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Seasonal Influenza Vaccine Safety: A Summary for Clinicians

Overview

Key Facts1

  • Annual influenza vaccination is the most important way of preventing seasonal influenza virus infections and potentially severe complications, including death. Vaccination reduces the likelihood of becoming ill with influenza or transmitting influenza to others.
  • For the 2013-2014 influenza season, trivalent and quadrivalent inactivated influenza vaccine (IIV) is available. All live, attenuated influenza vaccine (LAIV) in the U.S. is quadrivalent.
  • The trivalent IIV protects against three influenza viruses – one influenza A (H3N2) virus, one influenza A (H1N1) virus, and one influenza B virus. Quadrivalent IIV and LAIV protect against the same three viruses as the trivalent vaccine, but also protect against an additional influenza B virus.
  • Two influenza vaccines available this season, Flucelvax® and Flublok®, are manufactured using new production techniques: Flucelvax® is the first seasonal influenza vaccine licensed in the United States that is produced using cultured animal cells instead of fertilized chicken eggs. Flublok® is the first seasonal influenza vaccine made using recombinant techniques and does not use eggs at all in its production. Flublok® also does not use the influenza virus in its production.
  • Information and recommendations about all influenza vaccines available for 2013-2014 can be found here.

CDC and FDA monitor the safety of all vaccines licensed in the United States, including seasonal influenza vaccines. This summary provides the following information on seasonal influenza vaccines:

  • Safety of IIV, recombinant influenza vaccine (RIV), cell culture inactivated influenza vaccine (ccIIV), and LAIV, including adverse events, contraindications and precautions, screening, and safe vaccine administration
  • The Vaccine Adverse Event Reporting System (VAERS)
  • Additional resources for clinicians about influenza vaccines and vaccine safety
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Inactivated Influenza Vaccine (IIV)

Adverse Events

Because they have not been used in the general population yet, there are no post-licensure safety data for the new quadrivalent IIVs, ccIIV, and RIV. However, data from pre-licensure clinical trials indicate that these vaccines have similar safety profiles as trivalent IIVs. Studies support the safety of annual IIV vaccination in children and adults. IIV is administered as an injection and may cause reactions at the injection site, such as pain, redness, and swelling. Systemic events can occur after IIV but are usually mild and self-limited. IIV (which contains inactivated virus) cannot cause influenza. More information about IIV safety is provided below:

  • The most frequent reactions reported after vaccination in children and adults are pain and other injection-site reactions. Up to 64% of people vaccinated with IIV experience pain at the injection site, which usually resolves in <2 days without treatment.3
  • Fever, malaise, myalgia, and other systemic symptoms that can occur after vaccination with IIV most often affect persons who have had no previous exposure to the influenza virus antigens in the vaccine (e.g., young children). In adults the rate of having these events is similar after IIV and after a placebo injection.1
  • Ocular or respiratory symptoms (e.g., red eyes, hoarse voice, cough) have occasionally been reported within 24 hours after IIV administration in some studies, but are typically mild and resolve quickly without specific treatment.1
  • Vaccine components can on rare occasions cause allergic reactions, also called immediate hypersensitivity reactions. Symptoms of immediate hypersensitivity range from mild urticaria (hives) and angioedema (swelling beneath the skin) to anaphylaxis.1,4
  • In a study of more than 250,000 children aged <18 years, the investigators did not identify risk for any clinically important adverse events after IIV.‡5
  • Another study evaluated adverse events in adults across 15 years and showed that reporting rates for adverse events after IIV were reasonably consistent over time. This study did not identify any new safety concerns.§6
  • In the 2010-2011 and 2011-2012 seasons CDC monitoring detected an increased risk for febrile seizures in young children following IIV. During the 2012-2013 influenza season, no increased risk was detected. The reason for the difference from the previous two influenza seasons is not known. However, the composition of flu vaccines changed between the 2011-2012 and the 2012-2013 seasons. Flu vaccine composition often changes year-to-year, and CDC and FDA will continue to closely monitor the safety of influenza vaccines each season.
  • Temporally associated Guillain–Barré Syndrome (GBS) cases following IIV have been observed/reported; gastrointestinal and upper respiratory infections are known risk factors for GBS, which is a serious neurological condition that can cause paralysis.
    • Safety monitoring of seasonal IIV over the course of many years has not detected a clear link to Guillain-Barré Syndrome (GBS). However, if there is a risk of GBS from current IIV, it would be no more than 1 or 2 cases per million people vaccinated.1 This is much lower than the risk of severe influenza, which can be prevented by vaccination.
    • Each year, about 3,000 to 6,000 people in the United States develop GBS whether or not they received a vaccination — that’s 1 to 2 people out of every 100,000 people.
    • For comparison, an estimated 750 per million adults are hospitalized with seasonal influenza each year; many of these cases could be prevented by vaccination. In addition, studies suggest that the risk of developing GBS after having influenza is higher than the potential risk of developing GBS after vaccination.1
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Contraindications for IIV

IIV should not be administered to the following:1

  • People who have experienced a severe (life threatening) allergy to a prior dose of an seasonal influenza vaccine (IIV or LAIV)
  • People who have a severe allergy to a component of the IIV vaccine. Package inserts should be consulted for components3

Recommendations for vaccinating egg allergic patients are available. Most egg allergic patients can safely receive IIV. Individuals with a history of severe (life threatening) allergy to eating eggs should consult with a specialist with expertise in allergy prior to receiving IIV.

  • IIV should not be administered to infants less than 6 months of age.

Precautions

In general, vaccinations should be deferred when a precaution is present. However, a vaccination might be indicated in the presence of a precaution because the benefit of protection from the vaccine outweighs the risk for an adverse reaction. This is left to the healthcare provider to make a decision. The following are precautions for IIV: 1,4

  • Guillain–Barré Syndrome (GBS) within 6 weeks of a previous dose of an influenza vaccine (IIV or LAIV); and
  • Presence of a moderate or severe acute illness with or without a fever. Persons who were hospitalized with an acute illness but who are now well enough to be discharged from a hospital can be vaccinated.

Screening Before Vaccination

  • Before administering an influenza vaccine, people should be asked about the following: 1,4
    • Allergies – asking the persons if they can eat eggs without adverse effects is a good way to screen for egg allergy
    • Adverse events, including GBS, after prior doses of influenza vaccine
    • Current health status, including any current (acute) illness

Safe Vaccine Administration

To reduce the risk of adverse events after vaccination the follow steps should be taken:5

  • IIV should be administered by intramuscular injection, or intradermal injection in the case of intradermal IIV, using appropriate technique.
  • Providers vaccinating children and adolescents aged <19 years should be sure the IIV formulation is licensed for use in children in their patients’ age group and the proper dose is used. IIV is not licensed for use in infants aged <6 months.
  • Providers should consult the Advisory Committee on Immunization Practices (ACIP) General Recommendations regarding other steps to take that may help prevent adverse events after IIV vaccination.4
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Recombinant Influenza Vaccine (RIV)

RIV refers to recombinant hemagglutinin influenza vaccine, available as a trivalent formulation (RIV3) for 2013-2014. Flublok® is a newly licensed seasonal influenza vaccine made using recombinant techniques and does not use eggs at all in its production. Flublok® also does not use the influenza virus in its production and contains no egg proteins, antibiotics, or preservatives. It is indicated for active immunization against disease caused by influenza virus subtypes A and type B and is approved for use in persons 18 through 49 years of age. During clinical trials, the most common injection-site reaction was pain (>37%); the most common solicited systemic adverse reactions were headache (>15%), fatigue (>15%) and myalgia (>11%). Safety and effectiveness of RIV3 have not been established in pregnant women, nursing mothers, children, or adults 50 years of age and older. Postmarketing safety data are not yet available for RIV3.

Flublok® is contraindicated in individuals with known severe allergic reactions (e.g., anaphylaxis), to any component of the vaccine.

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Live, Attenuated Influenza Vaccine (LAIV)

Adverse Events

Studies support the safety of LAIV. LAIV is administered as an intranasal vaccine and replicates in the nose. Rhinitis (runny nose) and nasal congestion occur more commonly after LAIV than IIV or placebo in adults and children.8 More information on trivalent LAIV is provided below:

  • Most common adverse reactions are runny nose or nasal congestion in all ages, fever >100F in children 2-6 years of age, and sore throat in adults.9
  • One study of 8352 children aged 6 through 59 months showed that the younger children aged 6 through 23 months (an age group for which LAIV is not licensed) had increased rates of wheezing in the 42 days after LAIV (6%) than after IIV (4%). Children aged 24 through 59 months had similar rates of wheezing after LAIV (2%) and IIV (3%).10
  • In children aged 2 through 6 years, fever >100° F occurred more often after first dose LAIV (16%) than placebo (11%).9 Adults receiving LAIV did not have an increased risk for fever after vaccination compared with placebo.9
  • In adults the following other adverse events were reported more often after LAIV than after an intranasal placebo: headache, sore throat, tiredness/weakness, muscles aches, cough, chills, and sinusitis.9

In clinical trials, quadrivalent LAIV had a similar safety profile as trivalent LAIV, with the exception of slightly more fever after the first dose of quadrivalent LAIV compared to trivalent LAIV in a subset of children 2-8 years old.

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Contraindications

LAIV should not be administered to people who have had a severe allergic reaction to the following:

  • Severe allergy to eggs.
  • Severe allergy to another component of the LAIV vaccine. The package insert should be consulted for components.9
  • Severe allergy to a prior dose of an influenza vaccine (IIV or LAIV).

 

LAIV should also not be administered to people who are in the following groups because the effectiveness or safety of LAIV is not known:

  • Children aged <2 years or adults aged ≥50 years
  • Pregnant women
  • People with known or suspected immunodeficiency diseases or immunosuppressed states (including those caused by HIV)
  • Children or adolescents receiving aspirin or other salicylates (because of the association of Reye syndrome with wild-type influenza virus infection)
  • People who have other medical conditions that place them at increased risk for complications from influenza, including:
    • Asthma or reactive airways disease
    • Other chronic disorders of the pulmonary or cardiovascular system (except hypertension)
    • Neurological/neuromuscular diseases
    • Metabolic disease, such as diabetes mellitus
    • Renal or hepatic dysfunction
    • Hemoglobinapathies

Precautions

The following are precautions for use of LAIV

  • Guillain-Barré Syndrome (GBS) within 6 weeks of a previous dose of an influenza vaccine (IIV or LAIV)1
  • Presence of a moderate or severe acute illness with or without a fever.5 Persons who were hospitalized with an acute illness but who are now well enough to be discharged from a hospital can be vaccinated.
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Screening Before Vaccination

  • Before administering an influenza vaccine, people should be asked about the following:1,4
    • Allergies. Asking the persons if they can eat eggs without adverse effects is a good way to screen for egg allergy.
    • Adverse events, including GBS, after prior doses of influenza vaccine
    • Current health status
  • Young children may experience episodes of wheezing in association with certain respiratory viruses. Some young children might have a history of wheezing but have not had asthma diagnosed. The following screening recommendations should be used to assist persons who administer influenza vaccines in providing the appropriate vaccine for children aged 2 through 4 years.1
    • Screen for possible reactive airways diseases when considering use of LAIV for children aged 2 through 4 years, and avoid use of this vaccine in children with asthma or a recent wheezing episode.
    • Consult the medical record, when available, to identify children aged 2 through 4 years with asthma or recurrent wheezing that might indicate asthma.
    • Ask parents or caregivers of children aged 2 through 4 years: “In the past 12 months, has a healthcare provider ever told you that your child had wheezing or asthma?”
    • Do not administer LAIV to children whose parents or caregivers answer “yes” to this question and children who have asthma or who had a wheezing episode noted in the medical record during the preceding 12 months should not receive LAIV. IIV is available for use in children with asthma or possible reactive airways disease.
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Safe Vaccine Administration

  • Healthcare providers that are treating severely immunocompromised patients (e.g., patients with hematopoietic stem cell transplants) and close contacts of these patients should receive IIV, rather than LAIV. The rationale for these recommendations is the theoretical risk that a live, attenuated vaccine virus could be transmitted to the severely immunosuppressed person.1
  • LAIV should be administered by an intranasal squirt using appropriate technique (see package insert).9
  • Providers should consult the ACIP General Recommendations regarding other steps to take that may help prevent adverse events after LAIV vaccination.4

Reporting Adverse Events

  • Healthcare providers are encouraged to report all clinically significant adverse events after influenza vaccines and other vaccines to VAERS, even if the healthcare provider is not certain that the vaccine caused the event. Anyone may submit a report to VAERS.
  • VAERS data without identifiers may be accessed through the CDC Wide-ranging Online Data for Epidemiologic Research (WONDER) public database or for download at the VAERS web site.
  • Additional information about VAERS is available at the VAERS web site.

The National Vaccine Injury Compensation Program

The National Vaccine Injury Compensation Program (VICP) is a federal program operated by the Health Resources and Services Administration (HRSA). VICP exists to help pay for the care of certain persons found to have had a serious reaction to a vaccine covered by the VICP. For more information about VICP, call 1-800-338-2382 or visit the National Vaccine Injury Compensation Program (VICP) web site.

References

  1. Fiore T, Uyeki T, Broder K et al. Prevention and control of seasonal influenza with vaccines: Recommendations of the Advisory Committee on Immunization Practices. 2010. MMWR Recomm Rep. 2010;59:(RR-8):1-66.
  2. 2012-2013 CDC MMWR: Prevention and Control of Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP) — United States, 2012–13 Influenza Season.
  3. Package inserts for influenza vaccines licensed in the United States
  4. Kroger AT, Sumaya CV, Pickering LK, et al. General recommendations on immunization --- recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2011;60:1-64.
  5. France, EK, Glanz, JM, Xu, S, et al., Safety of the trivalent inactivated influenza vaccine among children: a population-based study. Arch Pediatr Adolesc Med, 2004. 158(11): p. 1031-6.
  6. Vellozzi C, Burwen DR, Dobardzic A, Ball R, Walton K, Haber P. Safety of trivalent inactivated influenza vaccines in adults: Background for pandemic influenza vaccine safety monitoring. Vaccine. 2009:27:2114-2120.
  7. Tse A, Tseng HF, Greene SK, et al. Signal identification and evaluation for risk of febrile seizures in children following trivalent inactivated influenza vaccine in the Vaccine Safety Datalink Project, 2010-2011. Vaccine. 2012;30:2024-31
  8. Grohskopf L, Uyeki T, Bresee J, et al. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2011. MMWR Morb Mortal Wkly Rep. 2011;60:1128-32.
  9. FluMist® package insert for 2012-2013 influenza vaccines [536 KB, 22 pages].
  10. Belshe RB, Edwards KM, Vesikari T, et al. Live attenuated versus inactivated influenza vaccine in infants and young children. N Engl J Med 2007;356:685-96.

‡ The study, conducted in the Vaccine Safety Datalink (VSD) assessed for associations between IIV and multiple medically–attended events in the 2 weeks after IIV. After chart review, an increased risk after IIV was observed only for impetigo, which was not considered by the investigators to be medically important.

§ The study was conducted in the Vaccine Adverse Event Reporting System (VAERS) to identify possible safety concerns that might warrant further association; it was not designed to quantify risk of specific adverse events after vaccination.

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