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Beran J.,Vaccination and Travel Medicine Center | Wertzova V.,Vaccination and Travel Medicine Center | Hobzova L.,Vaccination and Travel Medicine Center | Tichy P.,Glaxosmithkline | And 3 more authors.
Vaccine | Year: 2010

300 adolescents aged 12-15 years were randomised (1:1) into two groups to compare the long-term (10 years) immunogenicity profile of two doses of an Adult formulation [Group HAB_2D: 150; 0-6 months] vs. three doses of a Paediatric formulation [Group HAB_3D: 150; 0-1-6 months] of a combined hepatitis A and B (HAB) vaccine. At Year 10, anti-HAV seropositivity rate was 100% in both groups, while 85.9% and 85.1% subjects in the HAB_2D and HAB_3D groups, respectively, had anti-HBs antibody concentrations ≥10 mIU/mL. The anti-HAV antibody GMCs (HAB_2D: 429.3 mIU/mL; HAB_3D: 335.5 mIU/mL) and anti-HBs antibody GMCs (HAB_2D: 50.6 mIU/mL; HAB_3D: 60.1 mIU/mL) were similar in both groups. No vaccine-related serious adverse events were reported. Hence, with respect to long-term antibody persistence, the two-dose schedule of the combined HAB vaccine Adult formulation is an effective alternative to the conventional three-dose schedule of the Paediatric formulation in adolescents. © 2010 Elsevier Ltd.


Beran J.,Vaccination and Travel Medicine Center | Van Der Meeren O.,GSK Vaccines | Leyssen M.,GSK Vaccines | D'silva P.,GSK Pharmaceuticals
Vaccine | Year: 2016

Background: The exact duration of antibody persistence to hepatitis A and B and the need for booster dosing following primary immunisation remains undefined. A long-term study was designed to follow antibody persistence and immune memory on an annual basis for up to 15 years following vaccination during adolescence. Methods: Subjects received a combined hepatitis A and B vaccine (Twinrix™, GSK Vaccines, Belgium) at 12-15 years of age, either as 2-dose of the adult formulation or 3-dose of the paediatric formulation. Blood samples were taken every year thereafter to assess antibody persistence and immune memory to hepatitis A and B. Antibodies to hepatitis A virus (anti-HAV) and hepatitis B surface antigen (anti-HBs) were measured at Years 11-15. At Year 15 immune memory was further assessed by measuring the anamnestic response to a challenge dose of the monovalent vaccine, which was administered to subjects whose antibody concentrations fell below the pre-defined cut-offs (anti-HAV: <15 mIU/mL; anti-HBs: <10 mIU/mL). Results: 209 subjects returned for follow-up at Year 15 of whom 162 were included in the long-term according-to-protocol immunogenicity cohort. All subjects remained seropositive for anti-HAV antibodies, while 81.1% and 81.8% still had anti-HBs antibodies ≥10 mIU/mL in the 2- and 3-dose groups, respectively. Following hepatitis B vaccine challenge dose administration to 19 subjects, all except one in the 3-dose group, mounted a robust anamnestic response. The safety and reactogenicity profile of the hepatitis B challenge was consistent with previous experience. Conclusion: Immunity to hepatitis A and B persists 15 years after adolescent vaccination with a combined hepatitis A and B vaccine. Highly effective anamnestic response indicates that a booster dose should not be required for 15 years after primary vaccination. Trial registration: http://www.clinicaltrials.gov NCT00875485. © 2016 The Authors.


McElhaney J.E.,Health science North and Advanced Medical Research Institute of Canada | Beran J.,Vaccination and Travel Medicine Center | Devaster J.-M.,Glaxosmithkline | Esen M.,Institute For Tropenmedizin | And 27 more authors.
The Lancet Infectious Diseases | Year: 2013

Background: We aimed to compare AS03-adjuvanted inactivated trivalent influenza vaccine (TIV) with non-adjuvanted TIV for seasonal influenza prevention in elderly people. Methods: We did a randomised trial in 15 countries worldwide during the 2008-09 (year 1) and 2009-10 (year 2) influenza seasons. Eligible participants aged at least 65 years who were not in hospital or bedridden and were without acute illness were randomly assigned (1:1) to receive either AS03-adjuvanted TIV or non-adjuvanted TIV. Randomisation was done in an internet-based system, with a blocking scheme and stratification by age (65-74 years and 75 years or older). Participants were scheduled to receive one vaccine in each year, and remained in the same group in years 1 and 2. Unmasked personnel prepared and gave the vaccines, but participants and individuals assessing any study endpoint were masked. The coprimary objectives were to assess the relative efficacy of the vaccines and lot-to-lot consistency of the AS03-adjuvanted TIV (to be reported elsewhere). For the first objective, the primary endpoint was relative efficacy of the vaccines for prevention of influenza A (excluding A H1N1 pdm09) or B, or both, that was confirmed by PCR analysis in year 1 (lower limit of two-sided 95% CI had to be greater than zero to establish superiority). From Nov 15, to April 30, in both years, participants were monitored by telephone or site contact and home visits every week or 2 weeks to identify cases of influenza-like illness. After onset of suspected cases, we obtained nasal and throat swabs to identify influenza RNA with real-time PCR. Efficacy analyses were done per protocol. This trial is registered with ClinicalTrials.gov, number NCT00753272. Findings: We enrolled 43 802 participants, of whom 21 893 were assigned to and received the AS03-adjuvanted TIV and 21 802 the non-adjuvanted TIV in year 1. In the year 1 efficacy cohort, fewer participants given AS03-adjuvanted than non-adjuvanted TIV were infected with influenza A or B, or both (274 [1·27%, 95% CI 1·12-1·43] of 21 573 vs 310 [1·44%, 1·29-1·61] of 21 482; relative efficacy 12·11%, 95% CI -3·40 to 25·29; superiority not established). Fewer participants in the year 1 efficacy cohort given AS03-adjuvanted TIV than non-adjuvanted TIV were infected with influenza A (224 [1·04%, 95% CI 0·91-1·18] vs 270 [1·26, 1·11-1·41]; relative efficacy 17·53%, 95% CI 1·55-30·92) and influenza A H3N2 (170 [0·79, 0·67-0·92] vs 205 [0·95, 0·83-1·09]; post-hoc analysis relative efficacy 22·0%, 95% CI 5·68-35·49). Interpretation: AS03-adjuvanted TIV has a higher efficacy for prevention of some subtypes of influenza than does a non-adjuvanted TIV. Future influenza vaccine studies in elderly people should be based on subtype or lineage-specific endpoints. Funding: GlaxoSmithKline Biologicals SA. © 2013 Elsevier Ltd.


PubMed | GSK Pharmaceuticals, Vaccination and Travel Medicine Center and GSK Vaccines
Type: Journal Article | Journal: Vaccine | Year: 2016

The exact duration of antibody persistence to hepatitis A and B and the need for booster dosing following primary immunisation remains undefined. A long-term study was designed to follow antibody persistence and immune memory on an annual basis for up to 15 years following vaccination during adolescence.Subjects received a combined hepatitis A and B vaccine (Twinrix, GSK Vaccines, Belgium) at 12-15 years of age, either as 2-dose of the adult formulation or 3-dose of the paediatric formulation. Blood samples were taken every year thereafter to assess antibody persistence and immune memory to hepatitis A and B. Antibodies to hepatitis A virus (anti-HAV) and hepatitis B surface antigen (anti-HBs) were measured at Years 11-15. At Year 15 immune memory was further assessed by measuring the anamnestic response to a challenge dose of the monovalent vaccine, which was administered to subjects whose antibody concentrations fell below the pre-defined cut-offs (anti-HAV: <15mIU/mL; anti-HBs: <10mIU/mL).209 subjects returned for follow-up at Year 15 of whom 162 were included in the long-term according-to-protocol immunogenicity cohort. All subjects remained seropositive for anti-HAV antibodies, while 81.1% and 81.8% still had anti-HBs antibodies 10mIU/mL in the 2- and 3-dose groups, respectively. Following hepatitis B vaccine challenge dose administration to 19 subjects, all except one in the 3-dose group, mounted a robust anamnestic response. The safety and reactogenicity profile of the hepatitis B challenge was consistent with previous experience.Immunity to hepatitis A and B persists 15 years after adolescent vaccination with a combined hepatitis A and B vaccine. Highly effective anamnestic response indicates that a booster dose should not be required for 15 years after primary vaccination.http://www.clinicaltrials.govNCT00875485.


PubMed | University Hospital of Tuebingen, University Utrecht, University of Tampere, Ghent University and 7 more.
Type: Journal Article | Journal: Open forum infectious diseases | Year: 2015

Background. To investigate the relationship between hemagglutinin-inhibition (HI) antibody levels to the risk of influenza disease, we conducted a correlate of protection analysis using pooled data from previously published randomized trials. Methods. Data on the occurrence of laboratory-confirmed influenza and HI levels pre- and postvaccination were analyzed from 4 datasets: 3 datasets included subjects aged <65 years who received inactivated trivalent influenza vaccine (TIV) or placebo, and 1 dataset included subjects aged 65 years who received AS03-adjuvanted TIV (AS03-TIV) or TIV. A logistic model was used to evaluate the relationship between the postvaccination titer of A/H3N2 HI antibodies and occurrence of A/H3N2 disease. We then built a receiver-operating characteristic curve to identify a potential cutoff titer between protection and no protection. Results. The baseline odds ratio of A/H3N2 disease was higher for subjects aged 65 years than <65 years and higher in seasons of strong epidemic intensity than moderate or low intensity. Including age and epidemic intensity as covariates, a 4-fold increase in titer was associated with a 2-fold decrease in the risk of A/H3N2 disease. Conclusions. The modeling exercise confirmed a relationship between A/H3N2 disease and HI responses, but it did not allow an evaluation of the predictive power of the HI response.


PubMed | R.Ø.S.A., Vaccination and Travel Medicine Center and University of Trnava
Type: Journal Article | Journal: BMC infectious diseases | Year: 2016

Inosine pranobex (Isoprinosine) is an immunomodulatory drug approved in several countries for the treatment of viral infections. This study compared the efficacy and safety of inosine pranobex versus placebo in subjects with clinically diagnosed influenza-like illness, including subjects with laboratory-confirmed acute respiratory viral infections. Subgroup analyses evaluated the efficacy of inosine pranobex compared to placebo in otherwise healthy (without related ongoing disease) subjects that were less than 50years of age and healthy subjects that were at least 50years of age. The effect of body mass index (BMI) was evaluated in subjects less than 50years of age.A total of 463 subjects were randomly assigned to receive inosine pranobex (n=231) or placebo (n=232) in this Phase 4, randomised, double-blind, multicentre study. The primary efficacy endpoint was time to resolution of all influenza-like symptoms present at baseline to none. Safety was evaluated through analysis of adverse events, vital signs, and physical examinations.The difference in time to resolution of all influenza-like symptoms between treatment groups was not statistically significant but showed a faster improvement in subjects in the inosine pranobex group versus those in the placebo group - Hazard Ratio=1.175; (95% CI: 0.806-1.714). P-value=0.324. In the subgroup analysis for subjects less than 50years of age, statistically significant differences in time to resolution of influenza-like symptoms that favoured the inosine pranobex group over the placebo group were observed in those without related ongoing disease and those who were non-obese (BMI <30kg/mThe study results indicate the safety of inosine pranobex for the treatment of subjects with confirmed acute respiratory viral infections and confirm the efficacy of inosine pranobex versus placebo in healthy non-obese subjects less than 50years of age with clinically diagnosed influenza-like illnesses.EWO-ISO-2014/1, EudraCT 2014-001863-11 ; Date of registration: 29 APR 2014; Detail information web link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-001863-11/results.


Beran J.,Vaccination and Travel Medicine Center | Beran J.,University of Hradec Kralove | Peeters M.,Glaxosmithkline | Dewe W.,Glaxosmithkline | And 3 more authors.
BMC Infectious Diseases | Year: 2013

Background: Two phylogenetic lineages of influenza B virus coexist and circulate in the human population (B/Yamagata and B/Victoria) but only one B-strain is included in each seasonal vaccine. Mismatch regularly occurs between the recommended and circulating B-strain. Inclusion of both lineages in vaccines may offer better protection against influenza.Methods: This study (NCT00714285) assessed the immunogenicity and safety of two candidate quadrivalent influenza vaccines (QIV) containing two A- and two B-strains (one from each lineage) in adults (18-60 years). Subjects were randomized and stratified by age to receive either QIV (non-adjuvanted or low-dose adjuvanted [LD QIV-AS]) or trivalent influenza vaccine (TIV, non-adjuvanted or low-dose adjuvanted [LD TIV-AS]), N = 105 in all treatment groups. The study evaluated the statistical non-inferiority of the immunological response elicited by QIV and LD QIV-AS versus TIV and LD TIV-AS and the statistical superiority of the response elicited by the quadrivalent vaccines against the B-strain (B/Jiangsu) not included in the TIV.Results: Pre-defined non-inferiority and superiority criteria were reached for both QIVs compared to the TIVs. On Day 21 in all vaccine groups SCRs were ≥54.8%, SPRs ≥88.5% and SCFs ≥5.4 for the A strains and B strain included in all vaccines (B/Malaysia). This fulfilled the European (CHMP) and the US (CBER) licensing criteria for the assessment of influenza vaccines in adults (CHMP criteria: SCR > 40%, SPR > 70%, SCF > 2; CBER criteria: LL of 95% CI for SPR ≥ 70% or SCR ≥ 40%). Only the QIVs met the CHMP and CBER criteria for the B/Jiangsu strain. In the QIV and LD-QIV-AS groups, the SCFs were 9.1 and 8.1, respectively and the SPRs were 98.1% and 95.2%, whereas for the TIV and LD-TIV-AS groups, the SCFs were 2.3 and 2.5, respectively, and the SPRs were 75.0% and 63.8%, with the LLs of the 95% CI <70% for SPR and <40% for SCR.Conclusions: Addition of a fourth strain did not impact the immune response elicited by the three original strains contained in the TIV. A clear immunological benefit was seen with the QIV formulation for the second B-strain, indicating that quadrivalent vaccines could provide broader protection against influenza.Trial registration: ClinicalTrials.gov: NCT00714285. © 2013 Beran et al.; licensee BioMed Central Ltd.


Alberer M.,Ludwig Maximilians University of Munich | Burchard G.,University of Hamburg | Jelinek T.,Berlin Center for Travel and Tropical Medicine | Reisinger E.,University of Rostock | And 6 more authors.
Travel Medicine and Infectious Disease | Year: 2014

Conclusions MenACWY-CRM was administered with an inactivated adjuvanted JE and a purified chick embryo cell-culture rabies vaccine without compromising immunogenicity or safety of the individual vaccines. These data provide evidence that MenACWY-CRM could be effectively incorporated into travel vaccination programs. Trial number: NCT01466387.Background Potential interactions between vaccines may compromise the immunogenicity and/or safety of individual vaccines so must be assessed before concomitant administration is recommended. In this study, the immunogenicity and safety of travel vaccines against Japanese encephalitis (JEV) and rabies (PCECV) administered together with or without a quadrivalent meningococcal glycoconjugate ACWY-CRM vaccine were evaluated (NCT01466387). copy;2014 Elsevier Ltd.Method Healthy adults aged 18 to ≤60 years were randomized to one of four vaccine regimens: JEV + PCECV + MenACWY-CRM, JEV + PCECV, PCECV or MenACWY-CRM. Immunogenicity at baseline and 28 days post-complete vaccination was assessed by serum bactericidal assay using human complement or neutralization tests. Adverse events (AEs) were collected throughout the study period.Results JEV + PCECV + MenACWY-CRM was non-inferior to JEV + PCECV. Post-vaccination seroprotective neutralizing titers or concentrations were achieved in 98-99% (JE) and 100% (rabies) of subjects across the vaccine groups. Antibody responses to vaccine meningococcal serogroups were in the same range for MenACWY-CRM and JEV + PCECV + MenACWY-CRM. Rates of reporting of AEs were similar for JEV + PCECV and JEV + PCECV + MenACWY-CRM.


Long-term vaccination programs are recommended for individuals living in regions endemic for tick-borne encephalitis (TBE). Current recommendations suggest a first booster vaccine be administered 3 years after a conventional regimen or 12-18 months after a rapid regimen. However, the research supporting subsequent booster intervals is limited. The aim of this study was thus to evaluate the long-term persistence of TBE antibodies in adults and adolescents after a first booster dose with Encepur®. A total of 323 subjects aged 15 years and over, who had received one of four different primary TBE vaccination series in a parent study, participated in this follow-up Phase IV trial. Immunogenicity and safety were assessed for up to five years after a first booster dose, which was administered three years after completion of the primary series. One subset of subjects was excluded from the booster vaccination since they had already received their booster prior to enrolment. For comparison, immune responses were still recorded for these subjects on Day 0 and on an annual basis until Year 5, but safety information was not collected. Following a booster vaccination, high antibody titers were recorded in all groups throughout the study. Neutralization test (NT) titers of ≥10 were noted in at least 94% of subjects at every time point post-booster (on Day 21 and through Years 1-5). These results demonstrated that a first booster vaccination following any primary immunization schedule results in high and long-lasting (>5 years) immune responses. These data lend support to the current belief that subsequent TBE booster intervals could be extended from the current recommendation. NCT00387634. © 2014 Elsevier Ltd.


Beran J.,Vaccination and Travel Medicine Center | Abdel-Messih I.A.,Novartis | Raupachova J.,Vaccination and Travel Medicine Center | Hobzova L.,Vaccination and Travel Medicine Center | Fragapane E.,Novartis
Clinical Therapeutics | Year: 2010

Background: Preparedness for an H5N1 influenza prepandemic requires effective and well-tolerated emergency vaccination strategies that provide both pandemic strain-specific and heterologous protection.Objectives: This was a pivotal study for the regulatory approval process for a candidate MF59-adjuvanted H5N1 vaccine. Its goals were to identify the preferred primary 2-dose vaccination schedule in adults and to assess whether the vaccine met European Committee for Medicinal Products for Human Use (CHMP) licensure criteria.Methods: Healthy volunteers aged 18 to 60 years received 1 of 4 randomized schedules in which the 2 doses of vaccine were separated by a 1-, 2-, 3-, or 6-week interval. Three blood samples (~20 mL-1) were obtained from each subject: the first sample, immediately before administration of the first dose of vaccine; the second, immediately before administration of the second dose; and the third, 21 days after administration of the second dose. Hemagglutination inhibition (HI), microneutralization (MN), and single radial hemolysis (SRH) were assayed after each dose. Immunogenicity was assessed based on the CHMP licensure criteria for annual influenza vaccines (number of seroconversions or significant increase in HI titer >40%; mean geometric increase >2.5; and proportion of subjects achieving an HI titer ≥40 or SRH titer >25 mm2 should be >70% [seroprotection]). Subjects recorded all adverse events occurring within 7 days of vaccine administration; information on any serious adverse events was collected throughout the study (duration, 202 days).Results: All study participants (N = 240) were white, with a mean age of 33 years and a mean body mass index of 24.6 kg/m2. Equal numbers of men and women were assigned to each vaccination schedule. The CHMP criterion for seroprotection was achieved when the 2 doses of vaccine were separated by 2 (76%), 3 (72%), and 6 (79%) weeks; similar results were obtained on MN and SRH analysis. On the SRH analysis, the candidate vaccine showed a heterologous immune response to the H5N1/turkey/Turkey/1/05 (NIBRG-23; clade 2) influenza antigen. The vaccine met 2 of the 3 European licensure criteria, with seroconversion rates of 69% and 65% in the groups assigned to a 2- and 3-week interval between doses, respectively, and geometric mean ratios of 4.3 and 4.5. There were no serious adverse events related to vaccination. The most common adverse events reported within 7 days of the first and second doses of vaccine were mild to moderate injection-site pain (63%-73% and 34%-48%, respectively) and fatigue (25%-30% and 13%-24%).Conclusions: Two 7.5-μg doses of MF59-adjuvanted H5N1 influenza vaccine given 2, 3, or 6 weeks apart afforded H5N1-specific immunity and met the CHMP licensure criterion for seroprotection in these healthy volunteers. Clinically relevant levels of heterologous immunity were observed when the 2 doses of vaccine were administered either 2 or 3 weeks apart; however, the licensure criterion for seroprotection was not met in this case. © 2010 Elsevier HS Journals, Inc.

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