Tessa Braeckman

Effectiveness of rotavirus vaccination in prevention of hospital admissions for rotavirus gastroenteritis among young children in Belgium: case-control study

Objective To evaluate the effectiveness of rotavirus vaccination among young children in Belgium. Design Prospective case-control study. Setting Random sample of 39 Belgian hospitals, February 2008 to June 2010. Participants 215 children admitted to hospital with rotavirus gastroenteritis confirmed by polymerase chain reaction and 276 age and hospital matched controls. All children were of an eligible age to have received rotavirus vaccination (that is, born after 1 October 2006 and aged ≥14 weeks). Main outcome measure Vaccination status of children admitted to hospital with rotavirus gastroenteritis and matched controls. Results 99 children (48%) admitted with rotavirus gastroenteritis and 244 (91%) controls had received at least one dose of any rotavirus vaccine (P<0.001). The monovalent rotavirus vaccine accounted for 92% (n=594) of all rotavirus vaccine doses. With hospital admission as the outcome, the unadjusted effectiveness of two doses of the monovalent rotavirus vaccine was 90% (95% confidence interval 81% to 95%) overall, 91% (75% to 97%) in children aged 3-11 months, and 90% (76% to 96%) in those aged ≥12 months. The G2P[4] genotype accounted for 52% of cases confirmed by polymerase chain reaction with eligible matched controls. Vaccine effectiveness was 85% (64% to 94%) against G2P[4] and 95% (78% to 99%) against G1P[8]. In 25% of cases confirmed by polymerase chain reaction with eligible matched controls, there was reported co-infection with adenovirus, astrovirus and/or norovirus. Vaccine effectiveness against co-infected cases was 86% (52% to 96%). Effectiveness of at least one dose of any rotavirus vaccine (intention to vaccinate analysis) was 91% (82% to 95%). Conclusions Rotavirus vaccination is effective for the prevention of admission to hospital for rotavirus gastroenteritis among young children in Belgium, despite the high prevalence of G2P[4] and viral co-infection.

Clinical-grade manufacturing of autologous mature mRNA-electroporated dendritic cells and safety testing in acute myeloid leukemia patients in a phase I dose-escalation clinical trial

BACKGROUND AIMS RNA-electroporated dendritic cell (DC)-based vaccines are rapidly gaining interest as therapeutic cancer vaccines. We report on a phase I dose-escalation trial using clinical-grade manufactured mature RNA-electroporated DC in acute myeloid leukemia (AML) patients. METHODS CD14(+) cells were isolated from leukapheresis products by immunomagnetic CliniMACS separation and differentiated into mature DC (mDC). mDC were electroporated with clinical-grade mRNA encoding the Wilms tumor (WT1) antigen, and tested for viability, phenotype, sterility and recovery. To test product safety, increasing doses of DC were administered intradermally four times at 2-week intervals in 10 AML patients. RESULTS In a pre-clinical phase, immunomagnetic monocyte isolation proved superior over plastic adherence in terms of DC purity and lymphocyte contamination. We also validated a simplified DC maturation protocol yielding a consistent phenotype, migration and allogeneic T-cell stimulatory capacity in AML patients in remission. In the clinical trial, highly purified CD14(+) cells (94.5+/-3.4%) were obtained from all patients. A monocyte-to-mDC conversion factor of 25+/-10% was reached. All DC preparations exhibited high expression of mDC markers. Despite a decreased cell recovery of mDC after a combination of mRNA electroporation and cryopreservation, successful vaccine preparations were obtained in all AML patients. DC injections were well tolerated by all patients. CONCLUSIONS Our method yields a standardized, simplified and reproducible preparation of multiple doses of clinical-grade mRNA-transfected DC vaccines from a single apheresis with consistent mature phenotype, recovery, sterility and viability. Intradermal injection of such DC vaccines in AML patients is safe.

Rotavirus vaccines in Belgium: policy and impact.

Background: The current Belgian experience with rotavirus vaccination provides a unique perspective to look at the effect of vaccination. Shortly after introduction, a nation-wide recommendation was issued and despite the fact that both rotavirus vaccines are offered through partial reimbursement, vaccine uptake has already reached a high level (at least 90%). Methods: For the purpose of looking at the effectiveness of the Belgian rotavirus vaccination policy, 3 years after introduction, we retrospectively collated the publicly available data on the number of laboratory-confirmed rotavirus cases reported to a national network of sentinel laboratories during 1999 to 2010 and compared them with the available data on hospitalizations due to rotavirus gastroenteritis. Results: Both data sources (reported laboratory-diagnosed cases to a sentinel network as well as data on hospitalizations due to rotavirus gastroenteritis) show a decrease in the number of rotavirus infections and a 4- to 6-week delay in the onset of disease and the peak of incidence in the postvaccination period. Conclusions: Because this decline coincides with the increased vaccine uptake and is sustained during consecutive rotavirus seasons, the effect is mainly attributed to the rotavirus vaccination. The rapid increase in vaccine coverage, despite the partial reimbursement for the vaccines, is remarkable. Continued postlicensure surveillance is necessary to further investigate the effectiveness of the vaccines and to document the public health impact of the vaccination in reducing disease burden.

Timeliness of infant vaccination and factors related with delay in Flanders, Belgium

Achieving high vaccination coverage is a necessary, but not a sufficient indicator of the quality of a vaccination programme, in terms of control and prevention of childhood infectious diseases. For optimal protection of infants, timeliness of vaccination is increasingly recognized as another important target. The aim of this study was to assess the timeliness of measles-mumps-rubella (MMR) and diphtheria-tetanus-pertussis (DTP) vaccination in infants in Flanders (Belgium), and to identify predictors of vaccination delay. The timeliness was assessed using the Kaplan-Meier estimator in three consecutive vaccination coverage surveys among children aged 18-24 months, conducted in 2005, 2008 and 2012, respectively. Factors associated with delayed administration of the vaccines were identified using Cox regression analysis. Over the time period, vaccination coverage for the first dose of MMR ranged from 94.0 to 96.6% and for the third dose of DTP from 97.9 to 98.7%. However, up to 32% (for MMR1) and 95% (for DTP3) of infants received vaccine doses delayed according to the recommended schedule. Although some improvement was achieved over the last decade, further efforts are needed to reach risk groups with delays, more specifically children vaccinated outside the baby well clinics, born from a mother originating from outside the European Union, children with a higher ranking or in families with a lower income.

Higher proportion of G2P[4] rotaviruses in vaccinated hospitalized cases compared with unvaccinated hospitalized cases, despite high vaccine effectiveness against heterotypic G2P[4] rotaviruses

The overall vaccine effectiveness of the monovalent rotavirus vaccine in an observational, prospective, multicentre, hospital-based case-control study in Belgium (RotaBel) was 90%. However, rotavirus genotype and co-infecting pathogens are important parameters to take into account when assessing vaccine effectiveness. In this study we specifically investigated the effect of rotavirus genotypes and co-infecting pathogens on vaccine effectiveness of the monovalent vaccine. In addition, we also investigated the effect of co-infecting pathogens on disease severity. From February 2008 to June 2010 stool samples of rotavirus gastroenteritis cases of a random sample of 39 Belgian hospitals were collected and subsequently genotyped. Fishers exact tests were performed to investigate the relationships between rotavirus genotype, co-infecting pathogens and disease severity. The vaccine effectiveness of a full series of the monovalent rotavirus vaccine against hospitalized rotavirus gastroenteritis caused by G1P[8] rotavirus strains was 95% (95% CI 77.5-98.7). Against G2P[4], the vaccine effectiveness was 85% (95% CI: 63.7-93.8). G4P[8]- and G3P[8]-specific vaccine effectiveness was 90% (95% CI 19.2-98.7) and 87% (95% CI -5.2 to 98.4), respectively. A post-hoc analysis showed that the genotype distribution was significantly related to the vaccination status (p <0.001), whereby G2P[4] strains were proportionally more prevalent in vaccinated cases than in unvaccinated cases. No statistical associations were found between co-infection status and vaccination status, Vesikari severity score or rotavirus genotype. The high vaccine effectiveness against the individual genotypes implies robust protection of the monovalent rotavirus vaccine against hospitalized rotavirus gastroenteritis caused by the major human rotavirus genotypes. The prevalence of G2P[4] requires continued monitoring.

Breastfeeding after maternal immunisation during pregnancy: providing immunological protection to the newborn: a review.

Vaccination during pregnancy results in an augmentation of disease specific maternal antibodies. Immunoglobulin G (IgG) is mainly transferred through the placenta during the third trimester of pregnancy, while secretory Immunoglobulin A (sIgA) is passed through breast milk. At birth, newborns are partially protected against infectious diseases by these antibodies. This review aims to provide an overview of the effect of vaccination during pregnancy on the immunological protection of the newborn by the presence of disease specific sIgA antibodies in breast milk and their possible protective function against disease. Our search produced 11 relevant papers; 1 on pertussis, 7 on pneumococcus, 2 on influenza and 1 on meningococcus. All of the studies in this review that measured disease specific antibodies in breast milk (n=8 papers), stressed the beneficial effect of maternal vaccination during pregnancy on the amount of disease specific sIgA in breast milk. Only a few studies demonstrated a potential protective effect, particularly with influenza vaccines. In an era where maternal vaccination is increasingly considered as a valuable strategy to protect both the mother and infant, further research is needed to assess the effect on breast milk sIgA and to understand the potentially beneficial effects to the infant.

Rotavirus vaccination coverage and adherence to recommended age among infants in Flanders (Belgium) in 2012

In Belgium, rotavirus vaccination has been recommended and partially reimbursed since October 2006. Through a retrospective survey in 2012, we estimated the coverage rate of the rotavirus vaccination in Flanders among infants born in 2010. Using a standardised questionnaire, 874 families were interviewed at home, collecting information on demographic characteristics, socio-economic background and documented vaccination history (updated from medical files and vaccination database, if needed). Adherence to the recommended age for vaccination (8, 12 and 16 weeks) was also assessed. The coverage rate for two doses of rotavirus vaccination was 92.2% (95% confidence interval: 90.2-93.8). Respectively 31.7% and 10.1% of the children received their first and second dose at the recommended age. Incomplete vaccination was often a deliberate choice of the parents. Only eight children (1%) were vaccinated after the maximum age of 26 weeks. Factors identified by multiple logistic regression as related to incomplete vaccination were: living in the province of Antwerp, unemployed mother, and three or more older siblings in the household. Four years after introduction, the coverage rates were surprisingly high for a vaccine that is not fully reimbursed and not readily available in the vaccinators fridge, which is the case for the other recommended infant vaccines.

Maternal pertussis and influenza immunization coverage and attitude of health care workers towards these recommendations in Flanders, Belgium

In Belgium, pertussis vaccination is recommended for all pregnant women in every pregnancy. Adults in close contact with young infants are equally advised to receive a pertussis containing booster dose. Maternal influenza vaccination is likewise recommended in Belgium in the second or third trimester of pregnancy, within the influenza season. A quantitative multicenter survey study has been performed between October 2014 and May 2015 in both postpartum women (N=823, response rate=89.2%) and health care workers (HCWs) (N=261) to assess the coverage of both vaccines during pregnancy along with the coverage of the pertussis cocoon strategy, and to evaluate the knowledge and recommending attitude of HCWs towards the maternal vaccination strategies and the cocoon strategy among surveyed women and HCWs. Overall coverage of pertussis vaccination during pregnancy was 64.0%. Most women were vaccinated by their general practitioner (GP) (82.4%), and most often in the third trimester (74.0%) of pregnancy. Overall coverage of influenza vaccination during pregnancy was 45.0%. Again the GP administered most vaccines (67.6%); vaccines were equally administered in the second or third trimester of pregnancy. Educational level had a significant influence on both the pertussis and influenza vaccination coverage during pregnancy while working situation and parity had only an influence on the maternal pertussis vaccination coverage and country of birth only on the maternal influenza vaccination coverage. Overall, 78.4% of gynecologists and GPs recommends both maternal pertussis and influenza vaccination and 67.0% recommends both maternal vaccination strategies and the cocoon strategy. Within the group of the midwives, only 23.7% recommends both maternal pertussis and influenza vaccination and 10.5% recommends both maternal vaccination strategies and the cocoon strategy. High coverage is reached among pregnant women for pertussis and influenza vaccination. Several underserved populations of pregnant women regarding maternal immunization, are identified.

Induction of Cytomegalovirus-Specific T Cell Responses in Healthy Volunteers and Allogeneic Stem Cell Recipients Using Vaccination With Messenger RNA–Transfected Dendritic Cells

Background Infection with human cytomegalovirus (CMV) is a significant cause of morbidity and mortality in solid organ and hematopoietic stem cell transplant (HSCT) recipients. Methods The present study explored the safety, feasibility, and immunogenicity of CMV pp65 messenger RNA–loaded autologous monocyte-derived dendritic cells (DC) as a cellular vaccine for active immunization in healthy volunteers and allogeneic HSCT recipients. Four CMV-seronegative healthy volunteers and three allogeneic HSCT recipients were included in the study. Four clinical-grade autologous monocyte-derived DC vaccines were prepared after a single leukapheresis procedure and administered intradermally at a weekly interval. Results De novo induction of CMV-specific T-cell responses was detected in three of four healthy volunteers without serious adverse events. Of the HSCT recipients, none developed CMV disease and one of two patients displayed a remarkable threefold increase in CMV pp65-specific T cells on completion of the DC vaccination trial. Conclusion In conclusion, our DC vaccination strategy induced or expanded a CMV-specific cellular response in four of six efficacy-evaluable study subjects, providing a base for its further exploration in larger cohorts.

Assessing vaccination coverage in infants, survey studies versus the Flemish immunisation register: achieving the best of both worlds

Infant immunisation coverage in Flanders, Belgium, is monitored through repeated coverage surveys. With the increased use of Vaccinnet, the web-based ordering system for vaccines in Flanders set up in 2004 and linked to an immunisation register, this database could become an alternative to quickly estimate vaccination coverage. To evaluate its current accuracy, coverage estimates generated from Vaccinnet alone were compared with estimates from the most recent survey (2012) that combined interview data with data from Vaccinnet and medical files. Coverage rates from registrations in Vaccinnet were systematically lower than the corresponding estimates obtained through the survey (mean difference 7.7%). This difference increased by dose number for vaccines that require multiple doses. Differences in administration date between the two sources were observed for 3.8-8.2% of registered doses. Underparticipation in Vaccinnet thus significantly impacts on the register-based immunisation coverage estimates, amplified by underregistration of administered doses among vaccinators using Vaccinnet. Therefore, survey studies, despite being labour-intensive and expensive, currently provide more complete and reliable results than register-based estimates alone in Flanders. However, further improvement of Vaccinnets completeness will likely allow more accurate estimates in the nearby future.