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Influenza vaccination

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. Individuals can develop immunity to the different subtypes of influenza viruses, but there is little cross-immunity between subtypes. This is why several influenza strains must be included into combination vaccines. Currently all influenza vaccines contain three different influenza subtypes (trivalent): two influenza A subtypes (H1N1, H3N2) and one influenza B subtype (Victoria or Yamagata lineage).

Yearly updates of influenza vaccines

An update of seasonal influenza vaccines is needed regularly, since influenza viruses constantly evolve and sometimes recombine. The match between the selected vaccine viruses and circulating viruses influence vaccine effectiveness and may therefore vary from year to year. To overcome this, the precise vaccine viruses selected are reviewed annually by a strain selection meeting convened each year in February by the World Health Organization (WHO).

WHO has been coordinating global surveillance by National Influenza Centres for more than half a century through what is now called the Global Influenza Surveillance and Response System. The strain selection meeting involves specialists principally from the WHO’s Influenza Collaborating Centres and Essential Regulatory Laboratories, who review relevant virological and other information, especially from the new Northern Hemisphere season. Based on this review, new recommendations for the updated vaccines for the upcoming season are agreed upon.

The immunity that is given by vaccines is not as long lived as the immunity following infection. This is especially so among those in the Risk Groups, hence people have to be immunised annually.

Seasonal influenza vaccination strategies

There are three influenza immunisation strategies but the first is the most important and widely used in Europe.

  • Protecting the vulnerable: The main strategy of European Countries is to directly or indirectly protect the more vulnerable individuals. Direct protection involves immunising people who are more likely to develop severe disease if they are infected by influenza. This has led to the concept of Risk Groups, i.e. people who are more likely than others to develop severe disease should they be infected. Following an EU Council Recommendation of December 2009 in the European Union / EEA countries it is ECDC’s responsibility to summarise the evidence relevant to this. This does not produce ECDC recommendations but informs decisions by member states (MS) and other authorities. A number of MS also undertake an evidence-based approach and produce national recommendations. The consensus of MS policies as shown by ECDC supported VENICE surveys is that these are principally older people and people with chronic medical conditions, there is less consensus on other groups. While immunising risk groups means direct protection, there is also an indirect protection strategy of immunising those with close contact with people in the risk groups. This is growing in importance since it is now appreciated that the ordinary vaccines work rather well in healthy adults and less well in older people and those with chronic conditions. Examples of this strategy is immunising health care staff who otherwise can infect their patients, and offering immunisation to pregnant women who may infect their new-borns (as well as protecting themselves) since babies cannot be immunised until they are then 6 months of age.
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  • Protecting well children, adolescents and younger adults: Influenza vaccines are licensed not only for those in the risk groups, almost anyone can be immunised. Occasionally influenza causes severe disease even in healthy younger adults, adolescents and older children among whom the vaccine is especially effective. Influenza epidemics are also an important cause of many bouts of short lived but de-habilitating illness each year. Hence many people choose to get themselves immunised and some also have their children immunised. Due to the economic impact and social disruption employers often encourage immunisation to their staff and make it readily available. This includes employers of health care staff though the prime reason for immunising health care workers is protecting their patients.
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  • Reducing overall influenza transmission: This is a new approach and it is based on the observation that so much of the influenza transmission takes place in school age children that it may be worthwhile immunising school-age children to reduce transmission that may affect those in the risk groups.

 

Types of seasonal influenza vaccine

Injected trivalent inactivated influenza vaccines (TIVs) are most commonly used throughout the world. Influenza antigen preparation varies between manufacturers and the TIVs available on the EU market may contain either, whole influenza virions, split-influenza virus products, subunit influenza products or virosomes expressing the influenza antigens.

In 2011, a live attenuated influenza vaccine (LAIV) for intranasal use was approved in the EU for children (2-17 years of age). The current formulation contains the same two A subtypes and influenza B subtype as, TIVs . The LAIV vaccine was approved in the United States in 2002 and has been used since then.
In 2011, a quadrivalent LAIV, containing two influenza A strains, H1N1 and H3N2, and two influenza B strains, Victoria and Yamagata, was authorised by FDA. The quadrivalent LAIV is currently under evaluation by the European Medicines Agency ( EMA).

 Table 1. Overview of available seasonal influenza vaccine types in the EU/EEA

 

Seasonal influenza vaccine types

Trivalent inactivated (intramuscular or intradermal)

  • Unadjuvanted whole virion
  • Unadjuvanted split-virus
  • Unadjuvanted sub-unit
  • Unadjuvanted virosomes expressing subunit antigens
  • Adjuvanted sub-unit

Live attenuated influenza viruses (intranasal)

  • Trivalent (107FFU per strain)
  • Quadrivalent (approved by FDA and under evaluation in 2012 by EMA/EC)

 

Since seasonal influenza vaccines are needed in 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 dose of antigen, presenting the antigens in the form of a three-dimensional structure in a virosome, administering the antigen intradermally instead of intramuscularly to activate other arms of the immune system, and adding immunostimulating compounds such as adjuvants.

Products utilizing these new techniques are now authorised and available. 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. However, it is currently unknown if any of them perform better than the others. All inactivated vaccines should be administered either by the intramuscular or the intradermal route as recommended by the manufacturer.

Most influenza vaccines, both TIVs and LAIVs, are based on production of influenza viruses/antigens in fertilized hen’s 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, nine influenza vaccine manufacturers produce and deliver seasonal influenza vaccines to EU/EEA countries. These vaccines are mainly authorised by national regulatory agencies rather than centrally. This is because most of them were authorised before the creation of the European Medicines Agency in 1995. This means that confusingly influenza vaccines have been given different names in different countries in spite of them being the same product. The only exception is the recently introduced intranasal LAIV which was centrally authorised by the EMA and designated one name in the EU (Fluenz), but another in the US.

 

Immunity to influenza disease and influenza vaccines

For all infants and toddlers the first encounter with influenza viruses commonly occur first or second winter season of their life. Subsequently, each one of us acquires a number of influenza infections throughout life. It is expected that up to 15% of a European population in a temperate climate develop 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 including 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 adult individuals are most affected by seasonal influenza infections each year. I.e. paradoxically 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 severe disease.


 Table 2. Overview of available seasonal influenza vaccines in the EU/EEA

Manufacturer

Name of product*

Vaccine type

Adjuvant

Administration route

Produced in

Age recommended

Abbot healthcare

Influvac
Imuvac

Inactivated

None

im

Egg

From 6 mth

AstraZeneca

Fluenz
(US trade name Flumist)

Live attenuated

None

intranasal

Egg

From 24 mth to 17 yrs

Baxter

Preflucel

Inactivated

None

im

Cell

From 18 yrs

Crucell

Viroflu

Inflexal

Inactivated/virosomal

Inactivated/virosomal

 

None

None

 

im

im

 

Egg

Egg

 

From 6 mth, however increased fever reported in children 6 mth to 5 yrs

GlaxoSmithKline

Fluarix**

Inactivated

None

im

Egg

From 6 months

Novartis

Agrippal

Fluvirin

Optaflu

Fluad

Inactivated

Inactivated

Inactivated

Inactivated

None

None

None

Squalene (MF59)

im

im

im

im

Egg

Egg

Cell

Egg

From 6 mth

From 4 yrs

From 18 yrs

From 65 yrs

Omninvest

Fluval AB

Inactivated

None

im

Cell

From 6 mth

Pfizer/CSL Australia

Afluria***

Enzira

Inactivated

Inactivated

 

None

None

 

im

im

 

Egg

Egg

 

From 5 yrs, however increased fever reported in children 6 mo to 5 yrs

Sanofi Pasteur

Vaxigrip**

Intanza 9µg

Intanza 15µg

Inactivated

Inactivated

Inactivated

None

None

None

im

Intradermal

Intradermal

Egg

Egg

Egg

From 6 mth

From 18-59 yrs

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


The immune responses to updated influenza vaccine are evaluated each year through serological tests in a limited number of healthy individuals (n=~200 ). Currently this is according to set criteria established by the EMA CHMP* committee in 1997. Those immunogenicity criteria are:

For adults 18-59 years of age

  • Seroprotection rate must exceed a titre of >1:40 assessed by HAI in 70% of vaccinated individuals
  • Seroconversion rate by HAI 40%
  • Influenza-specific titre mean-fold increase 2.5 (assessed by HAI)

For older adults >65 years of age

  • Seroprotection rate must exceed a titre of >1:40 assessed by HAI in 60% of vaccinated individuals
  • Seroconversion rate by HAI 30%
  • Influenza-specific titre mean fold increase 2.0 (assessed by HAI)

No similar criteria exist for children. These criteria cannot by used for the intranasal LAIVs since mucosal vaccines elicit more mucosal and less systemic immune response. The 1997 criteria are now under review by the European Medicines Agency Committee for Medicinal Products for Human Use (CHMP).

Influenza vaccine efficacy and effectiveness

Before a new vaccine is authorised vaccine efficacy is evaluated in randomized controlled clinical trials conducted in healthy individuals of different age groups. Seasonal influenza infection disease may lead to complications mainly in individuals with chronic medical conditions and older people why those are targeted in many of the annual vaccination programs (see Risk Groups). These groups are commonly not included in any clinical trials before authorisation.

Table 3. Definitions

 



Vaccine efficacy
Estimates of the likelihood of a vaccine preventing laboratory confirmed infection under optimal circumstances – e.g. as determined in randomised controlled clinical trials when usually only healthy young adults are included.


Vaccine effectiveness
Estimates of the likelihood of a vaccine preventing laboratory confirmed infection when used in practice against a variety of groups including those in risk groups. Usually determined by well-designed observational studies allowing for possible confounding factors*.

Serological efficacy
Proportion of persons immunised with an influenza vaccine and whose blood shows the pre-agreed rise in antibody titres. Used for licensing and yearly updates of influenza vaccines.


Impact of vaccination
Impact of the influenza vaccination programme on a population level including reduction of disease and herd immunity when vaccine is offered to all recommended including those in the Risk Group i.e. expected lower responders due to aging immune system or clinically immunodeficient due to medical conditions or immunosuppressive therapy.

 

* Note: It is based on the definition in Last’s Dictionary of epidemiology, International Epidemiological Association, Oxford University Press 4th edition 2001. There is another definition of influenza vaccine effectiveness that is sometimes quoted which is estimates of the likelihood that vaccination will prevent the syndrome of influenza like illness (without laboratory confirmation). This second definition is not recommended by ECDC since such estimates will vary and will always underestimate true effectiveness because a proportion of influenza like illness is due to infections apart from influenza and this proportion will vary through the season.

 

Following the introduction of seasonal influenza vaccines in organised vaccination programs, vaccine effectiveness is best determined in observational studies. Obtained vaccine effectiveness in vaccination programs are expected to be lower than the initial vaccine efficacy seen in trials. However, the observational studies have demonstrated effectiveness in preventing complications and death. In Europe influenza vaccine effectiveness has been followed systematically since the influenza season 2008/2009. Although the current influenza vaccines are not as effective as we would wish them to be in preventing illness in those most at risk and they need to be improved, they remain the most effective single way that persons can protect themselves and their families against influenza.

Adverse reactions following vaccination

While no vaccine is risk free and there are some risks of adverse event following immunisation (AEFIs) with influenza vaccines they are far less common than influenza-related complications. The benefits of vaccination substantially out-weigh the risks.

Table 4. 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 (<1/1000)

  • Urticaria.
  • Febrile convulsions.

Rare complications

  • Septicaemia.
  • Encephalopathy.
  • Death.

Very rare adverse event (<1/10.000)

  • Anaphylaxis.
  • Paresthesies.
  • 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.

Contraindications and precautions

There are few individuals who cannot receive any influenza vaccine, however the individual Specific Product Characterization documents (SPCs) should be consulted before deciding on which vaccine should be given.
However, none of the influenza vaccines should be given to individuals that have experienced:

  • a confirmed anaphylactic reaction to a previous dose of the influenza vaccine, or
  • a confirmed anaphylactic reaction to any component of the vaccine (see precautions in the SPC documents).

Confirmed anaphylaxis is fortunately rare but other allergic reactions may occur such as development of a rash. Specialist advice must be sought when needed.

The live attenuated influenza vaccine should not be given to individuals with severe immunodeficient conditions or on immunosuppressive therapy including high dose corticosteroids. It is not contraindicated for use in children and adolescents with HIV infected individuals with good effect of antiretroviral treatment, allergic individuals receiving topical/inhaled corticosteroids. The live attenuated influenza vaccine is not recommended for children with active wheezing at the time of vaccination or severe asthma. For further details consult the SPC on Contraindications and Precautions.

Timing of influenza vaccination

Influenza activity is monitored year round in Europe but more intensely with combined clinical and virological sentinel surveillance from early October (week 40) in one year to the end of May (week 20) in the next year. It is rare that the annual influenza epidemics season starts before mid November and though there are often rises in influenza like illness in November this is almost always caused by other respiratory viruses notably respiratory syncytial virus (RSV).

After vaccination it is considered to take about 10 to 14 days before protection and an immune response develops. Therefore most countries start immunization in the early autumn. 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 holding back the vaccination campaigns to start in mid autumn.

Anticipated influenza vaccine developments

Besides an expected change for many of the authorised influenza vaccines to include a second influenza B strain in the future vaccines, there are other attempts to develop new influenza vaccines that would induce a better immune response in individuals that respond poorly to the current vaccines (due to aging immune system, affected immune system by either chronic disease or medications used to treat such conditions or the very young that never encountered influenza viruses before).

Optimally, new influenza vaccines should provide long-term protective immunity lasting for more than one season. An alternative development route could be and is already pursued by shortening the production time to significantly less than the current six months to enable a virological assessment and recommendation closer to the upcoming influenza season. Such vaccine candidates based on HA expressed in E.coli are in clinical trials. In addition, the EU DG RTD closed a research call in October 2012 focused on inviting researchers and manufacturers to development of new broader influenza vaccines. Only time will tell if such broader influenza vaccines inducing more long-term protective immunity can be developed.

Risk Groups

The Influenza Risk Groups are people who are more likely than others to develop severe disease should they be infected. Following an EU Council Recommendation of December 2009 in the EU/ EEA countries it is ECDC’s responsibility to summarise the evidence relevant to this. This does not produce ECDC recommendations but informs decisions by member states (MS) and other authorities. The most recent published ECDC review indicated strong evidence for immunising two large risk groups:

  • Older adults, and 
  • All persons (over six months of age) with chronic conditions

There is no sharp cut-off age for older adults and though the VENICE surveys show that many countries use age 65 years as a criteria, other countries use younger ages and no review of the data will achieve total consensus for Europe.

Some countries attempt to list all the chronic conditions. However ECDC does not take this route because the lists become endless and inconsistent between countries and the evidence for conditions involving low numbers will always be weak. Therefore ECDC prefers to recommend large groups of conditions and gives single examples.

All and any chronic conditions of the:

  • respiratory system e.g. asthma
  • cardiovascular system e.g. coronary artery disease
  • endocrine system e.g. diabetes
  • hepatic system e.g. 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) statement on immunisation delivered its opinion on seasonal influenza immunisation through the Weekly Epidemiological Record. This was supported by a background paper 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, all people with chronic conditions, and health care workers with patient contact.

WHO recognised that countries and circumstances vary, and the SAGE also recommended “the prioritization of specific target groups, local implementation timelines and target coverage goals should be determined at regional and country levels, as influenza immunization programmes are dependent on country-specific epidemiology, capacity and resources.”  See the WER page 208 The EU/EEA countries already have a target of 75% vaccination coverage in older people and those in the clinical risk groups from the 2009 Council Recommendation which will run until 2015.

The issue of immunising pregnant women and children are particularly difficult ones. The evidence for and against it was recently summarised by ECDC by  using a systematic review and an expert group and the issue of pregnant women was discussed in an ECDC Scientific Advance in November 2012

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