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Safety, immunogenicity and dose ranging of a new Vi-CRM??? conjugate vaccine against typhoid fever: randomized clinical testing in healthy adults.

ABSTRACT: Typhoid fever causes more than 21 million cases of disease and 200,000 deaths yearly worldwide, with more than 90% of the disease burden being reported from Asia. Epidemiological data show high disease incidence in young children and suggest that immunization programs should target children below two years of age: this is not possible with available vaccines. The Novartis Vaccines Institute for Global Health developed a conjugate vaccine (Vi-CRM???) for infant vaccination concomitantly with EPI vaccines, either starting at 6 weeks with DTP or at 9 months with measles vaccine. We report the results from a Phase 1 and a Phase 2 dose ranging trial with Vi-CRM??? in European adults.Following randomized blinded comparison of single vaccination with either Vi-CRM??? or licensed polysaccharide vaccines (both containing 25·0 µg of Vi antigen), a randomised observer blinded dose ranging trial was performed in the same center to compare three concentrations of Vi-CRM??? (1·25 µg, 5·0 µg and 12·5 µg of Vi antigen) with the polysaccharide vaccine.All vaccines were well tolerated. Compared to the polysaccharide vaccine, Vi-CRM??? induced a higher incidence of mild to moderate short lasting local pain. All Vi-CRM??? formulations induced higher Vi antibody levels compared to licensed control, with clear dose response relationship.Vi-CRM??? did not elicit safety concerns, was highly immunogenic and is therefore suitable for further clinical testing in endemic populations of South Asia.ClinicalTrials.gov NCT01123941 NCT01193907.

SUBMITTER: van Damme P

PROVIDER: S-EPMC3184126 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Safety, immunogenicity and dose ranging of a new Vi-CRM₁₉₇ conjugate vaccine against typhoid fever: randomized clinical testing in healthy adults.

van Damme Pierre P Kafeja Froukje F Anemona Alessandra A Basile Venere V Hilbert Anne Katrin AK De Coster Ilse I Rondini Simona S Micoli Francesca F Qasim Khan Rana M RM Marchetti Elisa E Di Cioccio Vito V Saul Allan A Martin Laura B LB Podda Audino A

PloS one 20110930 9

<h4>Background</h4>Typhoid fever causes more than 21 million cases of disease and 200,000 deaths yearly worldwide, with more than 90% of the disease burden being reported from Asia. Epidemiological data show high disease incidence in young children and suggest that immunization programs should target children below two years of age: this is not possible with available vaccines. The Novartis Vaccines Institute for Global Health developed a conjugate vaccine (Vi-CRM₁₉₇) for infant vaccination conc ...[more]

PMID: 21980445

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Project description:BACKGROUND:Typhoid fever remains a major public health problem in low- and middle-income countries where children aged 2-14?years bear the greatest burden. Vi polysaccharide is poorly immunogenic in children <2?years of age, and protection in adults is modest. The limitations of Vi polysaccharide vaccines can be overcome by conjugation of the Vi to a carrier protein. A typhoid conjugate vaccine composed of Vi polysaccharide conjugated to diphtheria toxoid (Vi-DT) has been developed. The Phase I study results are presented here. METHODS:This was a randomized, observer-blinded Phase I study to assess the safety and immunogenicity of Vi-DT compared to Vi polysaccharide vaccine, conducted in Manila, Philippines. Participants enrolled in an age de-escalation manner (18-45, 6-17 and 2-5?years) were randomized between Test (Vi-DT, 25?µg) administered at 0 and 4?weeks and Comparator (Vi polysaccharide, Typhim Vi® and Vaxigrip®, Sanofi Pasteur) vaccines. RESULTS:A total of 144 participants were enrolled (48 by age strata, 24 in Test and Comparator groups each). No serious adverse event was reported in either group. Solicited and unsolicited adverse events were mild or moderate in both groups with the exception of a 4-year old girl in Test group with grade 3 fever which resolved without sequelae. All participants in Test group seroconverted after first and second doses of Vi-DT while the proportions in the Comparator group were 97.1% and 97.2%, after first dose of Typhim Vi® and second dose of Vaxigrip®, respectively. Vi-DT showed 4-fold higher Geometric Mean Titers (GMT) compared to Typhim Vi® (adjusted for age strata, p?<?0.001). No further increase of GMT was detected after the second dose of Vi-DT. Anti-DT IgG seroresponse rates were 81.2% and 84.5% post first and second Vi-DT doses, respectively. CONCLUSIONS:Vi-DT vaccine was safe, well-tolerated and immunogenic in participants aged 2-45?years. ClinicalTrials.gov registration number: NCT02645032.

Project description:Background:Typhoid fever remains a major public health problem globally. While new Vi conjugate vaccines hold promise for averting disease, the optimal programmatic delivery remains unclear. We aimed to identify the strategies and associated epidemiologic conditions under which Vi conjugate vaccines would be cost-effective. Methods:We developed a dynamic, age-structured transmission and cost-effectiveness model that simulated multiple vaccination strategies with a typhoid Vi conjugate vaccine from a societal perspective. We simulated 10-year vaccination programs with (1) routine immunization of infants (aged <1 year) through the Expanded Program on Immunization (EPI) and (2) routine immunization of infants through the EPI plus a 1-time catch-up campaign in school-aged children (aged 5-14 years). In the base case analysis, we assumed a 0.5% case-fatality rate for all cases of clinically symptomatic typhoid fever and defined strategies as highly cost-effective by using the definition of a low-income country (defined as a country with a gross domestic product of $1045 per capita). We defined incidence as the true number of clinically symptomatic people in the population per year. Results:Vi conjugate typhoid vaccines were highly cost-effective when administered by routine immunization activities through the EPI in settings with an annual incidence of >50 cases/100000 (95% uncertainty interval, 40-75 cases) and when administered through the EPI plus a catch-up campaign in settings with an annual incidence of >130 cases/100000 (95% uncertainty interval, 50-395 cases). The incidence threshold was sensitive to the typhoid-related case-fatality rate, carrier contribution to transmission, vaccine characteristics, and country-specific economic threshold for cost-effectiveness. Conclusions:Typhoid Vi conjugate vaccines would be highly cost-effective in low-income countries in settings of moderate typhoid incidence (50 cases/100000 annually). These results were sensitive to case-fatality rates, underscoring the need to consider factors contributing to typhoid mortality (eg, healthcare access and antimicrobial resistance) in the global vaccination strategy.

Project description:BackgroundTyphoid fever caused by Salmonella enteric serovar Typhi (S. Typhi) is a common cause of morbidity in the world. In 2017, 14.3 million cases of Typhoid and paratyphoid fever occurred globally. School age children between 3 to 19 years old are the most affected. Poor sanitation and multi drug resistance have increased the need for vaccines to reduce the global burden of disease. Based on previous trials, typhoid conjugate vaccines have longer- lasting protection, higher efficacy, require fewer doses and are suitable from infancy that allows them to be incorporated into the routine immunization program. Our previous phase I trial proved that a novel Vi-DT typhoid conjugate vaccine is safe and immunogenic in subjects 2-5 and 18-40 years. Our phase II trial consisted of subjects 6 months to 40 years. Our previously published paper on subjects 6 to < 24 months proved that this vaccine is safe and immunogenic for this age group. Therefore, with this paper we aimed to evaluate the safety and immunogenicity in children 2-11 years.MethodsA randomized, observer-blind, superiority design of Vi-DT Typhoid conjugate vaccine compared to Vi-polysaccharide vaccine (Vi-PS) phase II study was conducted from October 2018 to December 2018 where 200 subjects aged 2-11 years were recruited. A blood sample prior to vaccination was taken, followed by administration of a single dose of either test vaccine (Vi-DT) or control vaccine (Vi-PS) and then a second blood sample was collected 28 days post vaccination. Adverse reactions were assessed and antibody increment was evaluated at 28 days post vaccination through collected serum sample.ResultsPain was the most common local reaction. Fever and muscle pain were the most common systemic reactions. Both Vi-DT and Vi-PS groups had roughly the same number of adverse reactions. At 28 days post vaccination, 100% of subjects in the Vi-DT group and 93% of subjects in the Vi-PS group produced antibody increment ≥4 times. The Vi-DT group produced a higher GMT as compared to Vi-PS.ConclusionVi-DT vaccine is safe and immunogenic in children 2-11 years old.Trial registrationTrial registration number: NCT03460405 .

Project description:BackgroundSalmonella enterica serovar Typhi (S Typhi) is responsible for an estimated 20 million infections and 200 000 deaths each year in resource poor regions of the world. Capsular Vi-polysaccharide-protein conjugate vaccines (Vi-conjugate vaccines) are immunogenic and can be used from infancy but there are no efficacy data for the leading candidate vaccine being considered for widespread use. To address this knowledge gap, we assessed the efficacy of a Vi-tetanus toxoid conjugate vaccine using an established human infection model of S Typhi.MethodsIn this single-centre, randomised controlled, phase 2b study, using an established outpatient-based human typhoid infection model, we recruited healthy adult volunteers aged between 18 and 60 years, with no previous history of typhoid vaccination, infection, or prolonged residency in a typhoid-endemic region. Participants were randomly assigned (1:1:1) to receive a single dose of Vi-conjugate (Vi-TT), Vi-polysaccharide (Vi-PS), or control meningococcal vaccine with a computer-generated randomisation schedule (block size 6). Investigators and participants were masked to treatment allocation, and an unmasked team of nurses administered the vaccines. Following oral ingestion of S Typhi, participants were assessed with daily blood culture over a 2-week period and diagnosed with typhoid infection when meeting pre-defined criteria. The primary endpoint was the proportion of participants diagnosed with typhoid infection (ie, attack rate), defined as persistent fever of 38°C or higher for 12 h or longer or S Typhi bacteraemia, following oral challenge administered 1 month after Vi-vaccination (Vi-TT or Vi-PS) compared with control vaccination. Analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT02324751, and is ongoing.FindingsBetween Aug 18, 2015, and Nov 4, 2016, 112 participants were enrolled and randomly assigned; 34 to the control group, 37 to the Vi-PS group, and 41 to the Vi-TT group. 103 participants completed challenge (31 in the control group, 35 in the Vi-PS group, and 37 in the Vi-TT group) and were included in the per-protocol population. The composite criteria for typhoid diagnosis was met in 24 (77%) of 31 participants in the control group, 13 (35%) of 37 participants in the Vi-TT group, and 13 (35%) of 35 participants in the Vi-PS group to give vaccine efficacies of 54·6% (95% CI 26·8-71·8) for Vi-TT and 52·0% (23·2-70·0) for Vi-PS. Seroconversion was 100% in Vi-TT and 88·6% in Vi-PS participants, with significantly higher geometric mean titres detected 1-month post-vaccination in Vi-TT vaccinees. Four serious adverse events were reported during the conduct of the study, none of which were related to vaccination (one in the Vi-TT group and three in the Vi-PS group).InterpretationVi-TT is a highly immunogenic vaccine that significantly reduces typhoid fever cases when assessed using a stringent controlled model of typhoid infection. Vi-TT use has the potential to reduce both the burden of typhoid fever and associated health inequality.FundingThe Bill & Melinda Gates Foundation and the European Commission FP7 grant, Advanced Immunization Technologies (ADITEC).

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Safety, immunogenicity and dose ranging of a new Vi-CRM??? conjugate vaccine against typhoid fever: randomized clinical testing in healthy adults.

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Safety, immunogenicity and dose ranging of a new Vi-CRM₁₉₇ conjugate vaccine against typhoid fever: randomized clinical testing in healthy adults.

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