Summary Background No published meta-analyses have assessed efficacy and effectiveness of licensed influenza vaccines in the USA with sensitive and highly specific diagnostic tests to confirm influenza. Methods We searched Medline for randomised controlled trials assessing a relative reduction in influenza risk of all circulating influenza viruses during individual seasons after vaccination (efficacy) and observational studies meeting inclusion criteria (effectiveness). Eligible articles were published between Jan 1, 1967, and Feb 15, 2011, and used RT-PCR or culture for confirmation of influenza. We excluded some studies on the basis of study design and vaccine characteristics. We estimated random-effects pooled efficacy for trivalent inactivated vaccine (TIV) and live attenuated influenza vaccine (LAIV) when data were available for statistical analysis (eg, at least three studies that assessed comparable age groups). Findings We screened 5707 articles and identified 31 eligible studies (17 randomised controlled trials and 14 observational studies). Efficacy of TIV was shown in eight (67%) of the 12 seasons analysed in ten randomised controlled trials (pooled efficacy 59% [95% CI 51–67] in adults aged 18–65 years). No such trials met inclusion criteria for children aged 2–17 years or adults aged 65 years or older. Efficacy of LAIV was shown in nine (75%) of the 12 seasons analysed in ten randomised controlled trials (pooled efficacy 83% [69–91]) in children aged 6 months to 7 years. No such trials met inclusion criteria for children aged 8–17 years. Vaccine effectiveness was variable for seasonal influenza: six (35%) of 17 analyses in nine studies showed significant protection against medically attended influenza in the outpatient or inpatient setting. Median monovalent pandemic H1N1 vaccine effectiveness in five observational studies was 69% (range 60–93). Interpretation Influenza vaccines can provide moderate protection against virologically confirmed influenza, but such protection is greatly reduced or absent in some seasons. Evidence for protection in adults aged 65 years or older is lacking. LAIVs consistently show highest efficacy in young children (aged 6 months to 7 years). New vaccines with improved clinical efficacy and effectiveness are needed to further reduce influenza-related morbidity and mortality. Funding Alfred P Sloan Foundation.

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Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis

The extent to which member states transpose EU directives in a timely fashion is often argued to be strongly associated with the general effectiveness of national bureaucracies. But what kind of institutional solutions ensure better performance? This paper examines the patterns and effects of departmental oversight across 28 ministries in Estonia, Hungary, Poland and Slovenia. In mapping the strength of oversight, it relies on around 90 structured interviews regarding the rules-in-use on transposition planning, legal review and monitoring of deadlines. The analysis of the impact of departmental oversight is based on an original dataset of over 300 directives with transposition deadlines between January 2005 and December 2008.

On the european union

Children (< 16 years old) and the elderly (above 65 years old) are the two age groups that appear to have the most complications following an influenza infection. Influenza has a viral origin and often results in an acute respiratory illness affecting the lower or upper parts of the respiratory tract, or both. Viruses are mainly of two subtypes (A or B) and spread periodically during the autumn-winter months. However, many other viruses can also cause respiratory tract illnesses.
Diffusion and severity of the disease could be very different during different epidemics. Efforts to contain epidemic diffusion rely mainly on widespread vaccination. Recent policy from several internationally-recognised institutions, recommend immunisation of healthy children between 6 and 23 months of age (together with their contacts) as a public health measure.
The review authors found that in children aged from two years, nasal spray vaccines made from weakened influenza viruses were better at preventing illness caused by the influenza virus than injected vaccines made from the killed virus. Neither type was particularly good at preventing 'flu-like illness' caused by other types of viruses. In children under the age of two, the efficacy of inactivated vaccine was similar to placebo. It was not possible to analyse the safety of vaccines from the studies due to the lack of standardisation in the information given, but very little information was found on the safety of inactivated vaccines, the most commonly used vaccine in young children.

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Vaccines for preventing influenza in healthy children

Summary Background Influenza vaccine effectiveness (VE) can vary by type and subtype. Over the past decade, the test-negative design has emerged as a valid method for estimation of VE. In this design, VE is calculated as 100% × (1 – odds ratio) for vaccine receipt in influenza cases versus test-negative controls. We did a systematic review and meta-analysis to estimate VE by type and subtype. Methods In this systematic review and meta-analysis, we searched PubMed and Embase from Jan 1, 2004, to March 31, 2015. Test-negative design studies of influenza VE were eligible if they enrolled outpatients on the basis of predefined illness criteria, reported subtype-level VE by season, used PCR to confirm influenza, and adjusted for age. We excluded studies restricted to hospitalised patients or special populations, duplicate reports, interim reports superseded by a final report, studies of live-attenuated vaccine, and studies of prepandemic seasonal vaccine against H1N1pdm09. Two reviewers independently assessed titles and abstracts to identify articles for full review. Discrepancies in inclusion and exclusion criteria and VE estimates were adjudicated by consensus. Outcomes were VE against H3N2, H1N1pdm09, H1N1 (pre-2009), and type B. We calculated pooled VE using a random-effects model. Findings We identified 3368 unduplicated publications, selected 142 for full review, and included 56 in the meta-analysis. Pooled VE was 33% (95% CI 26–39; I 2 =44·4) for H3N2, 54% (46–61; I 2 =61·3) for type B, 61% (57–65; I 2 =0·0) for H1N1pdm09, and 67% (29–85; I 2 =57·6) for H1N1; VE was 73% (61–81; I 2 =31·4) for monovalent vaccine against H1N1pdm09. VE against H3N2 for antigenically matched viruses was 33% (22–43; I 2 =56·1) and for variant viruses was 23% (2–40; I 2 =55·6). Among older adults (aged >60 years), pooled VE was 24% (−6 to 45; I 2 =17·6) for H3N2, 63% (33–79; I 2 =0·0) for type B, and 62% (36–78; I 2 =0·0) for H1N1pdm09. Interpretation Influenza vaccines provided substantial protection against H1N1pdm09, H1N1 (pre-2009), and type B, and reduced protection against H3N2. Vaccine improvements are needed to generate greater protection against H3N2 than with current vaccines. Funding None.

https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(16)00129-8.pdf

Variable influenza vaccine effectiveness by subtype: a systematic review and meta-analysis of test-negative design studies

AS03 is an Adjuvant System composed of α-tocopherol, squalene and polysorbate 80 in an oil-in-water emulsion. In various nonclinical and clinical studies, high levels of antigen-specific antibodies were obtained after administration of an AS03-adjuvanted vaccine, permitting antigen-sparing strategies. AS03 has been shown to enhance the vaccine antigen-specific adaptive response by activating the innate immune system locally and by increasing antigen uptake and presentation in draining lymph nodes, a process that is modulated by the presence of α-tocopherol in AS03. In nonclinical models of the AS03-adjuvanted prepandemic H5N1 influenza vaccine, increased levels of anti-influenza antibody afforded protection against disease and against virus replication of influenza strains homologous and heterologous to the vaccine strain. By incorporating AS03 in the pandemic H1N1/2009 vaccine, vaccine immunogenicity was increased compared with nonadjuvanted H1N1 vaccines. High H1N1/2009/AS03 vaccine effectiveness was demonstrated in several assessments in multiple populations. Altogether, the nonclinical and clinical data illustrate the ability of AS03 to induce superior adaptive responses against the vaccine antigen, principally in terms of antibody levels and immune memory. In general, these results support the concept of Adjuvant Systems as a plausible approach to develop new effective vaccines.

Development and evaluation of AS03, an Adjuvant System containing α-tocopherol and squalene in an oil-in-water emulsion

Background 
A multicentre case-control study based on sentinel practitioner surveillance networks from seven European countries was undertaken to estimate the effectiveness of 2009–2010 pandemic and seasonal influenza vaccines against medically attended influenza-like illness (ILI) laboratory-confirmed as pandemic influenza A (H1N1) (pH1N1).


Methods and Findings 
Sentinel practitioners swabbed ILI patients using systematic sampling. We included in the study patients meeting the European ILI case definition with onset of symptoms >14 days after the start of national pandemic vaccination campaigns. We compared pH1N1 cases to influenza laboratory-negative controls. A valid vaccination corresponded to >14 days between receiving a dose of vaccine and symptom onset. We estimated pooled vaccine effectiveness (VE) as 1 minus the odds ratio with the study site as a fixed effect. Using logistic regression, we adjusted VE for potential confounding factors (age group, sex, month of onset, chronic diseases and related hospitalizations, smoking history, seasonal influenza vaccinations, practitioner visits in previous year). We conducted a complete case analysis excluding individuals with missing values and a multiple multivariate imputation to estimate missing values. The multivariate imputation (n = 2902) adjusted pandemic VE (PIVE) estimates were 71.9% (95% confidence interval [CI] 45.6–85.5) overall; 78.4% (95% CI 54.4–89.8) in patients <65 years; and 72.9% (95% CI 39.8–87.8) in individuals without chronic disease. The complete case (n = 1,502) adjusted PIVE were 66.0% (95% CI 23.9–84.8), 71.3% (95% CI 29.1–88.4), and 70.2% (95% CI 19.4–89.0), respectively. The adjusted PIVE was 66.0% (95% CI −69.9 to 93.2) if vaccinated 8–14 days before ILI onset. The adjusted 2009–2010 seasonal influenza VE was 9.9% (95% CI −65.2 to 50.9).


Conclusions 
Our results suggest good protection of the pandemic monovalent vaccine against medically attended pH1N1 and no effect of the 2009–2010 seasonal influenza vaccine. However, the late availability of the pandemic vaccine and subsequent limited coverage with this vaccine hampered our ability to study vaccine benefits during the outbreak period. Future studies should include estimation of the effectiveness of the new trivalent vaccine in the upcoming 2010–2011 season, when vaccination will occur before the influenza season starts.



Please see later in the article for the Editors' Summary

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Estimates of Pandemic Influenza Vaccine Effectiveness in Europe, 2009–2010: Results of Influenza Monitoring Vaccine Effectiveness in Europe (I-MOVE) Multicentre Case-Control Study

Anne-Sophie Barret

Papers

Estimates of Pandemic Influenza Vaccine Effectiveness in Europe, 2009–2010: Results of Influenza Monitoring Vaccine Effectiveness in Europe (I-MOVE) Multicentre Case-Control Study