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Background Despite the approved use of live-attenuated intranasal influenza vaccine (LAIV) for seasonal immunization of patients with cystic fibrosis (CF), many questions remain unanswered regarding the timing, duration, and types of adverse events that occur following administration of this vaccine. Methods In 2012 and 2013, 264 LAIV doses were administered to 198 patients aged 2–19 with CF. Vaccinees were followed prospectively for 55 days after vaccination (day 0) and information on adverse events was collected. Bayesian change-point analysis was used to identify the risk period following LAIV during which participants had a higher risk of reporting adverse events. Multivariable zero-inflated Poisson regression models were then used to estimate the adjusted incidence rate ratio (aIRR) and 95% credible interval (CrI) of reporting each adverse event in the risk period versus the control period. Results There was a higher risk of reporting serious adverse events (SAEs) (aIRR 1.45, 95% CrI (0.29, 5.17)) and solicited symptoms during days 0–6 of follow-up compared to control period days 7–55. However, most SAEs were not causally related to LAIV and the solicited symptom episodes were brief, usually lasting 1–2 days. There was no increased risk of antibiotic prescriptions for respiratory conditions in the risk vs. control periods (aIRR 0.48, 95% CrI (0.23, 0.91)). Conclusions Adverse events were most common 0–6 days after LAIV administration but were generally benign and self-limiting. Pulmonary exacerbations did not increase in frequency.

When Canada chose a novel adjuvanted vaccine to combat the 2009 influenza pandemic, seasonal trivalent inactivated vaccine (TIV) was also available but compatibility of the two had not been assessed. To compare responses after concurrent or sequential administration of these vaccines, adults 20-59 years old were randomly assigned (1:1) to receive ASO3-adjuvanted H1N1pdm09 vaccine (Arepanrix, GSK, Quebec City, Quebec), with TIV (Vaxigrip, Sanofi Pasteur, Toronto) given concurrently or 21 days later. Blood was obtained at baseline and 21 days after each vaccination to measure hemagglutination inhibition (HAI) titers. Adverse effects were assessed using symptom diaries and personal interviews. 282 participants completed the study (concurrent vaccines 145, sequential vaccines 137). HAI titers to H1N1pdm09 were ≥ 40 at baseline in 15-18% of participants and following vaccination in 91-92%. Initially seropositive subjects (titer ≥ 10) had lower H1N1pdm09 geometric mean HAI titers (GMT) after concurrent than separate vaccinations (320.0 vs 476.5, p=0.039) but both exceeded GM responses of initially naïve participants, which were unaffected by concurrent TIV. Responses to TIV were not lower after concurrent than separate vaccination. Adverse event rates were not increased by concurrent vaccinations above those with H1N1pdm09 vaccine alone. This adjuvanted H1N1pdm09 vaccine was immunogenic and compatible with concurrently administered TIV.

Background Although decennial adult boosters of tetanus and diphtheria toxoids are recommended in Canada and the United States, a second dose of pertussis vaccine during adulthood is not currently recommended. Methods This open-label, multicenter study compared the safety and immunogenicity of a first dose of an adult formulation of tetanus, diphtheria, and acelluar pertussis vaccine (Tdap) with a repeat dose of Tdap in adults who had received Tdap 10 years previously. Results A total of 769 participants ranging in age from 20 to 72 years took part in this study; 92.3% of naive and 92.7% of repeat-dose participants had at least one solicited adverse event. Injection-site pain (84.4% and 87.8%), erythema (29.7% and 23.1%), and swelling (23.3% and 20.5%), and myalgia (53.5% and 60.1%), headache (37.6% and 40.6%), malaise (29.0% and 29.4%), and fever (4.9% and 4.2%) were the most common solicited adverse events reported in the naive and repeat-dose groups, respectively. Postvaccination antibody levels ≥0.1 IU/mL were achieved by 99.7% of the naive-group participants and all of the repeat-dose participants for tetanus and 96.1% of the naive group and 98.5% of the repeat-dose group for diphtheria, both meeting the predefined noninferiority criteria. For pertussis antibodies, anti-PT (89.2 EU/mL vs. 116 EU/mL) was higher in the repeat-dose group, anti-FHA (249 vs. 214) and anti-PRN (216 vs. 266) were similar, and anti-FIM (1015 vs. 779) was higher in the naive group. Noninferiority criteria were met for all antigens except for anti-FIM. Conclusion A repeat dose of Tdap vaccine 10 years after the first dose was well tolerated and immunogenic in adults (ClinicalTrials.gov identifier: NCT00712959 ).

A total of 324 pandemic H1N1 cases were reported to the Immunization Monitoring Program, Active from May 1, 2009 to August 31, 2009. As of August 31, 2009, case details were available for 73% (n=235) of these cases. The median age was 4.8 years and 69% of children were older than 2 years of age. In total, 95 (40%) of children were previously healthy. The proportion with an underlying health condition increased with age. Close to 50% of children received antiviral medication. Two children died from the infection. The pediatric risk groups affected and course of disease caused by pandemic H1N1 appear similar to seasonal influenza.

Active surveillance was conducted by the 12 centers of the Canadian Immunization Monitoring Program, Active from 2000-2007 in children 16 years of age and younger to determine the influence of 7-valent pneumococcal conjugate immunization programs on the prevalence, serotype and antibiotic resistance patterns of invasive pneumococcal disease (IPD) caused by Streptococcus pneumoniae. The absolute number of reported IPD cases decreased 48% (p

Two doses of measles-mumps-rubella vaccine (MMR) are widely recommended and consideration is being given to a similar schedule for varicella vaccine. A combined measles-mumps-rubella-varicella vaccine (MMRV) could be considered for this second dose in children previously vaccinated separately with MMR and varicella vaccines. Healthy children (N=390) aged 15-75 months (median 54 months) previously immunized with MMR and varicella vaccines were randomly allocated to receive MMRV or separate injections of MMR and varicella vaccines. Before administration of study vaccines, seropositivity rates were 96.4% for measles, 94.3% for mumps, 99.5% for rubella, and 97.9% for varicella. Post-immunization, seropositivity rates were 99.5% for measles and mumps and 100% for rubella and varicella in the MMR+varicella group and 100% for all four antigens in the MMRV group; a 26.2- and 27.2-fold increase in varicella titer was observed in the MMR+varicella vaccine and MMRV groups, respectively. Except for more frequent pain in the MMRV group (33.3% vs. 23.7%, p=0.043), there were no differences in the incidence of local and solicited symptoms between groups. In children primed with MMR and varicella vaccine, MMRV had non-inferior immunogenicity and similar safety profiles as a second dose of licensed MMR and varicella vaccine administered concomitantly.

Background Influenza vaccination among health-care workers is poor, and the effectiveness of hospital vaccination programs remains unclear. Little is known about the effectiveness of intensive evidence-based vaccination programs in nursing staff. We determined whether the recommended vaccination rate could be achieved among paediatric nurses during an intensive promotional program for influenza vaccination. We also sought to identify the reasons for which nurses refuse the influenza vaccine and predictors of future vaccination intent. Methods We offered influenza vaccination to nursing staff during an influenza season through a multi-component program that included intensive promotional activities. We analysed vaccination data to determine uptake rates. In a cross-sectional survey, self-administered questionnaires were distributed to all nurses with patient contact during that season. The questionnaire evaluated their vaccine use, site of work, absenteeism and physician visits due to respiratory illness, vaccination intent for the subsequent influenza season, and other items. We surveyed vaccinated nurses regarding their program experiences and the frequency and severity of adverse reactions. Unvaccinated nurses were asked their reasons for refusing vaccination. Multiple logistic-regression analysis was conducted to identify variables that predicted the likelihood of future vaccine acceptance. Results More than 75% (895/1182) of applicable nurses were vaccinated in the program. The questionnaire response rate was nearly 48% (585/1230). Vaccination in the program during the current season (odds ratio [OR] 101.99, 95% confidence interval [CI] 52.54–197.98), program convenience (OR 199.19, 95% CI 98.01–404.11), and a physician visit for respiratory illness (OR 2.44, 95% CI 1.29–4.61) were found to be independent predictors of intent to receive the vaccine the following season. A lack of perceived personal need was the most common reason for vaccine refusal, given in 30% (77/258) of unvaccinated respondents. Conclusions Adequate coverage of nurses is achievable during an intensive voluntary immunisation program against influenza, using best-known practices. Perceived lack of personal benefit is a major deterrent, while program convenience and previous vaccination strongly predict future vaccine acceptance. Our findings support interventions that improve the convenience of hospital immunisation programs for influenza, particularly those that are aimed at nurses and that promote vaccine efficacy and benefits.

We performed a randomized, controlled clinical trial to characterize the evolution of the adverse events associated with the fifth consecutive dose of an acellular pertussis vaccine, and to assess the level of discomfort associated with the injection and the attitude of parents concerning these events. A total of 505 children who had received either four doses of acellular pertussis vaccine or whole-cell pertussis vaccine were given a fifth dose of one of the two vaccines. Adverse events were monitored by parents and collected by telephone or home visit at 4, 8, 12, 24, 48 and 72 h, and 7 and 28 days after immunization. Rates of injection site redness ≥50 mm were similar in recipients of five doses of acellular pertussis vaccine (32.8%) or five doses of whole-cell pertussis vaccine (43.3%). Injection site swelling, tenderness, and decreased arm movement were all more frequent in children who received five doses of whole-cell pertussis vaccine. Antibody levels before or after immunization did not predict those children who had increased injection site reactions. The children rated the injection site reactions as significantly more severe after five consecutive doses of whole-cell vaccine. Parent satisfaction was higher after the acellular vaccine. We conclude that a fifth consecutive dose of a whole-cell pertussis vaccine is associated with high rates of tender redness and swelling at the injection site, in contrast to a fifth consecutive dose of an acellular pertussis vaccine which is associated with high rates of non-painful redness. However, parents will still need to be aware of the high rates of injection site reactions expected after a fifth dose of acellular pertussis vaccine.

This study compared immune responses of healthy Aboriginal and non-Aboriginal infants to Haemophilus influenzae type b (Hib) and hepatitis B virus (HBV) components of a DTaP-HBV-IPV/Hib combination vaccine, 1 month after completing dosing at 2, 4 and 6 months of age. Of 112 infants enrolled in each group, 94 Aboriginal and 107 non-Aboriginal infants qualified for the immunogenicity analysis. Anti-PRP concentrations exceeded the protective minimum (≥0.15μg/ml) in ≥97% of infants in both groups but geometric mean concentrations (GMCs) were higher in Aboriginal infants (6.12μg/ml versus 3.51μg/ml). All subjects were seroprotected (anti-HBs ≥10mIU/mL) against HBV, with groups having similar GMCs (1797.9 versus 1544.4mIU/mL, Aboriginal versus non-Aboriginal, respectively). No safety concerns were identified. We conclude that 3-dose primary vaccination with DTaP-HBV-IPV/Hib combination vaccine elicited immune responses to Hib and HBV components that were at least as high in Aboriginal as in non-Aboriginal Canadian infants.Clinical Trial Registration NCT00753649.

The Canadian Adverse Event Following Immunization Surveillance System (CAEFISS) receives reports via active syndromic surveillance for selected serious AEFI from the Canadian Immunization Monitoring Program Active (IMPACT) and via targeted passive surveillance from Federal/Provincial/Territorial health jurisdictions. Post-immunization seizure is a target of active and passive surveillance. Since 2009, the revised national AEFI reporting forms enable capture of terms specific to several Brighton Collaboration Case Definitions (BCCD) including generalized seizure and fever.To evaluate feasibility of applying the BCCD for generalized seizure to adverse event following immunization (AEFI) reports collected by IMPACT and targeted passive surveillance (non-IMPACT).Reports to CAEFISS coded as seizure in children2 years of age (vaccination dates 1998-2011) were reviewed retrospectively. A BCCD level (1-5 or unclassifiable) was assigned. The effects of reporting source (IMPACT versus non-IMPACT), seriousness [serious (e.g., hospitalized) versus non-serious], vaccination year (1998-2008 versus 2009-2011), and data submission method to CAEFISS (electronic versus paper) were assessed by stratified analysis.There were 459 IMPACT and 908 non-IMPACT cases analyzed, of which 99.6% and 27%, respectively, were serious reports. The revised reporting form that captured the BCCD components (2009-2011) was associated with increased proportions of IMPACT and non-IMPACT cases meeting the BCCD for generalized seizure.Incorporating the BCCD components (level of consciousness, motor manifestations and fever ≥38°C) into the national reporting form and guidelines appeared to improve the feasibility of their use in AEFI surveillance. This effect was more pronounced among active syndromic surveillance compared to targeted passive surveillance reports.

Background Hepatitis A virus (HAV) infection rates in Canada are low and declining. A nationwide pediatric serosurvey in 2003 confirmed that HAV infection is uncommon in children. Additional seroepidemiological data for adults would help to guide domestic use of HAV vaccines. Methods A country-wide survey of HAV antibody positivity and selected risk factors was conducted among 18–69 year olds identified by random digit dialing, in samples proportional to regional populations. Volunteers were sent study materials and returned oral fluid and completed questionnaires by mail. An ultra-sensitive assay was used to detect HAV antibody in oral fluid. Multiple logistic regression was used for risk factor assessment. Results Of 2104 potential study participants, 1552 (74%) returned an adequate oral fluid specimen and questionnaire. Anti-HAV was detected in 509 individuals (33%) and was associated with birth in HAV endemic areas, self-reported hepatitis A vaccination, prior travel to endemic areas, and increasing age. Only 15% reported having been vaccinated. Among Canadian-born, non-vaccinated participants anti-HAV was present in 20%, ranging regionally from 14% to 30%. Age-specific positivity rates in this subset were: 18–29 years 2.6%; 30–39 years 6.1%; 40–49 years 11.4%; 50–59 years 26.4% and 60–69 years 45.9%. Travel to HAV-endemic countries was reported by 55% of participants but only 24% of travelers had been vaccinated. Conclusions Past HAV infection rates among Canadian-born, non-vaccinated individuals are low in young adults and increase by two-fold per age decade. Travel to endemic areas is a significant risk factor, amenable to prevention by greater use of HAV vaccine.

This study assessed compatibility of concurrently administered 7-valent pneumococcal conjugate (PCV7), hepatitis B (HB) and DTaP.IPV/Hib vaccines. Infants were given DTaP.IPV/Hib and HB at 2, 4, 6 months and randomly assigned (2:1) to receive PCV7 concurrently or sequentially (at 3, 5, 7 months). Antibody levels were compared in 246 concurrent and 122 sequential vaccinees. Responses to PCV7, DTaP.IPV/Hib and HB were generally unaltered with concurrent administration except that Hib responses were increased (p=0.008) and HB responses were reduced (p=0.006) with concurrent dosing, the latter possibly from same thigh injection with DTaP.IPV/Hib. We conclude that PCV7, DTaP.IPV/Hib and HB are compatible with concurrent, separate injections.

Recent reports indicate that children receiving a fifth consecutive dose of DTPa vaccine have a moderate likelihood of developing a large injection site reaction, the etiology of which remains unknown. We assessed the frequency, severity and outcome of local reactions in 205 children who had participated in earlier studies of DTPa-based vaccines and were due for a fifth dose at 4-6 years. DTPa.IPV vaccine was given intramuscularly in the deltoid. To explore the role of cell-mediated immunity in local reactions we applied epicutaneous (patch) tests at the same visit, using code-labeled solutions of DTPa.IPV, DT, Pa, IPV, alum solution and saline, leaving them in place for 48 h. Subjects were assessed by research staff on the following day. Injection site redness or swelling/=50 mm diameter was present in 24.4 and 20.5%, respectively, but none of the subjects had fever or persistent limitation of arm movement. Large local reactions were more common in bigger children (P0.01) but not in those with allergy/atopy. Large reactions resolved within 14 days. Positive skin tests (erythema) occurred at 85 test sites in 51 of 187 evaluable children, principally with DTPa.IPV, IPV and alum solutions. However, only DT and Pa solutions caused positive tests significantly more often in children with injection site rednessor =50 mm than in non-reactors (P0.05, odds ratios 5.2 and 6.1, respectively). Presence of alum in most test solutions might have confounded the results as it caused non-specific inflammation when applied alone. We conclude that local reactions to a fifth dose of DTPa-type vaccine are frequent and sometimes extensive but not incapacitating and that concurrent skin testing has potential to identify the vaccine antigens and immune mechanism contributing to local reactions with more refinement of the method.

For infants immunized with Haemophilus influenzae type b conjugate vaccines, booster immunization is usually recommended in the second year of life, typically between 12 and 18 months. This study assessed the effect of age at booster immunization on pre-immunization antibody trough levels and on subsequent responses, for a PRP-T conjugate vaccine. Subjects were healthy children who had received PENTA vaccine (DPT-IPV/PRP-T combination) as infants. They were enrolled and given measles-mumps-rubella vaccine (MMR) at 12 months of age, then randomly assigned to receive PENTA vaccine concurrently with MMR or at 15 or 18 months of age. Parents were asked to note any adverse effects after PENTA vaccination. Blood samples were obtained prior to PENTA vaccination and 4 weeks later, and tested for antibodies to each antigen. In total 253 children received PENTA vaccine: 86 at 12 months, 85 at 15 months and 82 at 18 months. Injection site redness and swelling were least extensive in the youngest group (p < 0.001) but their rates of occurrence did not differ with age. Anti-PRP levels were similar in each age group prior to immunization; post-booster geometric mean concentrations (GMCs) ranged from 13.0 microg/ml in the youngest to 33.9 microg/ml in the oldest subjects (p < 0.0001). For each of the other antigens examined, booster responses were strongest at 18 months. We conclude that anti-PRP levels are stable between 12 and 18 months in children previously given PRP-T vaccine. PENTA boosters given at 12 months appear to cause milder injection site morbidity whereas those given at 18 months result in stronger responses to virtually every constituent antigen, although each age group responded satisfactorily.

A prospective, two center study of 319 children was undertaken to assess responses to booster immunization in healthy 18-month-olds who completed primary immunization 12 months earlier with Haemophilus influenzae type b (Hib) conjugate vaccine (either HbOC or PRP-T). Interchangeability of these products as boosters was also assessed, using combination products containing diphtheria, pertussis and tetanus components. The study was randomized and evaluator blinded. Sera obtained prior to booster vaccination and 4 weeks later were tested for anti-PRP using an IgG-specific enzyme immunoassay. Pre-immunization anti-PRP levels were low: unmeasurable levels (< 0.06 microgram ml-1) were present in 47% of those primed with HbOC and 35% of those primed with PRP-T (P < 0.05). Most children responded strongly to booster vaccination. Interchanging the products had no detrimental effect. Children who lacked measurable antibody prior to re-vaccination had significantly weaker responses 4 weeks afterward. Earlier Hib booster vaccination should be considered in Canada to avoid low anti-PRP trough levels. Extended follow-up of antibody levels and vaccine protective efficacy is also advisable given the observed heterogeneity of responses to booster vaccination.

A booster dose of Haemophilus influenzae type b conjugate vaccine in the second year of life is the final step in the recommended series of doses to protect infants from invasive infection. This study assessed the safety and immunogenicity of PRP-T conjugate vaccine booster doses (Act-HIB, Connaught Laboratories Ltd). The participants were 367 healthy children who had taken part in a study of primary immunization with PRP-T. At 18-19 months old, subjects were randomly assigned to receive diphtheria-pertussis-tetanus (DPT) and PRP-T vaccines either mixed in one syringe (n = 183) or separately in opposite limbs (n = 184). Adverse events were monitored for 48 h after immunization. Blood was obtained prior to vaccination in half of the subjects (combined injections group) and following vaccination in all subjects to test for antibodies to each of the antigens administered. Local adverse reactions were infrequent with PRP-T alone and equally frequent at sites of DPT or DPT/PRP-T injection, except for redness > or = 25 mm in diameter which was more frequent after the combined vaccines (25.1 versus 14.1%, p < 0.01). Systemic adverse events did not differ in type or frequency between groups. Before immunization, the geometric mean anti-PRP level in those tested was 0.41 micrograms ml-1; 26.7% had levels below 0.15 micrograms ml-1. Both treatment groups responded strongly to vaccination. In those serially tested, anti-PRP levels rose by over 90-fold, to 38.1 micrograms ml-1.(ABSTRACT TRUNCATED AT 250 WORDS)

A randomized, controlled comparison was made in 175 healthy 18-month-old children given either diphtheria and tetanus toxoids and pertussis vaccine, adsorbed (DTP) and haemophilus b diphtheria toxoid conjugate vaccine (PRP/D) concurrently at separate sites (66 children) or a new vaccine combining these products (109 children). Rates of local or systemic adverse effects postimmunization and antibody responses to each component did not differ significantly between groups. DTP-containing vaccines were better tolerated when given in the thigh than in the arm. The combination DTP-PRP/D vaccine performed satisfactorily at 18 months of age, avoiding the inconvenience of two injections.

Funded immunization programs are best able to achieve high participation rates, optimal protection of the target population, and indirect protection of others. However, in many countries public funding of approved vaccines can be substantially delayed, limited to a portion of the at-risk population or denied altogether. In these situations, unfunded vaccines are often inaccessible to individuals at risk, allowing potentially avoidable morbidity and mortality to continue to occur. We contend that private access to approved but unfunded vaccines should be reconsidered and encouraged, with recognition that individuals have a prerogative to take advantage of a vaccine of potential benefit to them whether it is publicly funded or not. Moreover, numbers of “approved but unfunded” vaccines are likely to grow because governments will not be able to fund all future vaccines of potential benefit to some citizens. New strategies are needed to better use unfunded vaccines even though the net benefits will fall short of those of funded programs.Canada, after recent delays funding several new vaccine programs, has developed means to encourage private vaccine use. Physicians are required to inform relevant patients about risks and benefits of all recommended vaccines, publicly funded or not. Likewise, some provincial public health departments now recommend and promote both funded and unfunded vaccines. Pharmacists are key players in making unfunded vaccines locally available. Professional organizations are contributing to public and provider education about unfunded vaccines (e.g. herpes zoster, not funded in any province). Vaccine companies are gaining expertise with direct-to-consumer advertising. However, major challenges remain, such as making unfunded vaccines more available to low-income families and overcoming public expectations that all vaccines will be provided cost-free, when many other recommended personal preventive measures are user-pay. The greatest need is to change the widespread perception that approved vaccines should be publicly funded or ignored.

Background In collaboration with the Canadian Immunization Monitoring Program Active (IMPACT), the National Microbiology Laboratory, the UK Health Protection Agency and Novartis Vaccines, we tested the potential of an investigational 4-component meningococcal B vaccine (4CMenB) to cover Canadian strains circulating from 2006 to 2009. Methods IMPACT meningococcal surveillance is population based and includes over 50% of Canadian adults and children. All isolates were characterized by Meningococcal Antigen Typing System (MATS) and sequencing for factor H-binding protein (fHbp), Neisseria Heparin Binding Antigen (NHBA) and Neisserial adhesin A (NadA). Results In total, 157 isolates were tested. Overall, 4CMenB MATS predicted strain coverage was 66% (95% CI: 46–78%), with 26%, 29% and 11% of strains covered by one, two and three vaccine antigens, respectively. The coverage of each antigen was as follows: 13% PorA, 1% NadA, 52% fHbp and 51% NHBA. The majority of strains for clonal complex (cc) 41/44 and cc60 were covered by NHBA; the majority of strains for cc269 and cc32 were covered by fHbp and NHBA. Coverage for two prevalent strains (sequence type (ST)-269 and ST-154) was 95% and 100%, respectively. Conclusions 4CMenB has the potential to protect against a significant proportion of Canadian invasive MenB strains.