Influenza Illness and Hospitalizations Averted by Influenza Vaccination in the United States, 2005–2011

Context

The goal of influenza vaccination programs is to reduce influenza-associated disease outcomes. Therefore, estimating the reduced burden of influenza as a result of vaccination over time and by age group would allow for a clear understanding of the value of influenza vaccines in the US, and of areas where improvements could lead to greatest benefits.

Objective

To estimate the direct effect of influenza vaccination in the US in terms of averted number of cases, medically-attended cases, and hospitalizations over six recent influenza seasons.

Design

Using existing surveillance data, we present a method for assessing the impact of influenza vaccination where impact is defined as either the number of averted outcomes or as the prevented disease fraction (the number of cases estimated to have been averted relative to the number of cases that would have occurred in the absence of vaccination).

Results

We estimated that during our 6-year study period, the number of influenza illnesses averted by vaccination ranged from a low of approximately 1.1 million (95% confidence interval (CI) 0.6–1.7 million) during the 2006–2007 season to a high of 5 million (CI 2.9–8.6 million) during the 2010–2011 season while the number of averted hospitalizations ranged from a low of 7,700 (CI 3,700–14,100) in 2009–2010 to a high of 40,400 (CI 20,800–73,000) in 2010–2011. Prevented fractions varied across age groups and over time. The highest prevented fraction in the study period was observed in 2010–2011, reflecting the post-pandemic expansion of vaccination coverage.

Conclusions

Influenza vaccination programs in the US produce a substantial health benefit in terms of averted cases, clinic visits and hospitalizations. Our results underscore the potential for additional disease prevention through increased vaccination coverage, particularly among nonelderly adults, and increased vaccine effectiveness, particularly among the elderly.     

Relationship between Humidity and Influenza A Viability in Droplets and Implications for Influenza’s Seasonality

Humidity has been associated with influenza’s seasonality, but the mechanisms underlying the relationship remain unclear. There is no consistent explanation for influenza’s transmission patterns that applies to both temperate and tropical regions. This study aimed to determine the relationship between ambient humidity and viability of the influenza A virus (IAV) during transmission between hosts and to explain the mechanisms underlying it. We measured the viability of IAV in droplets consisting of various model media, chosen to isolate effects of salts and proteins found in respiratory fluid, and in human mucus, at relative humidities (RH) ranging from 17% to 100%. In all media and mucus, viability was highest when RH was either close to 100% or below ∼50%. When RH decreased from 84% to 50%, the relationship between viability and RH depended on droplet composition: viability decreased in saline solutions, did not change significantly in solutions supplemented with proteins, and increased dramatically in mucus. Additionally, viral decay increased linearly with salt concentration in saline solutions but not when they were supplemented with proteins. There appear to be three regimes of IAV viability in droplets, defined by humidity: physiological conditions (∼100% RH) with high viability, concentrated conditions (50% to near 100% RH) with lower viability depending on the composition of media, and dry conditions (<50% RH) with high viability. This paradigm could help resolve conflicting findings in the literature on the relationship between IAV viability in aerosols and humidity, and results in human mucus could help explain influenza’s seasonality in different regions.     

Influenza—an emerging and re-emerging disease

Influenza A viruses continue to emerge from the aquatic avian reservoir and cause pandemics. There are periodic exchanges of influenza virus genes or whole viruses between avians and other species giving rise to pandemics of diseases in humans, lower animals and birds. It is hypothesized that pigs are an intermediate host and that China is an epicenter for the evolution of human pandemic strains. However, the transmission of avian influenza viruses to pigs in Europe in 1979 and detection of reassortants with human influenza genes in pigs raises the question of whether the next pandemic of influenza will emerge in Europe!     

Efficacy of Influenza Vaccination and Tamiflu? Treatment – Comparative Studies with Eurasian Swine Influenza Viruses in Pigs

Recent epidemiological developments demonstrated that gene segments of swine influenza A viruses can account for antigenic changes as well as reduced drug susceptibility of pandemic influenza A viruses. This raises questions about the efficacy of preventive measures against swine influenza A viruses. Here, the protective effect of vaccination was compared with that of prophylactic Tamiflu® treatment against two Eurasian swine influenza A viruses. 11-week-old pigs were infected by aerosol nebulisation with high doses of influenza virus A/swine/Potsdam/15/1981 (H1N1/1981, heterologous challenge to H1N1 vaccine strain) and A/swine/Bakum/1832/2000 (H1N2/2000, homologous challenge to H1N2 vaccine strain) in two independent trials. In each trial (i) 10 pigs were vaccinated twice with a trivalent vaccine (RESPIPORC® FLU3; 28 and 7 days before infection), (ii) another 10 pigs received 150 mg/day of Tamiflu® for 5 days starting 12 h before infection, and (iii) 12 virus-infected pigs were left unvaccinated and untreated and served as controls. Both viruses replicated efficiently in porcine respiratory organs causing influenza with fever, dyspnoea, and pneumonia. Tamiflu® treatment as well as vaccination prevented clinical signs and significantly reduced virus shedding. Whereas after homologous challenge with H1N2/2000 no infectious virus in lung and hardly any lung inflammation were detected, the virus titre was not and the lung pathology was only partially reduced in H1N1/1981, heterologous challenged pigs. Tamiflu® application did not affect these study parameters.In conclusion, all tested preventive measures provided protection against disease. Vaccination additionally prevented virus replication and histopathological changes in the lung of homologous challenged pigs.     

Influenza Vaccine Effectiveness against Hospitalisation with Confirmed Influenza in the 2010–11 Seasons: A Test-negative Observational Study

Immunisation programs are designed to reduce serious morbidity and mortality from influenza, but most evidence supporting the effectiveness of this intervention has focused on disease in the community or in primary care settings. We aimed to examine the effectiveness of influenza vaccination against hospitalisation with confirmed influenza. We compared influenza vaccination status in patients hospitalised with PCR-confirmed influenza with patients hospitalised with influenza-negative respiratory infections in an Australian sentinel surveillance system. Vaccine effectiveness was estimated from the odds ratio of vaccination in cases and controls. We performed both simple multivariate regression and a stratified analysis based on propensity score of vaccination. Vaccination status was ascertained in 333 of 598 patients with confirmed influenza and 785 of 1384 test-negative patients. Overall estimated crude vaccine effectiveness was 57% (41%, 68%). After adjusting for age, chronic comorbidities and pregnancy status, the estimated vaccine effectiveness was 37% (95% CI: 12%, 55%). In an analysis accounting for a propensity score for vaccination, the estimated vaccine effectiveness was 48.3% (95% CI: 30.0, 61.8%). Influenza vaccination was moderately protective against hospitalisation with influenza in the 2010 and 2011 seasons.     

Can Interactions between Timing of Vaccine-Altered Influenza Pandemic Waves and Seasonality in Influenza Complications Lead to More Severe Outcomes?

Vaccination can delay the peak of a pandemic influenza wave by reducing the number of individuals initially susceptible to influenza infection. Emerging evidence indicates that susceptibility to severe secondary bacterial infections following a primary influenza infection may vary seasonally, with peak susceptibility occurring in winter. Taken together, these two observations suggest that vaccinating to prevent a fall pandemic wave might delay it long enough to inadvertently increase influenza infections in winter, when primary influenza infection is more likely to cause severe outcomes. This could potentially cause a net increase in severe outcomes. Most pandemic models implicitly assume that the probability of severe outcomes does not vary seasonally and hence cannot capture this effect. Here we show that the probability of intensive care unit (ICU) admission per influenza infection in the 2009 H1N1 pandemic followed a seasonal pattern. We combine this with an influenza transmission model to investigate conditions under which a vaccination program could inadvertently shift influenza susceptibility to months where the risk of ICU admission due to influenza is higher. We find that vaccination in advance of a fall pandemic wave can actually increase the number of ICU admissions in situations where antigenic drift is sufficiently rapid or where importation of a cross-reactive strain is possible. Moreover, this effect is stronger for vaccination programs that prevent more primary influenza infections. Sensitivity analysis indicates several mechanisms that may cause this effect. We also find that the predicted number of ICU admissions changes dramatically depending on whether the probability of ICU admission varies seasonally, or whether it is held constant. These results suggest that pandemic planning should explore the potential interactions between seasonally varying susceptibility to severe influenza outcomes and the timing of vaccine-altered pandemic influenza waves.     

Influenza Infectious Dose May Explain the High Mortality of the Second and Third Wave of 1918–1919 Influenza Pandemic

Background

It is widely accepted that the shift in case-fatality rate between waves during the 1918 influenza pandemic was due to a genetic change in the virus. In animal models, the infectious dose of influenza A virus was associated to the severity of disease which lead us to propose a new hypothesis. We propose that the increase in the case-fatality rate can be explained by the dynamics of disease and by a dose-dependent response mediated by the number of simultaneous contacts a susceptible person has with infectious ones.

Methods

We used a compartment model with seasonality, waning of immunity and a Holling type II function, to model simultaneous contacts between a susceptible person and infectious ones. In the model, infected persons having mild or severe illness depend both on the proportion of infectious persons in the population and on the level of simultaneous contacts between a susceptible and infectious persons. We further allowed for a high or low rate of waning immunity and volunteer isolation at different times of the epidemic.

Results

In all scenarios, case-fatality rate was low during the first wave (Spring) due to a decrease in the effective reproduction number. The case-fatality rate in the second wave (Autumn) depended on the ratio between the number of severe cases to the number of mild cases since, for each 1000 mild infections only 4 deaths occurred whereas for 1000 severe infections there were 20 deaths. A third wave (late Winter) was dependent on the rate for waning immunity or on the introduction of new susceptible persons in the community. If a group of persons became voluntarily isolated and returned to the community some days latter, new waves occurred. For a fixed number of infected persons the overall case-fatality rate decreased as the number of waves increased. This is explained by the lower proportion of infectious individuals in each wave that prevented an increase in the number of severe infections and thus of the case-fatality rate.

Conclusion

The increase on the proportion of infectious persons as a proxy for the increase of the infectious dose a susceptible person is exposed, as the epidemic develops, can explain the shift in case-fatality rate between waves during the 1918 influenza pandemic.     

Improving the Clinical Diagnosis of Influenza—a Comparative Analysis of New Influenza A (H1N1) Cases

Background

The presentation of new influenza A(H1N1) is broad and evolving as it continues to affect different geographic locations and populations. To improve the accuracy of predicting influenza infection in an outpatient setting, we undertook a comparative analysis of H1N1(2009), seasonal influenza, and persons with acute respiratory illness (ARI) in an outpatient setting.

Methodology/Principal Findings

Comparative analyses of one hundred non-matched cases each of PCR confirmed H1N1(2009), seasonal influenza, and ARI cases. Multivariate analysis was performed to look for predictors of influenza infection. Receiver operating characteristic curves were constructed for various combinations of clinical and laboratory case definitions. The initial clinical and laboratory features of H1N1(2009) and seasonal influenza were similar. Among ARI cases, fever, cough, headache, rhinorrhea, the absence of leukocytosis, and a normal chest radiograph positively predict for both PCR-confirmed H1N1-2009 and seasonal influenza infection. The sensitivity and specificity of current WHO and CDC influenza-like illness (ILI) criteria were modest in predicting influenza infection. However, the combination of WHO ILI criteria with the absence of leukocytosis greatly improved the accuracy of diagnosing H1N1(2009) and seasonal influenza (positive LR of 7.8 (95%CI 3.5–17.5) and 9.2 (95%CI 4.1–20.3) respectively).

Conclusions/Significance

The clinical presentation of H1N1(2009) infection is largely indistinguishable from that of seasonal influenza. Among patients with acute respiratory illness, features such as a temperature greater than 38°C, rhinorrhea, a normal chest radiograph, and the absence of leukocytosis or significant gastrointestinal symptoms were all positively associated with H1N1(2009) and seasonal influenza infection. An enhanced ILI criteria that combines both a symptom complex with the absence of leukocytosis on testing can improve the accuracy of predicting both seasonal and H1N1-2009 influenza infection.     

Estimating Influenza Deaths in Canada, 1992–2009

Background

Poisson regression modelling has been widely used to estimate the disease burden attributable to influenza, though not without concerns that some of the excess burden could be due to other causes. This study aims to provide annual estimates of the mortality and hospitalization burden attributable to both seasonal influenza and the 2009 A/H1N1 pandemic influenza for Canada, and to discuss issues related to the reliability of these estimates.

Methods

Weekly time-series for all-cause mortality and regression models were used to estimate the number of deaths in Canada attributable to influenza from September 1992 to December 2009. To assess their robustness, the annual estimates derived from different parameterizations of the regression model for all-cause mortality were compared. In addition, the association between the annual estimates for mortality and hospitalization by age group, underlying cause of death or primary reason for admission and discharge status is discussed.

Results

The crude influenza-attributed mortality rate based on all-cause mortality and averaged over 17 influenza seasons prior to the 2009 A/H1N1 pandemic was 11.3 (95%CI, 10.5 - 12.1) deaths per 100 000 population per year, or an average of 3,500 (95%CI, 3,200 - 3,700) deaths per year attributable to seasonal influenza. The estimated annual rates ranged from undetectable at the ecological level to more than 6000 deaths per year over the three A/Sydney seasons. In comparison, we attributed an estimated 740 deaths (95%CI, 350–1500) to A(H1N1)pdm09. Annual estimates from different model parameterizations were strongly correlated, as were estimates for mortality and morbidity; the higher A(H1N1)pdm09 burden in younger age groups was the most notable exception.

Interpretation

With the exception of some of the Serfling models, differences in the ecological estimates of the disease burden attributable to influenza were small in comparison to the variation in disease burden from one season to another.     

Influenza virosomes: a flu jab for malaria?

The major attractions of vaccines based on viral carriers (vectors) include their immunogenicity without adjuvant and the relative simplicity of their associated production processes in comparison with recombinant protein-based approaches. Two influenza virosomal vaccines - for influenza and hepatitis A - are registered for human use, and the virosome platform is being evaluated as the carrier for a Plasmodium falciparum vaccine that targets both the exo-erythrocytic and erythrocytic stages. Although safe and immunogenic, the first such virosome-based malaria vaccine showed no protection in a Phase IIa clinical trial. Nevertheless, the established safety profile of virosomes and their flexibility with regard to antigen delivery - allowing for antibody induction via the conjugation of peptides and T-cell induction via encapsulation - indicate that they warrant further exploration.     

Forecasting the 2013–2014 Influenza Season Using Wikipedia

Infectious diseases are one of the leading causes of morbidity and mortality around the world; thus, forecasting their impact is crucial for planning an effective response strategy. According to the Centers for Disease Control and Prevention (CDC), seasonal influenza affects 5% to 20% of the U.S. population and causes major economic impacts resulting from hospitalization and absenteeism. Understanding influenza dynamics and forecasting its impact is fundamental for developing prevention and mitigation strategies. We combine modern data assimilation methods with Wikipedia access logs and CDC influenza-like illness (ILI) reports to create a weekly forecast for seasonal influenza. The methods are applied to the 2013-2014 influenza season but are sufficiently general to forecast any disease outbreak, given incidence or case count data. We adjust the initialization and parametrization of a disease model and show that this allows us to determine systematic model bias. In addition, we provide a way to determine where the model diverges from observation and evaluate forecast accuracy. Wikipedia article access logs are shown to be highly correlated with historical ILI records and allow for accurate prediction of ILI data several weeks before it becomes available. The results show that prior to the peak of the flu season, our forecasting method produced 50% and 95% credible intervals for the 2013-2014 ILI observations that contained the actual observations for most weeks in the forecast. However, since our model does not account for re-infection or multiple strains of influenza, the tail of the epidemic is not predicted well after the peak of flu season has passed.     

Surveillance and Vaccine Effectiveness of an Influenza Epidemic Predominated by Vaccine-Mismatched Influenza B/Yamagata-Lineage Viruses in Taiwan, 2011?12 Season

Introduction

The 2011−12 trivalent influenza vaccine contains a strain of influenza B/Victoria-lineage viruses. Despite free provision of influenza vaccine among target populations, an epidemic predominated by influenza B/Yamagata-lineage viruses occurred during the 2011−12 season in Taiwan. We characterized this vaccine-mismatched epidemic and estimated influenza vaccine effectiveness (VE).

Methods

Influenza activity was monitored through sentinel viral surveillance, emergency department (ED) and outpatient influenza-like illness (ILI) syndromic surveillance, and case-based surveillance of influenza with complications and deaths. VE against laboratory-confirmed influenza was evaluated through a case-control study on ILI patients enrolled into sentinel viral surveillance. Logistic regression was used to estimate VE adjusted for confounding factors.

Results

During July 2011−June 2012, influenza B accounted for 2,382 (72.5%) of 3,285 influenza-positive respiratory specimens. Of 329 influenza B viral isolates with antigen characterization, 287 (87.2%) were B/Yamagata-lineage viruses. Proportions of ED and outpatient visits being ILI-related increased from November 2011 to January 2012. Of 1,704 confirmed cases of influenza with complications, including 154 (9.0%) deaths, influenza B accounted for 1,034 (60.7%) of the confirmed cases and 103 (66.9%) of the deaths. Reporting rates of confirmed influenza with complications and deaths were 73.5 and 6.6 per 1,000,000, respectively, highest among those aged ≥65 years, 50−64 years, 3−6 years, and 0−2 years. Adjusted VE was −31% (95% CI: −80, 4) against all influenza, 54% (95% CI: 3, 78) against influenza A, and −66% (95% CI: −132, −18) against influenza B.

Conclusions

This influenza epidemic in Taiwan was predominated by B/Yamagata-lineage viruses unprotected by the 2011−12 trivalent vaccine. The morbidity and mortality of this vaccine-mismatched epidemic warrants careful consideration of introducing a quadrivalent influenza vaccine that includes strains of both B lineages.     

Influenza Excess Mortality from 1950–2000 in Tropical Singapore

Introduction

Tropical regions have been shown to exhibit different influenza seasonal patterns compared to their temperate counterparts. However, there is little information about the burden of annual tropical influenza epidemics across time, and the relationship between tropical influenza epidemics compared with other regions.

Methods

Data on monthly national mortality and population was obtained from 1947 to 2003 in Singapore. To determine excess mortality for each month, we used a moving average analysis for each month from 1950 to 2000. From 1972, influenza viral surveillance data was available. Before 1972, information was obtained from serial annual government reports, peer-reviewed journal articles and press articles.

Results

The influenza pandemics of 1957 and 1968 resulted in substantial mortality. In addition, there were 20 other time points with significant excess mortality. Of the 12 periods with significant excess mortality post-1972, only one point (1988) did not correspond to a recorded influenza activity. For the 8 periods with significant excess mortality periods before 1972 excluding the pandemic years, 2 years (1951 and 1953) had newspaper reports of increased pneumonia deaths. Excess mortality could be observed in almost all periods with recorded influenza outbreaks but did not always exceed the 95% confidence limits of the baseline mortality rate.

Conclusion

Influenza epidemics were the likely cause of most excess mortality periods in post-war tropical Singapore, although not every epidemic resulted in high mortality. It is therefore important to have good influenza surveillance systems in place to detect influenza activity.