Influenza is a vaccine preventable disease and influenza vaccines have been available for use in Europe since the 1960s.
A number of variants of the influenza viruses co-circulate each year. Immunity to the infecting influenza virus type develops following a natural influenza infection. However, there is little cross-immunity between influenza types/subtypes or lineages. This is why several influenza strains must be included into combination vaccines.
Currently most influenza vaccines contain three different influenza strains (trivalent): two influenza A (H1N1 and H3N2 subtypes) and one influenza B (Victoria or Yamagata lineages).
Starting from the influenza season 2014–15 new quadrivalent combination vaccines containing four different influenza strains are gradually becoming available in the European Union/European Economic Area (EU/EEA). These vaccines contain two influenza A (H1N1 and H3N2 subtypes) and two influenza B (Victoria and Yamagata lineages) strains.
Yearly updates of influenza vaccines
An update of seasonal influenza vaccines is needed yearly, since influenza viruses constantly evolve. How effective the seasonal influenza vaccine is each season depends on the match between the selected vaccine viruses and those found circulating, and will therefore vary from year to year.
In order to find the best match and increase the vaccine effectiveness, experts meet each February (for the northern hemisphere) to review the precise strains to include in the forthcoming season’s vaccine. This process is managed by World Health Organization (WHO).
The WHO influenza strain selection meeting involves specialists who review relevant virological, epidemiological, immunological and vaccine-performance information in the most recent seasons for the northern and southern hemispheres. Based on this review, new influenza vaccine strain recommendations for the forthcoming season are agreed upon.
Seasonal influenza vaccination strategies
The immunity that is offered by influenza vaccines is not as long lived as the immunity following natural influenza infection. This is especially so for those in the so-called risk groups, hence people have to be vaccinated annually.
There are three possible influenza immunisation strategies but the first is the most important and widely used in Europe.
Protecting the vulnerable: The main strategy of immunisation programmes in Europe is to directly or indirectly protect more vulnerable individuals. Direct protection involves immunising people who are more likely to develop severe disease if they are infected by influenza viruses.
In December 2009 the EU Council adopted a Council Recommendation on seasonal influenza vaccination. The recommendation encourages EU Member States to adopt and implement action plans and policies aimed at reaching seasonal influenza vaccination coverage among older age groups of 75%, and if possible that target be extended to people with chronic medical conditions. Member States are also encouraged to improve vaccination coverage among healthcare workers. ECDC has monitored progress towards the targets of the Council Recommendation drawing on data, analyses and actions undertaken in recent years.
While immunising members of risk groups means direct protection, there is also an indirect protection strategy of immunising those with close contact with people in risk groups. This is growing in importance since it is now appreciated that the ordinary influenza vaccines are more effective in healthy adults than older people and those with chronic conditions, including immunodeficiency. Further, children under six months of age that cannot be vaccinated may be protected by the indirect protection strategy.
Protecting healthy children, adolescents and adults: Healthy toddlers and younger children are prone to severe influenza disease. A number of EU/EEA countries, for example Finland and Latvia, have initiated immunisation programmes for these younger age groups.
Influenza epidemics are also an important cause of many bouts of short-lived but debilitating illnesses leading to school and work absence. Hence many people choose to get immunised and some also have their children immunised regardless of whether there is a formal recommendation or vaccination programme.
In addition, due to the economic impact and social disruption of absences, employers often encourage immunisation of their staff and make the vaccine readily available. This includes employers of healthcare staff, though the prime reason for immunising healthcare workers is protecting their patients.
Reducing overall influenza transmission: This is a new approach based on the observation that much of the influenza transmission takes place in children’s day care facilities and amongst school-age children. So immunising children and adolescents may reduce overall influenza transmission and protect those in risk groups. This is an approach recently adopted by the United Kingdom.
Types of seasonal influenza vaccine
Injected inactivated influenza vaccines are most commonly used throughout the world. Influenza antigen preparation varies between manufacturers. The inactivated influenza vaccines available in the EU/EEA may contain either split-influenza virus products or subunit influenza products. Adjuvanted inactivated influenza vaccine for older people is available in some EU/EEA Member States and is under evaluation for younger children.
Injected quadrivalent inactivated influenza vaccines, available from the 2014–15 season in some EU/EEA countries are expected to replace the trivalent vaccines over time. Vaccine authorisation in different countries, vaccine availability, observed vaccine effectiveness and the cost may influence the speed of the replacement.
In 2011, a live attenuated influenza vaccine for intranasal use was approved in the EU/EEA for children and adolescents (2-17 years of age). All live attenuated influenza vaccines currently available are quadrivalent combination vaccines containing two influenza A strains (H1N1 and H3N2 subtypes) and two influenza B strains (Victoria and Yamagata lineages).
Since seasonal influenza vaccines are usually recommended for several vulnerable populations that also are poorer immune responders due to age or disease, several attempts to improve the vaccines have been explored over the last 10-15 years, such as: increasing the antigen dose administered, intradermal administration to activate other arms of the immune system, and adding immunostimulating compounds such as adjuvants.
Products utilising these new techniques are now authorised and available in some EU/EEA countries. For human influenza vaccines, squalene and AS03 (squalene and α-tocopherol) have been approved as adjuvants by regulatory agencies in the EU, Canada and the United States. It is currently not clear if any of them perform better than the others although the first studies indicate better protection in the oldest age group .
Most influenza vaccines, both inactivated and live attenuated, are based on production of influenza viruses/antigens in fertilized hens' eggs. These vaccines can therefore not be given to egg-allergic individuals developing severe symptoms upon exposure to egg proteins. Hence, a few manufacturers have developed cell-based influenza vaccines which can be given to egg-allergic individuals. Due to limited yields in cell culture and general production limitations these are not yet available in all EU/EEA countries.
In total, seven influenza vaccine manufacturers produce and deliver seasonal influenza vaccines to EU/EEA countries. The majority of these influenza vaccines were authorised before the creation of the European Medicines Agency in 1995 and have therefore predominantly been approved by national regulatory agencies rather than centrally approved in the EU/EEA. As a result, some influenza vaccines are named differently in different countries, despite being the same product. The only exception is the recently introduced intranasal live attenuated influenza vaccine which was centrally authorised by the European Medicines Agency and uses one name in the EU/EEA (Fluenz tetra), but another in the US (Flumist quadrivalent).
Overview of available seasonal influenza vaccines in the EU/EEA (2015–16 season)
|Manufacturer||Name of product*||Vaccine type||Adjuvant||Administration route||Produced in||Age recommended|
|Abbot healthcare||Trivalent: Influvac Imuvac||Inactivated||None||Intramuscular||Egg||From 6 months|
|AstraZeneca||Quadrivalent: Fluenz tetra (Flumist quadrivalent)||Live attenuated||None||Intranasal||Egg||From 24 months to 17 years|
|GlaxoSmithKline||Trivalent: Fluarix** Alpharix Influsplit Quadrivalent: Fluarix Tetra Alpharix Tetra Influsplit Tetra||Inactivated/split||None||Trivalent: Intramuscular or subcutaneous Quadrivalent: Intramuscular||Egg||Trivalent: From 6 months Quadrivalent: From 3 years|
|Novartis||Trivalent: Agrippal Fluvirin Optaflu Fluad||Inactivated/subunit||None None None Squalene (MF59)||Intramuscular||Egg Egg Cell Egg||From 6 months From 4 years From 18 years From 65 years|
|Omninvest||Trivalent: Fluval AB||Inactivated||Aluminium phosphate gel||Intramuscular||Cell||From 6 months|
|Pfizer/ CSL Australia||Trivalent: Afluria*** Enzira||Inactivated Inactivated||None None||Intramuscular Intramuscular||Egg Egg||From 5 years, however increased fever reported in children 6 months to 5 years|
|Sanofi Pasteur||Trivalent: Vaxigrip** Intanza 9µg Intanza 15µg||Inactivated Inactivated Inactivated||None None None||Intramuscular Intradermal Intradermal||Egg Egg Egg||
From 6 months From 18-59 years From 60 yrs
*The same product may be sold under different names ** Split virion by Triton X-100 and formaldehyde inactivated *** Beta-propriolactone-inactivated and taurodeoxychelate split virion vaccine
As noted above two vaccine manufacturers currently offer tetravalent influenza vaccines on the EU/EEA market: AstraZeneca and GSK. These vaccines are as of 2015 only authorised in a limited number of EU/EEA countries. Ahead of the 2015–16 influenza season Fluenz Tetra produced by AstraZeneca was available in Austria, Belgium, Germany, Finland, Luxembourg, Norway, Sweden, Spain and UK, while Fluarix Tetra produced by GSK was available in Belgium, France, Germany, Italy, Spain and UK. In most countries where quadrivalent vaccines are available there are still also trivalent influenza vaccines being used dependent on procurement agreements with different health care providers.
Immunity following influenza disease and administration of influenza vaccines
For infants, the first encounter with influenza viruses commonly occurs in their first or second winter season. Subsequently, each individual acquires a number of influenza infections throughout life. It is expected that up to around 15% of a European population in a temperate climate is infected with influenza in any winter season with higher percentages in children and lower in older people.
Whether individuals fall ill when they are infected is dependent on a number of factors: these include previous exposure to a similar influenza virus that has induced a complete or partial protective immunity to the now circulating virus, or exposure through vaccination with an updated matching influenza vaccine strain. Commonly, the youngest children and the older adults are most affected by seasonal influenza infections each year. Older adults are less likely to be infected than children and young adults; however, when they are infected, these older adults are more likely to suffer from severe disease.
Until the 2014–15 influenza season the immune responses to updated seasonal influenza vaccine were evaluated each year through serological tests in a limited number of healthy individuals (n=~200) according to set criteria established by the European Medicine Agency Committee for Medicinal Products for Human Use (EMA CHMP) committee in 1997. Those immunogenicity criteria were:
For adults 18-60 years of age:
Seroprotection rate should be >70% - defined as the proportion of vaccinated individuals achieving a haemagglutination-inhibition (HAI) titre of >1:40;
Seroconversion rate should be >40% (seroconversion corresponds to negative pre-vaccination serum converting to an HAI titer >1:40 OR a significant increase in HAI antibody titre, i.e. at least a four-fold titre increase).
For older adults >60 years of age:
Seroprotection rate should be >60% - defined as the proportion of vaccinated individuals achieving an HAI titre of >1:40
Seroconversion rate should be >30% (seroconversion corresponds to negative prevaccination serum converting to an HAI titer >1:40 OR a significant increase in HAI antibody titre, i.e. at least a four-fold titre increase)
No similar criteria exist for children. These criteria could not be used for the intranasal live attenuated vaccines since mucosal vaccines elicit more mucosal and less systemic immune response.
However, these criteria are expected to be replaced in the EU by guidelines on product-specific effectiveness observational studies following adoption by EMA CHMP in 2016 and new safety requirements presented in interim guidance on enhanced safety surveillance for seasonal influenza vaccines in the EU in 2014. Immune response criteria are expected to be retained for the authorisation of new seasonal, pandemic and zoonotic vaccines.
Influenza vaccine effectiveness
To establish how well influenza vaccines work each season, influenza vaccine effectiveness is measured in observational studies. Vaccine effectiveness is an estimate of the likelihood that a vaccine prevents influenza infection when used in everyday practice.
In Europe influenza vaccine effectiveness studies were initiated by ECDC and have been followed systematically since the influenza season 2008–09 by a network of public health and academic researchers (I-MOVE). Results have been provided for influenza vaccines overall with no possibility to distinguish between different vaccine products. However, results have been presented by age group and by different influenza vaccine strain. In general, a vaccine effectiveness of ~40-60% has been estimated for the three different influenza A (H1N1, H3N2) and B strains (Victoria or Yamagata lineages) except in the last two seasons where only a limited effectiveness was observed against influenza induced by circulating H3N2 viruses due to mismatch.
Overview of articles on effectiveness of seasonal influenza vaccines estimated in multi-centre studies conducted by the I-MOVE network in Europe:
- Season 2013-2014: Valenciano et al The European I-MOVE Multicentre 2013-2014 Case-Control Study. Homogeneous moderate influenza vaccine effectiveness against A(H1N1)pdm09 and heterogeneous results by country against A(H3N2).
- Season 2012-2013: Kissling et al Influenza vaccine effectiveness estimates in Europe in a season with three influenza type/subtypes circulating: the I-MOVE multicenter case-control study, influenza season 2012/13
- Season 2011-2012: Kissling et al Low and decreasing vaccine effectiveness against influenza A(H3) in 2011/12 among vaccination target groups in Europe: results from the I-MOVE multicentre case-control study.
- Season 2010-2011: Kissling et al Overall and stratified estimates of influenza vaccine effectiveness in Europe for the season 2010-2011
- Season 2009-2010: Valenciano M et al. Estimates of Pandemic Influenza Vaccine Effectiveness in Europe, 2009-2010: Results of Influenza Monitoring Vaccine Effectiveness in Europe (I-MOVE) Multicenter Case-Control Study.
- Season 2008-2009: Kissling et al “I-MOVE” towards monitoring seasonal and pandemic influenza vaccine effectiveness: lessons learnt from a pilot multi-centric case-control study in Europe 2008-9
Adverse reactions following vaccination
The risk of an adverse event following influenza vaccination is far smaller than the risk of complications related to influenza itself. The benefits of vaccination substantially outweigh the risks.
Comparison of risks associated with influenza disease and inactivated seasonal influenza vaccination
|Risks associated with seasonal influenza infection||Risks associated with seasonal influenza vaccination*|
|Common symptoms Fever, sore throat, runny nose, dry cough, fatigue, headache, and muscle ache. Croup and bronchiolitis common in children.||Common adverse event (<1/100) Soreness/pain, redness and/or swelling around the injection site. Short-term fever (1–2 days), may be high (>39.0 C°) in children. Short-term fatigue (1–2 days). Muscle ache (1–2 days). Adverse reactions are more common in children not previously exposed to the vaccine or virus than in adults.|
|Possible complications Bacterial pneumonia. Ear infection. Sinus infection. Myocarditis. Pericarditis. Worsening of chronic medical condition present before influenza illness (e.g. congestive heart failure). Precipitation of severe cardiovascular or cerebrovascular event||Rare adverse event (<1/1 000) Urticaria. Febrile convulsions.|
|Rare complications Septicaemia. Encephalopathy. Death.||Very rare adverse event (<1/10 000) Anaphylaxis. Paresthesia. Guillain-Barré syndrome occurs less than one in one million doses, the same rate as in the general population**.|
*Reported risks refer to inactivated influenza vaccines commonly used in organised immunisation programmes in the European Union. For details see Summary of Product Characteristics for each vaccine available on national regulatory agency websites. **Lehmann HC, Hartung HP, Kieseier BC, Hughes RA. Guillain-Barré syndrome after exposure to influenza virus. Lancet Infect Dis. 2010 Sep;10(9):643-51.
Timing of influenza vaccination
It takes 10 to 14 days following vaccination, before an immune response and protection develops. Therefore most countries start immunisation in the early autumn. It is rare that the annual influenza epidemic season starts before mid-November, and the season commonly runs to the end of May the following year. The protection provided by the vaccine is expected to last for at least one influenza season but it does wane with time. Therefore some authorities have suggested delaying vaccination campaigns to start in mid-autumn.
Influenza vaccine developments
Besides the change for many of the authorised influenza vaccines to include a second influenza B strain in the future, there are other attempts to develop new influenza vaccines that would have increased effectiveness. The three main areas of development are:
- vaccines with protective immunity lasting more than one season
- shortening the production time to enable a virological assessment closer to the upcoming influenza season (currently the six month production time means that the vaccine composition is decided in February)
- a universal influenza vaccine that protects against influenza regardless of what influenza viruses are circulating.
The influenza risk groups include people who are more likely than others to develop severe disease should they be infected. The most recent published ECDC review indicated strong evidence for immunising two large risk groups:
- Older adults
- All persons (over six months of age) with chronic medical conditions
There is no universal agreement across the EU of what age is covered by the older adults group, though a survey conducted by the Vaccine European New Integrated Collaboration Effort network (VENICE III) shows that many countries use the age of 65 years as a criterion. Some countries use a younger age to define older adults.
The list of chronic medical conditions in patients often recommended for vaccination in EU/EEA Member States include diseases affecting the:
- respiratory system e.g. asthma
- cardiovascular system e.g. coronary artery disease
- endocrine system e.g. diabetes
- hepatic system e.g. liver cirrhosis
- renal system e.g. chronic renal failure
- neurological/neuromuscular conditions e.g. parkinsonism
In addition to the above:
- any condition compromising respiratory functions e.g. morbid obesity (BMI > 40), physical handicap in children and adults
- immunosuppression due to disease or treatment including due to haematological conditions and HIV infection.
In May 2012 a WHO SAGE (Strategic Advisory Group of Experts) delivered its opinion on seasonal influenza immunisation published in the Weekly Epidemiological Record. This was supported by a background paper that announced a change from the WHO 2005 guidance in declaring a new group, pregnant women, the priority for immunisation above all other groups. It also added young children to the groups that should be offered immunisation, emphasising at the same time the importance of immunising the groups mentioned in the 2005 guidance: older people, individuals >6 months with chronic conditions, and healthcare workers with patient contact. The evidence for and against immunising pregnant women and children was summarised by ECDC in 2012 by using a systematic review and an expert group. The issue of immunisation of pregnant women was discussed in an ECDC Scientific Advance in November 2012.
+The use of registered trade names for medicines is not an endorsement of the product by ECDC and is used only in instances where the use of the generic drug name is not possible.
1. P.G. Van Buyndera, S. Konrada, J.L. Van Buyndera, E. Brodkina, M. Krajdend, G. Ramlera, M. Bighama, The comparative effectiveness of adjuvanted and unadjuvanted trivalent inactivated influenza vaccine (TIV) in the elderly Vaccine Volume 31, Issue 51, 9 December 2013, Pages 6122–6128
2. Hayward et al Comparative community burden and severity of seasonal and pandemic influenza: results of the Flu Watch cohort study. Lancet Respir Med. 2014 Jun;2(6):445-54. doi: 10.1016/S2213-2600(14)70034-7. Epub 2014 Mar 17
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