Influenza vaccines

Influenza, commonly referred to as “flu,” is a major global public health concern and a huge economic burden to societies. Current influenza vaccines need to be updated annually to match circulating strains, resulting in low take-up rates and poor coverage due to inaccurate prediction. Broadly protective universal flu vaccines that do not need to be updated annually have therefore been pursued. The highly conserved 24–amino acid ectodomain of M2 protein (M2e) is a leading candidate, but its poor immunogenicity has been a major roadblock in its clinical development. Here, we report a targeting strategy that shuttles M2e to a specific dendritic cell subset (cDC1) by engineering a recombinant anti-Clec9A monoclonal antibody fused at each of its heavy chains with three copies of M2e. Single administration in mice of 2 µg of the Clec9A–M2e construct triggered an exceptionally sustained anti-M2e antibody response and resulted in a strong anamnestic protective response upon influenza challenge. Furthermore, and importantly, Clec9A–M2e immunization significantly boosted preexisting anti-M2e titers from prior flu exposure. Thus, the Clec9A-targeting strategy allows antigen and dose sparing, addressing the shortcomings of current M2e vaccine candidates. As the cDC1 subset exists in humans, translation to humans is an exciting and realistic avenue.

Objective: To evaluate the prevalence and factors associated with non-vaccination against influenza in the risk group. Methods: A cross-sectional, population-based study, carried out in the city of Rio Grande (RS). The outcome was defined as belonging to risk groups and not having been vaccinated in the last 12 months. Demographic, socioeconomic, behavioral variables, and access for health services were analyzed. Results: In this study, 680 individuals participated. The prevalence was 46.0% (95%CI: 41.8-50.3), ranging from 27.9% (elderly) to 81.8% (pregnant women). Young adults, single, intermediate socioeconomic bracket, smoker, with depressive symptoms, who did not perform physical activity and did not consult a physician in the last year, had a higher prevalence of non-vaccination. Conclusion: Half of the sample was not vaccinated in the period. Due to the similarity of influenza-like illness and the coronavirus 2019 disease (COVID-19), increasing vaccination would minimize mortality and use of hospital beds due to influenza, optimizing the response of hospital capacity.

To compare the proportion of Beijing children who have ever had pneumonia (%Pneumonia) to those in other locations, and to estimate by how much national vaccine coverage with Pneumococcal Conjugate Vaccine (PCV) and Haemophilus Influenzae Type b (Hib) could reduce Beijing %Pneumonia. %Pneumonia was obtained for each age group from 1 to 8 years inclusive from 5,876 responses to a cross-sectional questionnaire. Literature searches were conducted for world-wide reports of %Pneumonia. Previous vaccine trials conducted worldwide were used to estimate the pneumococcal (S. pneumoniae) and Hib (H. influenzae) burdens and %Pneumonia as well as the potential for PCV and Hib vaccines to reduce Beijing children's %Pneumonia. The majority of pneumonia cases occurred by the age of three. The cumulative %Pneumonia for 3-8 year-old Beijing children, 26.9%, was only slightly higher than the 25.4% for the discrete 3 year-old age group, similar to trends for Tianjin (China) and Texas (USA). Beijin...

 Case reports have suggested that vaccines may trigger transverse myelitis (TM) or acute disseminated encephalomyelitis (ADEM), but the evidence for a causal association is inconclusive. We analyzed the association of immunization and subsequent development of TM or ADEM.  We identified all cases of TM and ADEM in the Vaccine Safety Datalink population. Using a case-centered method, we compared vaccination of each case to vaccination of all matched persons in the study population, who received the same type of vaccine, with respect to whether or not their vaccination occurred during a predetermined exposure interval. We calculated a risk difference (excess risk) of TM and ADEM for each vaccine.  Following nearly 64 million vaccine doses, only 7 cases of TM and 8 cases of ADEM were vaccinated during the primary exposure window 5-28 days prior to onset. For TM, there was no statistically significant increased risk of immunization. For ADEM, there was no statistically significant incre...

Growing evidence suggests respiratory syncytial virus (RSV) is an important cause of respiratory disease in adults. However, the adult burden remains largely uncharacterized as most RSV studies focus on children, and population-based studies with laboratory-confirmation of infection are difficult to implement. Indirect modelling methods, long used for influenza, can further our understanding of RSV burden by circumventing some limitations of traditional surveillance studies that rely on direct linkage of individual-level exposure and outcome data. Multiple linear time-series regression was used to estimate RSV burden in the United Kingdom (UK) between 1995 and 2009 among the total population and adults in terms of general practice (GP) episodes (counted as first consultation ≥28 days following any previous consultation for same diagnosis/diagnostic group), hospitalisations, and deaths for respiratory disease, using data from Public Health England weekly influenza/RSV surveillance, C...

In the United States, annual vaccination against seasonal influenza is recommended for all persons aged ≥6 months. Each season since 2004-05, CDC has estimated the effectiveness of seasonal influenza vaccine in preventing medically attended acute respiratory illness (ARI) associated with laboratory-confirmed influenza. This season, early estimates of influenza vaccine effectiveness are possible because of widespread, early circulation of influenza viruses. By January 3, 2015, 46 states were experiencing widespread flu activity, with predominance of influenza A (H3N2) viruses. This report presents an initial estimate of seasonal influenza vaccine effectiveness at preventing laboratory-confirmed influenza virus infection associated with medically attended ARI based on data from 2,321 children and adults enrolled in the U.S. Influenza Vaccine Effectiveness Network (Flu VE) during November 10, 2014-January 2, 2015. During this period, overall vaccine effectiveness (VE) (adjusted for stu...

We analyzed seasonal influenza vaccination coverage among the Italian healthcare workers (HCW) in order to identify socio-demographic and clinical determinants of vaccination. We used data from the survey “Health and health care use in Italy,” which comprised interviews of 5,336 HCWs For each respondent, information on socioeconomic, health conditions, self-perceived health and smoking status were obtained. After bivariate analysis, we used multilevel regression models to assess determinants of immunization. Overall 20.8% of HCWs (95%CI 19.7–21.9) reported being vaccinated against seasonal influenza. After controlling for potential confounders, multilevel regression revealed that older workers have a higher likelihood of vaccine uptake (OR = 6.07; 95% CI 4.72–7.79). Conversely, higher education was associated with lower vaccine uptake (OR = 0.65; 95% IC 0.50–0.83). Those suffering from diabetes (OR = 2.07; 95% CI 1.19–1.69), COPD (OR = 1.95; 95% CI 1.31–2.89) and cardiovascular dise...

The feasibility of a linear expression cassette (LEC)-based influenza A DNA vaccine was demonstrated in mice, using a lethal dose (LD90) of a mouse-adapted A/Hong Kong/8/68 (H3N2) influenza strain. LECs expressing hemagglutinin (HA) from either the homotypic H3N2 or the heterotypic H1N1 (A/Puerto Rico/8/34) influenza virus were produced by polymerase chain reaction and either phosphodiester- or phosphorothioate-modified oligonucleotide primers. Survival subsequent to lethal viral challenge was used as a primary end point; weight loss was the secondary end point. Survival and weight loss data showed that protection can be achieved in mice with 50 microg of phosphate-buffered saline-formulated LEC DNA or 2 microg of Vaxfectin-formulated LEC DNA. Survival correlated with neutralizing antibody titers (hemagglutination inhibition, HAI); titers obtained after vaccination with LEC were equivalent to those obtained with HA (H3N2) plasmid DNA control. Vaccination with heterotypic H1 HA-LEC DNA provided no protection against viral challenge.

Based on an increasingly extensive literature expressing the large interest in the field, this paper gives an overview of different aspects of influenza prevention in children. It relies on paradoxes. First, the heaviest part of the burden is well demonstrated in the youngest infants by numerous epidemiological data elsewhere. On the contrary, with older children, the prevention by influenza vaccines is more efficacious-without notable side effects. Second, the available TIV vaccines are 60 years old and the requests of registration and regulation of vaccines have evolved. There is a specific need in children: it is time to re-discuss the pragmatic utilization of influenza vaccines (full dose in the youngest patient? More flexibility regarding the interval between the two required doses in vaccine-naïve children), and to change from a compassionate use to a targeted research and adapted vaccines considering the limits of TIV in the youngest children. Third, influenza virus transmiss...

Contemporary influenza B virus strains were generated encoding C-terminally truncated NS1 proteins. Viable viruses containing the N-terminal 14, 38, 57 or 80 aa of the NS1 protein were rescued in Vero cells. The influenza B virus NS1-truncated mutants were impaired in their ability to counteract interferon (IFN) production, induce antiviral pro-inflammatory cytokines early after infection and show attenuated or restricted growth in IFN-competent hosts. In Vero cells, all of the mutant viruses replicated to high titres comparable to the wild-type influenza B virus. Mice that received a single, intranasal immunization of the NS1-truncated mutants elicited an antibody response and protection against wild-type virus challenge. Therefore, these NS1-truncated mutants should prove useful as potential candidates for live-attenuated influenza virus vaccines.

According to the Centers for Disease Control and Prevention, approximately 5-20 % of people are affected by influenza annually, and influenza causes more than 200,000 hospitalizations each year. The purpose of this study is to estimate the prevalence of influenza vaccination among high risk adults in Kansas. The 2013 Kansas BRFSS data (n = 20,712) were analyzed to assess the prevalence of receiving influenza vaccination among Kansas adults, overall and for selected demographic characteristics within the past 12 months. Crude and adjusted prevalence rate ratios were computed using univariate logistic regression models with influenza vaccination as the dependent variable and health conditions or high risk groups as the main independent variables; these models were then adjusted for potential confounding. Overall, influenza vaccination rate was lower than the Healthy People 2020 target (42.2 % vs. 80 %). The prevalence of receiving influenza vaccination was higher among adults 65 years...

The World Health Organization (WHO) considers pregnant women to be a risk group for severe influenza disease. We conducted a systematic review to evaluate influenza disease incidence in pregnant women in order to inform estimates of influenza vaccine impact for low-resource countries. We performed electronic literature searches, targeting studies on the following outcomes in pregnant women: attack rate, hospitalization rate, intensive care unit admission rate, mortality rate, and disability-adjusted life years lost. Only original studies published in peer-reviewed journals that had laboratory confirmation for influenza virus infection and included population-based incidence rates with denominator data were included. We summarized study characteristics in descriptive tables and outcome-specific Forest plots. We generated summary incidence rates using random effects models and assessed statistical heterogeneity by visual examination of Forest plots, and by χ (2) and I(2) tests. We ide...

BackgroundPreventive service use among older adults is suboptimal. Unhealthy drinking may constitute a risk factor for failure to receive these services.ObjectivesTo determine the relationship between unhealthy drinking and receipt of recommended preventive services among elderly Medicare beneficiaries, applying the framework of current alcohol consumption guidelines.Design/MethodsThe data source is the nationally representative 2003 Medicare Current Beneficiary Survey. The sample included community-dwelling, fee-for-service Medicare beneficiaries 65 years and older (N = 10,523). Based on self-reported drinking, respondents were categorized as nondrinkers, within-guidelines drinkers, exceeding monthly but not daily limits, or heavy episodic drinkers. Using survey and claims data, influenza vaccination, pneumonia vaccination, glaucoma screening, and mammogram receipt were determined. Bivariate and logistic regression analyses were conducted.ResultsOverall, 70.3% received flu vaccination and 49% received glaucoma screening during the year, 66.8% received pneumonia vaccination, and 56.2% of women received a mammogram over 2 years. In logistic regression, heavy episodic drinking was associated with lower likelihood of service receipt compared to drinking within guidelines: flu vaccination (OR 0.75, CI 0.59–0.96), glaucoma screening (OR 0.74, CI 0.58–0.95), and pneumonia vaccination (OR 0.75, CI 0.59–0.96). Nondrinkers when compared with those reporting drinking within guidelines were less likely to receive a mammogram (OR 0.83, CI 0.69–1.00).ConclusionsHeavy episodic drinking is associated with lower likelihood of receiving several preventive services. Practitioners should be encouraged to screen all elders regarding alcohol intake and in addition to appropriate intervention, consider elders reporting heavy episodic drinking at higher risk for non-receipt of preventive services.

Since the end of March 2013, avian a influenza viruses of the H7N9 subtype have caused more than 130 human cases of infection in China, many of which were severe, resulting in 43 fatalities. Although this A(H7N9) virus outbreak is now under control, the virus (or one with similar properties) could reemerge as winter approaches. To better assess the pandemic threat posed by A(H7N9) viruses, NIAID/NIH Centers of Excellence in Influenza Research and Surveillance (CEIRS) investigators and other expert laboratories in China and elsewhere have characterized the wild-type avian A(H7N9) viruses in terms of host range, virulence, and transmission, and are evaluating the effectiveness of antiviral drugs and vaccine candidates. However, to fully assess the potential risk associated with these novel viruses, there is a need for additional research including experiments that may be classified as "gain-of-function" (GOF). Here, we outline the aspects of the current situation that most u...

Canine influenza virus (CIV) is a newly identified, highly contagious respiratory pathogen of dogs. The clinical disease has high morbidity and low mortality. Diagnosis of canine influenza is based on acute and convalescent serum samples, history, and clinical signs. Phylogenetic analysis has shown that the etiologic agent is an influenza A virus that is closely related to the equine influenza A (H3N8) virus. Data collected thus far support transmission from horses to dogs with horizontal spread in the canine population. This interspecies jump and the close companionship of dogs and people warrant close monitoring of CIV for potential transmission to humans.

The nonstructural protein 1 (NS1) of influenza A virus (IAV) enables the virus to disarm the host cell type 1 IFN defense system. Mutation or deletion of the NS1 gene leads to attenuation of the virus and enhances host antiviral response making such live-attenuated influenza viruses attractive vaccine candidates. Sublingual (SL) immunization with live influenza virus has been found to be safe and effective for inducing protective immune responses in mucosal and systemic compartments. Here we demonstrate that SL immunization with NS1 deleted IAV (DeltaNS1 H1N1 or DeltaNS1 H5N1) induced protection against challenge with homologous as well as heterosubtypic influenza viruses. Protection was comparable with that induced by intranasal (IN) immunization and was associated with high levels of virus-specific antibodies (Abs). SL immunization with DeltaNS1 virus induced broad Ab responses in mucosal and systemic compartments and stimulated immune cells in mucosa-associated and systemic lymph...

Background. A number of infectious agents have previously been suggested as risk factors for the development of Guillain-Barré syndrome (GBS), but robust epidemiologic evidence for these associations is lacking. Methods and Findings. We conducted a nested case-control study using data from the United Kingdom General Practice Research Database between 1991 and 2001. Controls were matched to cases on general practice clinic, sex, year of birth and date of outcome diagnosis in their matched case. We found positive associations between GBS and infection with Campylobacter, Epstein-Barr virus and influenza-like illness in the previous two months, as well as evidence of a protective effect of influenza vaccination. After correction for under-ascertainment of Campylobacter infection, the excess risk of GBS following Campylobacter enteritis was 60-fold and 20 % of GBS cases were attributable to this pathogen. Conclusions. Our findings indicate a far greater excess risk of GBS among Campylob...

Background: All influenza pandemic plans advocate pandemic vaccination. However, few studies have evaluated the cost-effectiveness of different vaccination strategies. This paper compares the economic outcomes of vaccination compared with treatment with antiviral agents alone, in Singapore. Methodology: We analyzed the economic outcomes of pandemic vaccination (immediate vaccination and vaccine stockpiling) compared with treatment-only in Singapore using a decision-based model to perform cost-benefit and cost-effectiveness analyses. We also explored the annual insurance premium (willingness to pay) depending on the perceived risk of the next pandemic occurring. Principal Findings: The treatment-only strategy resulted in 690 deaths, 13,950 hospitalization days, and economic cost of USD$497 million. For immediate vaccination, at vaccine effectiveness of.55%, vaccination was cost-beneficial over treatment-only. Vaccine stockpiling is not cost-effective in most scenarios even with 100 %...