Vaccine Preventable Diseases

Influenza

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Advisory Committee on Immunization Practices (ACIP) Recommendations

All Age Groups
- All persons witout contraindications who are 6 months of age and older should receive annual vaccination with inactivated influenza vaccine (abbreviation: IIV; trade names: see the table below).
- Live attenuated influenza vaccine (abbreviation: LAIV; trade name: FluMist®) was previously recommended for non-pregnant persons between 2 and 49 years of age; however, in June 2016, the ACIP recommended that LAIV not be used until problems with low effectiveness during the past several seasons are addressed [1].
- Influenza vaccine should be given as soon as it becomes available (usually between August and October in the U.S.) in order to ensure the highest possible level of protection before rates of transmission increase. Peak transmission season is usually between December and March in the United States [2].

Infants and Children
- Children less than 9 years of age receiving IIV for the first time ever should receive two doses at least one month apart; otherwise, one dose per year is sufficient [1].

For More Information
ACIP recommendations: https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/flu.html
Immunization schedules: http://www.cdc.gov/vaccines/schedules/index.html
 

Disease 

Influenza is caused by RNA viruses of three types. Type A influenza is the cause of most human illness and has many subtypes based on the variations in the surface antigens (i.e., hemagglutinin (H) and neuraminidase (N)), such as H1N1 or H3N2. Type B influenza also infects humans but generally causes milder illness. Type C only very rarely causes human disease.

The surface antigens on influenza viruses are always evolving, faster than most other viruses that cause human disease. This continuous stream of minor mutations is called antigenic drift and is what makes influenza so adept at evading immunity induced by prior infection or vaccination. In most years, at least some of the circulating influenza strains have drifted compared to prior years, thus even those who were infected or vaccinated in years prior may develop influenza disease again.

Occasionally a major change in one or both surface antigens occurs, known as antigenic shift; the majority of the population is usually susceptible to the new virus. The new strains generated in this manner, such as the 2009 influenza A H1N1, have the potential to cause a worldwide pandemic.

The incubation period for influenza is generally 2 days [2]. The major clinical symptoms typically last a median of 4 days without treatment and include sore throat, fever, headache, myalgia, and nonproductive cough [2, 3]. The CDC estimated an average of 23,607 annual influenza-associated deaths in the United States between 1976 and 2007, although these estimates ranged widely from year to year [4].

Vaccine

Two types of vaccines have been available to protect against influenza in recent years: inactivated influenza vaccine (IIV) and live attenuated influenza vaccine (LAIV). However, LAIV is no longer recommended.

In the United States, quadrivalent IIV (IIV4) vaccines include Fluarix® Quadrivalent, FluLaval® Quadrivalent, and Fluzone® Quadrivalent; trivalent IIV (IIV3) include Afluria®, Fluvirin®, and Fluzone®. There is one recombinant influenza vaccine (RIV3), Flublok®. Trivalent vaccines contain one A/H3N2 strain, one A/H1N1 strain, and one B strain from one of the two B lineages (Yamagata and Victoria). The Quadrivalent vaccines contain a second B strain [1, 2].

Inactivated influenza vaccine (IIV)

Route of administration Primarily intramuscular (IM), one intradermal (ID); specified for each vaccine listed below
Vaccine virus Inactivated, split or subvirion
Trade names, doses available, age range of approval Standard dose
Fluzone® Quadrivalent (0.5 mL single-dose vial or prefilled syringe) (IM), for persons > 36 months of age;
Fluzone® Quadrivalent (5.0 mL multi-dose vial) (IM), for persons > 6 months of age;
Fluarix® span Quadrivalent (0.5 mL single-dose prefilled syringe) (IM), for persons > 3 years of age;
FluLaval Quadrivalent (5.0 mL multi-dose vial) (IM), for persons > 3 years of age; Flucelvax® Quadrivalent (0.5 mL single-dose prefilled syringe) (IM), cell culture-based, for persons > 4 years of age;
Afluria® (0.5 mL single-dose prefilled syringe or 5.0 mL multi-dose vial) (IM), for persons > 9 years of age;
Fluvirin® (0.5 mL single-dose prefilled syringe or 5.0 mL multi-dose vial) (IM), for persons > 4 years of age;
Fluad® (0.5 mL single-dose prefilled syringe) (IM), adjuvanted, for adults > 65 years of age.
High dose
Fluzone® High-Dose (0.5 mL single-dose prefilled syringe) (IM) (higher antigen content), for adults > 65 years of age;
Recombinant
Flublok® ((0.5 mL single-dose vial) (IM), for adults > 18 years of age.
Intradermal
Fluzone® Intradermal Quadrivalent (0.1 mL single-dose prefilled microinjection system) (ID) (lower antigen content), for adults 18-64 years of age.


Vaccine Effectiveness: The effectiveness of influenza vaccines varies each year in relation to the match between the vaccine strains and the circulating strain. Effectiveness can also vary by the age and health status of the vaccine recipient [2].

Vaccine Safety: Common adverse reactions to IIV include local reactions such as soreness, erythema and induration at the injection site, which are reported at variable rates, but are usually mild and typically last no more than 2 days. Systemic symptoms such as sensation of fever, chills, malaise, and myalgia are also common. These symptoms typically begin within 6–12 hours of vaccination and usually last for only a few hours. Such symptoms are usually mild but have been reported in 4-<30% of children receiving IIV [5-11]. Myalgia within a week of vaccination has been reported among 14-16% of adults receiving unadjuvanted IIV and 31-39% of adults receiving adjuvanted IIV [12], with even higher rates among recipients of the 2009 pandemic H1N1 vaccine [13].

Rarely, allergic reactions such as hives, angioedema, allergic asthma, or systemic anaphylaxis occur after vaccination, probably due to hypersensitivity to a vaccine component. See the Do Vaccines Cause Hypersensitivity Reactions? summary for more details.

Influenza vaccination in recent years has been associated with a very small increased risk of GBS in adults, leading to about 1-3 excess cases of GBS per million persons vaccinated. This is much less than the estimated risk after wild-type influenza infection, providing further evidence that the benefits of influenza vaccination greatly outweigh the risks [14]. See the Do Vaccines Cause Guillain-Barré Syndrome (GBS)? summary for more details.

A large body of evidence demonstrates the safety of IIV for both pregnant women and their unborn children [15-21].

Contraindications and Precautions: An important contraindication is having had a severe allergic reaction (e.g. anaphylaxis) to a vaccine component or previous vaccination. However, this does not include egg allergies, even though most influenza vaccines are grown in embryonated chicken eggs (an exception being the egg-free recombinant influenza vaccine, Flublok®) [1]. The following is a direct excerpt from the 2016-17 ACIP recommendations regarding the use of influenza vaccine in persons with egg allergy:

Persons with a history of egg allergy who have experienced only hives after exposure to egg should receive influenza vaccine. Any licensed and recommended influenza vaccine (i.e., any age-appropriate IIV or RIV3) that is otherwise appropriate for the recipient’s age and health status may be used.
Persons who report having had reactions to egg involving symptoms other than hives, such as angioedema, respiratory distress, lightheadedness, or recurrent emesis; or who required epinephrine or another emergency medical intervention, may similarly receive any licensed and recommended influenza vaccine (i.e., any age-appropriate IIV or RIV3) that is otherwise appropriate for the recipient’s age and health status. The selected vaccine should be administered in an inpatient or outpatient medical setting (including but not necessarily limited to hospitals, clinics, health departments, and physician offices). Vaccine administration should be supervised by a health care provider who is able to recognize and manage severe allergic conditions.
A previous severe allergic reaction to influenza vaccine, regardless of the component suspected of being responsible for the reaction, is a contraindication to future receipt of the vaccine.
” [1]

Precautions include moderate to severe acute illness with or without fever, as well as a diagnosis of Guillain-Barré Syndrome (GBS) within 6 weeks after a previous dose of influenza vaccine [1]. The complete current recommendations of the ACIP regarding influenza vaccine delivery can be found at the following website: https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/flu.html.

Considerations in Pregnancy: Inactivated influenza vaccine (IIV) is routinely recommended during pregnancy. Live attenuated influenza vaccine (LAIV) is contraindicated during pregnancy.

Pregnant women and young children are at increased risk of complications and hospitalizations from influenza. Infection with influenza during pregnancy has been associated with an increased risk of adverse outcomes to the mother including, respiratory hospitalization, pneumonia, adult respiratory distress syndrome, overwhelming sepsis and death [22]. A recent CDC study estimated that 12% of all pregnancy-related deaths during the 2009-2010 pandemic season were attributed to confirmed or possible infection with pandemic influenza [23].

IIV was shown to reduce non-specific febrile respiratory illness in pregnant women by over one third. Vaccine effectiveness varied throughout the 15 months of observation, increasing during influenza season. Vaccination in pregnancy is beneficial not just for the mother, but for her unborn child as well. Maternal influenza vaccination was shown in one study to reduce proven influenza illness in infants under 6 months of age by up to 63% [24]. In several other studies, IIV was shown to reduce the risk of low birthweight and premature birth [25, 26].

A large body of evidence demonstrates the safety of IIV for both pregnant women and their unborn children [15-21]. Pregnant women who receive influenza vaccine have a lower likelihood of stillbirth than those who do not [27]. Concomitant administration of Tdap and influenza vaccines during pregnancy is not associated with a higher risk of adverse outcomes compared to sequential vaccination [28].

References

1. Grohskopf LA, Sokolow LZ, Broder KR, et al. Prevention and Control of Seasonal Influenza with Vaccines. MMWR Recomm Rep 2016;65:1-54.
2. Epidemiology and Prevention of Vaccine-Preventable Diseases. Washington D.C.: Centers for Disease Control and Prevention; 2015.
3. Fry AM, Goswami D, Nahar K, et al. Efficacy of oseltamivir treatment started within 5 days of symptom onset to reduce influenza illness duration and virus shedding in an urban setting in Bangladesh: a randomised placebo-controlled trial. The Lancet Infectious diseases 2014;14:109-18.
4. Estimates of deaths associated with seasonal influenza --- United States, 1976-2007. MMWR Morb Mortal Wkly Rep 2010;59:1057-62.
5. Brady RC, Hu W, Houchin VG, et al. Randomized trial to compare the safety and immunogenicity of CSL Limited's 2009 trivalent inactivated influenza vaccine to an established vaccine in United States children. Vaccine 2014;32:7141-7.
6. Greenberg DP, Robertson CA, Landolfi VA, Bhaumik A, Senders SD, Decker MD. Safety and immunogenicity of an inactivated quadrivalent influenza vaccine in children 6 months through 8 years of age. The Pediatric infectious disease journal 2014;33:630-6.
7. Baxter R, Jeanfreau R, Block SL, et al. A Phase III evaluation of immunogenicity and safety of two trivalent inactivated seasonal influenza vaccines in US children. The Pediatric infectious disease journal 2010;29:924-30.
8. Nolan T, Richmond PC, McVernon J, et al. Safety and immunogenicity of an inactivated thimerosal-free influenza vaccine in infants and children. Influenza and other respiratory viruses 2009;3:315-25.
9. Domachowske JB, Pankow-Culot H, Bautista M, et al. A randomized trial of candidate inactivated quadrivalent influenza vaccine versus trivalent influenza vaccines in children aged 3-17 years. The Journal of infectious diseases 2013;207:1878-87.
10. Langley JM, Carmona Martinez A, Chatterjee A, et al. Immunogenicity and safety of an inactivated quadrivalent influenza vaccine candidate: a phase III randomized controlled trial in children. J Infect Dis 2013;208:544-53.
11. Tregnaghi MW, Stamboulian D, Vanadia PC, et al. Immunogenicity, safety, and tolerability of two trivalent subunit inactivated influenza vaccines: a phase III, observer-blind, randomized, controlled multicenter study. Viral immunology 2012;25:216-25.
12. Beran J, Peeters M, Dewe W, Raupachova J, Hobzova L, Devaster JM. Immunogenicity and safety of quadrivalent versus trivalent inactivated influenza vaccine: a randomized, controlled trial in adults. BMC Infect Dis 2013;13:224.
13. Nicholson KG, Abrams KR, Batham S, et al. Immunogenicity and safety of a two-dose schedule of whole-virion and AS03A-adjuvanted 2009 influenza A (H1N1) vaccines: a randomised, multicentre, age-stratified, head-to-head trial. The Lancet Infectious diseases 2011;11:91-101.
14. Vellozzi C, Iqbal S, Broder K. Guillain-Barre syndrome, influenza, and influenza vaccination: the epidemiologic evidence. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2014;58:1149-55.
15. Tamma PD, Ault KA, del Rio C, Steinhoff MC, Halsey NA, Omer SB. Safety of influenza vaccination during pregnancy. Am J Obstet Gynecol 2009;201:547-52.
16. Bednarczyk RA, Adjaye-Gbewonyo D, Omer SB. Safety of influenza immunization during pregnancy for the fetus and the neonate. Am J Obstet Gynecol 2012;207:S38-46.
17. Keller-Stanislawski B, Englund JA, Kang G, et al. Safety of immunization during pregnancy: a review of the evidence of selected inactivated and live attenuated vaccines. Vaccine 2014;32:7057-64.
18. Vaccines against influenza WHO position paper - November 2012. Releve epidemiologique hebdomadaire 2012;87:461-76.
19. McMillan M, Porritt K, Kralik D, Costi L, Marshall H. Influenza vaccination during pregnancy: a systematic review of fetal death, spontaneous abortion, and congenital malformation safety outcomes. Vaccine 2015;33:2108-17.
20. Polyzos KA, Konstantelias AA, Pitsa CE, Falagas ME. Maternal Influenza Vaccination and Risk for Congenital Malformations: A Systematic Review and Meta-analysis. Obstetrics and gynecology 2015;126:1075-84.
21. Kharbanda EO, Vazquez-Benitez G, Lipkind H, Naleway A, Lee G, Nordin JD. Inactivated influenza vaccine during pregnancy and risks for adverse obstetric events. Obstet Gynecol 2013;122:659-67.
22. Tamma PD, Steinhoff MC, Omer SB. Influenza infection and vaccination in pregnant women. Expert Rev Respir Med 2010;4:321-8.
23. Callaghan WM, Creanga AA, Jamieson DJ. Pregnancy-Related Mortality Resulting From Influenza in the United States During the 2009-2010 Pandemic. Obstet Gynecol 2015;126:486-90.
24. Zaman K, Roy E, Arifeen SE, et al. Effectiveness of maternal influenza immunization in mothers and infants. The New England journal of medicine 2008;359:1555-64.
25. Rasmussen SA, Jamieson DJ, Uyeki TM. Effects of influenza on pregnant women and infants. Am J Obstet Gynecol 2012;207:S3-8.
26. Phadke VK, Omer SB. Maternal vaccination for the prevention of influenza: current status and hopes for the future. Expert review of vaccines 2016;15:1255-80.
27. Bratton KN, Wardle MT, Orenstein WA, Omer SB. Maternal influenza immunization and birth outcomes of stillbirth and spontaneous abortion: a systematic review and meta-analysis. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2015;60:e11-9.
28. Sukumaran L, McCarthy NL, Kharbanda EO, et al. Safety of Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis and Influenza Vaccinations in Pregnancy. Obstetrics and gynecology 2015;126:1069-74.