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Introduction: Because of variability in published A(H1N1)pdm09 influenza vaccine effectiveness estimates, we conducted a study in the adults belonging to the risk groups to assess the A(H1N1)pdm09 MF59-adjuvanted influenza vaccine effectiveness., Methods: VE against influenza and/or pneumonia was assessed in the cohort study (n>25000), and vaccine effectiveness against laboratory-confirmed A(H1N1)pdm09 influenza was assessed in a matched case-control study (16 pairs). Odds ratios (OR) and their 95% confidence intervals (95% CI) were calculated by using multivariate logistic regression; vaccine effectiveness was estimated as (1-odds ratio)*100%., Results: Vaccine effectiveness against laboratory-confirmed A(H1N1)pdm09 influenza and influenza and/or pneumonia was 98% (84-100%) and 33% (2-54%) respectively. The vaccine did not prevent influenza and/or pneumonia in 18-59 years old subjects, and was 49% (16-69%) effective in 60 years and older subjects., Conclusions: Even though we cannot entirely rule out that selection bias, residual confounding and/or cross-protection has played a role, the present results indicate that the MF59-adjuvanted A(H1N1)pdm09 influenza vaccine has been effective in preventing laboratory-confirmed A(H1N1)pdm09 influenza and influenza and/or pneumonia, the latter notably in 60 years and older subjects.

Objective: The main objectives of our study were to explore reasons for seasonal influenza vaccine acceptance and declination in employees of a large integrated healthcare system and to identify underlying constructs that influence acceptance versus declination. Secondary objectives were to determine whether vaccine acceptance varied by hospital location and to identify facility-level measures that explained variability., Design: A national health promotion survey of employees was conducted that included items on vaccination in the 2009-2010 influenza season. The survey was administered with two other institutional surveys in a stratified fashion: approximately 40% of participating employees were randomly assigned to complete the health promotion survey., Setting: National single-payer healthcare system with 152 hospitals., Participants: Employees of the healthcare system in 2010 who responded to the survey., Methods: Factor analysis was used to identify underlying constructs that influenced vaccine acceptance versus declination. Mean factor scores were examined in relation to demographic characteristics and occupation. Multilevel logistic regression models were used to determine whether vaccine acceptance varied by location and to identify facility-level measures that explained variability., Results: Four factors were identified related to vaccine declination and were labeled as (1) "don't care," (2) "don't want," (3) "don't believe," and (4) "don't know." Significant differences in mean factor scores existed by demographic characteristics and occupation. Vaccine acceptance varied by location, and vaccination rates in the previous year were an important facility-level predictor., Conclusions: Results should guide interventions that tailor messages on the basis of particular reasons for declination. Occupation-specific and culturally appropriate messaging should be considered. Continued efforts will be taken to better understand how workplace context influences vaccine acceptance.

Children have high rates of healthcare utilization due to influenza. In addition, children also transmit influenza to others in their households and the community. The costs of influenza in children include the direct medical care costs from increased outpatient visits and hospitalizations, and also indirect costs due to productivity losses especially for their parents and due to transmission of the virus to others. A variety of studies using different methods and assumptions have assessed the cost-effectiveness of influenza vaccination of children, and many find that vaccination is either cost saving or cost effective., (Published by Elsevier Ltd.)

Major national surveys do not collect the influenza vaccination status of all household members, thus limiting current understanding of household influenza vaccination patterns. In an early 2009 telephone survey of 800 households in the metropolitan Minneapolis-St Paul area, household respondents reported the age, gender, and 2008-2009 seasonal influenza vaccination status of all household members. After poststratification to adjust for nonresponse, the full household influenza vaccination rate for multiperson households is 35.2%, partial household influenza vaccination rate is 39.9% and the rate of complete household nonvaccination is 24.9%. Full household influenza vaccination is more common in households with an elderly resident, intermediate in households with a child under 5 years of age, and less common in the remaining households. No household members are vaccinated in approximately 10% of multiperson households with either an elderly adult or young child; the corresponding rate in other households is 32.8%. An estimated 51.4% of households with children over 1 year of age have all children vaccinated against influenza; 43.5% of households with children had no children vaccinated against influenza. Households with younger children are more likely to have all children vaccinated and less likely to have no children vaccinated. We believe this is the first study to describe the prevalence of household influenza vaccination patterns. Continued efforts to monitor and increase household vaccination may be a valuable strategy to protect individuals and communities from influenza., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: To examine the benefit-risk profile of live attenuated influenza vaccine (LAIV) across a range of clinical scenarios in which we varied assumptions regarding both the percentage of children who would receive LAIV in lieu of trivalent inactivated influenza virus (TIV) and the extent of off-label use., Study Design: Model of expected benefits and risks of immunization of young children against influenza., Methods: We estimated expected numbers of cases of influenza illness (FLU), medically significant wheezing (MSW), and hospitalization in a single influenza season under alternative assumptions regarding use of LAIV in lieu of TIV, based on projections from a large phase III trial., Results: Assuming no use of LAIV in nonindicated children (aged <24 months and those with history of recurrent wheezing or asthma), and 50% use in lieu of TIV among children in the indicated population, there would be 2099 fewer FLU cases per 100,000 children aged 12 to 59 months, and no change in MSW or hospitalization. If LAIV also were used in lieu of TIV among 20% of children aged 12 to 23 months and 20% of children aged 24 to 59 months with a history of recurrent wheezing or asthma, there would be a further reduction of 397 FLU cases and 12 hospitalizations per 100,000 children aged 12 to 59 months, but 51 additional MSW cases., Conclusions: Our study suggests that even if LAIV were sometimes used inadvertently in clinical practice in young children for whom it is not indicated, the overall balance of expected benefits and risks would remain favorable.

Objectives: To quantify employees' preferences, as measured by willingness to pay, to prevent influenza in themselves and in their child and adult household members and to examine factors associated with willingness to pay., Study Design: Prospective observational cohort study of a convenience sample of employees from 3 large US employers. Participants had at least 1 child (< or = 17 years) living in their household for at least 4 days per week., Methods: Each month from November 2007 to April 2008, employees completed Web-based surveys regarding acute respiratory illness in their household. In the final survey, employees were presented with descriptions of influenza and questions regarding their willingness to pay to prevent influenza. Factors associated with willingness to pay were examined using multivariate ordinary least squares regression analysis of the log of willingness to pay., Results: Among 2006 employees, 31.3% were female, the mean age was 41.7 years, 85.3% were of white race/ethnicity, and the mean household size was 4.0. Employees' median (mean) willingness to pay to prevent influenza was $25 ($72) for themselves, $25 ($82) for their adult household members, and $50 ($142) (P <.01) for children. However, influenza vaccination rates were approximately equal for children (27.5%), employees (31.5%), and other adult household members (24.5%). This finding may be explained by barriers such as cost, dislike of vaccinations, and disagreement with national influenza vaccination recommendations, which were significantly associated with lower willingness to pay for prevention of influenza (P <.05)., Conclusion: Employees expressed a stronger preference to prevent influenza in their children than in themselves or other household members; however, modifiable barriers depress vaccination rates.

Acute respiratory illnesses (ARI), comprising influenza-like illness (ILI) and other wintertime respiratory illnesses (ORI), impose substantial health and economic burdens on the United States. Little is known about the impact of ILI among household members (HHM), particularly children, on employees' productivity. To quantify the impact of employee and HHM-ILI and ARI on employee productivity, a prospective, observational cohort study was conducted among employees from three large US companies. Employees who had at least one child living at home (N=2013) completed a monthly survey during the 2007-2008 influenza season, reporting the number of days missed from work and hours of presenteeism due to: (1) personal ILI, (2) HHM-ILI, and (3) personal and HHM-ARI. Employee ILI ranged from 4.8% (April) to 13.5% (February). Employees reporting ILI reported more absences than employees not reporting ILI (72% vs 30%, respectively; P<0.001). Overall, 61.2% of employees surveyed had at least one child with an ILI; these employees missed more days of work due to HHM illness than employees without an ARI-ill child (0.9 days vs 0.3 days, respectively; P<0.001). Employees with ILI were less productive, on average, for 4.8h each day that they worked while sick, 2.5h of which was attributable to ILI. HHM illnesses accounted for 17.7% (1389/7868 days) of employee absenteeism, over half of which was due to HHM-ARI. ILI causes a significant amount of employee absence. Household members, particularly children, comprise a sizable proportion of general illness and injury-related employee absences., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Background: College and university students experience substantial morbidity from influenza and influenza-like illness, and they can benefit substantially from vaccination. Public health authorities encourage vaccination not only before the influenza season but also into and even throughout the influenza season. We conducted the present study to assess the impact of various vaccination strategies including delayed (i.e., in-season) vaccination on influenza outbreaks on a college campus., Methods/findings: We used a Susceptible --> Infected --> Recovered (SIR) framework for our mathematical models to simulate influenza epidemics in a closed, college campus. We included both students and faculty/staff in the model and derived values for the model parameters from the published literature. The values for key model parameters were varied to assess the impact on the outbreak of various pre-season and delayed vaccination rates; one-way sensitivity analyses were conducted to test the sensitivity of the model outputs to changes in selected parameter values. In the base case, with a pre-season vaccination rate of 20%, no delayed vaccination, and 1 student index case, the total attack rate (total percent infected, TAR) was 45%. With higher pre-season vaccination rates TARs were lower. Even if vaccinations were given 30 days after outbreak onset, TARs were still lower than the TAR of 69% in the absence of vaccination. Varying the proportions of vaccinations given pre-season versus delayed until after the onset of the outbreak gave intermediate TAR values. Base case outputs were sensitive to changes in infectious contact rates and infectious periods and a holiday/break schedule., Conclusion: Delayed vaccination and holidays/breaks can be important adjunctive measures to complement traditional pre-season influenza vaccination for controlling and preventing influenza in a closed college campus.

Randomized, controlled trials are the gold standard study design. However, ethical constraints and practical considerations may necessitate other types of studies for evaluating influenza vaccine effectiveness in the elderly--a high priority group for annual vaccination in many countries. Observational studies therefore comprise the bulk of the vaccine effectiveness evidence in older persons, but these types of studies can be susceptible to selection bias and residual confounding. All observational studies should utilize strategies to minimize the impact of bias and confounding. Recent studies questioning the plausibility of reported mortality benefits among vaccinated elderly persons may themselves be based on assumptions that are susceptible to important limitations and multiple biases. Future studies that incorporate prospectively collected information on functional status, life expectancy, and other types of data may provide additional insights into these concerns. At present, even after taking into account the potential for residual bias and confounding, most studies confirm the benefits of vaccination among the elderly for reducing hospitalization and death.

Older adults (> or =65 years of age) are particularly vulnerable to influenza illness. This is due to a waning immune system that reduces their ability to respond to infection, which leads to more severe cases of disease. The majority ( approximately 90%) of influenza-related deaths occur in older adults and, in addition, catastrophic disability resulting from influenza-related hospitalization represents a significant burden in this vulnerable population. Current influenza vaccines provide benefits for older adults against influenza; however, vaccine effectiveness is lower than in younger adults. In addition, antigenic drift is also a concern, as it can impact on vaccine effectiveness due to a mismatch between the vaccine virus strain and the circulating virus strain. As such, vaccines that offer higher and broader protection against both homologous and heterologous virus strains are desirable. Approaches currently available in some countries to meet this medical need in older adults may include the use of adjuvanted vaccines. Future strategies under evaluation include the use of high-dose vaccines; novel or enhanced adjuvantation of current vaccines; use of live attenuated vaccines in combination with current vaccines; DNA vaccines; recombinant vaccines; as well as the use of different modes of delivery and alternative antigens. However, to truly evaluate the benefits that these solutions offer, further efficacy and effectiveness studies, and better correlates of protection, including a precise measurement of the T cell responses that are markers for protection, are needed. While it is clear that vaccines with greater immunogenicity are required for older adults, and that adjuvanted vaccines may offer a short-term solution, further research is required to exploit the many other new technologies.

Background: Uncertainties regarding influenza disease impact and benefits of vaccination may contribute to low vaccination rates among adults aged 50-64 years., Methods: This prospective cohort study assessed the burden of influenza-like illness (ILI) among working adults aged 50-64 years and the effectiveness of influenza vaccination in reducing the rate of ILI and productivity losses. Employees of the University of Minnesota (Minneapolis) were invited via e-mail to participate in the study during October 2006. The study data were collected using internet-based surveys at baseline (October 2006) and during the follow-up period (from November 2006 through April 2007). Months included in the 2006-2007 influenza season were identified retrospectively from Minnesota Department of Health surveillance data. Vaccine effectiveness for reducing the rate of ILI, ILI-associated health care use, the number of days of illness, work loss, and reduced on-the-job productivity during the influenza season were assessed using multivariable regression models after controlling for important confounders., Results: Four hundred ninety-seven persons were included in the study, 85 (17.1%) of whom experienced an ILI. Among unvaccinated participants, ILI was responsible for 45% of all days of illness during the influenza season, 39% of all illness-related work days lost, and 49% of all days with illness-related reduced on-the-job productivity. In the multivariable regression analyses, vaccination was associated with a significant reduction in the rate of ILI (adjusted odds ratio, 0.48; 95% confidence interval, 0.27-0.86) and fewer days of illness, absenteeism, and impaired on-the-job performance., Conclusion: ILIs were common among our study participants, accounting for a large portion of illness, work loss, and impaired work performance during the influenza season. Vaccination was associated with substantial health and productivity benefits. Vaccine delivery should be improved for this high-priority group.

Objective: To assess influenza vaccine effectiveness against influenzalike illness (ILI) and ILI impact on health care use and school performance among college and university students., Design: Pooled analysis of 4 consecutive cohorts for the 2002-2003 through 2005-2006 seasons., Setting: Twin Cities campus of the University of Minnesota (2002-2003 through 2005-2006 seasons) and St. Olaf College in Northfield, Minnesota (2005-2006 season)., Participants: Full-time students received e-mail invitations to participate in single-season cohorts. Internet-based surveys collected baseline (October) and follow-up (November-April) data., Main Exposure: Influenza vaccination., Main Outcome Measure: Proportion of students with ILI. Multivariable regression models assessed the effectiveness of vaccination for reducing ILI during months when influenza was circulating while controlling for confounders and after pooling data across the 4 cohorts., Results: There were 2804, 2783, 3534, and 3674 participants in the 2002-2003, 2003-2004, 2004-2005, and 2005-2006 cohorts respectively, and overall, 30.2% were vaccinated. In the pooled analysis, 24.1% of students experienced at least 1 ILI during influenza seasons. Vaccination was associated with a significant reduction in the likelihood of ILI during influenza seasons (adjusted odds ratio, 0.70; 95% confidence interval, 0.56-0.89) but not during noninfluenza periods (adjusted odds ratio, 0.98; 95% confidence interval, 0.73-1.30). Vaccination was also associated with significant reductions in ILI-associated provider visits, antibiotic use, impaired school performance, and numbers of days of missed class, missed work, and illness during the influenza seasons., Conclusions: Influenza vaccination was associated with substantial reductions in ILI and ILI-associated health care use and impairment of school performance. College and university students can experience substantial benefits from influenza vaccinations.

With a retrospective nationwide cohort study in the Netherlands over 1992-2003, using mortality and viral surveillance data, the aim was to assess by means of rate difference methods the influenza-associated mortality in the elderly before and after the introduction of a nationwide influenza vaccination program in 1996 (vaccination coverage raised from below 50 to 80%). The average annual influenza-associated mortality declined in the years before and after the introduction from 131 to 105 per 100,000 persons (relative risk 0.80). The decline was largest in the age group 65-69 years (relative risk 0.54) and less in those aged 75 years and older. Validation by Serfling-type regression analysis revealed similar results. In conclusion, routine influenza vaccination among Dutch elderly was associated with a significant decrease in influenza-associated mortality, notably in those aged 65-69 years.

Influenza is a major causeof morbidity and mortality. Vaccination remains the most important means of preventing and controlling influenza. A review of the published literature shows that vaccination of children, healthy younger adults, the elderly, and both children and adults with high-risk medical conditions provides substantial benefits, although the types of benefits vary by age. Vaccination also generally provides benefit even during poor match seasons. Strategies to reduce transmission within households and communities throughthe vaccination of school children and to reduce transmission within health care settings through the vaccination of healthcare workers are also promising. Published by Elsevier Ltd.

Background: The US Advisory Committee on Immunization Practices (ACIP) recently expanded the influenza vaccine recommendation to include children 24-59 months of age. In a large head-to-head randomized controlled trial, live attenuated influenza vaccine, trivalent (LAIV) demonstrated a 54% relative reduction in culture-confirmed influenza illness compared with trivalent inactivated influenza vaccine (TIV) among children aged 24-59 months., Objective: To evaluate the relative cost and benefit between two influenza vaccines (LAIV and TIV) for healthy children 24-59 months of age., Methods: Using patient-level data from the clinical trial supplemented with cost data from published literature, we modeled the cost-effectiveness of these two vaccines. Effectiveness was measured in quality-adjusted life years (QALY) and cases of influenza avoided. The analysis used the societal perspective., Results: Due to its higher acquisition cost, LAIV increased vaccination costs by USD7.72 per child compared with TIV. However, compared with TIV, LAIV reduced the number of influenza illness cases and lowered the subsequent healthcare use of children and productivity losses of parents. The estimated offsets in direct and indirect costs saved USD15.80 and USD37.72 per vaccinated child, respectively. LAIV had a net total cost savings of USD45.80 per child relative to TIV. One-way and probabilistic sensitivity analyses indicated that the model was robust across a wide range of relative vaccine efficacy and cost estimates., Conclusions: Due to its increased relative vaccine efficacy over TIV, LAIV reduced the burden of influenza and lowered both direct health care and societal costs among children 24-59 months of age.

Background: Laboratory diagnosis of influenza has previously relied on viral isolation in culture. Rapid antigen tests (RATs) are now available but few studies have examined their use in older adults under routine clinical conditions., Objectives: To determine the utility of the RAT in older adults presenting to a large medical center and how test results impacted clinical care., Study Design: Retrospective chart review of patients tested for influenza during the 2003--2004 and 2004--2005 influenza seasons. Clinical data were correlated with the results of laboratory testing., Results: Eighty-four adults tested positive for influenza. Adding the results of the RAT to symptom complexes predictive of influenza significantly enhanced the ability to diagnose influenza in the acute setting. The positive predictive value of fever plus cough increased from 32% to 92% with a positive RAT. The RAT also directed appropriate antiviral therapy. 20/22 (91%) patients with a positive RAT and symptoms < or =48 h received antiviral treatment compared to only 1/12 (8%) patients with a negative RAT and a positive culture., Conclusions: Under routine clinical conditions rapid influenza testing enhances the ability to quickly diagnose influenza and can be used to guide early treatment decisions in older adults.

Objective: Influenza vaccination rates remain far below national goals in the US. Expanding influenza vaccination in non-traditional settings such as worksites and pharmacies may be a way to enhance vaccination coverage for adults, but scant data exist on the cost effectiveness of this strategy. The aims of this study were to (i) describe the costs of vaccination in non-traditional settings such as pharmacies and mass vaccination clinics; and (ii) evaluate the projected health benefits, costs and cost effectiveness of delivering influenza vaccination to adults of varying ages and risk groups in non-traditional settings compared with scheduled doctor's office visits. All analyses are from the US societal perspective., Methods: We evaluated the costs of influenza vaccination in non-traditional settings via detailed telephone interviews with representatives of organizations that conduct mass vaccination clinics and pharmacies that use pharmacists to deliver vaccinations. Next, we constructed a decision tree to compare the projected health benefits and costs of influenza vaccination delivered via non-traditional settings or during scheduled doctor's office visits with no vaccination. The target population was stratified by age (18-49, 50-64 and >or=65 years) and risk status (high or low risk for influenza-related complications). Probabilities and costs (direct and opportunity) for uncomplicated influenza illness, outpatient visits, hospitalizations, deaths, vaccination and vaccine adverse events were derived from primary data and from published and unpublished sources., Results: The mean cost (year 2004 values) of vaccination was lower in mass vaccination (dollars US 17.04) and pharmacy (dollars US 11.57) settings than in scheduled doctor's office visits (dollars US 28.67). Vaccination in non-traditional settings was projected to be cost saving for healthy adults aged >or=50 years, and for high-risk adults of all ages. For healthy adults aged 18-49 years, preventing an episode of influenza would cost dollars US 90 if vaccination were delivered via the pharmacy setting, dollars US 210 via the mass vaccination setting and dollars US 870 via a scheduled doctor's office visit. Results were sensitive to assumptions on the incidence of influenza illness, the costs of vaccination (including recipient time costs) and vaccine effectiveness., Conclusion: Using non-traditional settings to deliver routine influenza vaccination to adults is likely to be cost saving for healthy adults aged 50-64 years and relatively cost effective for healthy adults aged 18-49 years when preferences for averted morbidity are included.

Background: Reliable estimates of the effectiveness of influenza vaccine among persons 65 years of age and older are important for informed vaccination policies and programs. Short-term studies may provide misleading pictures of long-term benefits, and residual confounding may have biased past results. This study examined the effectiveness of influenza vaccine in seniors over the long term while addressing potential bias and residual confounding in the results., Methods: Data were pooled from 18 cohorts of community-dwelling elderly members of one U.S. health maintenance organization (HMO) for 1990-1991 through 1999-2000 and of two other HMOs for 1996-1997 through 1999-2000. Logistic regression was used to estimate the effectiveness of the vaccine for the prevention of hospitalization for pneumonia or influenza and death after adjustment for important covariates. Additional analyses explored for evidence of bias and the potential effect of residual confounding., Results: There were 713,872 person-seasons of observation. Most high-risk medical conditions that were measured were more prevalent among vaccinated than among unvaccinated persons. Vaccination was associated with a 27% reduction in the risk of hospitalization for pneumonia or influenza (adjusted odds ratio, 0.73; 95% confidence interval [CI], 0.68 to 0.77) and a 48% reduction in the risk of death (adjusted odds ratio, 0.52; 95% CI, 0.50 to 0.55). Estimates were generally stable across age and risk subgroups. In the sensitivity analyses, we modeled the effect of a hypothetical unmeasured confounder that would have caused overestimation of vaccine effectiveness in the main analysis; vaccination was still associated with statistically significant--though lower--reductions in the risks of both hospitalization and death., Conclusions: During 10 seasons, influenza vaccination was associated with significant reductions in the risk of hospitalization for pneumonia or influenza and in the risk of death among community-dwelling elderly persons. Vaccine delivery to this high-priority group should be improved., (Copyright 2007 Massachusetts Medical Society.)

There is substantial heterogeneity with regard to influenza case definitions used in the medical literature. These different case definitions can vary substantially with regard to their sensitivity, specificity and positive and negative predictive values for confirmed influenza. Because of this heterogeneity, it is important that the appropriate case definitions be used to answer the specific questions of the study, with more specific definitions likely being used to answer questions of vaccine efficacy and more sensitive definitions being used to assess overall disease burden. When interpreting the results of studies and comparing results across studies it is essential that the issue of heterogeneity of case definitions be addressed, and that absolute risk reduction be used as the main outcome measure of interest rather than just the relative risk reduction.

Influenza remains an important cause of illness and death in this country. Even though we have safe and effective vaccines, vaccination rates among the elderly and other high-risk groups remain static and well below national goals. Health care providers can boost these vaccination rates by educating themselves, by recommending that their patients be vaccinated, and by implementing evidence-based strategies such as programs to remind themselves and patients to be vaccinated, to utilize standing orders for nurses or other qualified professionals to offer and administer vaccines, and to provide feedback on performance. We should also consider alternative paradigms for vaccine delivery, and be sure to be vaccinated ourselves.

Seasonal influenza continues to have a huge annual impact in the United States, accounting for tens of millions of illnesses, hundreds of thousands of excess hospitalizations, and tens of thousands of excess deaths. Vaccination remains the mainstay for the prevention of influenza. In the United States, 2 types of influenza vaccine are currently licensed: trivalent inactivated influenza vaccine and live attenuated influenza vaccine. Both are safe and effective in the populations for which they are approved for use. Children, adults <65 years of age, and the elderly all receive substantial health benefits from vaccination. In addition, vaccination appears to be cost-effective, if not cost saving, across the age spectrum. Despite long-standing recommendations for the routine vaccination of persons in high-priority groups, US vaccination rates remain too low across all age groups. Important issues to be addressed include improving vaccine delivery to current and expanded target groups, ensuring timely availability of adequate vaccine supply, and development of even more effective vaccines. Development of a vaccine against potentially pandemic strains is an essential part of the strategy to control and prevent a pandemic outbreak. The use of existing technologies for influenza vaccine production would be the most straightforward approach, because these technologies are commercially available and licensing would be relatively simple. Approaches currently being tested include subvirion inactivated vaccines and cold-adapted, live attenuated vaccines. Preliminary results have suggested that, for some pandemic antigens, particularly H5, subvirion inactivated vaccines are poorly immunogenic, for reasons that are not clear. Data from evaluation of live pandemic vaccines are pending. Second-generation approaches designed to provide improved immune responses at lower doses have focused on adjuvants such as alum and MF59, which are currently licensed for influenza or other vaccines. Additional experimental approaches are required to achieve the ultimate goal for seasonal and pandemic influenza prevention--namely, the ability to generate broadly cross-reactive and durable protection in humans.

Background: We assessed the effects of an influenza season on patients with COPD. Data from 2,215 veterans in a multicenter, randomized, double-blind influenza vaccine efficacy study were analyzed for changes in spirometric and functional status, comparing patients with laboratory-documented influenza (LDI)-caused illness, non-LDI-caused respiratory illness, or no illness, and for association with influenza vaccination., Methods: Patients received either IM trivalent inactivated influenza virus vaccine (TIV) plus intranasal trivalent, live attenuated, cold-adapted influenza virus vaccine (TC) or TIV plus intranasal placebo (TP). We performed spirometry, measured the chronic lung disease severity index (CLDSI) score to assess functional status and well-being, and tested for influenza virus infection., Results: Worsening in FEV(1), percentage of predicted FEV(1), and CLDSI score (p < 0.001) was associated with acute respiratory illness in 585 illnesses including 94 LDI-caused illnesses. LDI-caused illness was more likely to be associated with worsening in FEV(1) and CLDSI score acutely than non-LDI-caused illness (p < 0.01). Logistic regression showed acute respiratory illness (odds ratio [OR], 1.78; 95% confidence limit [CL], 1.40 to 2.26) to be associated with worsening in CLDSI score, and receipt of TC (OR, 1.39; 95% CL, 1.10 to 1.74) and no illness (OR, 0.70; 95% CL, 0.53 to 0.91 for acute respiratory illness) to be associated with better CLDSI score at the end of the study. Hospitalization was more frequent in patients with acute respiratory illness (p < 0.0001)., Conclusions: Acute respiratory illness was associated with increased health-care utilization and obstruction to airflow, and worse functional status and well-being. At the end of the study, receipt of TC was associated with improvement and acute respiratory illness was associated with worsening in functional status and well-being.

Objective: Influenza vaccine uptake remains low among the high-risk group of patients with diabetes, partly because of conflicting evidence regarding its potential benefits. We assessed the clinical effectiveness of influenza vaccination in adults with diabetes and specifically examined potential modification of effect by age and prior influenza vaccine uptake., Research Design and Methods: The study was part of the Prevention of Influenza, Surveillance and Management (PRISMA) study, a nested case-control study conducted during the 1999-2000 influenza A epidemic, among 75,235 patients from primary care of any age recommended for vaccination. Among 9,238 adult patients with diabetes, 131 cases arose who were either hospitalized for diabetes dysregulation, acute respiratory disease, or cardiovascular disease and 61 cases who died, and we compared them with 1,561 control subjects. We evaluated the effect of (prior) influenza vaccination by means of logistic regression analysis controlling for age, sex, health insurance coverage, prior health care use, medication use, and comorbid conditions., Results: Vaccination was associated with a 56% reduction in any complication (95% CI 36-70%), a 54% reduction in hospitalizations (26-71%), and 58% reduction in deaths (13-80%). Among study subjects aged 18-64 years, we observed somewhat higher reductions in the occurrence of any complication than among those aged >65 years (72 vs. 39%). In first-time vaccinated subjects, the primary end point was reduced by 47% (0.2-72%), and in those who received vaccination in the year before, the reduction was 58% (4-81%)., Conclusions: Adults with type 2 diabetes, like other individuals from recognized risk groups, benefit considerably from influenza vaccination, and no difference in vaccine effectiveness was observed between first-time and repeat vaccination.

Nontraditional settings (NTS) are increasingly utilized for adult vaccination but concerns exist about their safety. We conducted this analysis of 542,445 persons vaccinated at an NTS in Minnesota to assess the safety of influenza vaccination in NTS. A total of 112 adverse events (AEs) were reported, 95 immediate and 17 late. Most AEs were mild and resolved within several minutes. 63 persons (.01%) had a vasovagal reaction to vaccination and 22 (.004%) reported an injection site problem. Immediate hypersensitivity reactions were very rare with only 10 (.002%) vaccine recipients having an immediate reaction for which epinephrine was required. Fifteen (.003%) individuals required evaluation in an emergency room or physician's office because of an AE. No deaths were reported. We conclude that influenza vaccine administration in mass vaccination clinics is safe and adverse events after influenza vaccination in NTS are extremely low.

Background: Influenza vaccination coverage remains unacceptably low among persons aged > or =65 years and younger high-risk adults. This study assessed locations at which US adults receive influenza (flu) vaccinations and the relative roles that traditional and nontraditional vaccination settings play in influenza vaccine delivery., Methods: We analyzed data on types of settings at which last flu shot was received, reported by adult respondents to the 1999 Behavioral Risk Factor Surveillance System, stratified by age group and medical condition. We used multivariable logistic regression to identify factors associated with nontraditional vaccination settings., Results: In 1998-1999, reported influenza vaccination coverage was 19% for persons aged 18-49 years, 36% for persons aged 50-64 years, and 67% for persons aged > or =65 years. Seventy percent of flu shots received by persons aged > or =18 years were reportedly administered in doctors' offices and other traditional settings. Vaccination in nontraditional settings (eg, workplace, stores, community centers) was more likely for young, healthy, employed, white, college-educated adults who had not had a recent routine checkup., Conclusion: Physicians should offer vaccination services at every opportunity. Increasing access to vaccination services in nontraditional settings should be considered as another strategy in pursuit of national vaccination coverage objectives.

Background: Upper respiratory tract illnesses (URIs) are a major cause of morbidity among adults, with substantial direct and indirect costs to society, but their impact among university students has not been well described. We sought to assess the impact of URIs (colds and influenza-like illnesses [ILIs]) on the health, academic and work performance, and health care use of university students., Methods: This was a cohort study of college students at the University of Minnesota, Twin Cities campus (Minneapolis-St. Paul), who were recruited during October 2002 and followed up from November 2002 through April 2003. All 42,000 registered students were invited via e-mail to participate. Baseline information was obtained in October 2002. Monthly follow-up information about colds or ILIs was obtained for the period of November 2002 through April 2003. Data were collected by use of Internet-based questionnaires., Results: Of 4919 volunteers, 3249 completed all follow-up surveys. The mean age was 22.7 years; 68% of the volunteers were female. Ninety-one percent had > or = 1 URI (83% had > or = 1 cold, and 36.7% had > or = 1 ILI). These URIs caused 6023 bed-days, 4263 missed school days, 3175 missed work days, and 45,219 days of illness. Of the cohort, 22.2% had > or = 1 health care visit, and 15.8% used antibiotics to treat a URI; 27.8% did poorly on a test and 46.3% did poorly on a class assignment. ILIs versus colds had a much greater impact on all parameters (e.g., general health level was 55%-60% lower with ILI vs. no URI and 33%-39% lower for colds vs. no URI; P < .001 for each)., Conclusion: Colds and ILIs were common and associated with substantial morbidity in university students. Enhanced efforts to prevent and control URIs, especially influenza vaccination, could improve the health and well-being of the 17 million college and university students in this country.

Influenza causes substantial morbidity across the age spectrum. However, the elderly are especially vulnerable to the serious complications of influenza that might result in hospitalisation or death, and high rates of influenza-associated excess hospitalisation or death that exceed by several-fold the rates seen among most other age groups have consistently been observed in many countries and across many seasons. Thus, the elderly are included among the high priority groups for routine influenza vaccination by many national health authorities. Inactivated influenza virus vaccines are widely available across the globe and are safe and effective. Vaccination of elderly persons has been associated with significant reductions in hospitalisations for pneumonia and influenza as well as hospitalisations for other cardiopulmonary disorders and even cerebrovascular disease. Vaccination has also been associated with reductions in influenza-associated and all-cause mortality during influenza seasons. The benefits of vaccination extend not only to community-dwelling elderly but also to elderly who reside in nursing homes. Likewise, vaccination provides benefits to the very old and to elderly persons with underlying co-morbidities as well as to the healthy elderly. Despite the substantially increased risk for serious complications and impressive benefits from vaccination among the elderly, influenza vaccine utilisation remains below target rates for this group in nearly all countries. The need for improved prevention and control of influenza is recognised as a priority for the global community--both to reduce the morbidity and mortality associated with epidemic influenza and to prepare for the next pandemic. Enhancing vaccine delivery to elderly persons would represent important progress toward that goal.

Objective: To better understand work-site-based programs for influenza vaccination., Design: Self-administered, mailed questionnaire., Setting: Healthcare and non-healthcare companies., Participants: Random sample of 2000 members of the American Association of Occupational Health Nurses., Results: The response rate was 55%, and 88% of the respondents were employed by companies sponsoring work-site influenza vaccination. Thirty-two percent of respondents worked for healthcare and healthcare-related services companies. Healthcare companies were more likely to sponsor worksite-based vaccination (94% vs 85%; P < .0001) compared with non-healthcare companies. Healthcare companies were also more likely to encourage vaccination of high-risk employees (70% vs 55%; P < .0001) and cover its cost (86% vs 61%; P < .0001). Multivariate logistic regression was used to determine factors associated with highly successful vaccination. Being a healthcare-related company (OR, 2.1; CI95, 1.4-3.2; P < .0001), employers covering the vaccination cost (OR, 3.1; CI95, 1.4-6.6; P = .004), having more experience with work-site vaccination (OR, 1.6; CI95, 1.0-2.4; P = .036), and management encouraging vaccination (OR, 2.6; CI95, 1.4-4.9; P = .002) were associated with highly successful programs., Conclusions: Most of the occupational health nurses surveyed work for employers sponsoring work-site vaccination, and 32% were employed by healthcare and related services companies. Healthcare companies were more likely to sponsor worksite-based vaccination and to vaccinate most of their employees; however, only 18% had vaccination rates higher than 50%. Strategies need to be developed to increase vaccination rates so that benefits of vaccination can be realized by employers and employees.

Clinical illness case definitions for influenza and methods used to define influenza seasons can vary substantially from study to study. These differences often result in differing levels of sensitivity, specificity and positive predictive value for the case definitions used. We explored the implications of different case definitions and outcome periods on estimates of influenza vaccine effectiveness and cost benefit by conducting additional analyses of data collected from a randomized, double blind, placebo controlled trial of the trivalent, intranasal, live attenuated influenza virus vaccine in healthy working adults. Febrile upper respiratory tract illnesses occurring during the peak influenza period was identified as the most specific clinical case definition expected to have the highest positive predictive value for true influenza whereas events occurring on a day with any symptom occurring during the entire outcome period was identified as the most sensitive clinical case definition with the lowest positive predictive value for influenza. As expected, the former provided the highest estimates of vaccine effectiveness (28.4% reduction in work loss days, 24.6% reduction in days with impaired productivity and 40.9% reduction in days with health care provider visits) but the lowest estimates of absolute reductions in events (42.4 work loss days prevented per 1000, 79.0 impaired productivity days per 1000, and 16.5 days with health care provider visits per 1000). On the other hand, events on days with any symptom during the entire outcome period provided the lowest estimates of vaccine effectiveness (18% reduction in work loss days, 18% reduction in days with impaired productivity, and 13% reduction in days with health care provider visits) but the highest estimates of absolute reductions in events (186.4 work loss days per 1000, 271.5 impaired productivity days per 1000, and 44.8 days with health care provider visits per 1000). When applied to a cost benefit analysis, the more specific case definition provided a break even cost for vaccination of US$ 6.58 whereas the more sensitive case definition provided a break even cost for vaccination of US$ 43.07. Clearly the latter combination is most appropriate when trying to assess the total population level impact of a vaccine preventable disease and the potential cost effectiveness of vaccination whereas the former may be most appropriate for assessing whether the vaccine actually works. The definitions of clinical influenza illness and outcome periods should be selected to match the study question.

Background: Uncertainties among health care providers and patients about the risk of serious influenza-associated complications and the potential benefits of vaccination may contribute to unsatisfactorily low influenza vaccination rates. To quantify the risk of serious outcomes (hospitalization due to pneumonia or influenza or death due to any cause) during influenza seasons, we developed a clinical prediction rule for the probability of hospitalization due to pneumonia or influenza or death among elderly persons., Methods: We developed the clinical prediction rule using data from linked administrative databases in a cohort of 16,280 noninstitutionalized and unvaccinated elderly persons. Validation of the rule was conducted in 5 unvaccinated and 6 vaccinated cohorts, each consisting of >11,000 elderly members of 3 managed care organizations. Logistic regression was used to produce a prognostic score on the basis of the following predictors: age; sex; presence of pulmonary, cardiac, and renal disease; dementia or stroke and cancer; number of outpatient visits; and hospitalization due to pneumonia or influenza during the previous year., Results: Reliability of the regression model was good (P=.65, by goodness-of-fit test), and it discriminated well between those who did and those who did not experience an outcome (area under the receiver-operating curve, 0.83; 95% confidence interval, 0.81-0.85). Validation revealed moderately lower but acceptable discriminating values (0.72-0.81). In the derivation cohort, the prognostic accuracy of the rule was high when a cutoff score for the upper 50th percentile was used: > or =10 of 1000 subjects with a score in the upper 50th percentile were predicted to have an outcome, and 89% of all outcomes were observed in this high-risk group, whereas <10 of 1000 subjects with a score in the lower 50th percentile were predicted to have an outcome, and only 11% of outcomes occurred in this group. Among unvaccinated subjects in the single-derivation cohort and the 11 validation cohorts combined, the outcome event rates were 35 events/1000 subjects in the higher-risk group and 6 events/1000 subjects in the lower-risk group. With vaccination, these event rates dropped by 15 events/1000 subjects and 2 events/1000 subjects, respectively., Conclusions: This prediction rule may be a useful tool to complement other age-based strategies, to further encourage vaccination, especially among those at the highest risk of serious complications due to influenza.

Background: With recent delays in influenza vaccine availability, practitioners have been encouraged to time vaccination activities to promote vaccination of high-priority groups first. This cross-sectional survey of persons vaccinated in nontraditional settings (NTS) by mass vaccinators was conducted to assess how effectively the mass vaccinators were able to implement these vaccination-timing guidelines., Methods: In Minnesota, the Minnesota Visiting Nurse Agency (MVNA) is a major mass vaccinator in NTS. For the 2001-2002 vaccination season, MVNA developed several strategies designed to facilitate adherence to vaccination timing guidelines adopted by the Minnesota Department of Health. All persons vaccinated in the MVNA NTS clinics from October 2001 through December 2001 were surveyed in order to evaluate whether they were in a high-priority group and whether the timing of their vaccinations coincided with the timing promoted in the guidelines., Results: A total of 46,174 of the 145,947 people vaccinated by the MVNA were vaccinated between October 14 and October 28, 2001, the time period designated for vaccination of high-priority groups. Of these, 41,143 (89%) responded to the priority group question and 27,211 (66%) indicated that they were in one of the targeted groups, including more than 19,000 Medicare recipients. At sites targeting senior citizens, more than 92% of initial vaccine recipients were in a targeted group. Overall, 48.4% of persons vaccinated at any time during the vaccination season were in a high-priority group., Conclusions: Mass vaccinators can successfully implement influenza vaccination timing guidelines in NTS.

We assessed whether trivalent live, cold-adapted influenza virus (CAIV-T) vaccine provides added protection when co-administered with trivalent inactivated influenza virus vaccine (TVV) in patients with chronic obstructive pulmonary disease (COPD). Subjects (N=2215) were randomly assigned to receive either TVV intramuscularly (IM) and CAIV-T intranasally (TC), or TVV and placebo (TP). The vaccines were well-tolerated. Efficacy of TC compared to TP was not statistically significant and was 0.16 for any influenza virus strain (95% confidence limit (CL): -0.22, 0.43), 0.26 for A (H3N2) virus (95% CL: -0.17, 0.53), and -0.05 for type B virus (95% CL: -1.13, 0.48). However, there was a possible advantage for TC over TP in reducing respiratory consequences of an influenza season measured by pulmonary function and symptoms at end of study.

Influenza is a major cause of morbidity and mortality worldwide. Currently available inactivated influenza virus vaccines are safe and effective in preventing influenza. Substantial health benefits are seen across all age and risk groups. Studies assessing the economic benefits of vaccination suggest that vaccination is highly cost effective and in many cases cost saving among the elderly. Influenza vaccination has also been associated with significant economic benefits in younger adults and children. Additional health economic studies from developing countries and from tropical/subtropical regions will be vitally important for better understanding of the global burden of influenza and potential benefits of vaccination.

A substudy analysis was conducted to determine the clinical characteristics associated with symptomatic, laboratory-documented influenza (LDI) among 2215 veterans with chronic obstructive pulmonary disease who participated in Department of Veterans Affairs Cooperative Study 448 and who received trivalent inactivated influenza virus vaccine with or without intranasal live-attenuated, cold-adapted influenza vaccine. Of 585 evaluable first occurrences of acute respiratory illnesses, 94 (16%) were LDI. Respiratory symptoms of cough, sputum production, and dyspnea occurred in >90% of patients with LDI; 68% had documented or subjective fever, and 81% had myalgias. Stepwise logistic regression identified only fever and myalgia as being statistically associated with LDI. During the influenza outbreak period, the positive predictive value of fever and myalgia was 41%. Clinical criteria were poor predictors of LDI in these older, vaccinated patients with chronic lung disease. Additional studies are warranted to define optimal methods for the diagnosis of influenza among older persons with chronic obstructive pulmonary disease.

Vaccine-preventable diseases remain a significant health problem for adults in the United States. Far more adults die from the complications of vaccine-preventable diseases than do children in this country. Available vaccines that are effective in preventing morbidity and mortality from these conditions are underutilized, and significant racial and ethnic disparities in rates of utilization of adult vaccines persist. A variety of important vaccine-preventable diseases affect seniors. However, influenza and pneumococcal infections stand out as being responsible for more cases and more deaths each year among seniors than all other vaccine-preventable diseases in the United States combined. Current vaccination rates for these two diseases are far short of the Healthy People 2010 target rates of 90% immunization of the population of adults aged 65 years or over. Despite state efforts to improve vaccination rates of seniors, efforts that have included regulatory and educational approaches, significant challenges remain in designing immunization programs for seniors that are universally effective.

This serial cohort study assessed the risk of hospitalization or death associated with influenza and the effectiveness of influenza vaccination among subgroups of elderly members of 3 managed-care organizations in the United States. Data on baseline characteristics and outcomes were obtained from computerized databases. A total of 122,974 (1996-1997 season) and 158,454 (1997-1998 season) persons were included in the cohorts. Among unvaccinated persons, hospitalizations for pneumonia/influenza or death occurred in 8.2 of 1000 healthy and 38.4 of 1000 high-risk persons in year 1, and in 8.2 of 1000 healthy and 29.3 of 1000 high-risk persons in year 2. After adjustments, vaccination was associated with a 48% reduction in the incidence of hospitalization or death (95% confidence interval [CI], 42-52) in year 1 and 31% (95% CI, 26-37) in year 2. Effectiveness estimates were statistically significant and generally consistent across the healthy and high-risk subgroups. The absolute risk reduction, however, was 2.4- to 4.7-fold higher among high-risk than among healthy elderly persons. All elderly individuals may substantially benefit from vaccination. However, the impact of influenza is greater in persons with high-risk medical conditions.