Marianne A. Riise Bergsaker

Effectiveness of a 2+1 dose schedule pneumococcal conjugate vaccination programme on invasive pneumococcal disease among children in Norway

The 7-valent pneumococcal conjugate vaccine (PCV-7) was licensed in Norway in 2001. In July 2006, PCV-7 was introduced in the Norwegian Childhood Vaccination Programme in a 2+1 dose schedule, with immunizations administered at 3, 5 and 12 months of age. PCV-7 was offered through the vaccination programme to all children born from January 2006, i.e. a catch-up for children aged 3-6 months. Prior to 2006 the use of PCV-7 was negligible. The effectiveness of the PCV-7 vaccination programme was assessed using data on invasive pneumococcal disease (IPD) incidence obtained from the Norwegian Surveillance System for Communicable Diseases, serotype distribution from the National Reference Laboratory for Pneumococci, and vaccine coverage and vaccination status from the Norwegian National Vaccination Register. Vaccine coverage quickly reached high levels; 95% of children >3 months born from January 2006 had received at least one immunization with PCV-7. The incidence rate of IPD among children <2 years rapidly declined; the rate of vaccine serotype IPD in this age group fell from an average of 47.1 cases/100,000 population in the 2 years prior to PCV-7 introduction to 13.7 cases/100,000 population in 2007. The incidence rate of nonvaccine serotype IPD remained stable. The vaccine programme effectiveness was estimated to be 74% (95% CI 57-85%). No vaccine failure was seen after complete primary immunization with two vaccine doses. Our findings indicate that PCV-7 provides highly effective protection against vaccine serotype IPD when administered in a 2+1 dose schedule.

Prompt effect of replacing the 7-valent pneumococcal conjugate vaccine with the 13-valent vaccine on the epidemiology of invasive pneumococcal disease in Norway.

The introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in the childhood immunisation programme in Norway in 2006 substantially decreased the incidence of vaccine-type (VT) invasive pneumococcal disease (IPD) in all age groups. Additionally, a slight increase in the non-vaccine (NVT) serotype IPD incidence (serotype replacement) was observed. After replacing PCV7 with PCV13 in 2011, a further decrease in IPD incidence is expected. However, the protection by the six additional serotypes opens new nasopharyngeal niches for colonisation, which favours conditions for serotype replacement. Close monitoring of IPD therefore remains important in order to quickly detect changes. In this observational retrospective population-based cohort study we used data notified nationally between 1 January 2004 and 31 December 2012 to determine the VT- and NVT-IPD incidences. The diversity in serotype distribution per year was analysed using the Simpsons index of diversity. Immunisation history of young children was obtained from the Norwegian Vaccination Registry to determine vaccine failure. The incidence of VT-IPD decreased in the targeted (<5 years) and non-targeted (≥5) age groups since PCV7 introduction and further decreased after the replacement with PCV13. Only two cases of vaccine failure were identified. This indicates very high effectiveness of the 2+1 schedules with PCV7 or PCV13 and suggests that non-vaccinated individuals profit through indirect protection. The decrease in incidence of PCV7-IPD in non-targeted age groups became larger in later years, indicating a lag phase for the indirect effects, and suggests that the indirect protection of PCV13 will increase in coming years. The incidence of some NVT, specifically serotypes 23B and 15A, increased after PCV13 introduction. This coincided with an increased Simpsons index of diversity in the targeted age group. As this suggests that serotype replacement is again occurring, continues monitoring of IPD is important so that adaptations to vaccine recommendations can be promptly issued.

Tracking parental attitudes on vaccination across European countries: The Vaccine Safety, Attitudes, Training and Communication Project (VACSATC)

The paper presents the first results from the European project VACSATC which aimed to track parental attitudes on vaccinations across several European countries. We compared five cross-sectional surveys of parents with children less than 3 years of age in England, Norway, Poland, Spain and Sweden carried out during 2008-2009. Data were collected from 6611 respondents. Two countries used face-to face interviews, one used telephone interviews, and two other countries used mail-in questionnaires. In all countries health professionals were indicated as the most important and trusted source of information on vaccination. The study results also show that parental attitudes on vaccinations in the childhood vaccination programs are generally positive. However, there were differences in attitudes on vaccination between the five countries, possibly reflecting different methods of sampling the respondents, context-specific differences (e.g. level of activity of governmental agencies), but also individual-level parental variation in demographic and socioeconomic status variables.

Indirect effect of conjugate pneumococcal vaccination in a 2+1 dose schedule.

In 2006, the heptavalent pneumococcal conjugate vaccine (PCV7) was introduced in the Norwegian Childhood Vaccination Programme in a 2+1 dose schedule; immunisations are administered at 3, 5 and 12 months. Changes in invasive pneumococcal disease in all ages from the baseline years 2004-2005 to 2008 were assessed, focusing on the indirect effect in the unvaccinated population. Following the introduction of PCV7, incidence rates of IPD caused by vaccine serotypes declined across all age groups, the decline being statistically significant for the age groups <5 years, 5-19 years, 40-64 years and > or = 65 years. In the unvaccinated population aged > or = 5 years the incidence rate of IPD caused by PCV7 serotypes declined by 48% from 12.34 cases/100,000 population to 6.44 cases/100,000 population, accounting for 74% of prevented cases of IPD in 2008. Among the adults aged > or = 65 years the incidence rate of IPD caused by serotypes not included in PCV7 increased. No vaccine failure was identified, indicating a very high effectiveness of the 2+1 dose schedule vaccination programme.

Persisting Immune Responses Indicating Long-Term Protection after Booster Dose with Meningococcal Group B Outer Membrane Vesicle Vaccine

ABSTRACT MenBvac is an outer membrane vesicle vaccine against systemic meningococcal disease caused by serogroup B Neisseria meningitidis. In this placebo-controlled double-blind study including 374 healthy adolescents, the safety and immunogenicity of a schedule of three primary doses 6 weeks apart followed by a fourth dose a year later were evaluated. Antibody responses to the vaccine strain and heterologous strains (non-vaccine-type strains) and the persistence of these antibodies were measured by the serum bactericidal assay (SBA) and enzyme-linked immunosorbent assay up to 1 year after the last dose. The proportion of subjects with SBA titers of ≥4 against the vaccine strain increased from 3% prevaccination to 65% after the third dose. Ten months later, this proportion had declined to 28%. The fourth dose induced a booster response demonstrated by 93% of subjects achieving a titer of ≥4. One year after the booster dose, 64% still showed SBA titers of ≥4. Cross-reacting antibodies were induced against all heterologous strains tested, although the magnitude of SBA titers differed widely between the different strains. All four doses of MenBvac were safe. Both MenBvac and the placebo had reactogenicity profiles of mild to moderate local and systemic reactions. Pain, the most common reaction, was reported with similar frequencies in both groups. No serious adverse events occurred in the MenBvac group. This study confirmed the good immunogenicity of the primary course of MenBvac and demonstrated prolonged persistence and increased cross-reactivity of functional antibodies elicited by a booster dose.

Protection against varicella with two doses of combined measles-mumps-rubella-varicella vaccine versus one dose of monovalent varicella vaccine: a multicentre, observer-blind, randomised, controlled trial

BACKGROUND Rates of varicella have decreased substantially in countries implementing routine varicella vaccination. Immunisation is possible with monovalent varicella vaccine or a combined measles-mumps-rubella-varicella vaccine (MMRV). We assessed protection against varicella in naive children administered one dose of varicella vaccine or two doses of MMRV. METHODS This study was done in ten European countries with endemic varicella. Healthy children aged 12-22 months were randomised (3:3:1 ratio, by computer-generated randomisation list, with block size seven) to receive 42 days apart (1) two doses of MMRV (MMRV group), or (2) MMR at dose one and monovalent varicella vaccine at dose two (MMR+V group), or (3) two doses of MMR (MMR group; control). Participants and their parents or guardians, individuals involved in assessment of any outcome, and sponsor staff involved in review or analysis of data were masked to treatment assignment. The primary efficacy endpoint was occurrence of confirmed varicella (by detection of varicella zoster virus DNA or epidemiological link) from 42 days after the second vaccine dose to the end of the first phase of the trial. Cases were graded for severity. Efficacy analyses were per protocol. Safety analyses included all participants who received at least one vaccine dose. This trial is registered with ClinicalTrials.gov, number NCT00226499. FINDINGS Between Sept 1, 2005, and May 10, 2006, 5803 children (mean age 14·2 months, SD 2·5) were vaccinated. In the efficacy cohort of 5285 children, the mean duration of follow-up in the MMRV group was 36 months (SD 8·8), in the MMR+V group was 36 months (8·5) and in the MMR group was 35 months (8·9). Varicella cases were confirmed for 37 participants in the MMRV group (two moderate to severe), 243 in the MMR+V group, and 201 in the MMR group. Second cases occurred for three participants (all in the MMR+V group). Varicella cases were moderate to severe for two participants in the MMRV group, 37 in the MMR+V group (one being a second case that followed a mild first case); and 117 in the MMR group. Efficacy of two-dose MMRV against all varicella was 94·9% (97·5% CI 92·4-96·6), and against moderate to severe varicella was 99·5% (97·5-99·9). Efficacy of one-dose varicella vaccine against all varicella was 65·4% (57·2-72·1), and against moderate to severe varicella (post hoc) was 90·7% (85·9-93·9). The most common adverse event in all groups was injection-site redness (up to 25% of participants). Within 15 days after dose one, 57·4% (95% CI 53·9-60·9) of participants in the MMRV group reported fever of 38°C or more, by contrast with 44·5% (41·0-48·1) with MMR+V, and 39·8% (33·8-46·1) with MMR. Eight serious adverse events were deemed related to vaccination (three MMRV, four MMR+V, one MMR). All resolved within the study period. INTERPRETATION These results support the implementation of two-dose varicella vaccination on a short course, to ensure optimum protection from all forms of varicella disease. FUNDING GlaxoSmithKline Vaccines.

Decline in Early Childhood Respiratory Tract Infections in the Norwegian Mother and Child Cohort Study after Introduction of Pneumococcal Conjugate Vaccination

Background: The 7-valent pneumococcal conjugate vaccine (PCV7) was introduced into the Norwegian Childhood Immunization Program in 2006. A substantial effectiveness of PCV7 immunization against invasive pneumococcal disease has been demonstrated, whereas evidence of its impact on respiratory tract infections are less consistent. Methods: This study included children participating in the Norwegian Mother and Child Cohort Study, which recruited pregnant women between 1999 and 2008. Maternal report of acute otitis media (AOM), lower respiratory tract infections (LRTIs) and asthma in the child was compared by PCV7 immunization status, as obtained from the Norwegian Immunization Registry. Generalized linear models with the log-link function were used to report adjusted relative risks (RRs) and 95% confidence intervals (CIs). Results: For children who had received 3 or more PCV7 immunizations by 12 months of age, the adjusted RRs of AOM and LRTIs between 12 and 18 months were 0.86 (95% CI: 0.81, 0.91) and 0.78 (95% CI: 0.70, 0.87) respectively, when compared with nonimmunized children. A reduced risk of AOM, RR 0.92 (95% CI: 0.90, 0.94), and LRTIs, RR 0.75 (95% CI: 0.71, 0.80), between 18 and 36 months of age was also identified among children who had received 3 or more immunizations by 18 months of age. No association was seen between PCV7 immunization and asthma at 36 months of age. Conclusion: Reduced incidences of AOM and LRTIs before 36 months of age were observed among children immunized with PCV7 through the childhood immunization program.

Usefulness of health registries when estimating vaccine effectiveness during the influenza A(H1N1)pdm09 pandemic in Norway

BackgroundDuring the 2009-2010 pandemic in Norway, 12 513 laboratory-confirmed cases of pandemic influenza A(H1N1)pdm09, were reported to the Norwegian Surveillance System for Communicable Diseases (MSIS). 2.2 million persons (45% of the population) were vaccinated with an AS03-adjuvanted monovalent vaccine during the pandemic. Most of them were registered in the Norwegian Immunisation Registry (SYSVAK). Based on these registries, we aimed at estimating the vaccine effectiveness (VE) and describing vaccine failures during the pandemic in Norway, in order to evaluate the role of the vaccine as a preventive measure during the pandemic.MethodsWe conducted a population-based retrospective cohort study, linking MSIS and SYSVAK with pandemic influenza vaccination as exposure and laboratory-confirmed pandemic influenza as outcome. We measured VE by week and defined two thresholds for immunity; eight and 15 days after vaccination.ResultsThe weekly VE ranged from 77% to 96% when considering 15 days or more after vaccination as the threshold of immunity and from 73% to 94% when considering eight days or more. Overall, 157 individuals contracted pandemic influenza eight or more days after vaccination (8.4/100,000 vaccinated), of these 58 had onset 15 days or more after vaccination (3.0/100,000 vaccinated). Most of the vaccine failures occurred during the first weeks of the vaccination campaign. More than 30% of the vaccine failures were found in people below 10 years of age.ConclusionsHaving available health registries with data regarding cases of specific disease and vaccination makes it feasible to estimate VE in a simple and rapid way. VE was high regardless the immunity threshold chosen. We encourage public health authorities in other countries to set up such registries. It is also important to consider including information on underlying diseases in registries already existing, in order to make it feasible to conduct more complete VE estimations.

Vaccination coverage for seasonal influenza among residents and health care workers in Norwegian nursing homes during the 2012/13 season, a cross-sectional study.

BackgroundWHO has set a goal of 75% vaccination coverage (VC) for seasonal influenza for residents and also recommends immunization for all healthcare workers (HCWs) in nursing homes (NHs). We conducted a cross-sectional study to estimate the VC for seasonal influenza vaccination in Norwegian NHs in 2012/2013 since the VC in NHs and HCWs is unknown.MethodsWe gathered information from NHs concerning VC for residents and HCWs, and vaccination costs for HCWs, using a web-based questionnaire. We calculated VC among NH residents by dividing the number of residents vaccinated by the total number of residents for each NH. VC among HCWs was similarly calculated by dividing the number of HCWs vaccinated by the total number of HCWs for each NH. The association between VC and possible demographic variables were explored.ResultsOf 910 NHs, 354 (38.9%) responded. Median VC per NH was 71.7% (range 0-100) among residents and 0% (range 0-100) among HCWs, with 214 (60%) NHs reporting that none of their HCWs was vaccinated. Median VC for HCWs in NHs with an annual vaccination campaign was 0% (range 0-53), compared to when they did not have an annual vaccination campaign 0% (range 0-12); the distributions in the two groups differed significantly (Mann–Whitney U, P = 0.006 two tailed).ConclusionMedian influenza VC in Norwegian NHs was marginally lower than recommended among residents and exceptionally low among HCWs. The VC in HCWs was significantly higher when NHs had an annual vaccination campaign. We recommend that NHs implement measures to increase VC among residents and HCWs, including vaccination campaigns and studies to identify potential barriers to vaccination.

Risk of Pertussis in Relation to Degree of Prematurity in Children Less Than 2 Years of Age

BACKGROUND A few previous studies reported increased risk of pertussis in children with birth weight < 2500g. The risk of pertussis by degree of prematurity has not been determined in a cohort study. The vaccine effectiveness (VE) against reported pertussis in preterm infants is unknown. METHODS Data were obtained from the Medical Birth Registry of Norway (1998-2010) and linked to other national registries. In total, 713,166 children were included in our study and followed until 2 years of age. Incidence rate ratios (IRRs) and confidence intervals (CIs) were estimated with Poisson regression. RESULTS We identified 999 reported cases of pertussis. We observed a higher rate of reported pertussis in preterm than in full-term infants, IRR = 1.65 (95% CI 1.32-2.07). Compared to full-term infants, the risk of reported pertussis in infants born at gestational age (GA) 35-36 weeks, GA 32-34 weeks and GA 23-27 weeks was higher (IRRs = 1.49 (95% CI 1.11-2.01), 1.63 (95% CI 1.06-2.51), and 4.49 (95% CI 2.33-8.67), respectively). Moreover, preterm infants had a higher rate of pertussis-related hospitalisation than full-term infants (IRR = 1.99 (95% CI 1.47-2.71)). The VE against reported pertussis for the 3rd dose was 88.8% (95% CI 84.3-92.0) in full-term infants and 93.0% (95% CI 85.8-96.5) in preterm infants. CONCLUSIONS In this cohort study preterm infants, including those born at GA 35 and 36 weeks had increased risk of reported pertussis. The VE was similar in preterm and full-term infants.Background: A few previous studies reported increased risk of pertussis in children with birth weight less than 2500 g. The risk of pertussis by degree of prematurity has not been determined in a cohort study. The vaccine effectiveness (VE) against reported pertussis in preterm infants is unknown. Methods: Data were obtained from the Medical Birth Registry of Norway (1998–2010) and linked to other national registries. In total, 713,166 children were included in our study and followed until 2 years of age. Incidence rate ratios (IRRs) and confidence intervals (CIs) were estimated with Poisson regression. Results: We identified 999 reported cases of pertussis. We observed a higher rate of reported pertussis in preterm than in full-term infants, IRR = 1.65 (95% CI: 1.32–2.07). Compared to full-term infants, the risk of reported pertussis in infants born at gestational age (GA) 35–36, 32–34 and 23–27 weeks were higher [IRRs = 1.49 (95% CI: 1.11–2.01), 1.63 (95% CI: 1.06–2.51) and 4.49 (95% CI: 2.33–8.67), respectively]. Moreover, preterm infants had a higher rate of pertussis-related hospitalization than full-term infants [IRR = 1.99 (95% CI: 1.47–2.71)]. The VE against reported pertussis for the third dose was 88.8% (95% CI: 84.3–92.0) in full-term infants and 93.0% (95% CI: 85.8–96.5) in preterm infants. Conclusions: In this cohort study, preterm infants including those born at GA 35 and 36 weeks had increased risk of reported pertussis. The VE was similar in preterm and full-term infants.