Seasonal Influenza Vaccine Safety: A Summary for Clinicians

Overview

Key Facts¹

• Seasonal influenza vaccination is the most important way of preventing seasonal influenza virus infections and potentially severe complications, including death. Seasonal influenza vaccination reduces the likelihood of becoming ill with influenza or transmitting influenza to others.
• The 2011-2012 seasonal influenza vaccine protects against an influenza A H3N2 virus, an influenza B virus, and the 2009 H1N1 virus that caused widespread illness in 2009-2010; initial doses of licensed vaccine are expected to be available by late August 2011.
  • Two types of seasonal influenza vaccine are licensed by the Food and Drug Administration (FDA) for use in the United States: trivalent inactivated influenza vaccine (TIV) and live, attenuated influenza vaccine (LAIV).
• TIV is injected into the muscle of the upper arm or thigh. It can be used for healthy people who are 6 months of age or older, and it can be used in people with chronic medical conditions and women who are pregnant. Healthy people are defined as people who do not have an underlying medical condition that predisposes them to influenza complications. Several TIV products are licensed for use in the United States (see Table 1 of Prevention and Control of Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2011).¹
• For the 2011-2012 influenza season, a new TIV product is available that uses a microinjection system with an ultra-fine needle that is 90% shorter than the typical needle for intradermal delivery. This vaccine is licensed and recommended for adults 18 through 64 years of age.¹
• LAIV is given as a nasal spray. It can be used for healthy people 2-49 years of age who are not pregnant.
• Both seasonal LAIV and TIV contain three strains of influenza viruses that are antigenically equivalent to the annually recommended strains: one influenza A (H3N2) virus, one influenza A (H1N1) virus, and one influenza B virus. Each year, before influenza season starts, one or more virus strains in the vaccine might be changed on the basis of global surveillance for influenza viruses and the emergence and spread of new strains.
• Influenza vaccines, like any medical product, carry some risks but serious adverse events after influenza vaccination are uncommon. Adverse events after vaccination may be causally related to vaccine or may be coincidental. When seasonal influenza vaccines are administered according to the licensed indication and usage information, the risk of clinically meaningful adverse events is very low.
• All seasonal influenza vaccines licensed in the United States are produced in eggs and they do not contain adjuvants. Some multidose TIV preparations contain thimerosal which is used as a preservative to prevent bacterial growth.

CDC and FDA routinely 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 TIV and LAIV, including adverse events, contraindications and precautions, screening, and safe vaccine administration;
• The Vaccine Adverse Event Reporting System (VAERS); and
• Additional resources for clinicians about influenza vaccines and vaccine safety.

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Trivalent Inactivated Influenza Vaccine (TIV)

Adverse Events

Studies support the safety of annual TIV vaccination in children and adults. TIV is administered as an injection and may cause reactions at the injection site, such as pain, redness, and swelling. Systemic events that may occur after TIV may or may not be caused by the vaccine. Some people experience symptoms after TIV that are also those seen in influenza infection, but TIV (which contains inactivated virus) cannot cause influenza. More information about TIV 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 TIV experience pain at the injection site, which usually resolves in <2 days without treatment.²
• Fever, malaise, myalgia, and other systemic symptoms that can occur after vaccination with TIV 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 TIV and after a placebo vaccine.¹
• Ocular or respiratory symptoms (e.g., red eyes, hoarse voice, cough) have occasionally been reported within 24 hours after TIV administration in some studies, but are typically mild and resolve quickly without specific treatment.¹
• Vaccine components can rarely cause true allergic reactions, also called immediate hypersensitivity reactions, among certain recipients. Symptoms of immediate hypersensitivity range from mild urticaria (hives) and angioedema (swelling beneath the skin) to anaphylaxis.^1,5
• In a study of more than 250,000 children aged <18 years, the investigators did not identify risk for any important adverse events after TIV.‡³
• Another study evaluated adverse events in adults across 15 years and showed that reporting rates for adverse events after TIV were reasonably consistent over time. This study did not identify any new safety concerns.§⁴

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• In April 2010, Australia suspended 2010-2011 seasonal trivalent influenza vaccinations for all children <5 years after reports of febrile seizures following vaccination.
  • Administration of CSL’s 2010 Southern Hemisphere influenza vaccine Fluvax has been associated with increased postmarketing reports of fever and febrile seizures in children predominantly below the age of 5 years as compared to previous years.
  • CSL has changed its package insert for its influenza vaccine licensed in the United States under the name Afluria to include this warning. Although the manufacturer will not be supplying the 0.25 mL presentation to the United States that is used in children 6 months - 35 months of age, the 0.5 mL single dose, prefilled syringe and 5 mL multi-dose vial presentation will be distributed.
  • The ACIP recommends that Afluria should not be used in children aged 6 months through 8 years. Other age-appropriate, licensed seasonal influenza vaccine formulations should be used for prevention of influenza in children aged 6 months through 8 years. If no other age-appropriate, licensed seasonal influenza vaccine is available for a child aged 5 years through 8 years old who has a medical condition that increases their risk for influenza complications, Afluria may be given, and providers should discuss the benefits and risks of influenza vaccination with the parents or caregivers before administering Afluria.⁶
• A study conducted during the 2010-11 influenza season using the Vaccine Safety Datalink (VSD) Project followed over 200,000 children 6 months through 4 years of age and showed that febrile seizures following flu and PCV13 vaccines did happen but were rare. The febrile seizures were most common in children ages 12 through 23 months when the two vaccines were given during the same healthcare visit. In this group about 1 additional febrile seizure occurred among every 2,225 children vaccinated.
  • CDC and FDA, in consultation with the Advisory Committee on Immunization Practices (ACIP), have reviewed vaccine safety data on febrile seizures in the United States following 2010-11 inactivated influenza (flu) and pneumococcal conjugate (PCV13) vaccines. After thoroughly evaluating the available data, CDC has determined that no changes in the immunization schedule are necessary at this time.
• In 1976, a type of influenza (swine flu) vaccine was associated with Guillain–Barré Syndrome (GBS), a serious neurological condition that can cause paralysis.¹ The 1976 influenza virus was different from the 2009 H1N1 virus.
  • 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.
  • In 1976, there was a small risk of GBS following influenza (swine flu) vaccination (approximately 1 additional case per 100,000 people who received the swine influenza vaccine). That number of GBS cases was slightly higher than the background rate for GBS.
  • Since then, numerous studies have been done to evaluate if other influenza vaccines were associated with GBS. In most studies, no association was found, but two studies suggested that approximately¹ additional person out of 1 million vaccinated people may be at risk for GBS associated with the seasonal influenza vaccine.¹ In addition, preliminary data from CDC’s Emerging Infections Program showed 0.8 excess cases of GBS per 1 million vaccinations for the H1N1 influenza vaccine, similar to that found in seasonal influenza vaccine.⁷ Further analyses are being conducted.
  • 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 TIV

• Persons who have had a prior severe allergic reaction to TIV, regardless of the component suspected to be responsible for the reaction.
• 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 TIV: ^1,5

• Guillain–Barré Syndrome (GBS) within 6 weeks of a previous dose of an influenza vaccine (TIV 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.

Influenza vaccination of persons with a history of egg allergy¹

• All licensed and recommended influenza vaccines in the US are made using egg-based manufacturing processes.

• Persons with a history reactions to egg involving angioedema, respiratory distress, lightheadedness, or recurrent emesis, or persons who required epinephrine or other emergency medical intervention, immediately or within minutes of exposure, or have had anaphylactic reaction upon reexposure to egg proteins, should be referred to an allergy specialist before receipt of vaccine.¹
• Updated recommendations for influenza vaccination of persons who have experienced only hives following exposure to eggs are available for the 2011-2012 influenza season.^1,5
• The updated recommendations include guidance and algorithms to help clinicians determine the appropriate approach to administering vaccines in these invididuals.

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Screening before vaccination

• Before administering an influenza vaccine, people should be asked about the following:^1,5
  • 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; and
  • Current health status, including any current (acute) illness.

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Safe vaccine administration

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

• TIV should be administered by intramuscular injection or intradermal infection if using the intradermal TIV using appropriate technique.
• Providers vaccinating children and adolescents aged <18 years should be sure the TIV formulation is licensed for use in children in their patients’ age group and the proper dose is used. TIV 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 TIV vaccination.⁵

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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 TIV or placebo in adults and children.⁸ More information is provided below:

• Most common adverse reactions (10% in FluMist and at least 5% greater than in control) are runny nose or nasal congestion in all ages, fever >100F in children 2-6 years of age, and sore throat in adults.⁸
• In a placebo-controlled safety study conducted in a large Health Maintenance Organization (HMO) in children 1-17 years of age (n = 9689), an increase in asthma events, captured by review of diagnostic codes, was observed in children <5 years of age (Relative Risk 3.53, 90% CI: 1.1, 15.7)⁸
  • One study of 8352 children aged 6 through 59 months showed that the younger children aged 6 through 23 months had increased rates of wheezing in the 42 days after LAIV (6%) than TIV (4%) (LAIV is not licensed for this age group). Children aged 24 through 59 months had similar rates of wheezing after LAIV (2%) and TIV (3%).^{8, 10}
• In children aged 2 through 6 years, fever >100° F occurred more often after first dose LAIV (16%) than placebo (11%).⁸Adults receiving LAIV did not have an increased risk for fever after vaccination compared with placebo.⁸
• 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.⁸

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Contraindications for LAIV

• Persons with a history reactions to egg involving angioedema, respiratory distress, lightheadedness, or recurrent emesis, or persons who required epinephrine or other emergency medical intervention, immediately or within minutes of exposure, or have had anaphylactic reaction upon reexposure to egg proteins, should be referred to an allergy specialist before receipt of vaccine.¹
• Persons who have had a prior severe allergic reaction to LAIV, regardless of the component suspected to be responsible for the reaction.

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 (TIV 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:^1,5
  • 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. TIV is available for use in children with asthma or possible reactive airways disease.

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Safe vaccine administration

• Severely immunosuppressed persons should not administer LAIV. However, persons with other high-risk conditions for influenza complications can administer LAIV. In addition, healthcare providers or other close contacts of severely immunocompromised persons should receive TIV, 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).⁸
• Providers should consult the ACIP General Recommendations regarding other steps to take that may help prevent adverse events after LAIV vaccination.⁵

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Reporting Adverse Events

• The Vaccine Adverse Event Reporting System (VAERS) is a US vaccine safety surveillance system, co-managed by CDC and FDA.
• VAERS is a voluntary post-marketing safety surveillance program, collecting information about reported adverse events (possible side effects) that occur after administration of vaccines licensed in the United States.
• VAERS is a key mechanism to identify potential vaccine safety concerns. Generally VAERS cannot determine if an adverse event was caused by vaccine but can help determine if further investigations are needed.
• 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 reports may be filed securely online (VAERS web site), by mail, or by fax. Report forms are available online or can be obtained by calling 1-800-822-7967 to request reporting forms or other assistance.
• Clinicians and other reporters of adverse events should be encouraged, when submitting a report to VAERS, to include as much information as possible (e.g., vaccination location, date, vaccine type, lot number and dose).
• VAERS data without identifiers may be accessed through the CDC Wide-ranging Online Data for Epidemiologic Research (WONDER) public database within about 1 week after CDC receives the VAERS report or for download at the VAERS web site within about 6 weeks after CDC receives the VAERS report.
• Additional information about VAERS is available at the VAERS web site.

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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.

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References

1. Prevention and Control of Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2011 
2. Package inserts for influenza vaccines licensed in the United States
3. 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.
4. 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.
5. 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.
6. CDC. Update: Recommendations of the Advisory Committee on Immunization Practices (ACIP) Regarding Use of CSL Seasonal Influenza Vaccine (Afluria) in the United States During 2010-11. 2010 ;59(31):989-992.
7. C Prothro, Kudish K, M Fiellin, et al. Preliminary Results: Surveillance for Guillain-Barré Syndrome After Receipt of Influenza A (H1N1) 2009 Monovalent Vaccine. United States, 2009–2010. MMWR 2010; 59(21);657-661.
8. FluMist® package insert for 2010-2011 influenza vaccines.
9. Belshe, RB, Ambrose CS, and Tingting Y. Safety and efficacy in live, attenuated influenza vaccine in children 2-7 years of age. Vaccine. 2008 (26S):D10-D16.
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.

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* The following are conditions are considered to increase risk for influenza complications: chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, neurological/neuromuscular, hematological, or metabolic disorders (including diabetes mellitus); immunosuppression (including immunosuppression caused by medications or by HIV); children or adolescents aged 6 months--18 years receiving aspirin or other salicylates (because of the association of Reye syndrome with wild-type influenza virus infection) and pregnant women.

†The following are classified as serious adverse events: death, hospitalization or prolongation of hospitalization, life-threatening illness, persistent or significant disability/incapacity, or certain other medically important conditions.

‡The study, conducted in the Vaccine Safety Datalink (VSD) assessed for associations between TIV and multiple medically–attended events in the 2 weeks after TIV. After chart review, an increased risk after TIV 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.

**Reye syndrome is a life-threatening medical condition characterized by acute encephalopathy and fatty degeneration of liver. Using aspirin in children aged <=18 years with viral infections, such as influenza, increases the risk of Reye syndrome.

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