Strengths and limitations of assessing influenza vaccine effectiveness using routinely collected, passive surveillance data in Ontario, Canada, 2007 to 2012: balancing efficiency versus quality.

Prompt evaluation of annual influenza vaccine effectiveness (IVE) is important. IVE is estimated in Ontario using a test-negative design (TND) within a national sentinel surveillance network (SPSN). To explore alternative approaches, we applied the screening method (SM) during five seasons spanning 2007 to 2012 to passive surveillance data to determine whether routinely collected data could provide unbiased IVE estimates. Age-adjusted SM-IVE estimates, excluding 2008/09 pandemic cases and cases with missing immunisation status, were compared with TND-IVE estimates in SPSN participants, adjusted for age, comorbidity, week of illness onset and interval to specimen collection. In four seasons, including the 2009 pandemic, the SM underestimated IVE (22­39% seasonal; 72% pandemic) by 20 to 35% relative to the TND-IVE (58­63% seasonal; 93% pandemic), except for the 2010/11 season when both estimates were low (33% and 30%, respectively). Half of the cases in the routine surveillance data lacked immunisation information; imputing all to be unimmunised better aligned SM-IVE with TND-IVE, instead overestimating in four seasons by 4 to 29%. While the SM approach applied to routine data may offer the advantage of timeliness, ease and efficiency, methodological issues related to completeness of vaccine information and/or case ascertainment may constitute trade-offs in reliability.

Surveillance summary of hospitalized pediatric enterovirus D68 cases in Canada, September 2014.

BACKGROUND: Enterovirus D68 (EV-D68) has been detected infrequently and has not been associated with severe disease in Canada. In the early fall of 2014, following an unusual case increase in the United States, clusters of EV-D68 among children and some adults manifesting severe symptoms were reported in Canada. OBJECTIVE: To provide an initial epidemiological summary of pediatric cases hospitalized with EV-D68 in Canada. METHODS: A time-limited surveillance pilot was conducted collecting information on pediatric cases (less than 18 years of age) hospitalized with EV-D68 between September 1 and 30, 2014. RESULTS: In total, 268 cases were reported from Ontario (n=210), Alberta (n=45), and British Columbia (n=13). Of the 268 reported cases, 64.9% (n=174) were male; the sex difference was statistically significant (p<0.01). Age was reported for 255 cases, with a mean age for males of 5.4 years and for females of 5.3 years. For cases with data available, 6.8% (18/266) were admitted to an intensive care unit. Of those where clinical illness was recorded, respiratory illness alone was present in 98.3% (227/231), neurologic illness alone was present in 0.4% (n=1), and both illnesses were present in 0.9% of cases (n=2); cases with neither respiratory nor neurologic illness were rare (n=1). Of the 90 cases with additional clinical information available, 43.3% were reported as having asthma. No deaths were reported among the 268 cases. CONCLUSION: The EV-D68 outbreak in Canada in September 2014 represents the beginning of a novel outbreak associated with severe illness in children. These findings provide the first epidemiological summary of severe cases of EV-D68 as an emergent respiratory pathogen in Canada. The continued investigation of this pathogen is necessary to build on these results and capture the full spectrum of associated illness.

Pertussis Surveillance Trends in British Columbia, Canada, over a 20-year Period: 1993-2013.

OBJECTIVE: To provide a surveillance update on overall and age-related pertussis trends in British Columbia (BC), Canada, spanning the 20-year period from 1993-2013. METHODS: Provincial surveillance data for confirmed pertussis cases were extracted from January 1, 1993 to October 31, 2013. Annual and age-specific incidence rates were derived using provincial and regional population estimates. RESULTS: BC experienced substantial pertussis epidemics in the late 1990s and early 2000s with incidence ranging from 20 to 40 per 100,000 overall and peaking in pre-teens aged 10-13 years at >200 per 100,000 during the epidemic of 2000. Overall incidence dropped to historical lows ranging from 1 to 6 per 100,000 between 2005 and 2011. This low-level activity was followed by resurgence in 2012 driven by outbreaks in Lower Mainland regions of BC with overall provincial incidence reaching 10 per 100,000. Age-specific incidence in 2012 was highest among infants <1 year old (64 per 100,000) and children 12-13 years old (56-57 per 100,000), with a shift in the age distribution away from preschool-aged children toward pre-teens and young teens evident since 2000. Adult incidence remained <10 per 100,000 throughout the study period and was 5 per 100,000 in 2012. Year-to-date provincial incidence rates overall for 2013 are 6 per 100,000, with ongoing asynchronous activity observed primarily on Vancouver Island. CONCLUSIONS: Pertussis activity in BC showed expected cyclical fluctuations, with a peak incidence observed in 2012, mostly affecting infants and pre-teens/teens but at lower levels than prior peaks. Following substantial epidemics in the 1990s and early 2000s and the incorporation of acellular pertussis vaccine into the routine immunization program, the immuno-epidemiology of pertussis may still be in transition. Further monitoring and evaluation are needed to guide possible program changes for BC.

The test-negative design: validity, accuracy and precision of vaccine efficacy estimates compared to the gold standard of randomised placebo-controlled clinical trials.

The test-negative design (TND) is an efficient form of case-control study commonly applied to influenza vaccine effectiveness (VE) estimation. TND validity is predicated on the core assumption that the intervention (vaccine) has no effect on other non-targeted aetiologies resulting in similar illness/disease. Here we verify this core assumption and compare efficacy estimates derived by the TND versus classical per-protocol analysis of four datasets obtained from randomised placebo-controlled clinical trials (RCT) of the live attenuated influenza vaccine (LAIV) in children ≤7 years-old and the elderly ≥60 years-old. We further assess generalisability of the TND approach in two other RCT datasets to evaluate monoclonal antibody in the prevention of respiratory syncytial virus (RSV) hospitalisation. Efficacy estimates and their confidence intervals were virtually identical for per-protocol RCT versus TND analyses of LAIV and also for RSV monoclonal antibody. Neither LAIV nor monoclonal antibodies affected the risk of disease aetiologies that were not specifically targeted by the respective interventions (e.g. other respiratory viruses). This study validates the core assumption of the TND approach for influenza vaccine efficacy estimation and confirms the accuracy and precision of its estimates compared to the gold standard of classic per-protocol RCT analysis of the same data sets. The TND approach is generalisable for other conditions such as RSV for which the core assumption is also met. However, when used in observational studies, the TND, like all designs, still requires assessment for bias and confounding that may exist in the absence of randomised participation and blinded follow-up.

Interim estimates of influenza vaccine effectiveness in 2012/13 from Canada's sentinel surveillance network, January 2013.

The 2012/13 influenza season in Canada has been characterised to date by early and moderately severe activity, dominated (90%) by the A(H3N2) subtype. Vaccine effectiveness (VE) was assessed in January 2013 by Canada's sentinel surveillance network using a test-negative case-control design. Interim adjusted-VE against medically attended laboratory-confirmed influenza A(H3N2) infection was 45% (95% CI: 13-66). Influenza A(H3N2) viruses in Canada are similar to the vaccine, based on haemagglutination inhibition; however, antigenic site mutations are described in the haemagglutinin gene.

Cross-reactive antibody to swine influenza A(H3N2) subtype virus in children and adults before and after immunisation with 2010/11 trivalent inactivated influenza vaccine in Canada, August to November 2010.

In pre- and post-immunisation sera from children (17-120 months-old) and adults (20-59 years-old) immunised with 2010/11 trivalent inactivated influenza vaccine, we assessed age-related patterns of sero-susceptibility and vaccine-induced cross-reactive antibodies to a representative swine H3N2 (swH3N2) and a related ancestral human H3N2 (A/Sydney/5/1997) influenza virus. Few children but a greater proportion of adults showed pre-immunisation haemagglutination inhibition titres ≥40 to either virus. Titres increased with age among children but decreased in adults. Fewer than 20% showed a four-fold rise in antibody titres to either virus following immunisation. Further investigation is warranted to guide ongoing risk assessment and response to emerging swine H3N2 viruses.

Age-related trends in the timeliness and prediction of medical visits, hospitalizations and deaths due to pneumonia and influenza, British Columbia, Canada, 1998-2004.

The influenza immunization program in North America has been primarily designed to provide direct benefit to vaccinated individuals at highest risk of serious influenza outcomes. Some evidence suggests that immunization of certain age groups may also extend indirect protective benefit to vulnerable populations. Our goal was to identify age groups associated earliest with seasonal influenza activity and who may have the greatest indirect impact at the population level. We examined age-based associations between influenza medical visits and population-wide hospitalization/mortality due to pneumonia & influenza (P&I) using administrative datasets in British Columbia, Canada. A peak week was identified for each age group based on the highest rates observed in a given week for that study year. Mean rates at the peak week were averaged over the study years per age group. Timeliness (T) was defined as the mean difference in days between the first peak in influenza medical visits and population-wide P&I hospitalizations/deaths. Poisson regression was applied to calculate prediction (Pr) as the average proportion of deviance in P&I explained by influenza medical visits. T and Pr were derived by age group, and the product (T x Pr) was used as a summary measure to rank potential indirect effects of influenza by age group. Young children (0-23 months) and the elderly (> or = 65 years) had the highest peak rates of P&I hospitalization. Children < 6m and the elderly had the highest peak rates of P&I mortality. We found no significant differences by age for influenza medical visits in predicting population-wide P&I hospitalizations or deaths. School-aged children (5-19 years) showed the best relative combination of T x Pr, followed by preschool-aged children (2-4 years). We conclude that the very young and old suffer the greatest morbidity due to P&I, and an indirect role for school-aged children in anticipating the risk to others warrants further evaluation.

Estimating vaccine effectiveness against laboratory-confirmed influenza using a sentinel physician network: results from the 2005-2006 season of dual A and B vaccine mismatch in Canada.

INTRODUCTION: We report a case-control design using a sentinel physician network to estimate vaccine effectiveness (VE) against laboratory-confirmed, medically attended influenza (LC-MAI) and provide results for the 2005-2006 season of dual A and B vaccine mismatch in Canada. METHODS: Participants were patients >or=5 years of age presenting with influenza-like illness (ILI) to a sentinel physician in British Columbia, Canada between November 1, 2005 and April 30, 2006. Cases were participants in whom influenza was identified; controls tested negative for influenza A and B by PCR, R-mix and culture. Isolates were characterized by gene-sequencing and hemagglutination-inhibition (HI) assays. Odds ratios (OR) for LC-MAI in vaccinated versus non-vaccinated persons were derived with adjustment for age and chronic conditions. VE was estimated as [1-OR (vaccinated/unvaccinated)]. RESULTS: The sample included 442 patient visits: median age was 26 years, 10% were >or=65 years, 15% had a chronic condition and 22% received the 2005-2006 trivalent inactivated influenza vaccine >or=2 weeks before ILI onset. Two hundred and six participants were positive for influenza; 107 (52%) had influenza A/H3N2 and 99 (48%) had influenza B/Victoria lineage. Gene sequencing identified mutations away from the vaccine strain at key antigenic binding sites of the hemagglutinin (HA) protein of H3N2 isolates; the neuraminidase (NA) protein was conserved. Based on HI assays, three-quarters of influenza A and all B isolates were mismatched to the 2005-2006 vaccine. Point estimates for VE against LC-MAI were in the range of 50 to 70% for both types of influenza. CONCLUSION: 2005-2006 was the third consecutive season of vaccine mismatch based on varying HA for the A/H3N2 component and the third also for the B component since 2001. Vaccine mismatch resulted in diminished VE but substantial cross-protection. More timely detection of drift variants through gene sequencing of isolates facilitates interpretation of VE results. Since it may be more antigenically conserved, the vaccine content and contribution of NA to overall VE should be further evaluated for both A and B components. Infrastructure for real-time epidemiologic assessment of vaccine performance is important annually and in preparation for a pandemic.

Influenza revaccination of elderly travelers: antibody response to single influenza vaccination and revaccination at 12 weeks.

The antibody response to a single influenza vaccination and the effect of influenza revaccination was assessed in healthy elderly persons. Travelers > or =65 years old who had received influenza vaccine before travel were enrolled in the study and were offered a second vaccination after 12 weeks. Geographic and age-matched control subjects received a single vaccination. A second influenza vaccination was not associated with increased adverse effects. There was no significant difference between log(10) hemagglutinin-inhibiting (HI) antibody titers or an HI antibody titer > or =1:40 (considered to be protective) in 28 control subjects and 28 revaccinated travelers for any antigen. Probable protection for influenza A antigens remained high 24 weeks after a single immunization and revaccination (A/Sydney/05/97 [H3N2], 92% and 96%, and A/Beijing/262/95 [H1N1], 80% and 96%, respectively). Response to B/Harbin was less throughout the study. A/Sydney antibody titer was lower with more times vaccinated in the previous 5 years. Therefore, a second vaccine did not enhance the immune response.

Previous creatinine levels safely predict amantadine dose for influenza A outbreak control.

BACKGROUND: Amantadine, an antiviral agent, is the only drug currently approved in Canada for prophylaxis of influenza A virus infection. To minimize side effects, the amantadine dose is adjusted for age and estimated creatinine clearance (CrCl) based on plasma creatinine (Cr) levels. As amantadine is used more frequently for influenza A outbreak control in care facilities for elderly people, physicians are increasingly called on to prescribe it for residents and to consider the necessity of requesting plasma Cr levels. OBJECTIVE: To determine whether previous Cr levels are predictive in estimating current CrCl and safe amantadine dose determination. DESIGN AND SETTING: Residents' charts were reviewed in two facilities in Vancouver, British Columbia. CrCl estimated using previous or current Cr results, current weight and age, as well as recommended amantadine doses based on Canadian National Advisory Committee on Immunization guidelines, were studied. RESULTS: 165 charts with Cr results in March 1998 were included; 122 had results before March 1998, and 103 had Cr results after March 1998. Pearson's correlation coefficient for CrCl estimated from current and previous Cr values was 0.929 for results less than six months previously, 0.974 for six to 12 months previously and 0.952 for 12 to 18 months previously. The same or a more conservative dose of amantadine was predicted in 92% of cases when using a Cr result taken within the previous year and in 76% of cases when using a Cr result taken 12 to 18 months previously. CONCLUSION: In long term care facilities, Cr levels measured up to 12 months previously can usually safely be used to estimate CrCl. Using previous Cr results permits advance preparation of doctor's orders for amantadine prophylaxis and avoids repeating Cr testing on every resident when an outbreak occurs, reducing related staff time and cost.