Vaccine effectiveness studies are subject to biases due to depletion-of-persons at risk of infection, or at especially high risk of infection, at different rates from different groups (depletion-of-susceptibles bias), a problem that can also lead to biased estimates of waning effectiveness, including spurious inference of waning when none exists. An alternative study design to identify waning is to study only vaccinated persons, and compare for each day the incidence in persons with earlier or later dates of vaccination to assess waning in vaccine protection as a function of vaccination time (namely whether earlier vaccination would result in lower subsequent protection compared to later vaccination). Prior studies suggested under what conditions this alternative would yield correct estimates of waning. Here we define the depletion-of-susceptibles process formally and show mathematically that for influenza vaccine waning studies, a randomised trial or corresponding observational study that compares incidence at a specific calendar time among individuals vaccinated at different times before the influenza season begins will not be vulnerable to depletion-of-susceptibles bias in its inference of waning as a function of vaccination time under the null hypothesis that none exists, and will – if waning does actually occur – underestimate the extent of waning. Such a design is thus robust in the sense that a finding of waning in that inference framework reflects actual waning of vaccine-induced immunity. We recommend such a design for future studies of waning, whether observational or randomised.

Influenza vaccination is the most practical means available for preventing influenza virus infection and is widely used in many countries. Because vaccine components and circulating strains frequently change, it is important to continually monitor vaccine effectiveness (VE). The test-negative design is frequently used to estimate VE. In this design, patients meeting the same clinical case definition are recruited and tested for influenza; those who test positive are the cases and those who test negative form the comparison group. When determining VE in these studies, the typical approach has been to use logistic regression, adjusting for potential confounders. Because vaccine coverage and influenza incidence change throughout the season, time is included among these confounders. While most studies use unconditional logistic regression, adjusting for time, an alternative approach is to use conditional logistic regression, matching on time. Here, we used simulation data to examine the potential for both regression approaches to permit accurate and robust estimates of VE. In situations where vaccine coverage changed during the influenza season, the conditional model and unconditional models adjusting for categorical week and using a spline function for week provided more accurate estimates. We illustrated the two approaches on data from a test-negative study of influenza VE against hospitalization in children in Hong Kong which resulted in the conditional logistic regression model providing the best fit to the data.

The activity and circulation of influenza viruses in Argentina was studied during 2012 as part of the Argentinean Surveillance for Influenza and other Respiratory Viruses, in the context of Global Influenza Surveillance. The antigenicity and molecular characteristics of haemagglutinins (HA) of circulating influenza A and B viruses were analysed to assess the emergence of virus variants. Susceptibility to oseltamivir and zanamivir was evaluated by enzymatic assay and results were backed-up by sequencing of the neuraminidase (NA) genes. During the 2012 season, influenza virus circulation in Argentina was detected from weeks 24 to 51. The HA sequences of the studied A(H1N1)pdm09 subtype viruses segregated in a different genetic group compared to those identified during the 2009 pandemic, although they were still closely related antigenically to the vaccine virus A/California/07/2009. The HA sequences of the A(H3N2) viruses analysed fell into the A/Victoria/208/2009 clade, genetic group 3C. A mixed circulation of virus variants belonging to B/Victoria and B/Yamagata lineages was detected, with B/Victoria being dominant. All viruses tested were sensitive to oseltamivir and zanamivir except one. This isolate, an A(H1N1)pdm09 virus possessing the substitution NA-N295S, showed highly reduced inhibition by oseltamivir and reduced inhibition by zanamivir. Virological and epidemiological surveillance remains critical for detection of evolving influenza viruses.

Influenza is rarely laboratory-confirmed and the outpatient influenza burden is rarely studied due to a lack of suitable data. We used the Clinical Practice Research Datalink (CPRD) and surveillance data from Public Health England in a linear regression model to assess the number of persons consulting UK general practitioners (GP episodes) for respiratory illness, otitis media and antibiotic prescriptions attributable to influenza during 14 seasons, 1995–2009. In CPRD we ascertained influenza vaccination status in each season and risk status (conditions associated with severe influenza outcomes). Seasonal mean estimates of influenza-attributable GP episodes in the UK were 857 996 for respiratory disease including 68 777 for otitis media, with wide inter-seasonal variability. In an average season, 2·4%/0·5% of children aged <5 years and 1·3%/0·1% of seniors aged ⩾75 years had a GP episode for respiratory illness attributed to influenza A/B. Two-thirds of influenza-attributable GP episodes were estimated to result in prescription of antibiotics. These estimates are substantially greater than those derived from clinically reported influenza-like illness in surveillance programmes. Because health service costs of influenza are largely borne in general practice, these are important findings for cost-benefit assessment of influenza vaccination programmes.

Several private boarding schools in England have established universal influenza vaccination programmes for their pupils. We evaluated the impact of these programmes on the burden of respiratory illnesses in boarders. Between November 2013 and May 2014, age-specific respiratory disease incidence rates in boarders were compared between schools offering and not offering influenza vaccine to healthy boarders. We adjusted for age, sex, school size and week using negative binomial regression. Forty-three schools comprising 14 776 boarders participated. Almost all boarders (99%) were aged 11–17 years. Nineteen (44%) schools vaccinated healthy boarders against influenza, with a mean uptake of 48·5% (range 14·2–88·5%). Over the study period, 1468 respiratory illnesses were reported in boarders (5·66/1000 boarder-weeks); of these, 33 were influenza-like illnesses (ILIs, 0·26/1000 boarder-weeks) in vaccinating schools and 95 were ILIs (0·74/1000 boarder-weeks) in non-vaccinating schools. The impact of vaccinating healthy boarders was a 54% reduction in ILI in all boarders [rate ratio (RR) 0·46, 95% confidence interval (CI) 0·28–0·76]. Disease rates were also reduced for upper respiratory tract infections (RR 0·72, 95% CI 0·61–0·85) and chest infections (RR 0·18, 95% CI 0·09–0·36). These findings demonstrate a significant impact of influenza vaccination on ILI and other clinical endpoints in secondary-school boarders. Additional research is needed to investigate the impact of influenza vaccination in non-boarding secondary-school settings.

This is a retrospective study using the test-negative case-control method to estimate seasonal 2010–2011 influenza vaccine effectiveness (VE) in Croatia. Of patients consulting a physician for influenza-like illness (ILI) and for whom a swab was taken, we compared RT–PCR influenza-positive and RT–PCR influenza-negative patients. We used a structured questionnaire and physicians' records to obtain information on vaccination status and potential confounders. We conducted a complete case analysis using logistic regression to measure adjusted VE overall, against A(H1N1)pdm09 and in age groups. Out of 785 interviewed patients, 495 eligible patients were included in the study, after applying exclusion criteria [217 cases, of which 92·6% were A(H1N1)pdm09 positive, 278 controls]. Crude VE was 31·9% [95% confidence interval (CI) −40·9 to 67·1] and adjusted VE was 20·7% (95% CI −71·4 to 63·3), with higher VE in youngest and oldest age groups. Results from this first VE study in Croatia suggest a low to moderate VE for the 2010–2011 season. Studies year on year are needed with a greater sample size to provide more precise estimates, and also by age group and risk groups for vaccination.

The US Center for Medicare and Medicaid Services (CMS) requires nursing homes and long-term-care facilities to document residents' vaccination status on the Resident Assessment Instrument (RAI). Vaccinating residents can prevent costly hospital admissions and deaths. CMS and public health officials use RAI data to measure vaccination rates in long-term-care residents and assess the quality of care in nursing homes. We assessed the accuracy of RAI data against medical records in 39 nursing homes in Florida, Georgia, and Wisconsin. We randomly sampled residents in each home during the 2010–2011 and 2011–2012 influenza seasons. We collected data on receipt of influenza vaccination from charts and RAI data. Our final sample included 840 medical charts with matched RAI records. The agreement rate was 0·86. Using the chart as a gold standard, the sensitivity of the RAI with respect to influenza vaccination was 85% and the specificity was 77%. Agreement rates varied within facilities from 55% to 100%. Monitoring vaccination rates in the population is important for gauging the impact of programmes and policies to promote adherence to vaccination recommendations. Use of data from RAIs is a reasonable approach for gauging influenza vaccination rates in nursing-home residents.

Objectives: Vaccinating healthy children is proposed as a strategy to produce a herd effect and protect vulnerable groups. The Hutterite Influenza Prevention Study investigated this strategy, comparing communities with or without childhood influenza immunization programs. There are costs associated with vaccination therefore there may be a trade-off between these costs and the benefits of avoiding influenza cases. This evaluation estimates the cost-effectiveness of immunizing only healthy children in preventing cases of influenza within entire communities.

Methods: Effect data and resource utilization were collected during the trial. Cost data were collected from payer, literature and Internet sources. A two-stage bootstrap (TSB) with shrinkage correction was used to estimate average costs and effects. The incremental cost effectiveness ratio (ICER) and sample uncertainty around this estimate were calculated from the TSB results.

Results: Mean costs per patient for the treatment and control arms were $69.07 and $32.66 (difference $36.41). Mean number of influenza cases for the treatment and control arms were 0.04 and 0.27 (difference 0.23). ICER was $164.12 ($28.38, $2767.75) per case of influenza averted.

Conclusions: Immunizing healthy children for influenza is more costly, yet more effective than no immunization in preventing cases in the sample. At a cost of $164.12 to prevent a case of influenza, immunizing healthy children to protect all community members may be considered costeffective. Estimated results are conservative as the influenza season was mild and the sample population was healthy. In a more severe season with a less healthy population the ICER is expected to decrease.

Vaccines are the cornerstone of influenza control policy, but can suffer from several drawbacks. Seasonal influenza vaccines are prone to production problems and low efficacies, while pandemic vaccines are unlikely to be available in time to slow a rapidly spreading global outbreak. Antiviral therapy was found to be beneficial during the influenza A(H1N1)pdm09 pandemic even with limited use; however, antiviral use has decreased further since then. We sought to determine the role antiviral therapy can play in pandemic and seasonal influenza control using conservative estimates of antiviral efficacy, and to assess if conservative but targeted strategies could be employed to optimize the use of antivirals. Using an age-structured contact network model for an urban population, we compared the transmission-blocking ability of a conservative antiviral therapy strategy to the susceptibility-reducing effects of a robust influenza vaccine. Our results show that while antiviral therapy cannot replace a robust influenza vaccine, it can play a role in reducing attack rates and eliminating outbreaks, and could significantly reduce public health burden when vaccine is either unavailable or ineffective. We also found that antiviral therapy, by treating those who are infected, is naturally a highly optimized strategy, and need not be improved upon with expensive targeted campaigns.

As influenza vaccination is now widely recommended, randomized clinical trials are no longer ethical in many populations. Therefore, observational studies on patients seeking medical care for acute respiratory illnesses (ARIs) are a popular option for estimating influenza vaccine effectiveness (VE). We developed a probability model for evaluating and comparing bias and precision of estimates of VE against symptomatic influenza from two commonly used case-control study designs: the test-negative design and the traditional case-control design. We show that when vaccination does not affect the probability of developing non-influenza ARI then VE estimates from test-negative design studies are unbiased even if vaccinees and non-vaccinees have different probabilities of seeking medical care against ARI, as long as the ratio of these probabilities is the same for illnesses resulting from influenza and non-influenza infections. Our numerical results suggest that in general, estimates from the test-negative design have smaller bias compared to estimates from the traditional case-control design as long as the probability of non-influenza ARI is similar among vaccinated and unvaccinated individuals. We did not find consistent differences between the standard errors of the estimates from the two study designs.

Methods for estimating vaccine effectiveness (VE) against severe influenza are not well established. We used the screening method to estimate VE against influenza resulting in intensive care unit (ICU) admission in England and Scotland in 2011/2012. We extracted data on confirmed influenza ICU cases from severe influenza surveillance systems, and obtained their 2011/2012 trivalent influenza vaccine (TIV) status from primary care. We compared case vaccine uptake with population vaccine uptake obtained from routine monitoring systems, adjusting for age group, specific risk group, region and week. Of 60 influenza ICU cases reported, vaccination status was available for 56 (93%). Adjusted VE against ICU admission for those aged ⩾65 years was −10% [95% confidence interval (CI) −207 to 60], consistent with evidence of poor protection from the 2011/2012 TIV in 2011/2012. Adjusted VE for those aged <65 years in risk groups was −296% (95% CI −930 to −52), suggesting significant residual confounding using the screening method in those subject to selective vaccination.

In response to the 2009 H1N1 influenza pandemic, public health authorities launched an ambitious vaccination program to protect tens of millions of Americans from the virus. In April and May 2010, the Institute of Medicine Forum on Medical and Public Health Preparedness for Catastrophic Events hosted a series of 3 regional workshops to examine the 2009 H1N1 vaccination campaign. The workshops brought together stakeholders involved in distributing and dispensing H1N1 vaccine to discuss successes and challenges and to identify strategies to improve future vaccination programs and other medical countermeasure dispensing campaigns. On the basis of the presentations and the discussions that followed, several themes and opportunities for future efforts were identified in the following areas: vaccine supply and demand; state and local implementation of Centers for Disease Control and Prevention/Advisory Committee on Immunization Practices recommendations, including prioritization for vaccination; vaccine formulations and priority groups; opportunities for developing partnerships; opportunities to increase seasonal vaccination rates among pregnant women and health care workers and to increase acceptance of live attenuated nasal spray vaccine; standardization and improvement of immunization information management systems; opportunities to simplify, systematize, and automate processes and practices; and research needs and opportunities.

(Disaster Med Public Health Preparedness. 2011;5:81-86)

We estimated the vaccine effectiveness (VE) of trivalent and monovalent influenza vaccines, respectively, against laboratory-confirmed influenza infections in patients with influenza-like illness who visited physicians participating in the Bayern Influenza Sentinel in Bavaria, Germany during 2010/2011. Swab specimens were analysed for influenza A(H1N1)pdm09, A(H3) and B by PCR. VE was estimated using the test-negative case-control study design and logistic regression. In total, 1866 patients (790 cases, 1076 controls) were included. The VE of trivalent vaccines administered in season 2010/2011 against laboratory-confirmed infection with any influenza virus, adjusted for age group, sex, chronic illness and week of arrival of the specimen, was 67·8% [95% confidence interval (CI) 39·2–82·9)]. The adjusted VE of monovalent influenza vaccines administered in season 2009/2010 against laboratory-confirmed influenza A(H1N1)pdm09 infection in 2010/2011 was 38·6% (95% CI −70·0 to 77·8). This is the first VE study conducted in Bavaria. We concluded that the trivalent influenza vaccines were effective in our study population.

An analysis was undertaken to measure age-specific vaccine effectiveness (VE) of 2010/11 trivalent seasonal influenza vaccine (TIV) and monovalent 2009 pandemic influenza vaccine (PIV) administered in 2009/2010. The test-negative case-control study design was employed based on patients consulting primary care. Overall TIV effectiveness, adjusted for age and month, against confirmed influenza A(H1N1)pdm 2009 infection was 56% (95% CI 42–66); age-specific adjusted VE was 87% (95% CI 45–97) in <5-year-olds and 84% (95% CI 27–97) in 5- to 14-year-olds. Adjusted VE for PIV was only 28% (95% CI −6 to 51) overall and 72% (95% CI 15–91) in <5-year-olds. For confirmed influenza B infection, TIV effectiveness was 57% (95% CI 42–68) and in 5- to 14-year-olds 75% (95% CI 32–91). TIV provided moderate protection against the main circulating strains in 2010/2011, with higher protection in children. PIV administered during the previous season provided residual protection after 1 year, particularly in the <5 years age group.

The effectiveness of influenza vaccination programmes is seldom known during an epidemic. We developed an internet-based system to record influenza-like symptoms and response to infection in a participating cohort. Using self-reports of influenza-like symptoms and of influenza vaccine history and uptake, we estimated vaccine effectiveness (VE) without the need for individuals to seek healthcare. We found that vaccination with the 2010 seasonal influenza vaccine was significantly protective against influenza-like illness (ILI) during the 2010–2011 influenza season (VE 52%, 95% CI 27–68). VE for individuals who received both the 2010 seasonal and 2009 pandemic influenza vaccines was 59% (95% CI 27–77), slightly higher than VE for those vaccinated in 2010 alone (VE 46%, 95% CI 9–68). Vaccinated individuals with ILI reported taking less time off work than unvaccinated individuals with ILI (3·4 days vs. 5·3 days, P<0·001).