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There is an association between excess winter mortality and epidemics of influenza and it has been suggested that annual influenza vaccination should be offered to all over 65 years old as in the United States. This paper identifies the number of people dying from influenza in Leicestershire UK during the 1989-90 epidemic and the factors associated with a fatal outcome. The findings show that deaths attributed to influenza occur predominantly in very elderly people with underlying ill-health. The risk of influenzal death is greater in residential patients and increases substantially with the number of underlying medical conditions. The estimated death rates in vaccinated and non-vaccinated groups were not significantly different, but there were trends towards protection in both residential and non-residential groups. Influenza vaccine is not reaching the principal target groups and improved methods of influenza control are required.

Public health administrators do not have effective models to predict excess influenza-associated mortality and monitor viral changes associated with it. This study evaluated the effect of matching/mismatching vaccine strains, type/subtype pattern changes in Taiwan's influenza viruses, and the impact of post-SARS (severe acute respiratory syndrome) public health efforts on excess influenza-associated mortalities among the elderly. A negative binomial model was developed to estimate Taiwan's monthly influenza-associated mortality among the elderly. We calculated three winter and annual excess influenza-associated mortalities [pneumonia and influenza (P&I), respiratory and circulatory, and all-cause] from the 1999–2000 through the 2006–2007 influenza seasons. Obtaining influenza virus sequences from the months/years in which death from P&I was excessive, we investigated molecular variation in vaccine-mismatched influenza viruses by comparing hemagglutinin 1 (HA1) of the circulating and vaccine strains. We found that the higher the isolation rate of A (H3N2) and vaccine-mismatched influenza viruses, the greater the monthly P&I mortality. However, this significant positive association became negative for higher matching of A (H3N2) and public health efforts with post-SARS effect. Mean excess P&I mortality for winters was significantly higher before 2003 than after that year [mean ± S.D.: 1.44±1.35 vs. 0.35±1.13, p = 0.04]. Further analysis revealed that vaccine-matched circulating influenza A viruses were significantly associated with lower excess P&I mortality during post-SARS winters (i.e., 2005–2007) than during pre-SARS winters [0.03±0.06 vs. 1.57±1.27, p = 0.01]. Stratification of these vaccine-matching and post-SARS effect showed substantial trends toward lower elderly excess P&I mortalities in winters with either mismatching vaccines during the post-SARS period or matching vaccines during the pre-SARS period. Importantly, all three excess mortalities were at their highest in May, 2003, when inter-hospital nosocomial infections were peaking. Furthermore, vaccine-mismatched H3N2 viruses circulating in the years with high excess P&I mortality exhibited both a lower amino acid identity percentage of HA1 between vaccine and circulating strains and a higher numbers of variations at epitope B. Our model can help future decision makers to estimate excess P&I mortality effectively, select and test virus strains for antigenic variation, and evaluate public health strategy effectiveness.

It is widely believed that influenza (flu) vaccination of the elderly reduces all-cause mortality, yet randomized trials for assessing vaccine effectiveness are not feasible and the observational research has been controversial. Efforts to differentiate vaccine effectiveness from selection bias have been problematic. The authors examined mortality before, during, and after 9 flu seasons in relation to time-varying vaccination status in an elderly California population in which 115,823 deaths occurred from 1996 to 2005, including 20,484 deaths during laboratory-defined flu seasons. Vaccine coverage averaged 63%; excess mortality when the flu virus was circulating averaged 7.8%. In analyses that omitted weeks when flu circulated, the odds ratio measuring the vaccination-mortality association increased monotonically from 0.34 early in November to 0.56 in January, 0.67 in April, and 0.76 in August. This reflects the trajectory of selection effects in the absence of flu. In analyses that included weeks with flu and adjustment for selection effects, flu season multiplied the odds ratio by 0.954. The corresponding vaccine effectiveness estimate was 4.6% (95% confidence interval: 0.7, 8.3). To differentiate vaccine effects from selection bias, the authors used logistic regression with a novel case-centered specification that may be useful in other population-based studies when the exposure-outcome association varies markedly over time.

Despite recommendations for annual vaccination against influenza, more than half of patients with chronic obstructive pulmonary disease (COPD) in developed countries do not receive this vaccine. Influenza is characterized by its potentially of causing epidemics and by excess morbidity and mortality in patients with COPD and other chronic medical conditions. Good evidence of the efficacy, effectiveness, and cost-effectiveness of influenza vaccination underlines the recommendation of use in patients with COPD. Influenza vaccination could reduce influenza-related complications and exacerbations in patients with COPD, therefore reducing hospitalizations and deaths. Each year, all persons with COPD should be vaccinated with the inactivated trivalent influenza vaccine containing the most frequent two influenza A viral strains and one influenza B viral strain detected in the influenza season of the previous year. To achieve a 100% vaccination rate in patients with COPD, all patients with COPD registered in health insurance companies and attended in health centers and specialized clinics should be vaccinated during the immunization period (October–December). Antiviral therapies could be used as an adjunct to vaccination and to reduce influenza transmission in outbreaks. Antiviral therapies could reduce the duration and complications of influenza when administered within two days of the onset of illness. Research is necessary for new antiviral therapies that could prevent influenza with cost-effectiveness similar to the influenza vaccine.

Background

Influenza epidemics have a substantial impact on human health, by increasing the mortality from pneumonia and influenza, respiratory and circulatory diseases, and all causes. This paper provides estimates of excess mortality rates associated with influenza virus circulation for 7 causes of death and 8 age groups in Portugal during the period of 1980–2004.

Methodology/Principal Findings

We compiled monthly mortality time series data by age for all-cause mortality, cerebrovascular diseases, ischemic heart diseases, diseases of the respiratory system, chronic respiratory diseases, pneumonia and influenza. We also used a control outcome, deaths from injuries. Age- and cause-specific baseline mortality was modelled by the ARIMA approach; excess deaths attributable to influenza were calculated by subtracting expected deaths from observed deaths during influenza epidemic periods. Influenza was associated with a seasonal average of 24.7 all-cause excess deaths per 100,000 inhabitants, approximately 90% of which were among seniors over 65 yrs. Excess mortality was 3–6 fold higher during seasons dominated by the A(H3N2) subtype than seasons dominated by A(H1N1)/B. High excess mortality impact was also seen in children under the age of four years. Seasonal excess mortality rates from all the studied causes of death were highly correlated with each other (Pearson correlation range, 0.65 to 0.95, P<0.001) and with seasonal rates of influenza-like-illness (ILI) among seniors over 65 years (Pearson correlation rho>0.64, P<0.05). By contrast, there was no correlation with excess mortality from injuries.

Conclusions/Significance

Our excess mortality approach is specific to influenza virus activity and produces influenza-related mortality rates for Portugal that are similar to those published for other countries. Our results indicate that all-cause excess mortality is a robust indicator of influenza burden in Portugal, and could be used to monitor the impact of influenza epidemics in this country. Additional studies are warranted to confirm these findings in other settings.

Avian influenza is an infection caused by the H5N1 virus. The infection is highly contagious among birds, and only a few known cases of human avian influenza have been documented. However, healthcare experts around the world are concerned that mutation or genetic exchange with more commonly transmitted human influenza viruses could result in a pandemic of avian influenza. Their concern remains in spite of the fact that the first United States vaccine against the H5N1 virus was recently approved. Under these circumstances the fear is that a pandemic of avian influenza could result in the kind of mortality that was seen with the Spanish influenza pandemic of 1918–1919, where the number of deaths was estimated to be as high as 40 million people.

Retrospective data gathered by the American Osteopathic Association shortly after the 1918–1919 influenza pandemic have suggested that osteopathic physicians (DOs), using their distinctive osteopathic manipulative treatment (OMT) methods, observed significantly lower morbidity and mortality among their patients as compared to those treated by allopathic physicians (MDs) with standard medical care available at the time. In light of the limited prevention and treatment options available, it seems logical that a preparedness plan for the treatment of avian influenza should include these OMT procedures, provided by DOs and other healthcare workers capable of being trained to perform these therapeutic interventions. The purpose of this paper is to discuss the characteristics of avian influenza, describe the success of DOs during the 1918–1919 Spanish influenza pandemic, describe the evidence base for the inclusion of OMT as part of the preparedness plan for the treatment of avian influenza, and describe some of the specific OMT procedures that could be utilized as part of the treatment protocol for avian influenza patients.

Surveillance and annual vaccination are needed for at-risk populations in tropical countries.

We used a regression model to examine the impact of influenza on death rates in tropical Singapore for the period 1996–2003. Influenza A (H3N2) was the predominant circulating influenza virus subtype, with consistently significant and robust effect on mortality rates. Influenza was associated with an annual death rate from all causes, from underlying pneumonia and influenza, and from underlying circulatory and respiratory conditions of 14.8 (95% confidence interval 9.8–19.8), 2.9 (1.0–5.0), and 11.9 (8.3–15.7) per 100,000 person-years, respectively. These results are comparable with observations in the United States and subtropical Hong Kong. An estimated 6.5% of underlying pneumonia and influenza deaths were attributable to influenza. The proportion of influenza-associated deaths was 11.3 times higher in persons age >65 years than in the general population. Our findings support the need for influenza surveillance and annual influenza vaccination for at-risk populations in tropical countries.

OBJECTIVES:

To determine the similarity between influenza vaccine antigens and viruses associated with laboratory-confirmed infections by virus type/subtype, strain and influenza season; to correlate pneumonia and influenza hospitalization and mortality rates with the number of laboratory-confirmed influenza infections in an influenza season; and to develop predictive indicators of the likely incidence of current strains in the following season.

DESIGN:

Ecological study using national laboratory, pneumonia and influenza hospitalization and mortality data.

SETTING:

Canada, influenza seasons from 1980 to 1992.

POPULATION STUDIED:

Individuals with laboratory-confirmed influenza infections, pneumonia and influenza hospitalizations or deaths.

INTERVENTION:

Influenza immunization.

MAIN RESULTS:

Similarity of circulating strains and vaccine antigens was 99% for A(H1N1), 65% for A(H3N2) and 65% for B strains. During outbreaks, pneumonia and influenza hospitalization, and mortality rates increased 19% or less and 21% or less for A(H1N1), respectively; 28% or less and 51% or less for A(H3N2), and 19% or less and 16% or less for B strains. There were usually fewer than 25 laboratory-confirmed A(H1N1) infections with a particular strain in a season if there had been more than 25 infections with similar strains the previous season. For A(H3N2), the figure was 100, and for B it was 150.

CONCLUSIONS:

Matches were excellent for A(H1N1) and good for A(H3N2) plus B strains. Hospitalization and mortality rates increased substantially during outbreaks, eg, estimated 1609 excess deaths during a widespread A(H3N2) outbreak. This study identifies relationships that provide some ability to predict the incidence of a particular influenza strain in a coming season based on the incidence of strains similar to it in the previous season.

The effectiveness of influenza vaccination in preventing serious illness and death was determined in an elderly population during the influenza epidemic of was determined in an elderly population during the influenza epidemic of was determined in an elderly population during the influenza epidemic of 1989-90. A retrospective cohort study was carried out using computerized general practitioner records on nearly 10,000 patients aged 55 years and over. After adjustment for potential confounding factors, recent immunization was found to have a protective effect of 75% (95% confidence intervals: 21-92%) against death. Protection did not appear to vary with either age or the presence of underlying chronic disease. As the complications of influenza are most common in those with underlying chronic disease, the study findings are consistent with the recommended policy for the use of influenza vaccine in the UK. Further work is necessary to determine the cost-effectiveness of extending immunization to other groups.

Objectives

To examine the risk of adverse effects of special interest in persons vaccinated against seasonal influenza compared with unvaccinated persons aged 65 and above.

Methods

We retrospectively observed 41,986 vaccinated elderly persons and 50,973 unvaccinated elderly persons in Taiwan from October 1, 2008, through September 30, 2009, using the National Health Insurance database. Neurological and autoimmune disorders and one-year hospitalization rates and in-hospital mortality rates were analyzed according to the vaccination status. Propensity score analysis was used to assess the relationship between adverse outcomes, hospitalization rates, and vaccination status.

Results

45% of the elderly received influenza vaccination. Multiple logistic regression showed that the probability of being vaccinated was related to more patients visiting for URI symptoms (odds ratio (OR), 1.03; 95% CI, 1.02–1.03), men (OR, 1.15; 95% CI, 1.12–1.17), increased age (OR, 1.02; 95% CI, 1.02–1.03), and more comorbidities (OR, 1.2; 95% CI, 1.17–1.23). There were no statistical differences in neurological and autoimmune diseases between the vaccinated and unvaccinated individuals using propensity score analysis, but vaccinated persons had a reduced hospitalization rate of 19% (odds ratio [OR], 0.81; 95% CI, 0.77–0.84) for the first six-months and 13% for one-year of follow-up (OR, 0.87; 95% CI, 0.85–0.9).

Conclusions

Based on data from the one-year follow-ups among 93,049 elderly persons in Taiwan, reassuring results for selected neurological and autoimmune diseases were found among the vaccinated individuals after adjusting other factors. Influenza vaccination decreased the risk for hospitalization. Public health strategies must continue to improve the influenza vaccination rate among the elderly with information based upon tangible evidence.

BACKGROUND: Influenza is an important cause of death in the elderly. The uptake of influenza vaccination, despite its effectiveness, is low. AIM: To examine beliefs about influenza vaccination in elderly patients at risk from influenza. METHOD: A qualitative study using semi-structured interviews with 50 patients aged over 75 years at risk from influenza, equally divided between vaccinated and non-vaccinated groups. RESULTS: Although they acknowledged their medical diseases, the patients regarded themselves as healthy in the sense of being independent and active. Few in either the vaccinated or non-vaccinated groups believed themselves at risk of dying from influenza even though they recognized it could be fatal for particular groups of people. Decisions to have the vaccination were based on other considerations, including whether it was thought likely to reduce (or increase) the number and severity of colds and influenza-like illnesses. Although the group with negative views towards vaccination placed more emphasis on the 'side-effects' from the vaccination (including colds and influenza), this was also common in the group who were more positive towards vaccination; however, the side-effects were interpreted in different ways. CONCLUSION: Recommendations to vaccinate according to individual risk status are not in keeping with lay beliefs. The policy to include all people aged 75 years and older as a group requiring influenza vaccination is supported by this study. The evidence that vaccination reduces morbidity from influenza and does not cause colds and influenza needs stressing.

OBJECTIVES: To understand the role of trust of medical institutions in the decision by elderly black Americans to receive pneumococcal and influenza vaccinations. DESIGN: Cross-sectional, qualitative study, using semistructured in-depth interviews. PARTICIPANTS: Twenty black Americans age > or = 65 years from two different socioeconomic groups. RESULTS: Six main themes were identified: prevention, vaccine-caused illnesses, vaccines as irrelevant to health, experience with healthcare, self-advocacy and attitudes toward childhood vaccinations. The majority of vaccinated participants viewed vaccines as a preventive measure, while the unvaccinated group viewed vaccines as irrelevant to their health. In addition, the majority of the participants in the unvaccinated group believed vaccines caused illness. Mistrust of medical institutions or the knowledge of the historical medical injustices was not a significant influence in participant's willingness to be vaccinated against pneumococcal or influenza disease. CONCLUSION: Mistrust of medical institutions was not a key concern affecting willingness to be vaccinated in this black community of elderly adults. Participant's willingness to be vaccinated was largely influenced by prior positive or negative experiences with healthcare systems.

Objective

In prior influenza pandemics, pneumococcal complications of influenza have caused substantial morbidity and mortality. The usefulness and cost-effectiveness of pneumococcal vaccination for healthcare workers during an influenza pandemic is unknown.

Study Design

Markov modeling was used to estimate the cost-effectiveness of pneumococcal polysaccharide vaccination (PPV) in previously unvaccinated healthcare workers during an influenza pandemic.

Methods

Invasive pneumococcal disease (IPD) incidence rates were incorporated into the model, assuming that IPD events occurred at twice the usual rate during the year of pandemic influenza. Both societal and hospital perspectives were examined. Assumptions were that: pneumococcal disease transmission from healthcare worker to patient did not occur, heightened IPD risk occurred for only 1 year, and PPV did not prevent noninvasive pneumonia, all of which potentially bias against vaccination.

Results

From a societal standpoint, pneumococcal vaccination of healthcare workers during an influenza pandemic is economically reasonable, costing $2,935 per quality adjusted life year gained; results were robust to variation in multiple sensitivity analyses. However, from the hospital perspective vaccinating healthcare workers was expensive, costing $1,676 per employee absence day avoided, given an IPD risk that, though increased, would still remain <1%.

Conclusion

Vaccinating all healthcare workers to protect against pneumococcal disease during a pandemic influenza outbreak is likely to be economically reasonable from the societal standpoint. However, pneumococcal vaccination is expensive from the hospital perspective, which might prevent implementation of a PPV program unless it is externally subsidized.

This study assessed the influence of influenza on mortality from heart and lung diseases in people over 70 years of age. The data used were obtained from the Dutch Bureau of Statistics. With a regression model, the observed monthly mortality from heart and lung diseases (influenza not included) in people over 70 years is explained with a yearly variable, a monthly variable and the overall monthly number of influenza mortality cases, assuming that monthly mortality has a Poisson distribution. The monthly excess mortality from heart and lung diseases (influenza not included) due to influenza among elderly people (greater than 70 years) is estimated. This study suggests that 1400 deaths per million per year were due to influenza in people over 70 years of age in the study period of 16 years. It can be concluded that one influenza death in the population over 70 years 'generates' almost two deaths diagnosed as heart and lung diseases in the elderly.

STUDY OBJECTIVES--This study aimed to assess total influenza mortality among the elderly (> or = 75 years old) in France, and to evaluate how many deaths may have been avoided through vaccination during the past 10 years. DESIGN--The monthly mortality rates related to different causes among the elderly were obtained from the national mortality statistics for the period 1978-90. For each cause, the proportion of the registered death rate attributable to influenza was estimated using time series models. Each model analysed the registered death rate for the considered cause as a linear function of the registered influenza death rate for that month, the secular trend, and the seasonal variations. This yielded yearly regression coefficients for influenza. Formulas were subsequently developed to estimate the death rates avoided as a result of influenza vaccination according to the level of vaccine coverage and the hypothetical effectiveness of the vaccine. MAIN RESULTS--Between 1980 and 1990 registered influenza death rates ranged from 11-81 per 100,000. The number of deaths attributable to influenza but registered as resulting from another cause was up to eight times the number of deaths registered as influenza. Total influenza death rates were estimated as ranging from 28 per 100,000 (1988-89) to 482 per 100,000 (1985-86). At the same time it was estimated that the use of influenza vaccine avoided from 7 per 100,000 deaths in 1981-82 to 697 per 100,000 deaths in 1989-90, depending on the intensity of the epidemic, the vaccine coverage, and the vaccine effectiveness. CONCLUSIONS--These results support the policy of promoting influenza vaccination among the elderly.

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Study objective: To quantify mortality attributable to influenza and respiratory syncytial virus (RSV) infection in children.

Design and methods: Comparison of death rates (all cause and certified respiratory) in England over winters 1989/90 to 1999/00 during and outside influenza and RSV circulation periods. Virus active weeks were defined from clinical and virological surveillance data. Excess deaths associated with weeks of either influenza or RSV activity over virus non-active weeks were estimated in each winter for age groups 1–12 months, 1–4, 5–9, and 10–14 years. The estimate obtained was allotted to influenza and RSV in the proportion derived from independent separate calculations for each virus.

Main results: Average winter respiratory deaths attributed to influenza in children 1 month–14 years were 22 and to RSV 28; and all cause deaths to influenza 78 and to RSV 79. All cause RSV attributed deaths in infants 1–12 months exceeded those for influenza every year except 1989/90; the average RSV and influenza attributed death rates were 8.4 and 6.7 per 100 000 population respectively. Corresponding rates for children 1–4 years were 0.9 and 0.8 and for older children all rates were 0.2 or less, except for an influenza rate of 0.4 in children 10–14 years.

Conclusions: Influenza and RSV account for similar numbers of deaths in children. The impact varies by winter and between age groups and is considerably underestimated if analysis is restricted to respiratory certified deaths. Summing the impact over the 11 winters studied, compared with influenza RSV is associated with more deaths in infants less than 12 months, almost equal numbers in children 1–4 years, and fewer in older children. Improved information systems are needed to investigate paediatric deaths.

Objective To examine the risk of neurological and autoimmune disorders of special interest in people vaccinated against pandemic influenza A (H1N1) with Pandemrix (GlaxoSmithKline, Middlesex, UK) compared with unvaccinated people over 8-10 months.

Design Retrospective cohort study linking individualised data on pandemic vaccinations to an inpatient and specialist database on healthcare utilisation in Stockholm county for follow-up during and after the pandemic period.

Setting Stockholm county, Sweden.

Population All people registered in Stockholm county on 1 October 2009 and who had lived in this region since 1 January 1998; 1 024 019 were vaccinated against H1N1 and 921 005 remained unvaccinated.

Main outcome measures Neurological and autoimmune diagnoses according to the European Medicines Agency strategy for monitoring of adverse events of special interest defined using ICD-10 codes for Guillain-Barré syndrome, Bell’s palsy, multiple sclerosis, polyneuropathy, anaesthesia or hypoaesthesia, paraesthesia, narcolepsy (added), and autoimmune conditions such as rheumatoid arthritis, inflammatory bowel disease, and type 1 diabetes; and short term mortality according to vaccination status.

Results Excess risks among vaccinated compared with unvaccinated people were of low magnitude for Bell’s palsy (hazard ratio 1.25, 95% confidence interval 1.06 to 1.48) and paraesthesia (1.11, 1.00 to 1.23) after adjustment for age, sex, socioeconomic status, and healthcare utilisation. Risks for Guillain-Barré syndrome, multiple sclerosis, type 1 diabetes, and rheumatoid arthritis remained unchanged. The risks of paraesthesia and inflammatory bowel disease among those vaccinated in the early phase (within 45 days from 1 October 2009) of the vaccination campaign were significantly increased; the risk being increased within the first six weeks after vaccination. Those vaccinated in the early phase were at a slightly reduced risk of death than those who were unvaccinated (0.94, 0.91 to 0.98), whereas those vaccinated in the late phase had an overall reduced mortality (0.68, 0.64 to 0.71). These associations could be real or explained, partly or entirely, by residual confounding.

Conclusions Results for the safety of Pandemrix over 8-10 months of follow-up were reassuring —notably, no change in the risk for Guillain-Barré syndrome, multiple sclerosis, type 1 diabetes, or rheumatoid arthritis. Relative risks were significantly increased for Bell’s palsy, paraesthesia, and inflammatory bowel disease after vaccination, predominantly in the early phase of the vaccination campaign. Small numbers of children and adolescents with narcolepsy precluded any meaningful conclusions.

Background

Influenza has been associated with a heavy burden of mortality. In tropical or subtropical regions where influenza viruses circulate in the community most of the year, it is possible that there are seasonal variations in the effects of influenza on mortality, because of periodic changes in environment and host factors as well as the frequent emergence of new antigenically drifted virus strains. In this paper we explored this seasonal effect of influenza.

Methods

A time-varying coefficient Poisson regression model was fitted to the weekly numbers of mortality of Hong Kong from 1996 to 2002. Excess risks associated with influenza were calculated to assess the seasonal effects of influenza.

Results

We demonstrated that the effects of influenza were higher in winter and late spring/early summer than other seasons. The two-peak pattern of seasonal effects of influenza was found for cardio-respiratory disease and sub-categories pneumonia and influenza, chronic obstructive pulmonary disease, cerebrovascular diseases and ischemic heart disease as well as for all-cause deaths.

Conclusion

The results provide insight into the possibility that seasonal factors may have impact on virulence of influenza besides their effects on virus transmission. The results warrant further studies into the mechanisms behind the seasonal effect of influenza.

Although vaccination significantly reduces influenza severity, seasonal human influenza epidemics still cause more than 250,000 deaths annually. Vaccine efficacy is limited in high-risk populations such as infants, the elderly and immunosuppressed individuals. In the event of an influenza pandemic (such as the 2009 H1N1 pandemic), a significant delay in vaccine availability represents a significant public health concern, particularly in high-risk groups. The increasing emergence of strains resistant to the two major anti-influenza drugs, adamantanes and neuraminidase inhibitors, and the continuous circulation of avian influenza viruses with pandemic potential in poultry, strongly calls for alternative prophylactic and treatment options. In this review, we focus on passive virus neutralization strategies for the prevention and control of influenza type A viruses.

Vaccination remains the primary preventive strategy in the elderly against Streptococcus pneumoniae and influenza infections. The effectiveness of this strategy in preventing pneumonia has been in doubt despite the increase in vaccination coverage among older adults. Randomized controlled trials (RCTs) and observational studies aimed at determining clinical outcomes and immune response following pneumococcal vaccination have yielded conflicting results. The protective efficacy of pneumococcal vaccination against pneumonia in older adults has not been firmly established due to a lack of RCTs specifically examining patients ≥ 65 years of age. Similarly, the reported benefits of influenza vaccination have been derived from observational data. The assessment of clinical benefit from influenza vaccination in the elderly population is complicated by varying cohorts, virulence of the influenza strain, and matching of vaccine and circulating viral strains. The presence of selection bias and use of nonspecific end points in these studies make the current evidence inconclusive in terms of overall benefit. The development of more immunogenic vaccines through new formulations or addition of adjuvants holds the promise of revolutionizing delivery and improving efficacy. Dismantling existing barriers through education, providing technology assistance predominantly to developing countries, and establishing clear regulatory guidance on pathways for approval are necessary to ensure timely production and equitable distribution.

Background

To evaluate the risk of foetal loss associated with pandemic influenza vaccination in pregnancy. Retrospective cohort study. UK General Practice Research Database Pregnancies ending in delivery or spontaneous foetal death after 21 October 2009 and starting before 01 January 2010.

Methodology/Principal Findings

Hazard ratios of foetal death for vaccinated compared to unvaccinated pregnancies were estimated for gestational weeks 9 to 12, 13 to 24 and 25 to 43 using discrete-time survival analysis. Separate models were specified to evaluate whether the potential effect of vaccination on foetal loss might be transient (for ∼4 weeks post vaccination only) or more permanent (for the duration of the pregnancy). 39,863 pregnancies meeting our inclusion criteria contributed a total of 969,322 gestational weeks during the study period. 9,445 of the women were vaccinated before or during pregnancy. When the potential effect of vaccination was assumed to be transient, the hazard of foetal death during gestational weeks 9 through 12 (HRunadj 0.56; CI95 0.43 to 0.73) and 13 through 24 (HRunadj 0.45; CI95 0.28 to 0.73) was lower in the 4 weeks after vaccination than in other weeks. Where the more permanent exposure definition was specified, vaccinated pregnancies also had a lower hazard of foetal loss than unvaccinated pregnancies in gestational weeks 9 through 12 (HRunadj 0.74; CI95 0.62 to 0.88) and 13 through 24 (HRunadj 0.59; CI95 0.45 to 0.77). There was no difference in the hazard of foetal loss during weeks 25 to 43 in either model. Sensitivity analyses suggest the strong protective associations observed may be due in part to unmeasured confounding.

Conclusions/Significance

Influenza vaccination during pregnancy does not appear to increase the risk of foetal death. This study therefore supports the continued recommendation of influenza vaccination of pregnant women.

Objective To investigate whether an adjuvanted pandemic A/H1N1 2009 influenza vaccine in pregnancy was associated with an increased risk of fetal death.

Design Nationwide register based cohort study.

Setting Denmark.

Participants All clinically recognised singleton pregnancies that ended between November 2009 and September 2010. Individual level data on exposure to an inactivated AS03 pandemic A/H1N1 2009 influenza vaccine (Pandemrix) and potential confounders were linked to the study cohort using a unique person identifier.

Main outcome measures The primary outcome measure was risk of fetal death (spontaneous abortion and stillbirth combined) in H1N1 vaccinated compared with unvaccinated pregnancies, adjusting for propensity scores. Secondary outcome measures were spontaneous abortion (between seven and 22 weeks’ gestation) and stillbirth (after 22 completed weeks’ gestation).

Results The cohort comprised 54 585 pregnancies; 7062 (12.9%) women were vaccinated against pandemic A/H1N1 2009 influenza during pregnancy. Overall, 1818 fetal deaths occurred (1678 spontaneous abortions and 140 stillbirths). Exposure to the H1N1 vaccine was not associated with an increased risk of fetal death (adjusted hazard ratio 0.79, 95% confidence interval 0.53 to 1.16), or the secondary outcomes of spontaneous abortion (1.11, 0.71 to 1.73) and stillbirth (0.44, 0.20 to 0.94). Estimates for fetal death were similar in pregnant women with (0.82, 0.44 to 1.53) and without comorbidities (0.77, 0.47 to 1.25).

Conclusion This large cohort study found no evidence of an increased risk of fetal death associated with exposure to an adjuvanted pandemic A/H1N1 2009 influenza vaccine during pregnancy.

Background

Influenza vaccination policy for elderly people in Britain has changed twice since 1997 to increase protection against influenza but there is no information available on how this has affected vaccine uptake, and socioeconomic variation therein, among people aged over 74 years.

Methods

Vaccination information for 1997–2000 was collected directly from general practices taking part in a MRC-funded Trial of the Assessment and Management of Older People in the Community. This was linked to information collected during assessments carried out as part of the Trial. Regression modelling was used to assess relative probabilities (as relative risks, RR) of having vaccination according to year, gender, age, area and individual socioeconomic characteristics.

Results

Out of 106 potential practices, 73 provided sufficient information to be included in the analysis. Uptake was 48% (95% CI 45%, 55%) in 1997 and did not increase substantially until 2000 when the uptake was a third higher at 63% (50%, 66%). Vaccination uptake was lower among women than men (RR 0.9), people aged 85 or more compared to people aged under 80 (RR 0.9), those in the most deprived areas (RR 0.8) compared to the least deprived, and was relatively high for those in owner-occupied homes with central heating compared to other non-supported housing (RR for remainder = 0.9). This pattern did not change over the years studied.

Conclusions

Increased uptake in 2000 may have resulted from the additional financial resources given to practices; it was not at the expense of more disadvantaged socioeconomic groups but nor did they benefit disproportionately.

Influenza is a vaccine preventable disease that causes severe illness and excess mortality in humans. Licensed influenza vaccines induce humoral immunity and protect against strains that antigenically match the major antigenic components of the vaccine, but much less against antigenically diverse influenza strains. A vaccine that protects against different influenza viruses belonging to the same subtype or even against viruses belonging to more than one subtype would be a major advance in our battle against influenza. Heterosubtypic immunity could be obtained by cytotoxic T-cell (CTL) responses against conserved influenza virus epitopes. The molecular mechanisms involved in inducing protective CTL responses are discussed here. We also focus on CTL vaccine design and point to the importance of immune-related databases and immunoinformatics tools in the quest for new vaccine candidates. Some techniques for analysis of T-cell responses are also highlighted, as they allow estimation of cellular immune responses induced by vaccine preparations and can provide correlates of protection.

Background

During the recent H1N1 influenza pandemic, excess morbidity and mortality was seen in young but not older adults suggesting that prior infection with influenza strains may have protected older subjects. In contrast, a history of recent seasonal trivalent vaccine in younger adults was not associated with protection.

Methods and Findings

To study hemagglutinin (HA) antibody responses in influenza immunization and infection, we have studied the day 7 plasma cell repertoires of subjects immunized with seasonal trivalent inactivated influenza vaccine (TIV) and compared them to the plasma cell repertoires of subjects experimentally infected (EI) with influenza H3N2 A/Wisconsin/67/2005. The majority of circulating plasma cells after TIV produced influenza-specific antibodies, while most plasma cells after EI produced antibodies that did not react with influenza HA. While anti-HA antibodies from TIV subjects were primarily reactive with single or few HA strains, anti-HA antibodies from EI subjects were isolated that reacted with multiple HA strains. Plasma cell-derived anti-HA antibodies from TIV subjects showed more evidence of clonal expansion compared with antibodies from EI subjects. From an H3N2-infected subject, we isolated a 4-member clonal lineage of broadly cross-reactive antibodies that bound to multiple HA subtypes and neutralized both H1N1 and H3N2 viruses. This broad reactivity was not detected in post-infection plasma suggesting this broadly reactive clonal lineage was not immunodominant in this subject.

Conclusion

The presence of broadly reactive subdominant antibody responses in some EI subjects suggests that improved vaccine designs that make broadly reactive antibody responses immunodominant could protect against novel influenza strains.