolated species, followed by Salmonella paratyphi A (13; 9.5%) and Salmonella paratyphi B (2;1.4%). Children with age 5-10 years was the most affected age group for infection with Salmonella, 50.0% (n=68). Nalidixic acid is resistant in 89.9% Salmonella typhi; followed by ciprofloxacin (31.8%), ofloxacin (18.2%), ampicillin (9.6%), azithromycin (8.4%), chloramphenicol (8.2%), cotrimoxazole (5.4%), cefixime (4%), ceftriaxone (2.5%) and cefotaxime (0.0%). Cefixime, ceftriaxone, cefotaxime are 100% sensitive to Salmonella paratyphi, followed by cotrimoxazole (92.9%), ofloxacin (81.8%), chloramphenicol (75%), azithromycin (66.7%), ampicillin (60%), ciprofloxacin (50%) and Nalidixic acid (23.1%).
CONCLUSIONS
Salmonella species culture isolatation are declining every year. Fluoroquinolones have more resistance than first line drugs of typhoid, azithromycin resistance is rising but 3rd generation cephalosporins are sensitive to Salmonella species.
Topics: Child; Humans; Child, Preschool; Anti-Bacterial Agents; Typhoid Fever; Typhoid-Paratyphoid Vaccines; Azithromycin; Cefixime; Ceftriaxone; Nalidixic Acid; Trimethoprim, Sulfamethoxazole Drug Combination; Nepal; Ciprofloxacin; Cefotaxime; Ofloxacin; Ampicillin; Chloramphenicol; Salmonella typhi
PubMed: 38196224
DOI: 10.33314/jnhrc.v21i02.4728