Sanofi Pasteur MSD Research Articles

Topical instillation of BCG immunotherapy for biopsy-proven primary upper urinary tract carcinoma in situ: A single institution series and systematic review.

Primary upper tract carcinoma in situ (UTcis) is a rare disease whose diagnosis and natural history are poorly understood. Radical nephroureterectomy is the standard of care but in imperatives or selected cases, topical instillations of Bacillus Calmette-Guérin (BCG) may represent a good alternative. The aim of this study was to report the histologic response to BCG instillations for the treatment of biopsy-proven UTcis and to systematically assess the current evidence on topical BCG instillation for the treatment of UTcis. This is a retrospective analysis of patients with biopsy-proven UTcis treated with BCG instillation between 1995 and 2020 in an expert center. The initial diagnosis was performed by a standardized random biopsy scheme during ureterorenoscopy (URS) in patients with positive cytology but negative CT and bladder biopsies. BCG course consisted of 6 weekly instillation of 81 mg Immucyst (Sanofi Pasteur MSD AG, Baar, Switzerland). Administration techniques were single-J, double-J and nephrostomy tube. The primary outcome was the rate of complete histological response at the 3-month 2nd-look-URS. Kaplan-Meier analysis curves assessed recurrence- and progression-free survival. A total of 22 patients (23 renal units) were included. Twenty-one (91.3%) patients completed the planned 6-week instillation cycle. Only one major complication was recorded (renal tuberculosis). Twenty patients had a 3-month 2nd-look-URS, with a complete histological response achieved in 17/20 cases (85%). After a median time of follow-up of 40 months (30-62), 8/20 patients harbored disease recurrence, including 5 cases of disease progression (≥pT2). The main limitations are the retrospective and non-comparative design of the study. Our systematic review (CRD42022324876) identified 15 studies (289 renal units). UTcis suffers from the lack of a standardized definition, and considerable heterogeneity has been found in making the diagnosis and assessing the response to treatment. Our study is the first to propose a histological diagnosis of UTcis as well as a histological re-evaluation of the response to treatment. Topical instillations of BCG appear to be a promising alternative, avoiding radical treatment in the majority of cases.

Comparing one dose of HPV vaccine in girls aged 9–14 years in Tanzania (DoRIS) with one dose of HPV vaccine in historical cohorts: an immunobridging analysis of a randomised controlled trial

Human papillomavirus (HPV) vaccines are given as a two-dose schedule in children aged 9-14 years, or as three doses in older individuals. We compared antibody responses after one dose of HPV vaccine in the Dose Reduction Immunobridging and Safety Study (DoRIS), a randomised trial of different HPV vaccine schedules in Tanzania, to those from two observational HPV vaccine trials that found high efficacy of one dose up to 11 years against HPV16 and HPV18 (Costa Rica Vaccine Trial [CVT] and Institutional Agency for Research on Cancer [IARC] India trial). In this immunobridging analysis of an open-label randomised controlled trial, girls were recruited from 54 government schools in Mwanza, Tanzania, into the DoRIS trial. Girls were eligible if they were aged 9-14 years, healthy, and HIV negative. Participants were randomly assigned (1:1:1:1:1:1), using permutated block sizes of 12, 18, and 24, to one, two, or three doses of the 2-valent vaccine (Cervarix, GSK Biologicals, Rixensart, Belgium) or the 9-valent vaccine (Gardasil 9, Sanofi Pasteur MSD, Lyon, France). For this immunobridging analysis, the primary objective was to compare geometric mean concentrations (GMCs) at 24 months after one dose in the per-protocol population compared with in historical cohorts: the one-dose 2-valent vaccine group in DoRIS was compared with recipients of the 2-valent vaccine Cervarix from CVT and the one-dose 9-valent vaccine group in DoRIS was compared with recipients of the 4-valent vaccine Gardasil (Merck Sharp & Dohme, Whitehouse Station, NJ, USA) from the IARC India trial. Samples were tested together with virus-like particle ELISA for HPV16 and HPV18 IgG antibodies. Non-inferiority of GMC ratios (DoRIS trial vs historical cohort) was predefined as when the lower bound of the 95% CI was greater than 0·50. This study is registered with ClinicalTrials.gov, NCT02834637. Between Feb 23, 2017, and Jan 6, 2018, we screened 1002 girls for eligibility, of whom 930 were enrolled into DoRIS and 155 each were assigned to one dose, two doses, or three doses of 2-valent vaccine, or one dose, two doses, or three doses of 9-valent vaccine. 154 (99%) participants in the one-dose 2-valent vaccine group (median age 10 years [IQR 9-12]) and 152 (98%) in the one-dose 9-valent vaccine group (median age 10 years [IQR 9-12]) were vaccinated and attended the 24 month visit, and so were included in the analysis. 115 one-dose recipients from the CVT (median age 21 years [19-23]) and 139 one-dose recipients from the IARC India trial (median age 14 years [13-16]) were included in the analysis. At 24 months after vaccination, GMCs for HPV16 IgG antibodies were 22·9 international units (IU) per mL (95% CI 19·9-26·4; n=148) for the DoRIS 2-valent vaccine group versus 17·7 IU/mL (13·9-22·5; n=97) for the CVT (GMC ratio 1·30 [95% CI 1·00-1·68]) and 13·7 IU/mL (11·9-15·8; n=145) for the DoRIS 9-valent vaccine group versus 6·7 IU/mL (5·5-8·2; n=131) for the IARC India trial (GMC ratio 2·05 [1·61-2·61]). GMCs for HPV18 IgG antibodies were 9·9 IU/mL (95% CI 8·5-11·5: n=141) for the DoRIS 2-valent vaccine group versus 8·0 IU/mL (6·4-10·0; n=97) for the CVT trial (GMC ratio 1·23 [95% CI 0·95-1·60]) and 5·7 IU/mL (4·9-6·8; n=136) for the DoRIS 9-valent vaccine group versus 2·2 IU/mL (1·9-2·7; n=129) for the IARC India trial (GMC ratio 2·12 [1·59-2·83]). Non-inferiority of antibody GMCs was met for each vaccine for both HPV16 and HPV18. One dose of HPV vaccine in young girls might provide sufficient protection against persistent HPV infection. A one-dose schedule would reduce costs, simplify vaccine delivery, and expand access to the vaccine. UK Department for International Development/UK Medical Research Council/Wellcome Trust Joint Global Health Trials Scheme, The Bill & Melinda Gates Foundation, and the US National Cancer Institute. For the KiSwahili translation of the abstract see Supplementary Materials section.

Immunogenicity and safety of one-dose human papillomavirus vaccine compared with two or three doses in Tanzanian girls (DoRIS): an open-label, randomised, non-inferiority trial

An estimated 15% of girls aged 9-14 years worldwide have been vaccinated against human papillomavirus (HPV) with the recommended two-dose or three-dose schedules. A one-dose HPV vaccine schedule would be simpler and cheaper to deliver. We report immunogenicity and safety results of different doses of two different HPV vaccines in Tanzanian girls. In this open-label, randomised, phase 3, non-inferiority trial, we enrolled healthy schoolgirls aged 9-14 years from Government schools in Mwanza, Tanzania. Eligible participants were randomly assigned to receive one, two, or three doses of either the 2-valent vaccine (Cervarix, GSK Biologicals, Rixensart) or the 9-valent vaccine (Gardasil-9, Sanofi Pasteur MSD, Lyon). The primary outcome was HPV 16 specific or HPV 18 specific seropositivity following one dose compared with two or three doses of the same HPV vaccine 24 months after vaccination. Safety was assessed as solicited adverse events up to 30 days after each dose and unsolicited adverse events up to 24 months after vaccination or to last study visit. The primary outcome was done in the per-protocol population, and safety was analysed in the total vaccinated population. This study was registered in ClinicalTrials.gov, NCT02834637. Between Feb 23, 2017, and Jan 6, 2018, we screened 1002 girls for eligibility. 72 girls were excluded. 930 girls were enrolled and randomly assigned to receive one dose of Cervarix (155 participants), two doses of Cervarix (155 participants), three doses of Cervarix (155 participants), one dose of Gardasil-9 (155 participants), two doses of Gardasil-9 (155 participants), or three doses of Gardasil-9 (155 participants). 922 participants received all scheduled doses within the defined window (three withdrew, one was lost to follow-up, and one died before completion; two received their 6-month doses early, and one received the wrong valent vaccine in error; all 930 participants were included in the total vaccinated cohort). Retention at 24 months was 918 (99%) of 930 participants. In the according-to-protocol cohort, at 24 months, 99% of participants who received one dose of either HPV vaccine were seropositive for HPV 16 IgG antibodies, compared with 100% of participants who received two doses, and 100% of participants who received three doses. This met the prespecified non-inferiority criteria. Anti-HPV 18 seropositivity at 24 months did not meet non-inferiority criteria for one dose compared to two doses or three doses for either vaccine, although more than 98% of girls in all groups had HPV 18 antibodies. 53 serious adverse events (SAEs) were experienced by 42 (4·5%) of 930 girls, the most common of which was hospital admission for malaria. One girl died of malaria. Number of events was similar between groups and no SAEs were considered related to vaccination. A single dose of the 2-valent or 9-valent HPV vaccine in girls aged 9-14 years induced robust immune responses up to 24 months, suggesting that this reduced dose regimen could be suitable for prevention of HPV infection among girls in the target age group for vaccination. UK Department for International Development/UK Medical Research Council/Wellcome Trust Joint Global Health Trials Scheme, The Bill & Melinda Gates Foundation, and the US National Cancer Institute. For the KiSwahili translation of the abstract see Supplementary Materials section.

Causal Effect Relationship in Medical Cases. An Old Problem in a New Scenario. Commentary to CJEU Judgment (Second Chamber) of 21 June 2017, N.W. & Others V. Sanofi Pasteur MSD & Others, Case C-621/15, EU:C:2017:484. Approbative Gloss

This commentary evaluates the problem in assessing the role of a causal connection between damage and the use of a defective medical product, specifically a vaccine. The judgment of the Court of Justice of the European Union (CJEU) in the Sanofi Pasteur Case, which allowed the possibility of recognizing damage claims, even in cases where the prevailing scientific theory claims that there is no scientific evidence of a causal link between a vaccination and the disease, became a base for consideration. Consequently, procedural solutions (such as the standard of proof required, the admissibility of prima facie evidence reasoning and other solutions in cases of an uncertain causation) remain to be decided by national law. The authors assessed two legal systems: the French and Polish legal systems in the context of how to resolve these dilemmas and to describe the impact of the above-mentioned judgment on the case-law of French and Polish courts as regards the application of Directive 85/374/EEC. As a result, they concluded that the most important interpretative motive has become the individual interest of the vaccination’s victim as a consumer of medical services. It seems to be in accordance with Directive 85/374/EEC, which is motivated by the necessity of approximation of the laws of the Member States concerning the liability of the producer for damage caused by the defectiveness of his products. However, since the existing divergences may distort competition and affect the movement of goods within the common market and entail a differing degree of protection of the consumer against damage caused by a defective product to his health or property, in countries belonging to the European Union, the authors wonder how the commented judgment will affect the further development of consumers protection against defective vaccines.

Presentation and Outcome of Severe Staphylococcal Pneumonia Depends Strongly on Age and the Presence of Panton-Valentine Leucocidin: A Prospective Multicenter Cohort Study

Background: The first characterisation of Panton-Valentine Leucocidin (PVL)-associated staphylococcal necrotizing pneumonia (SNP) was published in 2002. A major controversy regarding the role played by PVL in the severity of community-acquired pneumonia (CAP) ensued. To address this issue, all French intensive care units (ICU) were asked to prospectively include their cases of staphylococcal CAP between January 2011 and December 2016. Method: Patients with CAP who fulfilled the following criteria were included: clinical and radiological signs of lung infection, at least one assessment of S. aureus involvement (positive culture from blood/pleural fluid, respiratory sample), and admission to ICU. At the time of data collection, clinicians were not aware of PVL status. Patterns in patient age distribution were detected using a clustering procedure. Risk factors for mortality were identified using multivariate Cox regression. Findings: One-hundred and sixty-three patients, aged from one month to 87 years, were included; 52.1% were PVL-positive. Unexpectedly, PVL-positive cases distributed into two independent clusters, with a cut-off of around 3 years of age, whereas PVL-negative cases were only observed in adolescents and adults. Features of the <3 year-old patients matched with the historical description of staphylococcal pleuropneumonia (SPP) in toddlers with round-shaped infiltrates and mild severity. In older patients, PVL was associated with an enhanced severity and a higher case-fatality rate despite its occurrence in more favourable underlying conditions. Interpretation: This study demonstrates the association of PVL with two distinct facets of staphylococcal CAP with marked differences between toddlers and adolescents/adults regarding clinical presentation and outcome. The strong link between SPP and PVL was found and the association of PVL with severity of SNP in adults is confirmed. This dichotomy between SPP and SNP elucidates the conflicting results of previous studies assessing the role of PVL in staphylococcal pneumonia. Trial Registration: The study is registered with ClinicalTrials.gov, number NCT02798497. Funding Statement: Funded by the French Ministry of Health, PHRC 2010-A01132-37. Declaration of Interests: FV have received a grant from the French Ministry of Research for the submitted work, has received grants from bioMerieux, and has been a consultant for Pfizer and Acccelerate Diagnosis. YG has been a consultant for Pfizer vaccine, GSK Vaccines and Sanofi-Pasteur MSD vaccines. AT has received a grant from bioMerieux and R-biopharm. JPR has received a grant from bioMerieux; and honoraria for lecturing from Pfizer, MSD and Procter&Gamble. CB has received a grant from bioMerieux and Pathoquest. GL has received a grant from Pfizer, Novartis, Basilea, Diadenode and Pierre Fabre, and has been consultant for Eumedica, GenMark and Beckton Dickinson. OD has received a grant from the French Ministry of Research and from Pfizer. CD has received honoraria for lecturing from Correvi. PV has received personnal fees for expertise and consulting from GSK, Astellas, Pfizer and bioMerieux, and received research grant from Sanofi, MSD and ANIOS. The other authors declare no competing interests. Ethics Approval Statement: The regional ethics committee (Comite de Protection des Personnes Sud-Est IV) approved the study (number: A11-39). Written informed consent was obtained from all patients, and patient records were anonymised prior to analysis.

Type 2 Diabetes, Body Mass Index and Cancer Mortality: A Population-Based Matched Cohort Study of 1.0 Million Adults in England

Background: Individuals with type 2 diabetes (T2D) have higher cancer mortality than individuals without T2D. The underlying mechanisms are likely to be multi-factorial, but the mutual risk factor of excess body fatness (commonly approximated by body mass index, BMI) is thought to be important. We first tested the hypothesis that excess cancer deaths in T2D are mainly from obesity-related cancers (ORCs); and second, that increasing BMI among individuals with T2D is positively associated with ORC mortality. Methods: We conducted a matched cohort study in the Clinical Practice Research Datalink in England, linked with mortality statistics (1998-2015), and derived cohorts with incident T2D (176,886) versus never diabetes (control: 852,946), aged 30 to 85 years. Among individuals with T2D, we calculated peri-diagnosis (± 12 months date of T2D diagnosis) BMI. The primary outcome was risk for total cancer mortality, categorised into deaths from obesity-related (ORC: 13 cancer types) and non-ORC. Secondary outcomes were all-cause and cardiovascular disease (CVD) mortalities. We used Cox models with multiple imputations and estimated hazard ratios (HR) and 95% confidence intervals (CIs) for outcomes. We tested for several sources of bias, including accounting for cross-BMI category age differences; reverse causality; alternate time BMI determinations (for example, at 4 to 6 years prior to T2D diagnosis); and competing risks of death. Results: With a mean follow-up of 7.1 years, there were 47,459 cancer deaths (T2D: 9606; non-T2D: 37,853). Compared with the control population, T2D was associated with higher ORC mortality in men (HR: 1.708, 95% CIs: 1.564-2.865) and women (HR: 1.338 95% CIs: 1.240-1.444). Unexpectedly, there was an increase in deaths from non-ORC in women (HR: 1.185, 1.008-1.169), but not men. Among individuals with T2D, overall, associations were generally null or inverse, except for positive associations in specific cancers, such as endometrial (HR per 5 kg/m2: 1.416 95% CIs: 1.252-1.601) and ovarian (HR per 5 kg/m2: 1.144 95% CIs: 1.018-1.286) cancer mortalities. We found evidence of reverse causality, but no evidence of effect modification by age, associations with prior BMI, or competing risk. Interpretation: Individuals with T2D have higher obesity-related cancer mortality than those without T2D, supporting the notion that obesity is an important mechanism of excess cancer mortality in 2TD. The unexpected modest higher non-obesity-related cancer mortality suggests that factors beyond body fatness might be drivers of excess cancer mortality in 2TD. Funding Statement: This work was supported by CRUK via the funding to Cancer Research UK Manchester Centre: [C147/A18083] and [C147/A25254]. Declaration of Interests: AGR has received lecture honoraria from Merck Serona and Janssen-Cilag, and independent research funding and lecture honoraria from Novo Nordisk and Sanofi Pasteur MSD. DMA has received independent reaserch funding from Abbvie and the Leo Foundation. All other authors declare no competing interests. Ethics Approval Statement: This study is based on data from the Clinical Practice Research Datalink obtained under licence from the UK Medicines and Healthcare products Regulatory Agency. The data is provided by patients and collected by the NHS as part of their care and support. The study was approved by the independent scientific advisory committee (ISAC) for Clinical Practice Research Datalink research (protocol number: 17_137R).

Prognostic Significance of HPV DNA and p16 &lt;sup&gt;INK4a&lt;/sup&gt; in Anal Cancer: A Systematic Review and Meta-Analysis

Background: Human papillomavirus (HPV) DNA and p16INK4a are prognostic markers in several HPV-related cancers. We conducted a systematic review and meta-analysis of observational studies evaluating survival in anal cancer patients, according to HPV DNA, p16INK4a, and combined HPV DNA/p16INK4a status. Methods: In this systematic review and meta-analysis we searched PubMed, EMBASE, and Cochrane Library databases to identify studies published in English until July 25th 2018, directly providing or allowing estimation of survival of anal cancer patients according to presence of HPV DNA and/or overexpression of p16INK4a. We extracted information on overall survival (OS), disease-specific survival, and progression- or disease-free survival. We pooled published hazard ratios (HRs) and 95% confidence intervals (CIs) for OS using a random-effects model. I2 statistic described heterogeneity. Results: We included 16 studies, which comprised 1724 anal cancer patients tested for HPV DNA (65% positive), and 567 patients tested for p16INK4a (87% positive). The pooled HR for OS was 0·54 (95% CI 0·33 - 0·89) for HPV DNA-positive versus negative, 0·37 (95 % CI 0·24 - 0·57) for p16INK4apositive versus -negative, and 0·36 (95% CI 0·22 - 0·58) for HPV DNApositive/p16INK4a-positive versus HPV DNA-positive/p16INK4a-negative anal cancer patients. Interpretation: Patients with HPV DNA- or p16INK4a - positive anal cancer have significantly better OS compared to HPV DNA- or p16INK4a - negative. This points to the possible value of HPV DNA and/or p16INK4a testing when planning the individual management and follow-up strategy for patients diagnosed with anal cancer. Funding Statement: The authors stated: There was no funding source obtained specifically for this study. Declaration of Interests: SKK has received scientific advisory board and lecture fee from Merck, and research grant through the affiliating institute from Merck. Sciensano (employer of MA) collaborated with the University of Ghent to conduct the SEHIB (Surveillance of Effects of HPV Immunization in Belgium) study, funded by Sanofi-Pasteur MSD. ESP has received lecture fee from MSD SHARP & DOHME GmbH. AU, CLR, FB, TO, and FV declare no conflict of interest. Ethics Approval Statement: The authors used “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) guidelines to outline this study.

C-621/15 - W and Others v Sanofi Pasteur: An Example of Judicial Distortion and Indifference to Science

This case commentary examines the CJEU's recent decision in C-621/15 W and Others v Sanofi Pasteur MSD SNC [2017] ECR I. This commentary critically examines the decision through the lens of the cultural conflict between law and science. We argue that the CJEU's decision reflects both a distortion of scientific knowledge and an improper indifference to the legitimate methods by which scientific knowledge is generated in the context of vaccines. These judicial approaches may, the authors argue, inadvertently fuel the vaccine scepticism that is growing across the developed world, and in particular in Europe.

Immunogenicity, Safety and Reactogenicity of a Booster Dose of the 10-Valent Pneumococcal Nontypeable H. influenzae Protein D Conjugate Vaccine Coadministered With DTPa-IPV-Hib in Dutch Children: A Randomized Controlled Trial.

Immune responses and safety profiles may be affected when vaccines are coadministered. We evaluated the immunogenicity, safety and reactogenicity of a booster dose of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D-conjugate (PHiD-CV; Synflorix GSK Vaccines) and DTPa-IPV-Hib (Pediacel Sanofi Pasteur MSD) when coadministered. We performed booster assessment in a randomized controlled trial in the Netherlands. Of 780 enrolled healthy infants, 774 toddlers participated in the booster phase and received (1:1:1) (1) PHiD-CV + DTPa-HBV-IPV/Hib (Infanrix hexa, GSK Vaccines), (2) PHiD-CV + DTPa-IPV-Hib, or (3) 7-valent pneumococcal conjugate vaccine (7vCRM, Prevenar/Prevnar, Pfizer, Inc.) + DTPa-IPV-Hib at 2, 3, 4 and 11-13 months old. Blood samples were taken postprimary, prebooster, 1 and 12 months postbooster. Antipneumococcal antibody responses were comparable between both PHiD-CV groups, except for serotype 18C (conjugated to tetanus toxoid). Anti-18C antibody geometric mean concentrations (GMCs) were higher when coadministered with DTPa-HBV-IPV/Hib. For each vaccine serotype, the percentages of children with antibody concentration ≥ 0.20 μg/mL were within the same ranges between PHiD-CV groups (93.8%-100%). The same was observed for the percentages of participants with opsonophagocytic activity titer ≥ 8 (90.9%-100%). When comparing both DTPa-IPV-Hib groups, postbooster antidiphtheria antibody GMCs were higher when coadministered with 7vCRM, while antitetanus and antipolyribosyl-ribitol phosphate antibody GMCs were higher with PHiD-CV coadministration. Regardless, antibody levels to these antigens were well above thresholds. Safety and reactogenicity profiles were comparable between groups. Coadministration of a booster dose of PHiD-CV and DTPa-IPV-Hib was immunogenic and well tolerated.

Real-World Effectiveness and Safety of a Live-Attenuated Herpes Zoster Vaccine: A Comprehensive Review.

Herpes zoster (HZ) is a common, painful and debilitating disease caused by the reactivation of latent varicella-zoster virus in ganglia. This clinical event occurs more frequently in the elderly and those who are immunocompromised. The most common complication of HZ is post-herpetic neuralgia (PHN) which is responsible for the highest HZ-related burden of illness and is challenging to treat. Due to the important clinical and economic impact of HZ and PHN, and the suboptimal treatments that are currently available, HZ vaccination is an important approach to reduce the burden of illness. Currently, one-dose, live-attenuated vaccine is licensed in the United States and Europe to prevent HZ and it is included in some national immunization programs. The clinical efficacy, safety and tolerability of the vaccine has been demonstrated in two large phase III clinical trials, involving more than 38,000 and 22,000 individuals aged ≥60 and 50–59 years, respectively. This comprehensive review summarizes the extensive “real-world” effectiveness and safety data from both immunocompetent and immunocompromised individuals. These data confirm those from the clinical trials, supporting the use of HZ vaccine in clinical practice and provide evidence that the current recommendations for immunocompromised individuals should be revised. Funding: Funding for the editorial assistance, article processing charges, and open access fee for this publication was provided by Sanofi Pasteur MSD.

Long-term surveillance of the effect of PCV13: the future challenge in Africa

Long-term surveillance of the effect of PCV13: the future challenge in Africa

Immunogenicity of a low-dose diphtheria, tetanus and acellular pertussis combination vaccine with either inactivated or oral polio vaccine compared to standard-dose diphtheria, tetanus, acellular pertussis when used as a pre-school booster in UK children: A 5-year follow-up of a randomised controlled study

This serological follow up study assessed the kinetics of antibody response in children who previously participated in a single centre, open-label, randomised controlled trial of low-dose compared to standard-dose diphtheria booster preschool vaccinations in the United Kingdom (UK). Children had previously been randomised to receive one of three combination vaccines: either a combined adsorbed tetanus, low-dose diphtheria, 5-component acellular pertussis and inactivated polio vaccine (IPV) (Tdap–IPV, Repevax®; Sanofi Pasteur MSD); a combined adsorbed tetanus, low-dose diphtheria and 5-component acellular pertussis vaccine (Tdap, Covaxis®; Sanofi Pasteur MSD) given concomitantly with oral polio vaccine (OPV); or a combined adsorbed standard-dose diphtheria, tetanus, 2-component acellular pertussis and IPV (DTap–IPV, Tetravac®; Sanofi Pasteur MSD). Blood samples for the follow-up study were taken at 1, 3 and 5 years after participation in the original trial (median, 5.07 years of age at year 1), and antibody persistence to each vaccine antigen measured against defined serological thresholds of protection.All participants had evidence of immunity to diphtheria with antitoxin concentrations greater than 0.01IU/mL five years after booster vaccination and 75%, 67% and 79% of children who received Tdap–IPV, Tdap+OPV and DTap–IPV, respectively, had protective antitoxin levels greater than 0.1IU/mL. Long lasting protective immune responses to tetanus and polio antigens were also observed in all groups, though polio responses were lower in the sera of those who received OPV.Low-dose diphtheria vaccines provided comparable protection to the standard-dose vaccine and are suitable for use for pre-school booster vaccination.

Serological response following re-vaccination with Salmonella typhi Vi-capsular polysaccharide vaccines in healthy adult travellers

An injectable Vi-capsular polysaccharide vaccine against typhoid fever is available but vaccine-induced immunity tends to wane over time. The phenomenon of immunotolerance or hyporesponsiveness has earlier been described for polysaccharide vaccines such as pneumococcal capsular polysaccharide vaccine and some publications also suggest a possible immunotolerance after revaccination with Vi-capsular polysaccharide vaccines.In this study, post-immunisation antibody concentrations in adult travellers first vaccinated with a Salmonella typhi Vi-capsular polysaccharide vaccine (primary vaccination group) were compared with those having received one or more vaccinations previously (multiple vaccinations group). Vaccines administered were Typherix® (GlaxoSmithKline), Typhim Vi® (Sanofi Pasteur MSD) or Hepatyrix® (GlaxoSmithKline). Blood samples were obtained prior to vaccination (day 0) and on day 28 (−1/+14) after vaccination. Serum Vi-Antigen IgG concentrations were measured by ELISA.Of the 85 subjects included in the per protocol data set, 45 (53%) belonged to the multiple vaccinations group. In both groups, geometric mean antibody concentrations (GMCs) were significantly higher after vaccination than before vaccination. Pre-vaccination GMCs were lower in the primary vaccination group than in the multiple vaccinations group (3.40μg/ml versus 6.13μg/ml, P=0.005), while there was no significant difference in the post vaccination GMCs between groups (11.34μg/ml versus 14.58μg/ml, P=0.4). In the multiple vaccinations group, vaccination was performed 18 to 57 months after the last vaccination (median 38 months) and there was a negative correlation between time since last vaccination and antibody concentration on day 0.In conclusion, we were not able to demonstrate a relevant immunotolerance after multiple versus primary vaccination with S. typhi Vi-capsular polysaccharide vaccines.

Assessment of preparation time with fully-liquid versus non-fully liquid paediatric hexavalent vaccines. A time and motion study

Background and aimsSimplified vaccine preparation steps would save time and reduce potential immunisation errors. The aim of the study was to assess vaccine preparation time with fully-liquid hexavalent vaccine (DTaP-IPV-HB-PRP-T, Sanofi Pasteur MSD) versus non-fully liquid hexavalent vaccine that needs reconstitution (DTPa-HBV-IPV/Hib, GlaxoSmithKline Biologicals). MethodsNinety-six Health Care Professionals (HCPs) participated in a randomised, cross-over, open-label, time and motion study in Belgium (2014). HCPs prepared each vaccine in a cross-over manner with a wash-out period of 3–5min. An independent nurse assessed preparation time and immunisation errors by systematic review of the videos. HCPs satisfaction and preference were evaluated by a self-administered questionnaire. ResultsAverage preparation time was 36s for the fully-liquid vaccine and 70.5s for the non-fully liquid vaccine. The time saved using the fully-liquid vaccine was 34.5s (p≤0.001). On 192 preparations, 57 immunisation errors occurred: 47 in the non-fully liquid vaccine group (including one missing reconstitution of Hib component), 10 in the fully-liquid vaccine group. 71.9% of HCPs were very or somewhat satisfied with the ease of handling of both vaccines; 66.7% and 67.7% were very or somewhat satisfied with speed of preparation in the fully-liquid vaccine and the non-fully liquid vaccine groups, respectively. Almost all HCPs (97.6%) stated they would prefer the use of the fully-liquid vaccine in their daily practice. ConclusionsPreparation of a fully-liquid hexavalent vaccine can be completed in half the time necessary to prepare a non-fully liquid vaccine. The simplicity of the fully-liquid hexavalent vaccine preparation helps optimise reduction of immunisation errors.

Two consecutive randomized controlled pertussis booster trials in children initially vaccinated in infancy with an acellular vaccine: The first with a five-component Tdap vaccine to 5-year olds and the second with five- or monocomponent Tdap vaccines at age 14–15 years

Prior study children from a DTaP efficacy trial were recruited at ages 5 and 15 years to randomized booster trials addressing immunogenicity and reactogenicity; 475 preschool children received mixed or separate injections of a reduced antigen vaccine (Tdap5, Sanofi Pasteur MSD) and an inactivated polio vaccine, and 230 adolescents received the same or another booster vaccine (Tdap1, SSI, Denmark).Pre-vaccination antibody concentrations against pertussis antigens were significantly higher at 15 than 5 years of age, probably due to natural boosting between the studies. Tdap5 induced comparable anti-PT concentrations at both ages, but antibody responses were significantly higher to filamentous haemagglutinin, pertactin and fimbriae 2/3 in adolescents. As expected, a higher amount of PT (Tdap1, 20μg) induced a stronger anti-PT response than a lower amount (Tdap5, 2.5μg).The frequency of adverse events was low and there were no serious adverse reactions. All local reactions had an early onset and a short duration. A large swelling or redness of more than half of the upper arm circumference was reported in 8/475 5-year-olds and in 6/230 15-year-olds. Children vaccinated with Tdap5 reported more moderate pain in adolescence than at preschool age, whereas itching was only reported in preschool children.Sweden introduced DTaP vaccines in 1996 after a 17-year hiatus with no general pertussis vaccination and pertussis was still endemic at the time of the studies. The frequency of adverse events was nevertheless low in both preschool children and adolescents and antibody responses were adequate. These studies document immunogenicity and reactogenicity in a trial cohort consecutively vaccinated with acellular pertussis vaccines from infancy to adolescence.The adolescent study was registered at ClinicalTrials.gov on 26 March 2009 (NCT00870350).

European Society for Paediatric Infectious Diseases consensus recommendations for rotavirus vaccination in Europe: update 2014.

The first evidence-based recommendations for rotavirus (RV) vaccination in Europe were prepared at the time of licensure of 2 live oral RV vaccines (Rotarix, GlaxoSmithKline Biologicals, and RotaTeq, Sanofi Pasteur MSD) in 2006 and published in 2008. Since then several countries in Europe and more globally have adopted universal RV vaccination of all healthy infants as part of their national immunization programs (NIPs). The experience from these NIPs has produced a wealth of post-introduction effectiveness data that, together with the evidence from prelicensure efficacy trials presented in the 2008 Recommendations, support the case of RV vaccination in Europe. The prelicensure safety trials of Rotarix and RotaTeq, each in populations of more than 60,000 infants, did not reveal risk of intussusception (IS), but postvaccination surveillance in several countries, particularly Australia and Mexico, has established that the risk of IS for both vaccines after the first dose might be between 1:50,000 and 1:80,000. Although it may be argued that the risk is acceptable vis-à-vis the great benefits of RV vaccination, this argument alone may not suffice, and every effort should be made to reduce the risk of IS. Considerable evidence, including postvaccination surveillance data from Germany, suggests that the risk of IS can be reduced by early administration of the first dose of oral RV vaccine. The previous European Society for Paediatric Infectious Diseases/European Society for Paediatric Gastroenterology, Hepatology and Nutrition recommendations held that the first dose of oral RV vaccine should be given between 6 and 12 weeks of age; this recommendation is sustained but with an emphasis toward the lower range of the recommended age, that is, preferably between 6 and 8 weeks of age. At the time of the earlier recommendations, experience of RV vaccination in premature infants and other special target groups was limited. It is now recommended with greater confidence than before that prematurely born infants should be vaccinated according to their calendar age as recommended for full-term infants. It is now strongly recommended that all HIV-infected or HIV-exposed infants should be vaccinated with oral RV vaccine. Although specific information on many immunodeficiencies is lacking, infants with known severe combined immunodeficiency should not receive live RV vaccine.

O-147a Assessment Of Preparation Time With Fully Liquid Versus Reconstituted Paediatric Hexavalent Vaccines. A Time And Motion Study

<h3>Background and aims</h3> Simplified vaccine preparation steps would save time and reduce the potential of mishandlings. The aim of the study was to assess vaccine preparation time with fully liquid hexavalent vaccine (DTaP-IPV-HB-PRP-T, Sanofi Pasteur MSD, Lyon, France) versus hexavalent vaccine that needs reconstitution (DTPa-HBV-IPV/Hib, GlaxoSmithKline Biologicals, Rixensart, Belgium). <h3>Methods</h3> 96 Health Care Professionals (HCPs) participated in a randomised, cross-over, open-label, Time and Motion study in Belgium (2014). HCPs prepared each vaccine (time recorded using video equipment) in a cross-over manner with a wash-out period of 3–5 min. An independent nurse assessed preparation mishandlings by systematic review of the videos. HCPs satisfaction and preference were evaluated by a self-administered questionnaire. <h3>Results</h3> Average preparation time was 36 seconds for DTaP-IPV-HB-PRP-T versus 70.5 seconds for DTPa-HBV-IPV/Hib (p ≤ 0.001). Extrapolated yearly time savings was estimated to 664 days/year (based on 520 000 hexavalent vaccines administered per year in Belgium). On 192 preparations, 57 mishandlings occurred: 47 in the DTPa-HBV-IPV/Hib group (including one missing reconstitution of Hib component), 10 in the DTaP-IPV-HB-PRP-T group. 71.9% of HCPs were very or somewhat satisfied with ease of handling of both vaccines; 66.7% and 67.7% were very or somewhat satisfied with speed of preparation in DTaP-IPV-HB-PRP-T and DTPa-HBV-IPV/Hib groups, respectively. Almost all HCPs (97.6%) stated they would prefer the use of DTaP-IPV-HB-PRP-T vaccine in their daily practice. <h3>Conclusions</h3> Fully liquid DTaP-IPV-HB-PRP-T vaccine offers significant time gains for vaccine preparation. It has the potential to reduce mishandlings and could therefore be very useful in daily practice.

Safety, reactogenicity and immunogenicity of a novel pneumococcal protein-based vaccine in adults: A phase I/II randomized clinical study

BackgroundNew vaccines containing highly conserved Streptococcus pneumoniae proteins such as pneumolysin toxoid (dPly) and histidine-triad protein D (PhtD) are being developed to provide broader protection against pneumococcal disease. This study evaluated the safety, reactogenicity and immunogenicity of different pneumococcal protein-containing formulations in adults. MethodsIn a phase I double-blind study (www.clinicaltrials.gov: NCT00707798), healthy adults (18–40 years) were randomized (1:2:2:2:2:2:2) to receive two doses of one of six investigational vaccine formulations 2 months apart, or a single dose of the control 23-valent pneumococcal polysaccharide vaccine (23PPV; Pneumovax23™, Sanofi Pasteur MSD) followed by placebo. The investigational formulations contained dPly alone (10 or 30μg), or both dPly and PhtD (10 or 30μg each) alone or combined with the polysaccharide conjugates of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV; Synflorix™, GlaxoSmithKline Vaccines). Two groups primed with a formulation containing dPly and PhtD (10 or 30μg each) continued to the follow-up phase II study (NCT00896064), in which they received a booster dose at 5–9 months after primary vaccination. ResultsOf 156 enrolled and vaccinated adults, 146 completed the primary immunization and 43 adults received a booster dose. During primary and booster vaccination, for any formulation, ≤8.9% of doses were followed by grade 3 solicited local or general adverse events. No fever >39.5°C (oral temperature) was reported. Unsolicited adverse events considered causally related to vaccination were reported following ≤33.3% of investigational vaccine doses. No serious adverse events were reported for adults receiving investigational vaccine formulations. Formulations containing dPly with or without PhtD were immunogenic for these antigens; polysaccharide conjugate-containing formulations were also immunogenic for those 10 polysaccharides. ConclusionInvestigational vaccine formulations containing dPly and PhtD were well tolerated and immunogenic when administered to healthy adults as standalone protein vaccine or combined with PHiD-CV conjugates.

Humoral and B-cell memory responses in children five years after pertussis acellular vaccine priming

The resurgence of pertussis suggests the need for greater efforts in understanding the long-lasting protective responses induced by vaccination. In this paper we dissect the persistence of humoral and B-cell memory responses induced by primary vaccination with two different acellular pertussis (aP) vaccines, hexavalent Hexavac® vaccine (Hexavac) (Sanofi Pasteur MSD) and Infanrix hexa® (Infanrix) (GlaxoSmithKline Biologicals). We evaluated the specific immune responses in the two groups of children, 5 years after primary vaccination by measuring the persistence of IgG and antibody secreting cells (ASC) specific for vaccine antigens. Part of the enrolled children received only primary vaccination, while others had the pre-school boost dose. A similar level of antigen-specific IgG and ASC was found in Infanrix and Hexavac vaccinated children. The mean IgG levels were significantly higher in children that received the pre-school boost as compared with children that did not receive the boost dose. A longer persistence after the pre-school boost of IgG-Pertussis Toxin (PT) and IgG-pertactin levels was observed in Infanrix primed children, but it was not statistically significant. More than 80% of children presented a positive ASC B memory response. Around 50% of children still presented protective IgG-PT levels which are reduced to 36% in no-boosted children. The pre-school booster dose restores the percentage of protected children above 50%. In conclusion our data underline the importance of giving a booster dose 5 years after primary vaccination and suggest the need for a new vaccine able to induce a long lasting protective response.

Immunogenicity and safety results from a randomized multicenter trial comparing a Tdap-IPV vaccine (REPEVAX®) and a tetanus monovalent vaccine in healthy adults

In adults with a tetanus-prone injury, combined vaccines such as Tdap-IPV (REPEVAX®) can boost immunity against several diseases simultaneously. This Phase IIIb, parallel-group, open-label trial compared antibody responses to Tdap-IPV and tetanus monovalent vaccine (TMV; Vaccin Tétanique Pasteur® or Tetavax®) against tetanus toxoid 10 and 28 d post-vaccination. Between July and December 2009, four centers in France and five in Germany recruited healthy adults who had received a tetanus-containing vaccine 5−10 y previously. Participants were randomized 1:1 to receive at the first visit a single dose (0.5 mL) of Tdap-IPV or TMV, with follow-up visits at Day 10 and Day 28. Outcomes: per protocol (PP) population immunogenicity at Day 10 (primary) and at Day 28 (secondary); safety throughout the study. Of 456 adults randomized, 223 received Tdap-IPV and 233 received TMV (PP population: 183 and 199 participants, respectively). All participants receiving Tdap-IPV and 99.0% receiving TMV had an anti-tetanus antibody concentration ≥ 0.1 IU/mL, confirming non-inferiority of Tdap-IPV to TMV (95% confidence interval of the difference: –1.2, 3.6). Number of adverse events reported was comparable in each group. Injection-site reactions were reported by 76.6% participants receiving Tdap-IPV and 74.6% receiving TMV. Systemic events (e.g., malaise, myalgia and headache) were reported in 47.7% and 39.7% of the Tdap-IPV and the TMV groups, respectively. Tdap-IPV is effective and well-tolerated for use in the management of tetanus-prone injuries in emergency settings in persons for whom a booster against diphtheria, pertussis and poliomyelitis is also needed. ClinicalTrials.gov identifier: NCT00928785. Research sponsored by Sanofi Pasteur MSD.